 So, our first speaker is Jerry Menikoff, who used to be an associate professor at University Kansas in Law, Medicine, and Ethics. He spent time at NIH and he now works at the U.S. Department of Health and Human Services on issues of protecting human subjects. Jerry will speak today on how risky is research on standard care. Thank you. Thank you. I have no slides. I particularly want to thank Mark for the presentation. It means a great deal to me to be able to speak here and also thank Mark for far too many other things, too numerous to mention. It's not loud enough? No. Try again. Okay. Is that good? Can you hear me in back? Okay. Very good. So anyhow, Mark, thank you so much for so many things. I want to thank the McLean family for making a center reality and for allowing us all to be here. So much great stuff has happened from all of this. As Ellen Fox mentioned, I'm in a similar situation. I'm here in my personal capacity. Anything I say are just my personal views in no way should, they're very personal. So in no way should any of this be attributed to the Department of Health and Human Services. And I have no slides. Okay. I want to start out with a hypothetical case very, very hypothetical. There's no reality to this case at all. Let's assume we're doing a clinical study relating to prostate cancer. And we're looking at a particular treatment that is already currently being used by lots of doctors. And for whatever reason, some concern has developed among people in this field, among the physicians in this field, that let's assume there's one particular variable in terms of this treatment, the amount of time used for one aspect of the treatment, and it varies among physicians. Some physicians go up to a certain higher level in terms of the timing. Some start at a lower level. And let's assume the concern is that at the higher level, we might have an increased risk of impotence as a side effect. And at the lower end, there might be a concern about an increased risk of urinary incontinence. So we're sitting there. We're concerned about this sort of stuff and people think about doing a trial. And let me mention, again, this is a very, very fake trial. Any resemblance between this clinical trial and any real living or dead clinical trial is purely coincidental. This has nothing to do with any clinical trial out there that you may have ever heard of that. Okay, so we're sitting here with this degree of uncertainty about these two particular risks in this range of treatment. Want to make it clear, let's assume that both at the high end and below end and all in between in this continuum, various doctors are using these amounts of time in terms of this treatment. So all of this, if you think it's a meaningful concept, you could say it's standard of care. None of this would have been malpractice. Okay, so this is what's happening. As would be particularly appropriate, people wanted to do the clinical trial to answer this question. Perfectly reasonable thing to do, perfectly legitimate clinical trial. Hopefully all of us could appreciate. It would be a good thing to answer this question, to get a better sense of whether or not on the high end you really are getting more impedance and on the low end you're getting more urinary incontinence. So they actually proposed a randomized trial and let's assume they actually conduct it. Patient to enroll in the trial a randomized 50-50 to this high end in terms of the timing of this particular aspect of treatment or 50% of time to the low end. So that's the trial and they write a consent form. So let's go over what this consent form might say about the risk of participating in this treatment in this clinical trial. So the risk section is very short. It does mention that they're going to do a few blood draws while you're in the trial and this might be a little painful and there's a small risk if you're getting an infection. In particular, regarding some of the aspects that they're sort of studying, namely risk of impotence, risk of urinary incontinence, it actually doesn't mention either of those particular risks at least by name in the risk section of the trial, of the consent form. What it does have, it has this one sentence. And I'll quote you, because all of the treatments proposed in this study are standard of care, there is no predictable increase in risk to you. So that's what it says. All of the treatments proposed in this study are standard of care. There is no predictable increase in risk for you. So that's pretty much what it says in the risk section specifically gives you some details about the blood draws and then has this thing that it's all standard of care and no predictable increase of risk to you. It does have a benefit section and that benefit section actually points out, you may benefit. In fact, you may benefit from the fact that there may be a decrease in your actually developing impotence by participating in the study, although it notes you may end up receiving no benefit. So the question to be addressed here is, is this an acceptable consent form? And in particular, how acceptable is it? And in terms of this issue, there was another study out there that of course has no resemblance to this at all, that is called the support study. And again, these are my own personal comments. I obviously have a bias in terms of being involved in a lot of this. There was a letter written, and this is in particular what I want this group to think about. There was a letter written by a lot of prominent bioethicists and it was published in the New England Journal condemning what the federal government, particularly my office did in terms of saying there were problems with this consent form. Nobody was shut down, nobody was had to plug poll, they weren't fined, a letter was written that explained this was not a great consent form. Hopefully we could do better in the future because that's what it's ultimately all about. It's all about protecting the subjects. And so in any event, this letter was written and it got a lot of play. I could particularly tell you from my end, this was a very impactful letter. I wonder how much many people who have had these discussions today about professionalism of a bioethics, but letters coming from leaders in this community have a massive amount of impact. And this did have a massive amount of impact. And I think it's worth taking a look at some of the things the letter said because in particular this is about bioethics and personally I spent a lot of my career, I learned about informed consent from Mark and other teachers in the McLean Center and I still view this as it's all about autonomy and often, not 100% of the time, letting people make decisions. If we say that we need consent in a particular scenario, the question is, are we doing a good job vis-a-vis that? And to quote, let me quote again one aspect of this letter that was referring to the ethical aspects of this study because I'm aware we probably need many hours to discuss all the subtexts in terms of my guessing why this letter was written and certain groups don't like the federal government getting involved and saying anything is bad in terms of any particular study. And let's put that aside, but the question is this letter actually said some things about the underlying ethics here and among the things it noted was, and this is quoting, we disagree that the randomized assignment to a high oxygen saturation level. So this study involved infants, notice my other hypothetical study, no infants involved, no death involved, we don't have to actually worry about that. But in the real study we disagree that the randomized assignment to a high oxygen saturation level or a low oxygen saturation level imposed additional risks that the investigators failed to disclose. Now I'm not sure what they meant in terms of additional, but let's go back to basic concept. You're asking somebody to be in a clinical trial. The reason you're asking them is that you think they have a right to think about it and decide whether or not they want to be in the trial. And by and large I would have thought one of the premises of informed consent is we actually give people important pieces of information that lots of people in fact would in fact think is relevant to their making a decision. And this one sentence seems to be making an ethical pronouncement in terms of the sort of information that is relevant. And this is sort of part of a party line that a number of groups in addition to the group writing this letter have sort of glommed on to that, well, it's all standard care that gets back to the sentence I was quoting from you in the hypothetical study which actually bears a remarkably strange resemblance to the real consent form that was used in the support study. So the thinking is, well, you're doing things that are standard of care. Some doctor could have assigned a patient to get this particular treatment, therefore zero risk. Well, the risk is that unlike a study which is investigating some new treatment, yes, there might have been some unexpected risks. And you won't get that in these studies that involve looking at standard of care. On the other hand, there are differences between different aspects of standard care all over the place. And there's no, there may be studies that indeed are minimal risk that the two things you're comparing, two stents that we have no good reason at all to think there are any differences between, but often there are differences. And in these studies that we're talking about, there were very real differences between the two actual arms that people were being assigned to. Just because they're standard of care, how in any sense does it now follow that there is not a piece of information, namely we're sitting there thinking there might be particular differences in terms of risk in arm A versus the risk of arm B, we're asking the person to enroll in the trial, shouldn't they know the difference in terms of these particular risks? And again, when I think about this, I keep coming back to that great commercial, it's DAT&T commercial with the guy sitting with all the little kids around him and everything, and a bottom line, it's not complicated. And I don't think this actually is particularly complicated. What happened is though that certain groups and particularly a bunch of very prestigious bioethicists were pissed off in terms of what happened, in terms of the government saying a particular thing was bad, and going out on a limb to say things, to make it look, without even saying much in terms of actual arguments, that oh no, there's nothing ethically wrong in this study. Interestingly, the earlier version of this letter, which actually made its way to me, and I don't even know why this didn't go public, I guess somebody edited it at some point, but this came from Francis Collins, actually took on the other issue about death and said, and by the way, the risk section mentioned death. It mentioned death in the context of a child being resuscitated, a child that they end up having to be resuscitated may die. Had nothing to do with the risk that the study was about, namely at a low oxygen level, might there be an increased risk of death, but just showing you the extent to which versions of this letter went out on limbs and tried to say things that in terms of, I guess getting back to themes of professionalism, and what this field is all about. Because ultimately, you know, I was pointing out this letter had a lot of impact, and it will continue to have impact. This is an issue that, as a lot of you know, has not gone away, and it's an important issue in terms of ultimately the well-being of patients, of research subjects, and others, and there are consequences to using your authority, your professionalism, speaking out on behalf of the field of bioethicists, and making arguments that actually don't hold up in terms of what we were actually taught, in terms of what actually matters. And I'm just saying, in my personal view, this can be harmful to the field of bioethics, because there are newspapers out there waiting to see the resolution of all this, and are very interested in this, because people pick this up, the public pick this up when they hear about this. As in the hypothetical study I'm talking to you about, you could figure it out. Of course, a man would want to know whether or not there's, you know, the fact that this is all standard of care. If you're thinking about a higher risk of impotence, or a higher risk of urinary competence, you know, incontinence, there are reasons why one man might choose one thing or another, similar reasons in the other study. And let me just put this as part of a bigger picture. I'm sure many of you are well aware of this. This is actually one of the other reasons this got so much traction, and that the bioethics, the people who wrote this letter, and my thanks to those, you know, many of you actually wrote a counter letter, and I know it took quite a bit of courage to sign that letter going in the other direction. It's actually interesting that that actually managed to see the light of day. But the bottom line is this is actually part of a much bigger debate taking place. A lot of you are familiar with Ruth Faden, Nancy Casta, and of course Tom Beecham, and others who are proposing a change in how we even view there being a line between research and clinical care. And the bottom line is they will say in these sorts of studies, or at least some of them will say, you didn't need consent. So that's why it's so important for everybody in this group to forcefully make the argument that this was all wrong, the government was off the wall or something. It wasn't not only that, you know, you didn't say enough, you actually don't need consent at all. This ultimately could have majorly repercussions for the field of bioethics. It goes back to when Mark created this center. It was about clinical ethics, the interaction between doctors and patients. People are now proposing to dramatically rewrite that and basically say you can routinely have clinical trials in which had the patient known about this, they would vehemently have wanted one arm as opposed to the other arm and we're not going to tell them about it. And God knows where this is going to go, but it is getting major league traction. Major players in the healthcare and research establishment are pushing this and we should be very wary of where this leads us. Thank you for allowing these very personal views. Questions? Thank you. Rick. One of the people that signed the letter, I have a lot to say, but I'm going to try to keep it brief. Maybe I'll start by saying that in about two months we're going to be using the support study to teach our medical students and I'm very interested and I'm going to reflect a lot on what you said to try to figure out what to teach medical students about this story. It's a very important story, I think we would all agree. I totally agree on that. I think where I'm leaning toward going is a disagreement with your statement that it's all about protecting human subjects. Because I think what for me is at the bottom of this is that it's all about a balance between the ethical imperative to make progress and help future premies in this case with the imperative of protecting human subjects. And I think it's that balance that made me sign the letter, I would have to say. And I'm interested in if you think there's an ethical imperative to make progress. Yeah, no, and we've had this discussion before. I fully appreciate the notion that perhaps there are scenarios in which we don't need quite so much informed consent. But partly what this gets back to is the claim was being made that we were getting good consent in this trial. And I think there were legitimate reasons for parents had they been given the appropriate information to actually have preferences. In another scenario we could particularly look at what was happening to this is getting probably more into the details of the trial than I ideally want to. But a lot of the institutions, this was a continuum from 85 to 95 in terms of oxygen levels, a lot of institutions set at the outset that they were keeping infants in a narrow range from 88 to 92 right in the middle of this range. And over the past several years the actual range that in general has been used was gradually going lower and lower. And so the goal was could we verify that the really low end 85 was acceptable. And the question was to what extent can we try to get these trials done without really sort of needing ideal consent. And I think I want to be fair to you the direction a lot of people go in terms of what you're saying is right we don't really need informed consent in this sort of trial. What troubles me is saying we're getting good consent and then defending a consent form that is clearly not revealing information that I suspect people talk about empirical bioethics. If we picked a hundred sets of parents out there and told them what was going on I suspect very few of them would say of course it's acceptable never to have told me this. So I'm very appreciative of the need to basically try to get trials done then let's have the debate that Ruth Faden and others are in fact conducting and defend if you want to do that moving toward not needing consent for a quote standard of care trials or some subset of them. Well we have both Ellen and Lanny you have a quick question also but if you guys can be brief and Jerry if your time has refunded to us. First thanks for your courage in that presentation bringing up this very controversial issue that affects many in the audience many were personally involved and I am not involved in the details of this since it's pediatrics and we don't do that but but my interest is in your use of the concept of professionalism and applying it to you know the the nature of these letters and I don't want to say anything about either letter that you alluded to because I don't you know I don't know the details but but I'm interested in your thoughts about you know as as a somebody who also works for the federal government in my experience the work of working for the federal government is just very different from the work of being in academia because you when you make recommendations or pronouncements you're very much aware that the it affects the lives in a very immediate way of millions of people and I think when you're in academia it's a very different endeavor and so I wanted you to comment on the relationship between this professionalism concept and being in the academy you know and is there a different standard for you know the level of of vetting or you know the opinions being measured is there a different standard than there is in the federal government yeah I mean that's a great issue I could say in terms of how people thought of that on on our end in terms of our office we actually try to be you know very aware of what we're doing when we make you know when we criticize a letter and it's interesting we we frequently I mean we actually don't put out that many letters criticizing people and that sort of thing a lot of thought went into this and the bottom line is we often when we do these things it's precisely because so much is at stake and the bottom line is it wasn't about punishing these institutions I have to say I know some of you here went to primer the big research ethics convention which was like a week or so ago and the person from running the IRB at the lead institution of this site came up to me and he was smiling and introduced himself and we had a nice discussion I mean it was like he thought this was actually pretty appropriate and again so it was not about finding and we never actually got a chance to impose a penalty generally our penalties are let's have remedial education that sort of thing but the bottom line is if things are happening on serious issues and again this was a serious issue because this is getting to this big argument all about do we do we not need informed consent in these sorts of trials and if you want to go that way we're all open I mean I'm certainly open personally to that discussion taking place but that is a huge change in terms of the thinking in this field I think it's humongous in terms of going back to the core principles I learned at a McLean Center so it's a great issue and and of course in the government side you should be aware of that sorry for taking too long Jerry I also want to thank you for being brave enough to talk about the case and yeah I'll admit my bias I was a signer of the letter that you're talking about I actually wanted to talk about a different issue which is what you raised when the parents may have had a preference because the fact is is that some physicians may have had a preference and yet the fact is that we really didn't know which was better and which was worse in the two arms right and so from a community perspective we were in Benjamin Friedman's concept of clinical equipoise right some of us may have preferred one some of us may have preferred the other but overall we were in clinical equipoise the parents may have had preferences but based on no medical data because we don't have the medical data to have a preference and so I guess I'm asking you there is a concept that actually John Lantos and Jason Carlawish raised about a decade ago do we also need in order to make a trial ethical do we need the community to be an equipoise or is enough to say that if you give somebody the opportunity to refuse to participate that's enough so are you really looking for parents to be an equipoise in order to make these trials ethical okay I don't think I'm looking for well it depends on what you say when parents parents is a class in equipoise no I mean again we on the government side we never said the trial was unethical in fact we went out of our way multiple times as it was important trial to do but the fact that something is in equipoise virtually any trial again if you follow medical ethics there better be equipoise if you're going to go ahead and do the trial so if you follow your argument is the point that basically there's no good reason for for patients being asked to be in a trial to actually prefer one arm or the other outside of the trial instead of getting standard of care and I just think that's not true the example I gave you about the prostate cancer trial I think there's very good reason for men a man who basically is not having sex or whatever it is probably couldn't care less about impotence and having been given that piece of information would clearly say I want to be at the urinary incontinence the greater risk of urinary incontinence on in terms of the the particular support trial the one thing and this is just it puzzles me the move had been toward the lower end for quite some time you gave them a consent form that basically actually didn't say there are any risks at the low end or something I'm curious about why and a lot of the centers were actually keeping everybody in the middle close to 90 not near 95 given that the actually was a fair amount of information on the high end about the risk of retinopathy and developing blindness why was it good for any of those infants to end up being randomized closer to 95 particularly in the centers where they would have been in 88 to 92 or even lower than that and and if the parents actually knew what was going on I'm curious about what the clinicians would say about that because I'm aware of this aggressive argument from the pediatric community in terms of this thing there was no good reason to pick but clinicians in fact were picking and what's ironic I think is we live in a world in which we do more and more in terms of making decisions with incomplete data and now it's suddenly like physicians are clueless and we're now using that as a reason to say you can't get informed consent. Thanks very much Jerry.