 Good afternoon, everybody. Welcome to the NeuroLethics Seminar Series. I am Ross Cochran, Director of NeuroLethics at the Center for Bioethics. As always, I want to thank the Center for Bioethics, the Brain, Brain, Behavior Initiative and the Harvard Brain Initiative for their support of this seminar. Once again, we've got a great seminar, and their funding allows us to bring folks in from out of town and around the world, and we've done it again to bring you a great topic today. We're going to be talking about the therapeuticness conception in trials of ALS or in myotropic lateral sclerosis. And I'll introduce our three speakers, and they will take it away as usual. As usual, if you're watching via the Webex, you can tweet questions to us at HMS Bioethics. And we do monitor the feed, and we have occasionally been able to include questions from Twitter. So please feel free to chime in electronically. And as always, we will have dinner afterwards upstairs, and everyone who is here is welcome to join us for that. This will go until 6 o'clock, and the dinner will run until 7 or a little bit thereafter. So our three speakers today, the first is James Berry, who is the unit chief of the MGH ALS Multidisciplinary Clinic, and a former fellow with me at Brigham and Women's in the neuromuscular division. And he's got the personal and professional experience with ALS that we will build on tonight. Spencer Hay is a faculty member with me at the Center for Bioethics. He's a research fellow in the Department of Medicine at Brigham and Women's. And his PhD is in philosophy, and a major focus of his work has been about the ethics of trial design and trial conduct. And then finally, Scott Kim is our guest from the NIH. He's an HMS grad, so welcome back, once again, and a PhD philosopher. He's now a senior investigator in the Department of Bioethics at NIH. And his recent work has centered on assessment of decision-making capacity for persons with neuropsychiatric disorders, as well as research and informed consent. And this topic tonight is a particular work that he has done here. So he's going to be sharing with us some of his work. And I'm sure we're going to have you back as I've been foreshadowing to you. So welcome, everybody. And first up, we'll have James. Thanks. This is, I think this is, so I spent a lot of time seeing people with ALS in clinic and caring for them, and then also doing clinical research and clinical trials. So this is a topic that is really near and dear to my heart, not only conceptually, but actually on a day-to-day basis. It's something that we sort of think about and talk about. So it's good to have some time to actually sit down and sort of digest what I see day to day. Just for everybody to kind of review, so ALS is, or Amitrophic Lettuce Thorosis, is a motor neuron disease. It's a neurodegenerative motor neuron disease. So the onset is, on average, 55 years old. But I've seen patients from 19 years old to 91 years old. And there are even some reports of childhood onset of disease. So it's a wide spectrum of ages. It occurs in sort of two forms. One is familial, that is inherited in an endelium genetics way in families. And we're learning more and more about that. That accounts for about 10% to 15%, even maybe 20% of ALS at this point. That number has increased as we learn more about the genetics of ALS. We used to say 5% to 10%. The other 80% to 85% is sporadically occurring. And we don't really understand all of the triggers for it. We know a lot about the cascades of pathology that go wrong in the motor neurons and in surrounding cells, but we don't know exactly why it occurs. So that's an active area of research. The disease has an average survival of three to five years average of the onset. So once people first notice weakness of the average survival of three to five years, the most aggressive case is people who come to the disease in under a year. And there are some sort of long survivors who might fall for a decade or more, but they are very uncommon. So it's an aggressive disease. And we have one FDA-approved medication in clinical trials in the early 90s that was shown to extend survival by three months. It was not shown, not demonstrated. Those trials have been effected on function. And there have been subsequent observational studies that maybe show more of the benefit. One might summarize the data in a simple way by saying perhaps it extends. It slows, of course, the disease by 10%. That's a very broad summary. And there's a lot of discussion about that. But it's a modest effect. We have many symptomatic therapies, but that's our one disease modifying therapy. So there's an urgent need for drug development. And in fact, we spend a lot of time, we see people in clinic about every three months. And every three months we have most people fairly dramatic clinical changes and we're often, you know, attending to those. But many patients ask about research, being becoming involved in research. I sort of divide my activities in research into two categories, clinical research and clinical trials. That's the way I conceptualize it, with research being things to understand the disease in Virginia and bio food biomarkers and so on. Clinical trials are testing an intervention to see if it's a potential therapy. And many patients come to us because we're an active research center seeking out clinical trials. And which is, you know, which is good for women and it's good to have a motivated patient population. And many people are very involved in helping to think about what we should do to bring trials faster to patients. But there are a few phenomena that bring up this question of therapeutic misconception in ALS. One is, what is this? And this was actually a conversation that we had with the Tostli hand that we led to. We've seen patients who enter a trial, minimize clinical trials, and after some time, feel that they're not having a benefit. Their assessment of their situation that they don't see benefit. And they then initiate a conversation about leaving the trial and potentially entering a different trial. If we're lucky enough to have two trials, two or more trials between us. A very, very understandable conversation I have and we have this conversation fairly frequently and so I have to be honest many times I don't think about it all that deeply. It's such a common conversation that it doesn't trigger a sort of build. But when I take a step back and think about it, I think, you know, if we go into the trial understanding that this is, one, to see what controls number two, not a therapy but an intervention for testing to see if it potentially, in some cases we're only testing to see if it's safe and tolerant. What does that conversation mean about the understanding of the patient as they enter the trial? That's one of the sort of phenomena that leads to this tension about their big misconception. The other one is this. We recently ran a trial of autologous in the Zangarmal Girat stem cells. This was an industry-sponsored study. And study of stem cells. We were deluged with requests so much so that we had to hire a nurse to answer the phone, to answer questions about the study. It was a sort of phase two A design. And calls came in from around the world, literally around the world, around the country, loved ones and from the patients. And we had 16 spots of limited enrollment. That phenomenon of a very early phase trial was primary outcomes for safety and tolerability. Generating that kind of interest. And people really, it's what I'm doing with saying this, and I'm dying of this disease, I need to be in this trial this and my way. This is my last reason. That sort of also kind of sets off this question of what is there therapy in this conception? So I think there's a lot more to say, but I think that's the rest of the discussion. Okay, thanks James for that introduction. I think I have to skip over one slide and talk about trial skipping. Is that right? But that's okay. We can talk about that in the discussion if we need to. Okay, so thanks also to Toss for inviting me forward to talking to you a little bit about what I know about therapeutic misconception and then also one other topic that I think is important to bring into the discussion, which is optimism bias. And I'll say a bit about what that is. So just quick outline for what I'm gonna talk about. I just wanted to do a very brief overview. Dr. Kim is gonna say a lot more about therapeutic misconception as for research, looking into it. I'll just sort of introduce the topic a little bit. What is therapeutic misconception? Why is this a serious problem for research? Okay, let's trial skipping. I'll skip over that and then talk about that. But we can come back to it. And then I want to transition to sort of contrast this idea of therapeutic misconception to sort of locate in patient populations. But optimism bias is a related phenomenon that is located in the clinical investigators of what it is to. And it's intersected in an interesting way and an important way for understanding that these are trials and sort of where the burden of understanding is called. So I'll say what optimism bias is, why that's a serious problem Okay, so therapeutic misconception is really sort of an important idea in the research that they said has generated a lot of attention. Many, many authors have sort of taken this out talking about where it's about patients who enroll in phase one cancer trials. They expect to benefit when they're like the, actually experiencing any benefit is very low. But of course, what this means for models of competency is how ubiquitous this problem is that so many patients who went to studies with this idea that sort of there's a, they're expecting some therapy event for themselves. And you know it's a really popular important topic when you sort of get, you know, there are papers it's like a body of literature that is actually talking about the body of literature that talks about therapeutic misconception as well. So you know it's a really important thing. But I mean, so what is this idea? So in a nutshell, therapeutic misconception is this idea that research subjects fail to understand the purpose of the experiments that they were participating in and contemplating participating in how that experiment deviates from what would happen. And some of the consequences perhaps of experimental design with a classic one that they always talk about is randomization to explain the process of randomization to participants who enroll in the study. And you know, you might end up being allocated a C-morm or something like that. And then sort of there are studies where you follow up with these patients after, you know, they said, yes, I understand. You know, they signed the document. They thought still that they were gonna get, you know, be assigned the therapy that was the best for them. So it seems like a serious problem, you know, sort of at root, it really sort of calls into question the validity of informed consent. The Ed Rock idea is one of the foundations of ethical research is that we need to get informed consent from participants. We want them to understand exactly what is their consent into. And if therapeutic misconception is as common as some of these analyses suggest, then it appears to undermine these competitions. Okay, so pausing there momentarily, I mean, I think there's lots of more, many facets to this problem. I mean, one of the issues that this sort of therapeutic misconception brings out for me is I think it sort of identifies really a difficulty with the notion of informed consent itself. So I think even setting aside therapeutic misconception, we might ask other questions about informed consent in ways that might be problematic. So for example, we were sort of, we want to, it seems like kind of a robust, genuine notion of informed consent. We have to assume that the participants who are kind of playing the role in studies have some measure of scientific literacy and numeracy. I attended a, or sat in on a conference last weekend it was all about science education where there was a vigorous debate in sort of the science educator world about just how difficult it is to sort of, on the one hand, assess people's health and literacy but also sort of get them, get sort of students, get the general population sort of to understand exactly what was on in science and to understand the scientific results with all of their uncertainty. Informed consent also needs to assume, I think at least some familiarity with the realities of the research that it provides. So for example, therapeutic misconception, one of the sort of underlying, or one of the ideas that sort of we become more familiar with what was on in research and sort of just how many trials fail, how many experimental medications don't work, how many negative results there are, right? That participants don't understand that that's really the reality of the research that most drugs that are put into clinical trials do not end up being factory therapies. So as far as they understand that, that's okay but there's concerns that that sort of, that reality is not what we appreciated. At a more philosophical level, I think sort of, you know, the important incentive to build upon this idea about autonomy and free will and I won't sort of go into deeply into the discussion today. We can talk about that more in the question period if people are interested in it but these are problematic concepts in and of themselves. Figuring out exactly, well what is autonomy? Where does autonomy come from? How do we know that people actually have autonomy and same thing with free will? These are debates that thousands of years old. It's not clear to me there are actually sort of really good answers to those questions in philosophy and yet sort of a robust notion of informed consent is in some way contingent upon having answers to those questions so of course we have doubts perhaps about autonomy and free will, that's sort of again now what exactly is informed consent about, I think sort of, the answer to that becomes much more problematic. So while I rely so heavily then on informed consent on research, it seems to me that therapeutic misconception is really only a giant problem if we think informed consent is sort of a paramount ethical concern that we don't have sort of true robust informed consent or important in traveling research. But if we take a step back from that I don't want to dismiss that idea entirely but if we take a step back and instead think about sort of centering our ethical concern around for example minimizing harms and maximizing benefits to society then I think there's another problem optimism bias that actually made you more problematic than therapeutic misconception. So what is optimism bias? So optimism bias is investigators who mis-estimating parameters that their study is not. So that would be things like they're overestimating the experimental interventions of that size, overestimating their capacity to recruit and retain participants. Eventually underestimating the time and resources needed to complete the study, underestimating the likelihood of harm. So these are all sort of aspects that if we don't get these parameters correct what we can end up with is an uninformative study at the end. That's a serious problem. So there's a smaller body of literature that is actually trying to probe optimism bias and the extent to which trials are designed on the basis of unrealistic assumptions about effect sizes, about the capacity to recruit participants. And in some way it goes in so far as sort of these are mistakes that could be identified before the trial is carried out. These are sort of failings of the research enterprise because we're getting inconclusive results out of these things. We're failing to answer the question that we're interested in. That means that we're failing to redeem the burdens that participants assume in terms of benefits in general and in collaboration. This has been looked at in cancer studies, for example, where sort of the estimates of benefit are overestimated. We're going to put them in the form of a study. I also want to put this in context of a much larger debate that's going on in research ethics and the research community about waste and inhibitions. So it is the research enterprise as a whole looking at lots of studies that don't produce informative results, lots of programs that sort of fail to put all these resources into testing because I'm sort of failing to get out of the research, the sort of new therapies that we're interested in. And part of this is potentially explained by optimism about these sort of mistakes that we've been correct for to design the time that our studies can get better results. I've talked a little bit about this in an ethics piece where I argue one way that we could get a better read on the extent of optimism bias would be to actually ask investigators to make explicit predictions about what likely it's going to be. So when they're conducting a study or they're submitting a protocol for review, they should actually make an explicit prediction of how likely it is that they think, for example, their study is going to find a statistically significant result. How likely is it that they're going to close by the date that they say they're going to close and go to a group of participants to think and recruit? And then in doing this by making explicit predictions, this actually becomes a modality not only for assessing whether or not the investigators actually are systematically optimistic, but also that really investigators and the cells are going to improve over time if they start to get feedback and they realize, wait, I'm consistently thinking that I'm going to see a bigger effect than I do. This is problematic not only for the harm it does to the participants or not contributing as much as they could. Not a large right, so then they can use this feedback to try to design a lot of better studies. So how does optimism bias relate to the therapeutic misconception? Also at bottom, the point is that even a fully informed participant who enrolls in a study that is not designed on the basis of the most robust realistic parameters, they expose unnecessary and avoid risks. These burdens may never be redeemed by benefits of science. So it seems to me that informed consent is an ideal and it's an important ideal. But I think that whether therapeutic misconception gets at what optimism bias gets at, it shows us that consent really can't do all the moral work. So I want to leave you with one final thought. I think alternative is to think about really the goal in research, the goal is in getting consent from participants. Shouldn't be this ideal information, absolute autonomy where they understand everything and they make this fully rational decision theoretic decision, but rather is an alignment of scientific understanding and trust, it would look something like this. So the investigator is responsible to communicate faithfully what they believe to be true, not what they wish to be true about the realities of the effects that they're likely to see, but what they actually believe to be the case about the risks and benefits and the uncertainty that underlies their study. And then participants can choose to accept or reject that those risks and uncertainty consistent with their knowledge and values. But I think just giving the power and knowledge differential between that participant and researcher, still the case that the participant is going to have to place some limit, some measure of trust, is that there's not going to sort of ever be fully informed understanding of the realities. I shouldn't say there's not ever going to be that, but that's sort of, you know, that's really an ideal, right? But nevertheless, participants have to place some trust in the investigator and the research system to ultimately guarantee the risk benefit. So we'll leave you there here or something reference it. Thanks. Thank you, Koss, for participating in this session. It's really fun to be back. I assume some of you were incredible students, right? I turn to believe that it's been like 30 years since I was a student here. We didn't have sessions where this many people would show up and have professors and have discussions. So it's really a wonderful opportunity to participate. First I want to say that I think, what's especially good is that something's true. If I could summarize what he said, it's something like, you know, research design is a bigger issue for research that makes that important sense. And I think it's, I think that a really important sense is true. Justifying whether a research is ethical is different from justifying whether a participant of this person is ethical and a participant of that person is ethical. That's important to say. Now today, I'm going to mostly restrict my talk to the important and said aspect. Centered around this notion of therapy as a conception because it is such a, you might say, a received view in the field that this happens all the time. You saw an article that says that you dig with the therapy as a conception. And it does happen to a very important ethical concern. But I think the way we traditionally have thought about it isn't as helpful as it could be. So that's going to be my brief. That's the claim I'm going to make. I apologize to some of you who have heard the same parts of this talk. I've cut my hour talk to 30 minutes and then we'll see how it works. So if there are gaps, you can always ask questions and we'll fill them in after a good discussion. Okay. I'll have to say this because I work for the government. Nothing I say is very important. All right, so Dr. Berry mentioned some patients with what they are on us who are honestly primarily motivated by getting therapy benefit out of being a researcher. And that really kind of makes people rightly self-concerned because they really understand this is kind of an experiment. We don't let this work in a risk support. So what we really want is somebody like this, right? Somebody who says this, that is one of my interviewees, one of my studies. I feel an obligation to you fill in the disease. This person has to have to have to have Parkinson's. Parkinson's community that I need to do what I can do to improve a lot of the people. You know, I'm not a Washington person. I'm not a lobbyist. I can't do those things, but I can participate in studies. This is what our, you know, this would make ethnicists happy, right? This person doesn't have their being this deception. We like to think, correct? Now, however, this is what happens in the same interview few minutes earlier. This is what this person said. It didn't take long for me to decide that it was really the best thing for me to be in this study. There aren't too many other things I can try out there, you know, and I need to try something. So this sounds also like the kind of behavior that concerns that we just heard about. So what's going on? I guess my point, my whole talk is trying to explain this particular patient as a paradigm because for most people like me and Dr. Berry who have talked to patients with serious illnesses entering clinical research, this is not unfamiliar, okay? But we have to make sense of it. Which part of this person is really driving the decision, let's say. Things like that, okay? So I will try to run through this and see how we do. Okay, we're gonna talk about some problems with theory, community conception and misconception as a concept, a couple of issues. But mostly I'm going to give you some research, some explanations as to how to understand what sounds like a misconception with an alternative way of understanding what's going on, and that's gonna be a bulk of my talk. And then at the very end, I'm gonna just suggest some ways to think about this, what the actual problem probably is and how we can address it, okay? So just an example, the way we think about for theory, community conception is a little bit hard because there are many definitions out there. Spencer actually used one. Can I ask you which one that came from? Or was that your best summary of what you... I sort of took it from your slides. Okay. So I had a slide, I had to delete because I had no time, but basically it was kind of close. I mean, there are usually people mentioned things like, do they know they're in research? Not treatment. Do they know that this is unlikely to benefit them? So false views about benefit. And then the individualization lack of it in research. So those are the three elements usually. But this is what often happens. Primary example is of a common confusion in what I call the received view of a therapeutic conception or something like this. If a research subject seems to be motivated by therapeutic benefit, that by itself is an indication of something as well. That's commonly accepted. So motivation per precipitation is seen as part of it. Now, so I'm not making this up. There's actually been studies in which the measurement of TM is done by using an instrument, an index, and one of the questions in that index is just this motivation question. Okay, so that has been used, but that doesn't quite make sense, right? Motivation and understanding are different. So I did buy a lottery ticket for the first time in my life, about a month ago. Do you remember that one billion dollar power bill? So my secretary sent out an email, who wants to do it? So it turned out the only people who did it was me and my department kind of secretary. Everybody else was too rational. We have a lot of philosophers in our department. And he said, this is, and you know, exploitation of the Florence was so, we didn't want to do it, but we thought, hey, we might win, so we bought it. So I knew it was one in 10 billion chance or whatever it is, but if you ask me, why did you buy a head? Of course, to explain to sort of decrease my shame, I had to say things like, oh, you know, it gives me some entertainment value, you know, stuff like this, but deep down everybody thinks headache. I had the same chance as everybody else, right? This is what people typically say. But I didn't, but I don't think that the lottery was designed to benefit me, right? So it's the same thing happens, I think with patients. Patients who are desperately ill often might sign up and they will say, look, I'm doing it because I'm going to benefit, but do they actually misunderstand that it's just a specialized treatment or do they think it's an experiment on which they would have been thinking, yeah. Sometimes I think you might actually misunderstand that I have spoken to one patient in a early phase of Parkinson's study in which that was the case, but usually I don't think they really misunderstand that it's not a search. Okay. There's a lot of data about the presence of their human sensations. People who've done this research, they typically cite like 60, 70% of the open research show some signs of their human sensations, so I asserted that as the received view. I think one of the reasons is because the way this research is done, if a subject shows any evidence at the end that those people are counted as having data, okay? And I'm not making this up because this is explicitly laid out in the methods of the papers in which they do these studies. So for example, in this one paper it says, in keeping with their usual procedure, any clear evidence of TM was coded as TM messed, even as some other point in the interview the subject gave a contradictory response. So having seen my first slide, you'll see that person would automatically categorize this and then it shows TM. All right. So my thought is actually, well why is there a period of contradiction? It seems to me the agenda for research is to figure out why do people say these complex sounding things, right? So there's a researcher at Duke, Nick Kevin-Weimer, who's really written some really nice papers for me to figure out what's going on. I had some really nice studies. And I learned not from his work and I designed some studies using his work. And at that just the point, people say different things instead of assuming they have TM, what's going on? So this is just an example in a study where they found half the people at TM. But if you look at one of the questions they used, which is this, you ask people, research is done to gain knowledge for future use. It may help the people who participated, but that is not the main goal of the research. Pretty clear. If a person said, if a person had therapy with this inception, they should disagree, correct? Okay. So this question was asked in two different ways, positively like this and negatively. And you get the exact same result. The result looks like this. Overwhelming, almost nine out of 10 people answered correctly. However, this, there are many TM studies in which people can contribute results. So if your rule of cutting up people is that if there's any sign that you've got very high numbers, right? Okay. In our studies, we find very few people who explicitly say, yeah, the primary purpose of this research is to benefit me. Now people do say that, okay? Given the way we ask this, that this is a qualitative interview and we ask this person, ask people, is the primary goal of being in this study. This study was a sham-controlled Parkinson's study. So either G-transfer for some type of modified cellular transfers to the UK. And we interviewed 89 people. So virtually everybody who was, or subset of every one of the studies done at some time. Five people in the 89 actually said, yes, it's intended to benefit me, the participant, right? Everybody else gives some combination. It's both in science, to get knowledge to benefit me and some combination. But the top line, primarily intended health subjects participating in the study. So it sounds like there is about 6% of people who really don't get it. And what's interesting is this. In our qualitative interview where it's semi-structured, we probe, go back and forth, we asked them questions about design in the study. We asked them to describe how many arms are in there. What's the difference? If you had one arm, what did they get? If you had the other arm, what do you get? Why did they have those two arms? What's the nature of those arms? What's the purpose? We asked all those questions. So let's see how those five people did. Who said what? Primarily intended health subjects participating in the study. This is what we find. Meditative assignment, which is randomization. Four people got it correct. One person said, not sure. Probability of placebo assignment. I'm talking about the exact number. Not every study was 5050, so I can't remember exactly, but one person got it incorrect. Not because they thought it wasn't randomized, but they gave a wrong number. He had one in eight, something like that. Purpose of the sham arm. Everybody got that correct. In fact, four of the five people gave us kind of a mini lecture on the fact that in Parkinson's disease, placebo effect is a particularly problem because of the dopamine system, right? So four, and all five understood why you needed the placebo arm. And they also were able to describe the placebo effect system. So it's very hard for me to believe that their response to this question, in combination with this, says that these five people don't know that they're in a research and really a scientific study. I find that really difficult to believe. Now, should we label these people as TM? Okay, what are the alternative explanations? Why might some people say that the primary purpose is to help the participants? So why did they say that? I mean, that wasn't just thinking of odds. That was in a conversation. We were going back and forth, and people actually said this. So why would they say that? So one option is people really can't tell the difference between a research study and getting treatment. Now, this is the conventional TM view, and it's a cool start when, I mean, plain, it's a pretty strong claim, and we don't really appreciate that as much as we should, I think, sometimes. The question we use to measure TM doesn't work well. That's a set-get alternative. So maybe, we're not quite measuring what we think we're measuring when people say these things. Okay, so that's another hypothesis. So my natural question was, how do participants interpret the question used to measure TM? And this is what we did. We, at the time we were developing this, we looked for the latest study on TM, and there was a paper by Becky Betts, who's a bioticist at the cancer center associated with Seju. Seju? No, in Atlanta. So anyway, she published this paper in which she used this question to people with cancer entering cancer trials. She asked that, is the research study that you're in mostly intending to help research and gain knowledge, or mostly intending to help you as a person? When she did that with 90, asked that question of 95 people who were entering oncology clinical trials, almost 40% said mostly intending to help me as a person. So that's where you said, that's there sort of doing what my five people did, right? And when you combined it with another question she used, she found the typical close to 70% presence of her previous assumption. Now how did the respondents interpret the question? That's the question we had, right? So what we did was, we just thought, well, why don't we ask them? We'll ask people the question, and then after they answer, we'll go, which of the following do you think best captures how you understood the question? Now we developed this in two ways, and I'm just gonna give you the actual closed-ended options that we used. One option was, okay, the question was asking you about your personal motivation, why you wanted to be in the study, or it was asking about knowledge for knowledge, the same versus actually helping people, because the way they phrased it, I thought it was confusing, maybe people thought that was the case, or it was asking about the official purpose of the study. Now, what we did was we started by actually just getting a convenient sample of what people wanted to do, because we wanted to figure out how people understand the language of these things. So, we had a one-page description of ALS, thought like the way you described it, really. Terrible, terrible disease, most people die, it happens fast, there isn't really a treatment that changes things. So, and we asked them, well, here's a phase one study at Leagee, the background, and asked them if they would be willing to participate. And, you know, when you give them this very green picture of what ALS is, the layperson who reads this and how it goes, yeah, I consider being in the study. And so, everybody's, we get them in that therapeutic mindset, even with lay people on the internet. So, total number of people, we had the 234, the way we did it was two-stage, one was we actually randomized people on the first group, 100, and had them answer open-ended, so we could validate or close-end options for the follow-up questions. And then, after we did that study, we had a second survey, but I'm gonna just give you the entire shabang in one table. Okay, all right, this is what we found. This is kind of complicated, so we just walk you through it. So, the top row is answers to the, you can keep in mind, let's call it the purpose of research question. What is the purpose of research that you're in? The column before left is answered to the follow-up. How did you interpret that question? Okay, all right. So, if you do a cross-tabulation, this is what you find. You have only about 52% of the people say, oh, what they were asking me was what the official purpose of the study was. Okay. About 24% thought they were being asked for at least their self-report. It was asking me why I'd want to participate, okay. And then, the middle 24% chose this option. This was kind of a red-bearing option that we gave, which is, oh, we're asking about knowledge, knowledge-safe versus helping people as people. Not even short, it's only about half the people understood it as intended. Now, if you look at this column, this column is people who gave the TM answer, right? Because to the question, what's the purpose? They answered, help me as a person, correct? About 15% answered that, 35%. But notice, if among those people, if you understood the question as intended, only 3 out of the 35 actually understood as intended. So, I'm gonna summarize this in this slide. 48% failed to understand the TM question as intended. Out of everybody, only 1.3% kind of showed true TM, meaning understood how the question was meant to be understood and said, yes, it's to help me as a person, 1.3%. Now, granted, these are people without the skills and they're just sort of doing the hypothetical thing. And as I said, 91% of those people who apparently showed TM actually didn't interpret the purpose question as intended. Now, 93% of those who interpret the question as intended give the correct answer. So, we can skip the last point. That's just the theoretical framework I used to do this. Okay. What we did then was to recruit people with ALS because it, you know, obviously these were just, the first study was people, N-term. Anybody do a survey in N-term? But anybody know what that is? It's an Amazon service, you know. It's like, what's the, Raul, what's the term for that? Crowd or something. Yeah, like the crowds are saying, you know, doing like little work jobs. That's right. Yeah, yeah. So, you know, you can have people prove that you're paid per se. You just pay them like 60 cents per cent. But you do that on Amazon, so that's what we use. So, you think that's not a good sample. So, what we did was we recruited people through various research, recruited portals, and he was from Michigan, he was from Rochester, and some of the Northeast patients had to see sites. Yeah, I forget the name, but we advertised there, and they said, if you're interested, contact us. And then 72 people actually went through the internet survey and answered this. And you essentially get very similar results, as you can see, about 50% say, yeah, does that help you as a person? But if they understood it as, oh, you're asking what the official person's study is, only one out of those 10 people had none, okay? So, the results are pretty similar. I'd like to say that if you exhibit therapeutic misconception, at least for the purpose of research, that's a much better indicator of you having misunderstood a question than it is that you have therapeutic misconception. Now, what are the alternative explanations? So, we've done studies using these experimental formats, but before that, we did a lot of qualitative interviews. And I'm just gonna give you some quotes from those, just to get a flavor for what we think is happening. So, a pair of TM statements regarding one and one randomization. So, we asked, you know, what's the chance that you would get randomized, or you would get either placebo or the real gene therapy for Parkinson's. And you hear the comments like this, well, it's hopefully expected 50. Now, 50-50 was actually the correct answer again. Or they would say things like, well, if I don't get one, the gene transfer, I'm going to be really surprised. Now, this is exactly the kind of codes you get when you interview researchers that it's common. That's what we call cognitive ambiguity of your gene misconception. Now, what's interesting is this, you put it in context, and this is what the context of that quote is, so I kind of cheated. Hope, well, hopefully it's going to 50-50, but statistically it isn't. It's English. Most of you kind of understand what this person's saying, right? But it's not mathematical language, right? Okay. Well, how about this other person? If I don't get one, I'm going to be surprised. I've got a lot of people praying for me, a lot of people believing, and I think I'm going to be, I'm going to go in there hoping with the positive energy I'm going to get. That's what it means, but I'm going to be surprised. How about luck? So, we've covered hope, faith, luck. The subject 12, I'm going to be the other half. You're going to be the other half? Yeah. You feel pretty sure about that? Real faith, I'm pretty sure. Now, what's the context? My wife is convinced that I'm going to get the real thing. She says I have a feeling I'm going with that. That sounds good to me, right? So, you have to understand the whole context of why people are saying that. Consider subject 11, who correctly stated that probability of randomization is that it was 50%. You have to see about where the gene transferred. He later says this, our interviewer says, do you think he had a 50% chance of getting the gene transferred? I hope so. We know he gets it, because he stated it just previously. Now, TM Theory would say that is an example of how people understand in the abstract, but when it comes to their own situation, people don't understand it. That's been the traditional interpretation, yeah, people will give you the right answer, but when it comes to their own situation, they don't get it. Well, now, this is what he says later in the interview. Do you think you have a better than 50% chance which I've got already? He says I hope so. Now, the full context is I'm good, I'm a gambler, I like my odds, I'm a good guy too, so you know, I figure I'm lucky. If you, in general, you're lucky and it might be the same way here. Yes, I feel really lucky, and that's when I got the vote, you see. So like I said, I feel lucky. So people will often say things like that because whatever luck means, luck is a very slippery concept. I try to, in fact, there's actually a whole philosophical work by Nicholas Rescher on luck. I try to read it, I got really confused because it's not an easy concept. We all use it intuitively in the right moments, but trying to theorize about it is very difficult. And it's a huge percentage of our population who don't make sure they don't get science. Oh, I see, yeah. So you think these people are kind of still, not? So we're gonna get to that. So maybe some people feel that hope, faith, and luck are all irrational kind of manifestations that we can have a conversation on. Okay, great, thanks for the point. So social norms and how we talk, I think it's actually, I'm gonna propose how to understand these statements. A typical statement during a sports interview. Unless you're a non-evolutionary sports person, I guess, whatever. So this is, I don't know, what's the name I am? Boston. Okay, so, all right. So when the Celtics were playing the Cavaliers last year, and you went, remember that? Okay. I mean, come on. So, you've got my favorite coach in this city. He's a terrific coach, anyway. Okay, so, I mean, I know what you really thought the Celtics were gonna win, but if Brad Stevens, the coach, had said during an interview, well, you know, we're practicing really well. I think we have a good chance at an upset. Well, you understand that, right? Have you ever heard something like this from a sports person, a lot about an interview? You have, right? Okay. Note that as a statistical statement, this makes no sense, right? Because if you put it literally, this is what it means. There is a high probability of a no problem only that I have there. That's what it means, literally. Okay, so, it seems to me we accept certain kind of irrationality in our language, but it's still rational because there are certain conventions we follow. In fact, this is what these psychologists in Germany have stated in studying these kind of phenomena. What they say is this, adherence to social norms is rational, although it conflicts with classical rationality defined by many research as adherence to the laws of probability theory and logic. So, a lot of the behavioral economics experiments, you know, that show that people kind of use heuristics that get them into all these different kind of, some of those can be explained, I believe, by the fact that the people answering either are being very rational. It's just that they're following different rules of conversation and what the psychologists are intending when they ask those questions. Okay, so, what we did with this ALS sample was ask the following question too, just to follow up about the notion of expectations of benefit. Because one of the things that's often talked about in therapeutic misconception is also this view that people have really falsely inflated that's the benefits of benefit and they minimize the chance of this. That's the view. So, in fact, if you ask cancer patients who are into clinical trials, they often say, oh, you know, 60%, 70% chance of my cancer getting much better. And that sounds a lot like hot, right? Because it doesn't correspond to reality. So, when we asked that question to this sample of people with actual ALS, who gave them this scenario that sounded very scientific and understandable in terms, they said, an average estimate was 31%. I thought it was actually lower than what I expected, but still pretty high. If I said to Dr. Barry here, just like what Spencer said you should do, you're asking for money to do research, I want you to put your bet down and tell me what's the probability that people in this research study would bet it that I bet you would not say 30%, you would give a much lower number than usual. Okay, so this is what happened. So, we asked the follow up question. So, after they gave the number, we said, okay, we're gonna give you some statements, we gave them in random order. Which statement below best describes your responses to your estimate question? And this is what they say. You see the pattern is pretty obvious. There is one group that gives a really high number on average, okay, and those are the people who chose that is what I hope will happen, and it's important to have a positive attitude. People who gave much more realistic low numbers were the ones who chose the following responses. Those are just the facts, or that's what I fear will happen. And then people say, you know, they're just a lot of uncertainty. And those people gave much lower estimates. So, I think we have, this is an indication that we really have to understand that we're communicating on the same page because there's different planes of implication when you have a fatal disease and you're struggling, I mean, every day is a battle, you gotta beat this thing. Your language changes. And when we stand in front of them so to speak and then expect people to use the same logic that we do, I think sometimes we get in trouble. So, that hope based on false or misleading information should be minimized. So one of my pet peeves and important standpoints for phase one studies is what they say. It is not guaranteed that you will benefit from it, right? Because what does that say? Well, you're gonna benefit, yeah, just can't guarantee it. Which kind of, and I'm actually, this bothered me so much, I actually did an M3 experiment testing this. And it's true. If you give this statement versus kind of a factual statement saying, you know, this is an experiment, there's a possibility you could benefit, but it's low. If you compare the responses of estimates, the numbers go way up if you use this. So, we should minimize that. I think that's no one's good about that. But here's getting back to what we talked about here, is that what about hope based on other factors, getting lucky faith? General views about science. Some people have very glowing views, you know? You wouldn't be sitting in these beautiful buildings if somebody didn't really reach into their pockets and really had good feelings about science and get stuff done. No, seriously. So, now the problem is this, almost by definition, this kind of hope and desires that come from it, almost by definition beyond the level of what the data will bear. I mean, it's almost part of the definition of hope, really. Yet, it's compatible with appreciation and understanding of the actual facts. It's researching, you know, the chances of actual benefit, just like I can understand what the odds of winning a lottery are. And it is possible to exploit this hope. That's where I think the danger is. But I do think it's also not good to stigmatize people, research subjects, for wanting something for themselves. I remember when I gave this talk in front of research participants, one of the comments that struck me was that, you know, I feel like I'm getting stigmatized for wanting something out of being in this study. Okay? All right. I mean, really, why are we talking about important consent? I think that unless we understand why this bothers us, the remedy that we suggest will be the wrong one. So, if the problem is seen as misunderstanding of what's gonna happen, well, we need to put more detail into the consent part. We have to inform that further. We have to, you know, and then the whole thing escalates into an education issue, not an issue of the other than anything about seeing things from the subject's perspective. So, I'm just gonna close with a couple practical tips. One, if you read the federal regulations about important consent, it has all these elements that have to go into it. Nowhere does it ever say, you should ask your research subjects why they wanna be in your study. It's not, it's not required. I personally think that every researcher who enrolls a subject should sit down and ask them. I've explained it, you said you wanna be in it. Can you tell me in your own words why you wanna be in the study? Right? And what's gonna happen? You better tell you, doc, there's nothing out there. I really want something. Now to me, that's a beautiful opportunity to juxtapose their motivation with your understanding of what the purpose of the search is. That moment, you can say, I understand that's what really driving you and it's very understandable given the situation. But let me take this opportunity to understand, to explain why we're doing this study and some of the priorities that we have that you should understand before you sign up. If people sign up after that, I'm not worried about this understanding of the purposes. Okay, second practical tip is, we found that there's some hint that people who are really motivated by their benefit, their big benefit, tend to be actually severe about the risks of the study that people who say they have an altruistic motivation. Okay, it's not a robust effect, but now in retrospect, it makes sense because we've been so focused on this idea that people shouldn't be motivated by benefit when they enter studies. We fail to see the whole context, which is if you're really motivated to get something out of it, then you're gonna look at all signs and say, well, is this worth it? Okay, so there's the flip side, which is that people who are really, really think, oh, I'm at Harvard Medical School, and I wanna contribute to science and so forth, you do whatever you want, I trust you. I think those people could have a altruistic misconception because they don't bother listening to what the details are. Maybe there's some risk that if they really took the time to understand, they might have wanted to be in the study. Okay, so the papers and everything that's at the website, these are my colleagues who helped me over many years in this room. Thank you all very much. This is really fascinating to me. I take care of the patients for ALS II, and just last week I sent somebody to James, who I worried had either the therapeutic misconception or the subjects version of an optimism bias, right? So the type of optimism bias that Spencer's talked about is on the researcher's side, but I still worry that she has a sort of optimism bias that Scott, you kind of expressed as a type of rationale that comes out as hope or faith or luck, and I'm very reassured you helped me reconceptualize therapeutic misconception, but I still have this nagging worry about that optimism bias that the subject has, and I still don't know how I feel about how strongly to fix it for her, right? When it comes to the lottery, my favorite joke is that the lottery is a tax on people who don't know how to do math. And for you, I don't mind if you spend a few bucks on the lottery, but for people who don't have any money, I feel like I need to protect them against that hopeful feeling that you are tempted to describe as a type of rationality. Similarly here, there's some amount of protection but I think we, I want to sort of extend to subjects so that their thoughts of hope don't mislead them, right? And so I don't know what the right level is there, and maybe James, you've got some concrete suggestions about how to actually approach these discussions. Yeah, I said this is such an interest, there's a, there are a thousand things who are running my head in conversation, this is some of them. One of the, so I sort of draw from my own experiences as well when I think about this, and I think about, so I think honestly early when I started consenting people in trials, I felt very strongly that what I should be doing is making sure that they can tell me and believe and understand the actual chance that this is gonna help them. And it's gotta be, they've gotta tell me it's two percent or lower and they've gotta believe it. And I don't think that's true anymore because I think that there's a part of us that's guided by hope. And this probably ties deeply into what we call survival instinct, and this is the reason that you see a horror movie and at the end there's still one protagonist running away from the monster when everybody else is running, I wanna just let the monster eat you. It would be so much easier. It's, I think it's deeply building that who we are. I don't think that it's at all beneficial to go in and sort of scoop that out. I just don't see it as helpful. I do think that people can have both sides of the rational, both sides of the conversation, the rational conversation and the whole conversation. And I've taken to, I think I told you this, I've taken to being overt when I consent people and say we're allowed to be hopeful about this experiment, but we're not allowed to expect that there's no expectation of what we've got. I don't know if that does it justice or not, but at least throws out that there are two sides to this, that there are overtly as hope and expectation and there's a difference. And I think yesterday I told the patient that I was coming here to talk about this and he was in a trial actually and we're talking about it and I said, you know, we're gonna talk about this thing called therapeutic misconception, which is that the idea that people enter trials and think that the trial is a treatment. People will benefit from the trial. And he said, yeah, we'll take that. He said, oh. And I said, oh, but it's a, like in this trial it's an experiment if we don't know if you're gonna get the drug and we don't know if the drug is helpful. He said, right. And I said, I really, I mean, I was like, I don't know where to take this conversation, but he said, no, we all hope that we're gonna have benefit. And I said, so you think, or you hope? He said, well, I understand that he laid out the trial and everything we talked about the consent. But I think I'm gonna back to it. And I mean, I think he's using the word think and hope and I think he's using them interchangeably. But I think that's very interesting. You know, can I just add something? He's like, so what? I thought, you know that slide, I had that hope slide. I have like, probably 20 different versions of that because every time I think of a talk, I really think, how do I categorize this and so forth? I used to do it by separating hope and expectation. And at one point I got, the way to do it is go to the dictionary and find out what that truly means. So I went to every single dictionary I could find and wrote it down and gave it as a quiz to people. You know, the problem is that definitions of those things are so similar. No, I used to quiz people at talks. This is hope or expectation, expect. And I would read the definitions. You would think that everybody would get it right. They don't. It's just that we don't have precise language. It's like there's a context that who you're talking to that could make a difference. I mean, for example, if that patient, what makes it really difficult is that he's a scientist talking to a patient, okay? If that patient you were just talking to that sounded worse than what they were saying. If you thought that patient was another patient that they were talking and you could tell they were just trying to tumble each other up, so to speak, you wouldn't think twice to get worried about as worried that's right. So it's very complicated. I guess what I'm not trying to say there is no problem, so to speak. What I'm saying is that I think to simply assume based on some of these observations that people misunderstand that they're not getting is what's, I think that's the long way to go because then the, what's the remedy? Suppose you just give them the information, they go, uh-huh, okay, now you have the problem. Did they really understand it or not understand it? So. The other thing is I think, I mean, I really struggle with just the idea of probability, but I remember thinking very, thinking about this very deeply when I was a resident and I had a patient who needed a private or an email and said, I have a tiny stroke, I can't remember really, but it's either as it might have been very, very tight or it was just had a tiny stroke. And we talked about the risks, you know, the risks of the intraoperative stroke and it will say it's 5%. And it wasn't happening, I didn't interact with intraoperative stroke. It was very, very, very, very angry. And I know that I had a conversation with them with a surgeon that had a conversation that he was handing out a funny note and I was in or around those conversations. But it occurred to me that on a population basis you can put a probability on things. But when you're an individual, it either happens or it doesn't happen to you. And so the understanding of probability really, really hard. And so I don't even know how to, I just think it's in that simple kind of behavior. So we'll take some questions from the audience. If you ask a question, please try and speak loudly because the microphone for the webcam is here on the table. And if you're soft, we may want to repeat the question. Well, first of all, thanks to all three of you for a great conversation. It's got my imagination just spinning. But after listening all of this, I want to ask you maybe about just a more direct way of going at this that seems to be honest, but more direct. So James, I mean, what if you said do a patient, you know, I'm an expert in this disease. We're interested in this new medication. I think it might work. It's gone through animal studies and it's been very promising. And we have a study going on. We do have a rule, our government has a rule though that before we can distribute this widely, we need to prove that it works. And we haven't proved that it works yet or even that it doesn't do more harm than good. So, you know, the deal is that you're gonna have to agree to go into a situation where you got a 50-50 chance of getting it or not. You know, I kind of hope that you will begin the group that gets it, but you gotta understand I have no control over that. And what's wrong with that conversation? I mean, it... I don't think you're... So I would say that that's actually much more rosy a picture than I paint when I consent people. You know, because there are a few words in there that I think are fine, but I try to maybe avoid them or be able to watch those about them. What makes it there promising? What does that mean to be promising? What percent... You would not be doing this if you didn't think that we're promising. You're spending an enormous part of your time in career doing this. I think that's right. You do believe it's promising. That's just being honest. So, Bob, do you have the therapeutic misconception? Well, this is why I think maybe we're just thinking out of the wrong way. Well, so I think that what you've said, I don't take huge issue with anything you said. I try to be a little more factual because I probably do have optimism bias from a researcher at Research ALS. Probably do. I try to... I mean, I think that we try to keep that in check by having lots of reviews of a project that's forwarded us forward. And honestly, I think we all probably just... I think we all... I told you in the beginning, I think hope is deeply ingrained in what motivates us to do anything. And so I don't really have a huge problem with it. I think that basically is the conversation we have. And I also said in the beginning to Toss, I used to worry about it a lot more than I do now. Because I've also had the experience of going back to the people who've been in a trial that do the true positive results more times than I would like to say we didn't see results and we were up to see what went. And it's disappointing. But I mean, nobody has ever strangled me with a phone call or that. You know, like it's disappointing, it is. It's disappointing while disappointing if the trial isn't positive. And we did go into it with something. And we balanced that against the reality that this is a tough nut to crack. So I don't worry too much about it. This is such an interesting conversation. I do both that new research and I do ethics work and I also work on ALS. So many things. One is that people go to Vegas with way worse odds of getting a placebo. And they are still hopeful about themselves. I think one question you could ask is to just distinguish between faith, hope, and probability is like, well, do you think you're gonna get the drug James saying? And James like, oh, I think I'm gonna be lucky. Say, well, do you think the guy in the cross the hall that's gonna come in here next is he gonna get it? Like, well, I don't know. I mean, everybody's hopeful about themselves because everybody's in the slot machine just pulling the lever. Like they are gonna be the one, they're gonna be the lucky one out of everybody. So I think the question about whether you're gonna get it or not is sort of meaningless. What you're gonna be lucky or not is it? And second thing is these people are gonna die from ALS. Who cares what they think? I really don't understand. I mean, it's not a, we're not trying to find it ever a different painkiller. Like you were asking people, should they feel lucky or not lucky? They're alternatives. Like, yeah, I really feel like I'm not gonna get a drug that will help me. They're all you guys are wasting all your time. You know what? I might as well just go home and die now because there's no hope. You're giving, there's no alternative. There's not really rational thing. When you talk about rationality, there's no rational reason to think that you have no hope of getting help because your alternative is to go home and die the normal way. So the only reason they're even talking to James or any of you in front of her trial is because they're hopeful. They think that Harvard or NGH is gonna do something great and maybe they'll be able to help themselves or somebody else, but I don't really understand who cares if they're hopeful. So maybe I wouldn't put it, I think I'm paraphrasing what you're gonna point you said and I think it's relates very much to what Hal Spencer put it at the beginning, which is that the real issue really, it seems to me, is society interests researchers, reviewers, you know, IRBs and various committees that because we know about this bias among other biases, we did talk about careerist biases and all these other things that can come into play. People aren't just allowed to decide for themselves when they come up with people. It has to be, you literally have them committees reviewing it. In fact, when I used to do a lot of research with people who went on gene transfer, the poor gene transfer clinical researchers, they had so many committees they had to go through. It took years before the conception of actual implementation was just incredible. So what I'm saying is this, I think our society has set up a system that's supposed to work something like this. You know, we really need to set up this system so that when we invite people, it's already not an unreasonable bet. So that is set up. And then we also have this thing called autonomy that we really like to talk about bioethics, which is something like, well, if you're adults, they make decisions, they can harm them, they could not benefit them so much, but within the parameters we set aside, you have as honest a conversation as possible. How they actually process it, is it, do they believe in evolution or not? Do they believe in luck, is that irrational? We basically made a decision as a society, it seems to me to say, well, to that person, you could say it's the libertarian angle to the informed consent, you know? So that seems to be what we're sort of doing. I think it's still, though, even that we're all part of the helping profession, when we consider the possibility that people who may not have wanted to be in a study might be in it because they were just headed 100 minutes ago. That does bother people, and that's why I think this whole thing about therapeutic misconception is such a big issue. But I think what I said is very compatible with what you're saying, right? So I have to say that the conversation in ALS is actually, in the patient case, is beginning to move back toward the first part that you said, which is sort of how we define, how we define the parameters for what is an acceptable bet to be done with. To offer. To offer to be done with. In other words, people with ALS are saying, I'm consenting to the stuff you're bringing to me. If you're not being aggressive enough, you're not allowing me to make a big enough risk-benefit rate offer. And you, I mean, you, there's lots of fall to the system. And the FDA takes the front of that, and they're like, there's lots and lots of steps that's just a mix of priorities. But that seems like, I mean, that to me is more worrisome than the hope, where it's like people going, even though that doesn't, I agree with that, I don't think that's particularly problematic. I mean, part of what we've been saying today, but that would, like that does seem problematic though, what people are saying. Like, I want to take a bigger risk than you're allowing and let, you know, under the presumption that they don't have the expertise to really understand sort of the extent of that risk for sort of what the science, I mean, if they understand the scientific reality, and then they want to consent to it, that's one thing that it seems like that would be a situation where you really want to make sure that they do appreciate exactly what is that they're asking for. I think you want to, so there's, I mean, you have to kind of unpack that into, when you have a project in front of you, and you're consenting them to it. Again, I think it's very, I do not think you want to stop on hope. I do think you want to be realistic about the risks on it. I mean, because there are patients who say, oh, you realize that risk came with it, and actually, you know, that doesn't fit into my life. I mean, I have a very bad disease, but this summer, my daughter's getting married, and I just, I don't want to put that much risk before that. So I think people are doing that calculation if you want them to. But, and then what they're saying is, look, you know, some people are saying, I'll take even more risk if you can attach that to the same or better benefit. And it's true that our systems are only set up to scale risk benefit a little bit. So if you're researching neuropathy and you're researching ALS, the risk-benefit ratios are not allowed to be that much different for those two diseases. You don't have a mechanism for that. And our patients say, wait a minute, you know, I think actually the risk-benefit ratios maybe should be balanced for you again. We have these sort of examples. When people are researching treatment for HIV, the researchers here that help me know how to do this ourselves is kind of very severely challenged that FDA had to make different rules about how to move friends and so forth. So I think that they have people have to be, we have to be careful that some of the scientific decisions I made in this very important value of judgments that we made. So every design that you have, Bob and I talked about the support study where you think your children make you and temperature involved. When they set up a study, that was the test to see what level of oxygen would be these kind of folks that are most beneficial. The designers of that study had to make a choice which was what is the margin of error in terms of mortality? Are we gonna tolerate people who start to detect it if there is a different potential arms? So, and you know, I can tell you that parents who are entering their children's studies like that might have different views than researchers who have various other considerations because they don't wanna have a study with 10,000 people which is gonna be too expensive. They can't get it done. It'll be too complicated. So they're incentive is to make it as small as possible and tolerate fairly big margins before they start detecting something really bad happening. But research subjects might have a different view. So in that case, I think the design itself sounds scientific but embedded in it is a hugely important moral question about what trade it is worth it if my child unfortunately has to be in a situation where they have to make a choice. So I think it's both. Thank you very much for the wonderful presentations. I just want to ask you a question regarding, as a doctor, as a researcher, why is this? What is the fundamental ethical problem that you see with a misconception? Obviously, your heart is clearly there. It's all about the core concerns. So the patient is coming in with the attitude that something is there that isn't really there for them and you're recruiting people and shouldn't be there or either make an alternative decision to not participate. However, I mean, let's consider your ultimate goal to have the most ideal research participant on that. This is to have an altruistic research guinea pigs. I mean, that's not the alternative. Your own participants are there, fully understanding this could not benefit them and they're still willing. Like that number three in Dr. Kim's presentation with the three, four percent that understood the question and yet still gave it the unresponsive So is there any difference between your participants or is it just for the conscious mind to be, as a doctor, for example, you're happy that this patient is in because they understand and yet they still make a decision. What's the difference between the first patient which is an naive lay member has now understood the whole purpose is why it's all hopeful and keen to participate as opposed to someone who hasn't said exactly what you're saying, yet still making a decision that no rational person would actually make it. Obviously the thing in the little hindsight is that patients in ALS, which the alternatives of, we're talking about people that are fully healthy going to research. It's about someone who's got no other way to actually say. Do you find that the ethical dilemma the second one? I guess I would say that what we want to avoid so that the reason that we all get a little uncomfortable when we talk about shifting how much risk the risk benefits that people are willing to accept. It's at least one of the reasons that I understand a little time for you. But I mean, one of the reasons is this idea that people are vulnerable. So another phenomenon that we see a lot of in ALS is step cell clinics or snake oil cells. And I personally want to draw a very bright line between me and them. The way that I can draw a very bright line is to try to be as clear about what we're doing as possible. And what we know and what we don't know and what the potential risks are. But because if I don't spend time saying, we don't really know that there's a benefit or in fact, if I did the reverse and said, I want to do something that's going to help, there is no difference. It seems like the fundamental ethical concern in TM and maybe in overly optimistic subjects is exploitation, right? The snake oil system is exploited in their hope for personal gain. The researchers could exploit the misunderstanding or the overly hopeful patient in order to get the research study done. And in order to prevent that exploitation, we need to come up with some way of either minimizing their hope without eliminating it. Yeah, yeah, I mean, I don't, again, I think understanding and hope can be divorced that I made a wrong about that. Some of this actually really comes from personal experience. My sister called me one day and said, I have ovarian cancer. I said, I'm gonna be okay. I mean, that's crazy. That's a crazy thing to say to somebody with ovarian cancer because that's a very bad disease. No big numbers about ovarian cancer. But that was my immediate reaction, right? If she, I mean, I didn't say it because I was saying, oh gosh, I know that these numbers, I know I can get you into that group that's gonna survive. And I just wanted it to be nice. I'm just wondering if, given that, a lot of this is about communication and understanding. If in the consent process might not, this optimism bias, would be kind of a useful tool to be right up front about the existence of an optimism bias. Might that not be a way to communicate this? I think that's right. I mean, my ideal picture would be, or I think in ideal world, what you really want are participants. You don't want to sort of participants who aren't hopeful or optimistic, but I think you want them to really understand what's sort of the underlying uncertainty that's sort of the whole point for doing the research and scientific enterprise, right? And so yeah, you can go in and sort of educate them. Part of consent could be explaining what optimism bias is, what therapeutic misconception is for that matter, right? And just sort of put it on the table and say, look, we want to get the best informed consent we can. And so it's important to acknowledge that there are sort of potential cognitive barriers to that process. So I think that's right. I mean, that could be a part of a conversation. I mean, I think, I mean, just to touch on it again, the comments that I was at about sort of science education in the public, there the discussion was all about climate change and how do we get people to understand climate change and believe it and recognize we need to act on it. But the whole time I'm sitting there listening to them talk about climate change and I'm thinking this is all like therapeutic misconception, not like this is all the same stuff. It's just in a different arena where it's about really understanding kind of what science is and what we're dealing with. I think that's what we want. They team lead from participants. They have sort of, I think that some sort of understanding that you can sort of allow them to hope and be hopeful and you, the investigator, can both be hopeful. I don't think that's a problem. Kind of. There's a lot of evidence that shows that people who are more optimistic or more religious or terminal disease live longer. So is it possible that their participation is actually inherently therapeutic? I mean, there have been some sales mail, I'd say that people who are in trials are better than people who are not. I think it's not that trial. It's probably systematically flawed and lost. Yes. Right? But, and you know, there are a thousand reasons for that that have nothing to do with whether their whole business is helping them. You know, part of it is that assuming that, I mean, I, research, understanding what research is about a particular study, I mean, it's kind of challenging because there's a lot of science behind it and so forth. But on the other hand, among the things that people who are in that terrible situation they have to sort of think about, read about, and learn and make a decision. Let's say if you use an analogy like the stock market or something, the available information is pretty good overall, you know, there is, so that I think if you had to make this very broad, overly simplistic generalization, which is if you look at the people, if you look at clinical trials and see which ones have difficult in rolling versus which ones, you know, have no trouble in rolling, that gives you a barometer of a lot of stuff actually, I think. One, if you look at, let's say Alzheimer's disease, a couple of trials, I mean, they have trouble finding poor minority people entering those trials because they tend to be highly educated, what will you be able to seek out? I would say, I wouldn't think that if you were poor with ALS living in some place, you know, remote part of Montana, they wouldn't have been calling MGH to try to get in the trial. You see what I'm saying? So one of the reasons why, so when we talk about, you know, people with the trials do better, I mean, geez, you know, wealthier, healthier people, people who look like people in this room actually and are doing better in most things in life. So it's not a surprise. So I think there's a huge element in that. I think they're all kind of like that. At the same time, I mean, there's one more problem in ALS, which is that there are lots of decisions that people make about their health care along the way that really impact survival. And there are rational ways to make those decisions that extend survival and don't extend survival just based on how people want to. And so hope is very tied to how aggressive people may, I just think, I don't know, I think that's a really hard question to answer. But it certainly is a chance to reason that it's a nice thing for us. We are right at six o'clock, so I want to thank our speakers once again. Please, anyone who wants to, we should have enough food for anyone who wants to come to room 447 upstairs. We can continue the conversation. Thank God.