RESEARCH WITH DECISIONALLY IMPAIRED SUBJECTS: DRAFT REPORT Discussion: Led by Jonathan Moreno, Ph.D. DR. MORENO: It seems as though we should start by talking about the status of the Research Advance Directive Concept, either the nomenclature or the substance. It would be very helpful, I think, to start there and resolve that question. CHAIR CHILDRESS: And I'm going to try to get everybody to use microphones. MS. FLYNN: It would be helpful to me, and maybe I'm -- little discussion on substance, I'd like to hear a little bit from Rich and others before we go further. I feel that, yes, the discussion was useful, but I don't think we got a chance to complete it and I'd like to share a little bit more substantively. DR. MORENO: Can I just say one thing about that discussion? I'm not sure that in the discussion a key element of the Research Advance Directive Concept was suitably addressed, namely for people who -- actually, Trish has talked about this with me, and I think is reflected in the text. For people who are anticipating a period of incapacity, who've already experienced it, these truly would be advance directives. I'm not sure that that concept was fully appreciated in the discussion yesterday. So that even if, in other respects, the concept of an advance directive for this kind of research proves not to be importantly different from informed consent, garden-variety informed consent, at least in that kind of situation it would seem to be useful. CHAIR CHILDRESS: Good point. Trisha? PROFESSOR BACKLAR: Yes. That is -- it's terribly hard for me to hear people speak, I must say, even when they're speaking into the mike. And it may be my advanced age, but I urge all of you to speak clearly as possible. MR. CAPRON: Because this is an airplane hanger and there seems to be some loud noise coming. PROFESSOR BACKLAR: It gets distorted. Yes. It's really horrible. Now that I've said that, let me put it aside. Yes. Exactly and precisely as you said, Jonathan. These are people who have experienced, and may experience again, periods of an inability to do decision making, periods of incapacity. So what the advance concept is planning for those periods where they may not be able to make decisions about their involvement in the research -- so it is not a misnomer, for that particular group, to call it an advance directive. In that same way, it's no different from an advanced directive for psychiatric treatment, so that there are certain things that will fall into place should that capacity for decision making be lacking. I don't think I need to spell out the rest of it, because what we tried to build into it were protections inasmuch as there would be a top decision maker, there would be an outside provider who was not connected to the research, and that provider did not need to be a physician, it could be a case worker, et cetera. CHAIR CHILDRESS: I think it's very important because it clarifies what this is about, but also limits it. I think that the -- limitation group of subjects to whom it would apply is also very important. PROFESSOR BACKLAR: And because there was this -- it is also important to understand that what was intended in this process of planning was that during the consent process that takes place in any research protocol, one hopes, is the appointment of the -- the proxy should be involved for somebody who is in that situation where they may lose their capacity. So if the proxy doesn't come in later, in other words, people are -- the proxy is educated at the same time and learning about it along with the person, the subject. DR. MORENO: And it's worth knowing that the current, much maligned chart on page 150, for the category of greater than minimal, non-beneficial research, the current framework calls for having -- whether there's informed consent or an advance directive, calls for having the necessary involvement of a legally authorized representative, as well as the health professional monitor, which would go to Trish's wish to ensure the involvement of such an other person in the process. PROFESSOR BACKLAR: And there seemed to be some confusion yesterday, and I'm not certain it is in the document, Jonathan, as you've written it--I tried to find it last night, but I'm afraid my eyes were closing--about whether or not that surrogate could be a family member. DR. MORENO: Absolutely. PROFESSOR BACKLAR: I is my intention that it absolutely could be. DR. MORENO: Yes. PROFESSOR BACKLAR: It didn't have to be, but it certainly could be. DR. MORENO: Could be. And I had tried to work Number 4 on page 145 in such a way that would invite the local jurisdictions to develop their legislation for regulations in such a way that there could, indeed, be a default mechanism. That's what people wanted yesterday. PROFESSOR BACKLAR: I also would like to say one thing that I don't think was clarified yesterday. There was a lot of discussion about people didn't think -- advance directives. I wasn't seeing it as a matter of choice, that if you had a subject who could lose their capacity for decision making, it would be built into the process of consent. So it wasn't, oh, you won't have -- if you're not going to have consent to a research protocol, then you might not have an advance -- whatever we're going to call it, you might not have this particular operation. DR. MORENO: Well, the incentive is -- if you look at the chart. For greater than minimal, non-beneficial research, largely, is the language I'm using to describe that kind of study. You have to either get the informed consent of the subject, which is presumably proximate within a matter of hours or days of initiation. CHAIR CHILDRESS: A couple or three of us are having problems hearing you. I'm not sure it's the microphone. DR. MORENO: Let me try again. MR. MESLIN: And speak a little more slowly, if you would, Jonathan. DR. MORENO: For greater than minimal, non-beneficial research, I would be -- as the current framework is written, the investigator would have to get either the informed consent of the subject, which is presumably pretty much proximate to the initiation of the study itself, the matter of hours, but at the most a few days, or an advance directive authorizing this kind of research. Now, we can argue about what this kind of research means. I'm not sure the research sorts itself into actual kinds a l… Aristotle, but, nevertheless, it's a way to get started in this discussion. So the pressure on the investigator is precisely of the kind that Trish has just described for this category of this research. That would not be the case for potentially beneficial research in which you would get either the informed consent of the subject if the certain situation is right, or we get the advance directive, or permission of the legally authorized representative, which could be, again, the family member. But when there is a greater than minimal amount of risk and it's not beneficial, this framework would encourage the investigator to get either informed consent or, alternatively, the advance directive. PROFESSOR BACKLAR: Again, this, of course, brings us back to something we need to talk about and which we are maybe talking about, because I find it very confusing not to know what we are meaning when we talk about these breakdowns, more, thus, and so on and so forth, because intuitively I want to say that there are a group of people which -- and I think we'll get back to this, that almost anything that you're going to do -- research with a particular group of people, that you may want to have certain protections in place. CHAIR CHILDRESS: Let me just point out that this draft also, for those of you who have memorized it, as with the previous draft, on page 146 it tries to deal with the minimal risk definition problem by using examples and actually suggests that those examples might even be written into regulation. PROFESSOR BACKLAR: I couldn't hear you. CHAIR CHILDRESS: Okay. This draft, as in the previous draft, tries to deal with the question of the definitional problem for risk by using examples that might even be written into regulation. Now, one could go further and do as the Canadians have done recently and stipulate that there is perhaps a different scale that is appropriate for people who are lacking capacity with respect to what counts as risk. So one could even add that kind of statement to make the point clearer. Thanks to Eric Meslin, for providing me with that document. PROFESSOR BACKLAR: But again, I want to say that I'm hoping that the discussions we have with Gary Ellis is going to sprint us forward in being able to make this -- CHAIR CHILDRESS: So we'll come back to the minimal risk part. I have Alex -- just a moment. Laurie, does this help get under way the kind of discussion -- I think it's helped clarify some of the issues and I think one of the critical things you have to decide is basically whether we pay too high a price in terms of research if we have restrictive conditions of this sort, and that was the debate between Zeke and Alex yesterday. MS. FLYNN: Yes, I think it is helpful and it reinforces my concern that I expressed yesterday, that we are, indeed, I think unwittingly, erecting too great a barrier to research that I think is a modest increase over minimal risk and is, in fact, quite essential at this point in terms of basic neuroscience. CHAIR CHILDRESS: Trish, did you want to get a response in? DR. SCOTT-JONES: I just wanted to say that I don't think that there's -- that when you have vulnerables on any subject, that one must be very concerned about their protection. The costs may be very small in comparison to the kinds of costs that go into research anyway. MS. FLYNN: My concern, and I certainly agree, was actual limitation and whether, in fact, this current structure would essentially obviate much of the research that is now going on. CHAIR CHILDRESS: Did you want to address this -- DR. SCOTT-JONES: I wanted to ask Laurie to just say a little bit more about the point that she just made, because I think it's important at this stage because we want to come to some sort of consensus to really hear what each of the commissioners is saying. Laurie, I was just wondering if you could be more specific. Do you think it means that there would be additional costs, there would be too much time taken up with the consent process, or what specifically would you see as the obstruction to the research process? MS. FLYNN: I guess I would want to recommend that we hear from some who are directly involved in administering or conducting research, because I'm not one of those people. But it seems to me that the large number of studies that are now under way that represent a minor increment over minimal risk needs to be analyzed. I guess my concern has been that we've looked at this in terms of, how do we try to stop certain kinds of research or how do we try to limit certain kinds of research. My focus has always been on, how do we extend, expand, and improve both the informed consent process itself, which I think we don't have nearly enough attention to here, how do we educate IRBs and engage the community of interest in the work of the IRB so that the design of the studies, including the protections and consent procedure, can be strengthened? This appears to me to be moving to a kind of narrower approach of, some research is okay and some research is not. I'm not comfortable that we know enough about that research and about the vulnerability of that population in any particular study to make those kinds of final judgments. CHAIR CHILDRESS: I guess one question would be, and this came up yesterday, what additional information we would want from whom to help think about this matter. Jonathan, then I'll get Alex's response. DR. MORENO: I think this is an empirical question. How much research is going on that involves a minor -- right now that could not be done under the conditions described in this proposal? I think that is a very important question. I'm not sure anybody really knows, Jim, with a high degree of reliability the answer to that question, but it's one that we might well want close to the OPRR. CHAIR CHILDRESS: Alex. MR. CAPRON: I endorse that view, but I wanted to address something else, if it's all right. CHAIR CHILDRESS: I'm sorry. MR. CAPRON: We're sort of having two discussions. You're talking about advance directives, then we're talking about what seemed to me to be a very fundamental point that arose in the meeting yesterday, which is, if we had made the categories too simple we'd collapse too much in. We need to unpack some of that so that we don't protect people out of the opportunity to benefit from new science. I'm very concerned that we figure out how to go about this, because I don't think it is just a matter in this case of hearing from OPRR. I think it is probably a matter of hearing from, on the one hand, researchers, and on the other, some who have observed the abuses of research. Among the researchers, also, to find out whether there are colleagues who say, well, it's true, you could do the research that way, but you would also do the research this way with a group that has the ability to provide consent. To me, the hardest case that Laurie raised was, if there were fundamental scientific questions that would only be answerable in subjects who, throughout their life, had a permanent incapacity to provide consent and where you were automatically putting in a surrogate, and if some of that research fell within our more than minimal risk category, it would never be doable because we see some requirement for the individual to consent. What I wanted to do, however, was come back to the discussion that Trish was having a moment ago because the one thing that did come out yesterday in our discussion with the larger Commission, and I feel that in that discussion I was a proponent of, more or less, what we had here about the advance directives. But I realized that in the discussion we may have been using the terms in different ways. There is the circumstance which is, I think, and correct me if I'm wrong, Trish, the one which you seem to have in mind most of the time when we're talking about this is the person who not only has fluctuating capacity so that they have some experience with their illness and they have periods when they are quite able to participate in their decisions, but for whom it is possible to specify with a good deal of accuracy what the research protocols would likely be that they are being asked to participate in. And it's just a matter that, we won't do this research on you while you're in the state that you're in when you're able to consent, the time we need the study, whether it's a physiological study or whatever, metabolic study, or a study of a medication, or whatever, is at the point where you have manifestations of your illness that would not make you able to consent. That seems to me to be captured by avoiding the phrase "advance directive" simply by some notion of prospective consent. That is to say, you are actually going through a consent process the way you would if you were going to have an intervention tomorrow, but the understanding is that this intervention will not occur for weeks or months, or it is even possible never, in your case. If you never went back down in that part of the cycle of your illness, you would never be a suitable subject. That is just a hypothetical. That is not very problematic, it seems to me. We could address that with some phrase about prospective consent. Now, when you can join that with durable powers of attorney for health care, which are not just about end-of-life care, you can have a situation in which the person is able, under the law in most states, to also appoint an agent at that time, and one would hope that right from the beginning from that point the agent is involved with the researcher in learning about the research and being really prepared, with the subject, to take on that role of the on-the-spot decision maker. The harder cases are the ones which I thought were also encompassed in looking at the materials here on pages 121-125 or so, or 127 or so, I wasn't at all clear whether we now were saying this or not. I thought we were also thinking about something which really comes closer to me to being an advance directive because of its generality for patients who are sliding toward a state where they won't be able to make decisions, the dementia patients, in particular, but whose course is not so advanced that you can't engage them in discussion, but they're clear enough about the fact that they know that's where things are going and they may have a number of years of life there where the question would be -- at least one question one could ask is, are you willing when you are in that state to be involved in a study which wouldn't be for your immediate benefit, which would have no potential for benefit for you, and would have some increment over just minimal risk of the type that is more or less part of daily life. For that, some phrase about advance directive is certainly suitable. But I couldn't tell, Trish, whether you, in the exchange with Zeke, were actually saying, well, no, I'm not thinking about advance directives for that group. And I obviously don't know what the rest of the commissioners say. It seems to me that there really still is a difference, and my sense was that you had two categories of potential subjects, those who have told you, I'm willing to have this happen, and those who haven't told you this. Now, this is relevant to the pages we have in front of us because--I think it's on page 123--there's some suggestion of -- the top of 123. For instance, "Research Advance Directives might only be valid when the research presents some prospect of patient benefit and strict time limits could be imposed that require the renewal of a living will." Then there's a reference to the option of the appointment of the legal representative, which is really the discussion of the next section here, so it's kind of out of place. I would like us to highlight at some point here, if we're in agreement, that the advance directives has the ability to play this useful role of separating people who are willing to say now, I will take greater risk for something that won't benefit me, from those who aren't willing to make that commitment. I disagree with Zeke on the notion that if you took a poll among this category of people and you had 80 percent of them saying it would be all right to do this, but only 20 percent of them will sign a directive, that that's an indication that the directive method doesn't work, the same way it doesn't work when we know that the public says they want a certain kind of end-of-life care and they don't get around to filling out advance directives about their end-of-life care. One of the things that I believe is valid about the end-of-life care, and I would certainly say is valid about this, is there's a huge difference between expressing a general opinion and committing yourself that this is a course you're willing to follow, and that barrier of not signing the papers isn't just due to laziness. There are psychological factors that would lead a person to say, if asked generally, well, do you think that's research that ought to be able to go on, yes, will you sign up for it, well, let me think about it, and then they never sign up for it because they actually have a reluctance. They don't want to be the subject of such research. So it seems to me that it's a reasonable sorting process between those people who ought to be made unavailable for such research by the fact that they haven't committed themselves to be available. Now, one final note. All of this is against the context of what used to be the law, and I have not researched this recently, but one of the conundrums for research with children and with those who can't make decisions is, the old view used to be, people in this situation cannot be used for something that doesn't have some prospective benefit for them. You can't be a surrogate decision maker and allow someone to be used. Now, we've said, well, let's make a small exception to that. If there really is no more than minimal risk, isn't this the kind of thing that most people could be presumed to be willing to run? Sort of a consensus grew up, yes, that's all right after all. But when we get beyond that more than minimal risk, it seems to me that we are correct in saying that the old view really ought to be adhered to, which is a surrogate, appointed or otherwise, who can't go around consenting people to something that isn't going to benefit them. I mean, it's the archetype of the exploited person. PROFESSOR BACKLAR: That's right. MR. CAPRON: Maybe we should have a discussion on that, and I have a couple of other points in here, Jonathan, about what we say along those lines. CHAIR CHILDRESS: Let me let Trish respond directly, if I could, Eric, from there. PROFESSOR BACKLAR: I do think that it would be extraordinarily helpful, instead of -- in this more abstract way, and I have -- is to situate a situation in which one would use an advance directive like this, and of course, the infamous now UCLA protocol would be a perfect place for this. I'm not going to repeat what that -- is, because I've done it enough times. So you could use a little scenario. It would work in this. Then you'd start to move it along to these other scenarios. When I responded to Zeke yesterday it was because I had thought it through very carefully in terms of some research protocol like UCLA. As we moved along, for instance, into prospective dementias, Alzheimer's, you need to alternate the model somewhat. It doesn't stay rigidly the same. There has to be some way in which we could describe this not being quite so rigid, at the same time keeping those protections in place. That's why when we discussed about Greg Sachs, who's done quite a lot of work here in this, we could use some of his models. So it isn't just one rigid model. CHAIR CHILDRESS: Absolutely. But I think it's also the case, at least judging from my conversations with you, that you would have no objection to our getting rid of the term "Research Advance Directive" to cover the whole area. PROFESSOR BACKLAR: Absolutely. CHAIR CHILDRESS: I think it is misleading. PROFESSOR BACKLAR: I'm not married to a term, I'm married to a concept. CHAIR CHILDRESS: Well, and I think that the term, though, brings in some other things -- association. So we're clear about that. I have no problem with that. We'll try to find some alternative way to do it. That still leaves the question of whether there's something very close to the advance directive in a certain area, and that's what Alex focused on also. PROFESSOR BACKLAR: Right. CHAIR CHILDRESS: That will have to tie in more closely with what actually occurs in some areas. PROFESSOR BACKLAR: And I go back to using the words that I'm very comfortable with, which is anticipatory planning. DR. CASSELL: The whole thing is anticipatory. It seems to me that we're talking about two separate kinds of people. If we could separate them out, we would have an advantage. One has to do with a psychiatric patient who has a disease of fluctuating capacity, and also fluctuating clinical states. That's not at all unusual in medicine, even in patients who have no psychiatric disorder. They sign up at the beginning of a research project and they give consent for the project, and good consent, and discusses what's going to happen in the possible stages of the disease. They have given consent when they have the capacity to give that consent, and I don't see any fundamental difference--I'll come to what I think is one difference in a moment--between other medical states and the psychiatric disorders, in which case the person is not giving prospective consent, they are giving consent and the consent has to specifically cover that time when they might not want it. However, we also know that this group of patients might not just wish -- when they are confused, agitated or extremely upset they might not simply not wish to take part, they might refuse to take part, and they have to be protected in both cases. So we have added in a representative -- advance directive or advance consent. It's consent for research. If a patient comes onto a research unit in the agitated state, never has been seen before, that person does not qualify. They can't give consent. They shouldn't be used as a research subject. It hasn't been discussed with them when they are in a state when they could discuss what they think is in their own best interests. I don't think a prospective aspect applies. I think we have to make clear the consent for research, greater than minimal risk, requires a full discussion of what might occur, and so forth and so on, and also the protection which we already had in there. Then we have this other problem where people who become permanently decisionally incapacitated, such as the dementias. They are the group that I can -- I can't think of another group, actually, where permanent incapacity is the issue. There the idea that somebody may say in advance, I would like to be considered a part of research, I think that makes perfect sense also, although they, too, may have to be protected by a representative. But we're not talking about advance directives, really. The name does matter. I think we ought to separate those two groups out clearly, otherwise -- it may be my confusion, that's why I'm saying all this, but otherwise we keep getting around to that problem. As far as this, I agree with Trish, the people like the dementias, they make a statement ahead. Their care-givers, the people who are taking care of them, may discuss it with them just like they discuss any other advanced aspect of their care, which they should assent to and sign to while they still have their capacity. CHAIR CHILDRESS: Let's see if there are a few more comments around this part of the discussion. I know Alex has some others to get in as well. But what we'll do is, after getting more comments around this area we've talked about as advance directives, but with all the important qualifications in language and the situations to which this might apply, once we've done that, then we'll get Gary Ellis on on minimal risk and then we'll come back to some of these. But anything else around this particular set of issues? Arturo? DR. BRITO: I want to respond to something that Alex said. I agree with most of what he said, except at the end, I'm not sure. I might have misunderstood something, and I want you to clarify it, that concerns me a little bit. When we're talking about greater than minimal risk, and I'm interested to hear what Gary Ellis has to say about that to clarify it a little bit for us, but their major research has greater than minimal risk, that do not have obvious or immediate direct benefit to the patient, but may later prove useful for that patient, 10, 20 years down the line because of the findings of that study. What concerns me is that blanket policy that does not permit consent for this type of research, even if it is above greater than minimal risk, it may actually prove to cause more harm in the long run. So I'm not sure. Were you saying that if there is greater than minimal risk that there should be a -- and if there is no direct benefit, it's obvious -- I mean, after all, it is research so sometimes during the research process we find what the benefit can be. So are you saying that your opinion is that there should be no means for being able to consent for someone that can't make their own decisions for that? MR. CAPRON: Well, I think, Arturo, this is the issue that we're all struggling with and, in part, is not an empirical question, as it was being posed yesterday, but it is a question about which information might cause us to refine how we go about it. That is to say, how much research are we talking about, what kinds of things are at issue here? As a general matter, however, I was saying, more or less, what you heard me to say and what you may disagree with. My experience in looking at human experimentation for the last, almost, 30 years is that the history of human experimentation is littered with victims of good intentions on people's part, too much enthusiasm for the value of the knowledge, the knowledge often not really quite as forthcoming, very often not as beneficial to the people it was supposed to benefit, and too much willingness -- the more disabled the subject is, the more different the subject is, to go ahead and do the research and have that thought that there may be some benefit there override a sense that this person is just being used. I mean, I think that there are circumstances, extremely moving circumstances, in which a person with any kind of a disease, mental, physical, whatever, agrees to take on, on behalf of others, risks. Sometimes great advances come and sometimes those are, as the mind run of science is, they don't add at that moment to anything that can be used, but it was still a heroic thing for a person faced with that to do. I think that we degrade that choice when we treat as though they are equally extraordinary gifts from people the use of other people who haven't made that choice and who have not said, faced with this, this is how I want my life to unfold, this is a sacrifice which I am prepared to make. I mean, I think the people who do it, it's a supererogatory thing to do. It's not a required thing. We are not all required to be in science simply because we are, in a large sense, the beneficiaries of past researchers. It's a wonderful impulse. It's a grand thing to do that. It's a terrible thing when you do it under misimpression of what you are doing, but it's a grand thing to do when you do it -- DR. BRITO: I want to -- what I heard from the public testimony and from reading historically what has gone awry in research in the past, all the atrocious research endeavors, what I keep hearing over and over is not so much whether or not there's greater than minimal risk, whether or not the type of research necessarily, but the process in which it was done, under deceit, to the person or the person taking care of that person. In other words, I think that maybe if it's not so much we shouldn't be worried so much about -- I mean, of course we should worry about the risk involved, but maybe we should be concentrating a little bit more on the informed consent process and not be worried so much about saying this policy that you can't involve somebody in research -- you could involve somebody that has a valid representative in research if it is clearly explained and it is clearly understood that there may not be a direct benefit to that person. Once again, therapeutic misconception, that's the common problem in research, it is not explained whether or not you're decisionally impaired. MR. CAPRON: Well, I agree with just about everything you've said. I guess I just draw the limit on the authority of the surrogate to make a decision which has not been in some sense also chosen. Now, we're talking about these advance directive sorts of things, we're getting away from the term if we can, but the choice is a generalized choice. It would not, itself, meet the requirements for informed consent but it is some sort -- what I'm looking for is some sort of commitment from that person to say, I'm in Category A rather than Category B. I'm in the category of people who -- I'm willing to make a sacrifice. And without that, I'm not comfortable with the surrogate doing that. It just seems to me -- and I entirely do -- one of the things you've said. For most of what we're talking about, the important issues are avoiding deception, avoiding the therapeutic misconception, and other things where people go into something think that they're doing X when they're really doing Y, because there hasn't been good communication. I entirely agree, and I think Laurie said this before and I agree with her about that. We need more attention to that issue throughout all our research stuff and in our document still. But there's still this residual category. CHAIR CHILDRESS: Okay. We'll get Laurie, then let Alex respond, then we'll turn to Gary Ellis and we'll obviously come back to these issues. MS. FLYNN: This has been very, very helpful, I think, and I think we have identified clearly that box, if you will, in which we have some concern and some difference of view. Just two thoughts. One, I do want to stress again my concern that we may want to look at, because of the issues of those who may really not be able, by virtue of their illness, to ever give fully informed consent or participate in the ways we would like to see strengthened, I would look to surrogacy, particularly in terms of someone who has durable power of attorney or who is a guardian as something to be explored for research that is a minor increase over minimal risk, and this includes a vast array of things like PET scans. These are not intrusive, these are not risky in the sense that many of us may be thinking about. One needs to ask ourselves whether our perception of this and the research enterprise has been unduly skewed by some of the kinds of testimony that we heard. We did indeed hear, and we need to pay close attention to, allegations of abuses in psychiatric or other research. There clearly is a very vulnerable subject population here and there clearly have been significant abuses. But we don't know anything yet about the scope, the scale, the standard that's out there. We really may be over-responding and thereby preventing some important research and the benefits of that research. That's why I think there is an empirical issue here, as well as perhaps the value of looking again at some work I think the Alzheimer's people have done, developing more of a sliding scale, looking at a little bit more of a complex layout that increases the protections and supports for the individuals as the increases in risk advance. So I wonder if we might be helped as we think through this with the different kinds of subject populations and the different degrees of risk, which again, we all need to hear more from Gary about. CHAIR CHILDRESS: Jonathan? DR. MORENO: Could I just point out that the current framework does permit potentially beneficial diagnostic studies to be permitted, or consent, if you will, by a legally authorized representative. PET scans could be beneficial to the subject, insofar as they are a monitoring procedure. MS. FLYNN: Well, I guess one would need to discuss what we mean when we say diagnostic study. If it's diagnostic to the individual -- DR. MORENO: Yes. MS. FLYNN: -- that's not the only way in which those studies are valuable. Those studies look at the basic interactions going on in mental disorders and they may or may not directly benefit that individual, but they clearly benefit the advance of knowledge about what goes on with -- DR. MORENO: Sure. I've heard them described as also a potential benefit to an individual subject. DR. DUMAS: I don't think there's any research project where anyone knows a priori that it's definitely going to benefit the subject, because you don't know, a priori, what the findings are going to be. So there is no situation in which we can assure people that they are going to be directly benefitted from this research. I think that in the case of people who have difficulty or some impairment in making decisions where there is greater than minimal risk, we have to have appropriate protections. We are disagreeing about what those protections should be, but I worry about using people in that category because of the very reason that we are having to spend this time with this population: they have been exploited. And I want to make sure that we have guidelines that will minimize the possibility of that type of exploitation. Now, we know that it happens and we know it's continuing to happen, even among people who try or who think that they have made provisions to protect. So I don't think that we can be too zealous in our efforts to impose some limits on how human subjects are used, and under what conditions, for research. CHAIR CHILDRESS: Okay. We'll get Trish, and see if Alex wants to say anything in response, then we'll turn to Gary. PROFESSOR BACKLAR: I just want to remind us about the limits of consent and why we're so eager to put protections in place with any population. MR. CAPRON: One further concern, Jonathan, also on page 123, where you talk about one of the other objections to advance directives. Then you go on and say that it may be necessary for the states, if this became part of regulation, to adopt legislation. If what we are talking about is something in the category of a prospective consent, I hope we'll be very clear that, for something of that sort, one really doesn't need -- DR. MORENO: Right. MR. CAPRON: Yes. And I think that that doesn't come through here and it sounds as though that would be a problem. I'm going to hold my other comments, because we've been trying to get to Gary for quite a while. CHAIR CHILDRESS: All right. Let me just mention, what Alex is proposing in terms of some detailed alteration, we really need to do this as individuals now, let's say in the next few weeks. This report has been a long time in gestation. We've had discussions surrounding it. There are clearly some other things we need to do in terms of getting additional information, but we also need to be working over this draft very, very carefully, making sure that we get the changes in that we think are important. Jonathan is putting those in bold, so the next time we look at this we can check and see if Alex has proposed something on page 123, that it's been incorporated, and then we can see very quickly, well, wait a minute, we don't like the way that's going. But we really have to do that, otherwise we won't be able to bring this to a close. So this is for future steps or further steps. Let's commit ourselves to doing that over the next two weeks so we can really bring this to closure. DR. CASSELL: Will we see any changes as a result of this meeting before we do that, or will we -- CHAIR CHILDRESS: Oh, I think you should -- no, no. You see, basically, other than the discussion we've had right here we haven't had a lot of discussion of the text. DR. CASSELL: It seems like -- you're in trouble now. MS. FLYNN: Jim, don't -- tried to incorporate the NIH's group's views. They have not yet been articulated for us, but I think there was some substantial expertise there. A useful review of that material might also enrich our -- CHAIR CHILDRESS: Two things. One, is a lot of that has already been incorporated. Arturo, Diane, Trish, I, Jonathan, and Eric, and Henrietta--did I catch everyone there--met for a good while after that conference. Actually, if you go back and look at the bold, particularly in the early parts of this, you will see a lot of that already reflected. So we did a lot of that. However, we will have in a few weeks a fuller statement from that conference, and we'll want to make sure that we've incorporated and attended to what's -- Now, the bottom line was, no further regulation. We are apparently going to make some recommendations in the area of regulation. Is it urgent? No. We can hold off. Okay. We are glad to welcome Gary Ellis to help us think about minimal risk. We're always glad to have you help us clarify matters. Thank you for joining us.