 In moderating this session, it's my privilege to first introduce Eric Kodish, the Director of the Cleveland Clinic Center for Ethics, Humanities, and Spiritual Care. He also serves as the O'Neill Professor and Chairman of the Department of Bioethics at Case Western, and he will speak to us about ethics and research with children enduring themes. Please welcome to the podium Eric Kodish. Thank you. Thank you, Dan. Always great to be back on the South Side. Kudos to Mark, of course, and thank you to the McLean family for having all of us. I was reflecting before coming up here about the topics that I've talked about in the last several McLean conferences, and I think eclectic is what comes to mind. A few years back I talked about immunization with children and the ethical issues around that. I think we moved on to uterus transplants, and then last year I talked about board certification for ethics consultants, and today I'm going to talk about what I really love, which is the ethical issues in research involving children, enduring themes. This is prompted by the fact that we're working on the second edition of our book called Ethics and Research with Children, a Case-Based Approach. We have chapters coming in, and there are going to be some great chapters. I have a consulting relationship with SaladGT, which I wanted to disclose to give them advice about research ethics, and the Belmont Report, I think there's been discussion about the need for a revision of the Belmont Report. It's hard for me to see a lot of weaknesses, quite frankly, in the Belmont Report, not just when it comes to pediatric research ethics, but globally. I think it gives us a very solid foundation. With regard to beneficence, I don't know if Norm is still here, or you hear Norm? Gone. Okay, but Norm Foster would like this quote. Research also makes it possible to avoid harm that may result to children from the application of previously accepted routine practices that on closer investigation turn out to be dangerous. It's really interesting, sort of hidden gem within the Belmont Report. It says that beneficence is not always so unambiguous, a double negative. In other words, if we prohibit research that poses more than minimal risk without immediate prospective direct benefit to children involved, that limits the potential for great benefit to children in the future. So Belmont is keenly aware of the trade-offs in pediatric research ethics. I always like to show this slide because it shows us all that things in pediatric ethics are a bit more complicated than they are in adult medical ethics, and we try to remember to keep the child at the top of the pinnacle of the triangle, but investigators and parents have important ethical roles as well. So one could say that this is one of the enduring themes in pediatric research ethics to keep the triangle in mind. Another way to think about the ethics of research with children is to think about three stages before a study begins, during the conduct of a study, and after the conduct of the study. So what matters before a study begins is that it has to be significant science. It has to have the potential benefit of helping children, and as a child advocate I would say I'm pretty clear that it's children as a class, a study that might be designed to use children to help adults. I'm not very supportive of that kind of study, but there is something to be important for those of us in the pediatric research community, the pediatric ethics community, at being very clear at saying if it's going to help other kids, that's a different story. And is it going to help healthy kids or sick kids to get back to the immunization question that I mentioned before? Think about the general area of immunization research, right? Yes, in general, research that is done on healthy children to prevent them from getting sick or to prevent other children from getting sick. I read this morning that every day 350 children die of measles around the world, 350, a completely preventable disease, and through immunization that could be prevented. So before a trial, thinking about the need to help children, is it going to help kids? Thinking about the risk-benefit assessment and a design that's going to answer the question but does not subjugate the interest of any single child subject to the needs of the research. That's a very high bar, but I think that's what matters. So one of the enduring themes I wanted to mention is this really interesting question that goes back to the regulations and to the Ramsey McCormick debate, which some of you are familiar with, should we think differently about research on healthy children compared to research on sick children? It's my view that the architecture of the regulations right now promotes this sort of dichotomy, and perhaps the potential of benefit to the child from the research provides a justification for this sort of dichotomized framework. I'll leave it to you to see what you think, but I think the regs have us thinking differently about sick kids and healthy kids. In general, the regulations give us these criteria for all of research. One of the talks earlier was about the subcategories of vulnerable subjects. These are the regulations and the criteria for the ethical conduct of research, but then specifically, we get into these four categories of approvable research in subpart D, when children are the research subjects. To me, the 405 is the one that really has us thinking differently about sick kids compared to healthy kids. The 405 says that IRBs are allowed to approve research on children if it involves greater than minimal risk, and there's no ceiling on the level of risk here, but it has to present the prospect of direct benefit to the child if the risk is justified by the benefit to the child, if the risk-benefit ratio is less than or equal to the alternatives, and if you have parental permission and if appropriate ascent. So that 405 category is probably never used on research in healthy children because a prospect of benefit to them, if they're not sick, is sort of a non-starty. You don't want to expose kids who are healthy to risk in exchange for benefits to others. Minimal risk is the ceiling in the 404 category. As some of you know, I've been particularly interested in phase one oncology research in children, and I think it gives us a good case example to think about some of these enduring themes. When you're developing a new drug for cancer, safety comes before efficacy in the traditional dogma of our approach to developing new treatments for cancer. So phase one studies have to be done to determine a safe dose to move on to phase two. Subject selection has not been a controversy. These studies have been done on children who have cancer that is refractory, that there are no curative options available, and I think most IRBs approve this as research with the prospect of direct benefit, and the potential for benefit mitigates but does not eliminate the need for protection from research risk. And this goes way back to the early 80s when I was a fellow here and we were working on the ethics of phase one studies in adults. I think if you take that and apply it to the pediatric age group, it gets real interesting. It got so interesting that we had an R01 a few years back to look at this where we audio taped 85 consent conferences. And we found that the conferences were about 45 minutes in length. There were an average of about five participants per consent conference and there were about 15 research related questions per informed consent conference. So one question every three minutes on average. And of the 85 conferences, how many of them do you think the child was present for? This is a multiple choice, 27. I'll give you all the choices and then ask you to raise your hand. How many think 27 of the 85 had the child present for the conference? Okay, that looks like about half. How many think 52? Much fewer. How many think 83? One person. You read the paper. That's right. So we were pretty shocked that in the room for these conferences about these phase one studies, 85 conferences that we looked at, the child was in the room for 83 of them. So now you may be wondering, well, how old were the kids? Maybe these are two-year-olds or three-year-olds who needed a babysitter, but they weren't participating in a meaningful way. And here's the distribution of ages. And you can see there were certainly a few younger children, but quite a few older children, and even we counted 21 up to pediatric in this. So clearly the children are there. Moreover, I won't share it with you now, but we have evidence that they were pretty active participants. We also had concern about how much parents understood. And you can see from this that the basic components of phase one informed consent, parents did not do so well in understanding that half of them did not understand that safety was one of the basic goals of the study. And the same thing for dose escalation and dose finding. One was a perfect score. And dose finding, I think, did the best of the different concepts for parental understanding. You can't think about informed consent purely with understanding. You have to think also about what gets disclosed. And this shows in the diamonds a level of physician disclosure, description of the content, and the orange dots that you see are parental understanding scores. So you have a lot of conferences here where the docs did a pretty decent job describing the goals of the study and the parental understanding fell short. But interestingly, you also have over here parents who had good understanding and the doctors didn't explain it at all in the study, so in the consent conference. So parents get information from other places. And parental consent, especially parental permission, I should say, when you're talking about younger children, is another one of these enduring themes in pediatric research ethics. So informed consent matters in pediatric research ethics, ongoing monitoring of a study if it's a risky study with the data safety monitoring board, and the ethical action of suspending a study and doing it at the right time, which means not too soon, because if you do it too soon, you're not going to get the scientific information to help future children and not doing it too late because you don't want a single child to suffer unnecessarily. I'm going to go through the consent and assent stuff here pretty quickly so I can get to some of my concluding points. But we had a talk about the 50th anniversary of Beecher. I guess we're probably going on 75-ish since Nuremberg. And if you read the Nuremberg code, you know, black and white, you can't do pediatric research because the individual involved has to give legal consent. So we found a way around that in pediatric research ethics, another one of the enduring themes. We have a way of protecting children without getting their own consent when it comes to younger children. We use parents as surrogates. If appropriate, we involve children and get their assent. And most importantly, I think we have societal protections in the form of IRBs. And I'm a little worried as we move toward the learning healthcare system about that protection remaining in place. But I'm also excited about the learning healthcare system because it allows us to calibrate risk level and to think a little bit more in a more nuanced way about research ethics. So we could talk about learning healthcare system later. After a trial has closed, monitoring for late effects of the therapy or the intervention that's done, ethically obligatory to publish results even in negative studies and returning results to subjects is another newer but important ethical idea. So as I've tried to show you one of the enduring themes in research with children is science to benefit others, specifically other children, balanced against the best interests of the child's subject. And a few of my opinions to wrap things up. The first is that the protection of children from research risk and the imperative to improve the treatment of children who are suffering from disease are both ethically important. The risk-benefit assessment I think is more important than informed consent. The studies that we've done over the years and other studies in the literature have shown that informed consent is important, but not very effective at protecting people from research risk because it's hard for potential subjects to understand. And we need to do better at effective communication so that potential subjects can understand. But in the end, investigators and IRBs, I think, have the responsibility for doing a good risk-benefit assessment. And I've seen too often in my career regulatory fervor that's intended to protect children from research risk that can threaten the ethical conduct of pediatric research. So kids are vulnerable subjects who need protection and they're a neglected class that needs better access to the benefits of research. And the last slide is some enduring themes again. I think non-therapeutic research with children will always remain ethically problematic if it's associated with risk. This is the core of the Ramsey McCormick debate for those of you that are students of ethics. I urge you to go back and read it. Therapeutic research, on the other hand, is all about that calibration of risk against potential benefit to the child. Who gets to decide is a question that gets more difficult as children get older. And there's heterogeneity in our country. We saw that on Tuesday in the election, right? That heterogeneity may have something to tell us about the view of proper parental authority. And that's going to lead to ethical controversy when it comes to sex and drugs and rock and roll. Thank you. Terrific plenty of time for questions. I have a question. Thank you very much. This I'm Maggie Moon from Hopkins. And I've been worried lately about the notion of ascent with children and a few months ago, I read an IRB with a protocol review and they had reported a protocol deviation where they didn't get some of the safety labs for a drug study. And they didn't, but in their description of why they didn't get the safety labs, they described even though four adults held this child down to get the blood, we were unable to get the blood. So this is a child who had ascented to the study and was very obviously withdrawing ascent. And we felt very comfortable ignoring the withdrawal of ascent. And it made me start to really get concerned that ascent is sort of this charming myth. And I wondered what you think about how we can handle that. Well, I think the first thing to stipulate is that ascent for research and ascent in clinical care are quite different from one another. And I hear you're asking a question about ascent for research. Research, yeah. And I think we should have more teeth in it. I'm troubled to hear that they were holding a child down and it was an optional, it wasn't for his benefit at all that they were getting her benefit. Well, they were safety labs for a drug study, but I don't know how important. Yeah, so I mean, safety first when it comes to children. And there are times when one needs to violate the ascent and apologize to the child afterwards. But I think that heterogeneity around parental authority is a real issue too. In states like New York and places like Chicago, there's a lot of child empowerment and a lot of thinking that kids who were 11, 12, 13, 14 get to make their own decisions. I think in places that are more conservative, more rural with all due respect, parental authority is a more powerful thing. So I guess my approach would be kind of to be culturally sensitive around it and apply ascent differently depending on how children are viewed there. This was Baltimore. It was Baltimore, okay. And then the other thing to say is that kids who are in that ascent age range often really want to help other kids and want to be in research because they want to help other kids. And I think that's important to enable that while still probably, I'm gonna say this in Los Angeles on Monday when I talk at the primer conference, we should do more one-on-one with the investigator and the ascent-aged child to hear what they really think and move it outside of the room where their parents are there and can have a lot of influence. So that's one practical approach maybe. Thank you. Sure, Laney. Hi Rick, Laney. I was curious that you showed that so many of the kids were present for the phase one trials. I'm going to imagine that these kids have already been through one or two courses of chemo, radiation, surgeries and they're either relapsed or still quite ill because they're on phase ones. How many would be present more or less at the first meeting after a newly diagnosed cancer? Just, I mean my recollection of our studies which were done on newly diagnosed leukemia is that it's just as high. It's 90, 95% and I think part of that is that parents just don't want to leave the kids at all, especially at the time of diagnosis. If ever a time a parent would be emotionally comfortable leaving the child, it might be more in the phase one. They're not critically ill. They're outpatients at that time. Their prognosis is bad but I'm much more surprised in the presence of the child for the phase one than I am at new diagnosis. Okay, thanks. Please join me in thanking Dr. Kodish. Thank you.