Discussion Continues on Research Involving Subjects with Mental Disorders that May Affect Decisionmaking Capacity

DR. CHILDRESS: All right, if we could return to the bottom of page 2, and pick up the recommendation number two that we were discussion from pages 161-162, and think about how to formulate what we want to say if we've not been able to do so. And I'll just make one comment again and then I know that Bernie and Alta both want to get in on this. In fact, you had your hands up before we took the break this morning. This is the question that...basically—and I had a chance to talk with Jonathan and someone else since the session this morning—it does seem to me that we have two sorts of concerns here. One concern is, again, that we not exploit a particular group or class as those with mental disorders that affect or may affect decisionmaking capacity, by targeting them in a research protocol that could be done as well with some other group. And that's basically a nonexploitation requirement of a principle of justice. But we also have another concern and that is that individuals who have mental disorders that may affect their decisionmaking capacity not be excluded from protocols that, just because they have those conditions, particularly, for instance, if they could give consent. So...and some of those may be valuable to them as members of the group or individuals with particular conditions. So the critical question is how we state this and whether we want to change what we've written in a way to clarify the points we want to make. Bernie, do you want to get on this now?

DR. LO: I'll pass.

DR. SHAPIRO: My view of this is that if it is a study related to mental disorder from which they are suffering, such as the example of Larry in proposals and text here, then I don't see...there's certainly no reason to exclude them, every reason to include them under appropriate circumstances and so on. That's not an issue, I think, although we discussed it, we all agree with that. Then there's a second question of whether what... what is said here, research that is indirectly related to their mental disorder. I don't know quite what that means, but if it means it has some but not very direct relationship, if that's what it means, then I would come down the same place. I would favor under appropriate circumstances that they be included. If it bears no relation, or no known relation to their mental disorder, to me it seems that the benefit of having them be able to participate if they consent are outweighed by my other concern, maybe that we not be in a position of taking advantage of this group. If it could be as easily and as well done in other groups, I'm a little worried about that.

DR. CHILDRESS: That's as a group because we think, again, the individual who may want to enter a chemotherapy protocol for cancer, who has a mental disorder that may affect decisionmaking capacity, but who knows that? It seems to me that at that point we're treating them not as a member of a group of those with mental disorders but rather the protocol can be done with, and is being done with the general population, then it seems to me that a person who has a mental disorder that may affect decisionmaking capacity can give consent. That's why I distinguish targeting those with mental disorders as a population or group or protocol, and that I think is ruling out, unless it really is necessary to do with that population, versus a study that is being done with the general population for which a particular individual with mental disorders that may affect decisionmaking capacity might benefit.

DR. SHAPIRO: I agree. It's hard to distinguish the individual level from the group level.

DR. MORENO: In that spirit, Jim, maybe we should replace the word "involving" with the word "targeting" in the statement that appears on page 162. "An IRB should not approve research targeting, or may not approve research targeting subjects with mental disorders," etc.

DR. CHILDRESS: All right, there were several hands. Trish.

MS. BACKLAR: I'm actually going to repeat what I said when we broke off...what if you have somebody who has a bipolar disease and cancer and is perfectly capable of making a decision about involving herself or himself in a cancer study? Mary Claire's study or whatever?

DR. CHILDRESS: We would also actually permit such a person being involved even without his or her consent. In a therapeutic trial.

MS. CHARO: If I'm understanding correctly, what Jonathan is suggesting is that the language make it clear that what you could not do is target people with bipolar disorder in order to recruit them primarily or specifically into this study. But if one happens to respond to a general recruitment call and is capable of consent, there's no problem.

DR. MORENO: Right, that's the spirit of it anyway, Alta.

DR. CHILDRESS: Is this direction one that we think is workable?

MS. BACKLAR: And of course at the same time we want to make sure that people are not being recruited into a study just because they're mentally ill and they could be easily used in a study which has nothing to do with their illness.

DR. SHAPIRO: That's what the target, I think, is supposed to mean.


DR. COX: No, I really think that to be so paternalistic, because someone falls in this class, to abrogate their options as an individual, is just too much. I mean, it’s too much to handle. So, I think that's one of the points that Laurie was trying to make about this, so we have to really maintain the individual's right to choose. If we take that away in terms of protecting them, then what are we doing?

DR. CHILDRESS: Other points, Bernie?

DR. LO: Yes, I just would like to suggest that the explanation that you gave, Jim, about four minutes ago be incorporated so that it really clarifies things.

DR. CHILDRESS: Okay, other points on this one? All right, if not, let's turn now to...let's actually go back and pick up the first page and the second bullet because it's closely connected to the one at the top of page three, and that is whether we're going to stay with two categories of risk, whether we want to go in the direction of three. So let's deal with that question first, the two categories of risk versus three. And then we'll see how this works out on the top of page three. So, back on page one, two categories of risk...Alta?

MS. CHARO: Jim, especially in light of Mary Claire King's presentation, which gave us what Eric Meslin calls a boundary case, that is a kind of example of exactly what might be lost if the regulations that exist or that are being proposed can't accommodate it, I feel like in this area of two categories of risk where the second category prohibits research to a large degree if consent can't be obtained, with very few exceptions, that it might be very illuminating to find out what would be lost. And although I'm hoping in the public reaction that we're going to get some proposals about what might be lost, it also occurred to me that we might find out a little bit by looking backwards. If we were to have on our staff or by a contractor somebody go to a few of the most prominent journals in these fields for the last 20 years and just take a sample of some of the publications and the studies that are described there, and ask for the methodology of each study, could it be done under the rules that we're proposing, and help us understand which ones couldn't have been done so we'd have a very concrete idea of what would have been lost had the things we're proposing today been adopted 20 years ago. It might help us to understand exactly what the quid pro quo here is for the protection of subjects that up until now has been adopted as the view of the majority of the Commissioners, although not without Laurie Flynn's dissent. I would find that helpful in getting confident in my own judgment.

DR. CHILDRESS: I think that's a very good point, and let's say if others want to comment on it. Bernie.

DR. LO: I agree, that you've been concerned at the way a lot of research which is maybe not a whole lot more than minimal risk will be for all intents and purposes virtually impossible to carry out. And I guess I would be more forward-looking and go to reputable, thoughtful, sensitive, investigators who care about patients and not harming them, and say what types of pivotal studies would be either precluded or virtually impossible to carry out if Appendix 2 were really implemented?

DR. CHILDRESS: We could provide a summary of our recommendations and the flow chart and actually get feedback. Eric, and then I have some other comments.

DR. MESLIN: Just as a reminder, the purpose of the public comment, period, is twofold. One, the document is out on the Web, was placed there last week, and as a reminder, we sent over a hundred letters with copies of the report, the entire report, to individuals, both ofthe kind that Bernie has described and individuals reflecting advocacy organizations, patients' organizations, researchers-what we felt was a broad cross-section of the community. And the letter, a copy of which is in your briefing book in advance of this section, which describes what we were asking for, I hope...gets to some of these issues. We did not specifically ask the question that Alta has, I think, quite appropriately raised, what would be lost if the document that you now have in front of you were implemented tomorrow. But we're hoping that by reading through that letter that that kind of message will come through. In the event that it doesn't, we do have the luxury of continuing that process. And the second point is just to remind about the protocol and consent form review which won't go back 20 years. It will only be going back at this point to 1995, and that will give us at least a sense on the permission side as to what research looks like now or has looked like over the last few years. So, not exactly what you're asking for, Bernie, but that solicitation was intended to elicit some of those points.

MS. CHARO: I'm hoping we get all that, and I will value it tremendously. I'm suggesting a retrospective look as well for a very specific reason. My experience, my limited experience, has been that under some circumstances people in the scientific community will promise the moon. When they need money or they offer restrictions they'll talk about all the great things that will happen. And then when somebody worries about the consequences of all this, then they'll say "oh, it's not really going to happen" or "it's really decades away." I mean that's just a human tendency. And by doing a retrospective, you get away from speculation about what would be lost and what the conditions of research would be in terms of the harms or the fears or the discomforts that would be suffered by the subjects. You can actually look in a more concrete way at actually what precisely would have been lost and what exactly was the experience of those subjects who might have been enrolled without having been able to adequately excuse themselves from the research. So, I'm still kind of interested in doing this if it's not too unwieldy, which it may well be.

DR. MORENO: I think the results of such a sampling would be interesting. However, we know in advance that there is only one set of circumstances in which studies that may have been done would be precluded under these recommendations without Secretarial approval. And that is greater than the minimal risk, no benefit studies, without informed consent. Now that...either that is a very small universe and/or it is universe that most people on the Commission, I gather, would not prefer to see continue anyway.

MS. CHARO: But this is the place where the two categories thing becomes crucial because the question would be, Would some of the things that we would have lost been retained under a rule that had a slight increment over minimal risk third category? In other words, a kind of test of the effect of having a third category.

DR. MORENO: Yes. What concerns me, of course, and I know you've thought about this too, is how we assess what counts as falling into greater than or a little more or a lot more. And that's why I am somewhat concerned that the information that might be available with a lot of effort from such an investigation may be minimal.

DR. LO: You know, again, I think what I most need is a real-life example. I mean it's one thing in the abstract think that we may be missing some important...we may be precluding some important research. And some like Mary Claire King say, let me tell you about a study, let me tell you how we tried our best to make it work, and why we decided to do it in a way that very clearly, I think, compromises extremely valuable knowledge, that's really important. So I can't tell what the size of this box is until I hear some real examples. I think it's very hard to do this abstractly without thinking of some specific studies in mind. And that's why I think we need some help with it.

DR. CHILDRESS: Before I get Diane and Trish, would it be possible to select a dozen or so of the people to whom have already written and say, look, we've had this particular concern? We know it really doesn't matter, in many ways it's a biased group, because what we're really interested in is can you identify some studies that are really important, that would not be...that could not be done under our framework. And actually it's important to have those who would be most suspicious of our recommendations look at that. To show us the studies, and if we could find that then that would actually be helpful to us, I think. Would that be a plausible way to proceed? See any reason not to do that?

DR. COX: We need to remember though, that they could not have been done with this kind of subject. Many studies have...the way the brain lights up under various conditions can be done with other subjects.

DR. MIIKE: Can I ask a point of clarification? If we have a third category, what are the additional conditions that we would impose on it compared to the two categories that we have now?

MS. CHARO: It's hard to see what the value is if it increases the number of categories.

DR. SHAPIRO: I agree with that.

MS. CHARO: You might accomplish the same thing just by allowing some of the procedures to be placed in the minimal risk category. I think when you start with ill-defined, fuzzy categories like slight increment over minimal risk, you step out on the slippery slope that might allow you to infinitely increase the categories when you wanted to allow more research to be done with fewer restrictions. If we could categorize procedures or techniques as risky or involving only minimal risk or no risk, I wouldn't see what the category would be.

DR. CHILDRESS: One problem with that is that there already is a set of regulations and tradition of interpretation of minimal risk versus more than greater minimal risk and so we have to be able to tie into those. We can't simply say well, this procedure you want to do, this as minimal risk. It seems to me that that's going to end up with a similar set of problems. Trish?

MS. BACKLAR: As I'm listening to this, I'm worried that we're going to go down the slippery slope of the human genome of the human biological material report. And that we're going to get terribly slowed down. But I think that one of the things that's extremely difficult here, and in all of these reports, is that when we identify these things we do it in a sense with thick fingers, and the cases themselves are going to explain themselves so the research protocol will give us, or hopefully give the reviewers some better idea of where it will fit. Also, the aspect of this which is so very difficult—and from the very beginning we've known that—is that we are identifying a population which is very buried. And what may be minimal risk for some members of this population and not for others will be altered by what their particular disease category may be.

MS. CHARO: I've been an advocate of keeping the two category regime with a highly protective standard for the greater than minimal risk category all along. But I'm still searching for something that'll help me be confident in that judgment. Now, we have a model for a three-tiered system in the area of research with children in which they do use this intermediate category and in which they have a three-tiered protectionist scheme. I wonder if it would be possible to supplement the letters that have been sent already, perhaps, with a smattering of letters to perhaps the chairs of IRBs around the country, at children's hospitals perhaps, as well as at a couple places that don't have a large pediatric population asking them about their experience in applying a three-tiered system for children's research, how hard has it been to be confident in their own judgments about what belongs in what categories. This would be a prelude to, Larry, worrying about what should belong in each of these three categories as far as protective measures should we decide to backtrack and move toward a three-tiered system. But one of the objections to a three-tiered system has been that it can be unwieldy, complicated, difficult to enforce, etc. And maybe some feedback on the one example we have out there would be helpful.

DR. LO: I think this discussion needs to tie in with the discussion of what's in the boxes on the bottom level. So one of my concerns is not so much with the yes/no dichotomy as to what the implications of being in the no column now as I read down the page. Again, I think in our draft I don't think we give a convincing explanation of why we chose what is contained in these two boxes. So although it certainly makes sense to be more stringent for the no rather than the yes in terms of unable to give informed consent under the no direct benefit, greater than minimal risk, why are we going to prohibit it without Secretarial approval and not some other set of protections that are less stringent than that? So part of it is sort of what the implications are being in the sort of most restrictive set of shoeboxes.

DR. CHILDRESS: And I think that really is not spelled out clearly in the text. I think the Secretary aside, wouldn't you agree, Jonathan, that something we would need if we're going to keep that- to really work up further, and that obviously is the connecting question on page 3, that's connected to the one we're just dealing with. Let's see if there's anything else you want to say about the proposal out on the table about how we might get some additional information out. Eric, then Jonathan, then there was a hand here.

DR. MESLIN: I was just going to make a proposal on behalf of staff, if that would be helpful, which uses Alta's suggestion. We can both contact directly individuals to whom we have already sent letters and ask them to provide us with some specific examples. I think phone conversations might be a helpful way of emphasizing our interest. We have, as I say, 114 folks. I can assure the Commission that probably 15 or 20 at the very least would be delighted to provide us with some specific case examples of the kind that Alta is describing, plus or minus the IRB Chair idea. I think the idea of the two or three categories in IRB Chairs being asked for their experience can also be done through either a telephone solicitation or a letter solicitation. Jonathan was going to interrupt me, sorry.

DR. MORENO: Sorry. But I think the critical question surely is not how hard or easy has it been for IRBs to use the three boxes for kids. The critical question is how appropriate have those choices been. And I have some doubts, speaking professionally, about how appropriate some of those choices have been. This methodology will not get to that. The only way to do that is to convene a subcommittee, a super-IRB, to look retrospectively and reevaluate some of those judgments. I think to get a meaty result from this aspect of what you're suggesting is going to be harder than just asking IRB Chairs to respond in a simple fashion.

DR. SCOTT-JONES: I would just like to again try to make a case for the two categories over the three. I think that when you put any study into categories, whether two or three, you could always possibly make a ranking of those experiments or studies within the category and claim that some are more risky than others. So you will never create a situation where when you use the categories you have a homogenous grouping of studies within the categories. So I think it's futile to try and create another category so that you're always putting in those categories studies that are at the same level of risk. That just isn't the way studies will be. Studies will be very diverse, they'll be very different. So I think there's futility in this effort to resolve a problem by creating categories. I think the way you resolve it is really by having the investigators and IRBs, anyone who's in a position to comment on the work, be very careful in how you go about assessing risk because that's something that's very difficult to do. And I think that's where the energy needs to be placed, not in the number of categories that one uses. Three categories isn't superior to two when you have a very difficult decision and you're still going to have a lot of variability that's more than three points.

DR. CHILDRESS: Before we get Harold in, let me I understand sort of the direction we've gone from Alta, and I hope I don't misinterpret you here, it's something I share hearing the previous conversation, namely, not that we're calling into question the two categories. What we want to do is get the best information we can to test those categories before our final report. We heard some things in the previous discussion that at least might cast light on some of the issues and the genetics of stored tissues, now we'll report a little different way. What we'd like to know are there some cases like that that would pose problems for us here. So it's not so much that we’re challenging the two tier but really sort of testing it to see if we have actually been able to want to. Is that the direction you were going, Alta? I just wanted to share that.

MS. CHARO: Absolutely. Jonathan has impressed me with how difficult a task it will be, and I simply commend the staff with the task of seeing if it's possible.

DR. CHILDRESS: It's possible.

MS. CHARO: It may not be, but if it's possible to get anything useful.

DR. SHAPIRO: Can I make a comment about this? This is not...I don't think we should think about this as whether we like two or three or even asking the question which couldn't go ahead with two or three, which incidentally is impossible to answer, unless you know what level of protections are you going to put within each category. Now if we distinguish three, but two of them have the same level of protections, it's totally irrelevant to the question. So...the question we've been talking about, then, is not well-defined. And so I think if I could suggest that if we go ahead of it and then see what protections come along the bottom line here. Then ask ourselves the question, if something were a minimal increase over, excuse me, whatever the terminology, a small increase over minimal risk, would the protections vary at all? If the answer is no, then the whole study's not necessary. And so if we get to that point, maybe we again can circle back here and see if we have a well-defined question to ask. And as I look at it, if you look at the diagram, which is the simplest thing to look at to get a quick look, what Bernie's been referring to, it's on 173, and ask yourself all right, if there were a small increase over minimal risk, would it need any boxes here or just leave the same old boxes. That's exactly what we found out, incidentally, when we got bogged down in the biological materials. We had all these different boxes and they all mounted to the same thing.

MS. CHARO: But the answer here is actually that there would be a difference, and this is what Laurie has been so upset about, that if we had...

DR. SHAPIRO: Only if we say there will be a difference. We have to decide that.

MS. CHARO: Now we're moving into the land of totality, of course, but this is the essence of her objections. She would like to have possibility of some kind of surrogate consent process or nontherapeutic studies that are only a minor increment over minimal risk. And that would be the new category. A full panoply of all the protections, all the other stuff might—

DR. SHAPIRO: That's right, it would be if you looked down at our diagram or something, it's that it could get into the box that's second from the left.

MS. CHARO: Essentially nontherapeutic, minor increment over minimal risk would be treated the way we now treat therapeutic greater than minimal risk. It would move this small group of nontherapeutic studies into a regime of protectiveness akin to what we now use for therapeutic but risky studies. And that's what she would like to have done, and that's where this fight has been focused. I think.

MS. BACKLAR: I think it's helpful to get out of the boxes for a minute and to go back to the reasoning that we originally were talking about-why we saw it as minimal risk or not minimal risk. And that was because we looked at many members of this population, even in minimal risk studies—I just have to use as an example my own studies in which it's clearly minimal risk —in which there are certain things that can obtain that I would, even in this study, be concerned about if I had someone in the study and I did not have an outside provider for them in case something went wrong. Not even during the interviews, but for instance because the person was upset about something that occurred in the interview. Now we've already agreed, you don't need to have all these things in place for minimal risk. Right? And so knowing that even in studies which were minimal risk, there is risk for many people in this population. I don't know what differences you would make with a third group. Am I making sense?

MS. CHARO: All my understanding of Laurie was that she would want the same protections for therapeutic but risky research to apply to nontherapeutic, only a minor increase over minimal risk research. So that would give you the answer of what those protective measures would be.

DR. LO: Let me try to take a different tack, which is to offer an example of the study that I'm concerned about landing in the "prohibited without special Secretarial approval" category. So I'm going to try and develop a scenario for a study which is more than minimal risk, of no therapeutic, no potential direct benefit to subjects, and the subjects are unlikely to be capable of giving informed consent. Okay, and that's a study where you pick your disorder—severe schizophrenia, severe bipolar disease—and the aim of the study is to try and correlate, just to test an association between results on imaging studies and levels of neurotransmitters in the brain. And the goal of the study is to try and find surrogate endpoints for screening candidate new therapies so that you can more effectively screen out candidate new drugs. And I think it fits with the notion that there's going to be a lot clearer design of drugs and a lot more candidate drugs and they want to test them more efficiently, to throw out the ones that aren't going to be of benefit. So the goal would be to try to develop surrogate markers by using imaging studies where you could identify drugs and new therapies that might be potentially beneficial. So I'm trying to construct a case that although it's not directly beneficial, it provides basic knowledge of the pathophysiology of the person's condition, which could then lead to therapy. So I'm trying to understand the concepts that underlie some of the boxes in the children's research thing. We've already said that certainly a lot of our puncture and also MRI studies are more than minimal risk for this population. And I guess I would like to argue that to make those studies acceptable only with special Secretarial approval basically means you're not going to do the studies, realistically. And I'd like to say is there something short of that that involves surrogate consent, prior research office directions when they're in remission, no apparent dissent, health care advisor.... But is there any sentiment that, for those clients who have started, are people willing to have some other box that's filled with something other than just "prohibited without special Secretarial approval"? And I don't know if that's the stone answer I'd like to get. You know people are in the field to help construct a scenario but it seems to me that there may well be studies where we'd want to have more protection than is now available but something not quite as stringent as Secretarial approval.

DR. CHILDRESS: Just pick up on part of that before we get others in...if you could, for instance, get the advanced planning as sort of discussed here which your example seemed to suggest, and that would actually pull it over in the category of "yes" in terms of capable of giving consent. That is, if a person would have a period where a person could engage in advance planning, that is actually included as a possibility.

DR. LO: But you're saying it would be under the left column.

DR. MORENO: Yes, it would fit. So that would be taken care of, but there may be other, even beyond that, there may be other situations where you might be proposing other kinds of ....

DR. LO: Jim, but this was not direct benefit to subject.

DR. CHILDRESS: That's right. So that would be included.

DR. MORENO: If they could do advance planning, the other alternative that I've heard some people talk about advocating is using less affected subjects in the beginning, try to develop strategies that are more likely to be beneficial, and again in that box the subsequent studies.

DR. LO: But the box doesn't reflect that though.

DR. CHILDRESS: includes it. If you look at 154 for example, page 154, it's included. But the box doesn't clearly capture that. That's one of the shortcomings of the box, but it's in the text.

DR. MESLIN: It's 154, lines 3 to 5 in the text, which I don't think are captured in the boxes of 173. And the sentence reads, "As is the case for studies that present a potential direct benefit", and this is still under the category of no direct benefit, "their consent to a particular study may be obtained in advance of a period of incapacity." That line which I just read on 154 is included under the section, "greater than minimal risk for research that is not potentially beneficial to subjects." And the appendix does not actually have a box. An error in the appendix we've got, an omission, I'm sorry.

MS. BACKLAR: And there is something here that I'm concerned about in this box that we have where it doesn't offer potential benefit, the box that Bernie has been looking at. And you get down, "Are subjects likely to be capable of giving informed consent." Now I've lost the box where we were looking...that's the if they're likely to be able to give informed consent, well then there is much less problem, right? And so what is the ... I'm not quite certain what you're concerned about.

DR. LO: Well, it's the difference between giving informed consent at the time you're actually going to do the procedure, and giving the informed consent in remission when you're eligible for the study because that's not what the study's about.

DR. CHILDRESS: And so what we're saying is the box doesn't match the text, and the text does include possibility of advanced planning.

MS. BACKLAR: But that is then what concerns me. I want to make sure that that advance planning is always for a particular study.

DR. MORENO: The text also does say that.

MS. BACKLAR: I don't want to see that kind of blanket. I'm saying it's okay to anything.

DR. MORENO: It's not a blank check, it's a particular study.

MS. BACKLAR: Okay, that's what I ... just wanted to verify that.

DR. MORENO: The text shows that.

DR. CHILDRESS: Other points on this? There's...Bernie, do you, excuse me, there may be other aspects you're concerned about as well.

DR. LO: Again, there are different types of advance directives, and some are more to specific than others. If we're saying you may only give an advance directive to one specific protocol, we're going to run into the same troubles that Mary Claire King told us about with, say dementia, where you give one crack you're giving your consent, two years later there's something else which is very comparable to what you've consented for but you're saying but no, you didn't specifically consent to that so we can't do it. So I'm a little...I mean I don't want a blanket consent to anything. But it seems to me that if I want to consent when I'm demented to imaging studies that, as best as people can tell, create the risk of anxiety and minor irritation from getting an IV put in, if there's a new type of imaging study that isn't a PET scan and I didn't consent to it, I'm a little concerned of someone saying well, you didn't consent to this specific thing so you can't do it. Where capacity is fluctuating, you can always go back. But you know, all the research on Alzheimer's you can't do.

DR. SCOTT-JONES: Could I just ask a question following up on what Bernie's saying? Bernie, I guess it's not clear to me, why would you want the person to be in one study and then another and then another?

DR. LO: No, no, I'm not saying one study, then another, then another. But I'm's a different issue, but if I'm saying prospective consent and by the time I'm eligible for the study, it's a different protocol, it's a different generation scanner, different type of scan, or something. I mean how precise do I have to be in a degenerative condition. I'm not saying use me for every single study that comes along. And you can say you only get to be in one of these studies.

DR. MIIKE: I don't think that's our notion on what consent is. I thought that we're talking about consent very close to the onset of a particular study. So you're talking more like an advance directive like....

DR. LO: Yes, I'd be interested in it but they're spreading the research apart. I don't think we've ever considered that as a consent, right?

DR. SHAPIRO: Bernie, is it tough at all to observe, maybe there's just diversion for which I apologize, that if two new generations' ideas and procedures come along, as was presented to you this afternoon. And in lots of cases, unfortunately new generations of potential subjects come along. And therefore you don't ... now there was a very special case here because they want to follow pedigrees over a long period of time and that was a very special, important case. I don't know, I just ask that question now, I don't know whether there are analogous cases for these kinds of procedures or not. I just don't know enough about the ideology of the diseases and so on.

DR. MORENO: Some of you have heard my take on this issue before. In general, my view is that our society has not endorsed a notion of anybody being able to give blanket endorsement to research participation in advance-for any population. I don't know why we would want to start with a population that has instrumental disorders. I need help from the lawyers here, but I don't know any state legislation that creates a legal device that would enable me as a relatively competent person, still in spite of my work for NBAC, to authorize my use in a blanket sense 70 years from now, 50 years from now in research.

DR. LO: I guess it seems to me there's a big difference between blanket consent and consent for a more well-defined study. I mean it's the problem with advance directives. I mean if you're going to restrict it only to guessing the specific interventions of specific study, it's going to be very, very narrow.

DR. MORENO: But again in the case of traditional advance directives, at least, as a notion of therapeutic benefit, we lack that here. What we're really talking about here is giving one's body to science, while one is still alive. And that's understanding is that so far we haven't discussed that question.

DR. LO: Well, I think that if, again to use the analogy from children's choices, if pathophysiology of that condition is important to study as the basis for future benefit, there is some value to wanting to do it. And also it seems to me there are different types of risks. So I think blanket consent means you can do anything. I'm saying that drawing on this notion of a little more than minimal risk seems to me there are some things that are risky but we're not talking about the kinds of side effects you get with chemotherapy or major surgery. You're talking about things which are transient, which people may not necessarily remember which are not...don't lead to further problems. I think to put everything together and say you can't do that without Secretarial approval, I think we may be giving up a lot and I think I'll just wait and see what people in the field have to say.

DR. MIIKE: But if they can give consent it doesn't fall in that category. It's only when they're incapable of giving consent.

DR. LO: Right, right, and I'm saying that if they gave consent before but not to that exact study but something awfully, awfully close, and it's just pathophysiology, and not a whole lot more than minimal risk, are we going to say can't do it without Secretarial approval?

MS. BACKLAR: I would be terribly afraid that somebody who is eagerly doing research in an area that you would say is not so different that this would bend in ways that you might end up having people in research protocols which were far away from what they would precisely have agreed to be in. And then I think about Al Jonsen yesterday talking about how their view was shaped by Hans Jonas's view that they weren't going to have this utilitarian consequence on list balancing. And I'm concerned about the same thing here. I want to make sure that we have adequate protections for people who may not be able to protect themselves.

DR. CHILDRESS: Are there other points that should be made now, particularly about the section on page 3 and then the materials that follow? Under the heading of "Research Involving Greater than Minimal Risk that does not offer the prospect of direct benefit to subjects." We've already touched on a fair amount of this, moving from the two categories of risk. But are there other things we need to say about this? Again, one thing we don't have in the text is a very clear explanation of the approval by the secretary. We do discuss it on page 152, I think it's some place in the text that I found it. But are there other points that you want to make about this, and then about ways to harmonize what we say in the text? Again, I think most of those can be handled in an editorial way. But Harold had recommended that people look over pages 3 and 4 particularly carefully for these related points.

DR. MIIKE: You know the top of page 3 is also related to the last point on page 4.

DR. CHILDRESS: These all four go together here. Pages 3 and 4 work together involving the point at the top, plus then how you'd work out the understanding of individuals who can consent and those who cannot, and then the last part that you know. So what do you want to say about these two pages?

DR. MIIKE: Can I comment on the last part of page 4? It seems to ... it doesn't make sense because it says, "for individuals who cannot consent," you're going to require before they even go to Secretarial approval that they would have given their consent in advance. Well but you're recommending that they be changed to include both conditions. Aren't you doing that?

DR. MESLIN: They would not be jointly necessary but one could occur or not. That's a confusion in the text which we would like to clarify. But there are two places where individuals who cannot now consent could participate.

MS. CHARO: You want to be consistently A or B.

DR. MIIKE: Okay, I was reading that recommendation and I thought that you were adding the A to B.

MS. BACKLAR: We are now looking at for individuals. We skipped over this middle section that I thought we were looking at and we're looking at this now on page 4, the bottom of page 4 for individuals who cannot consent? Is that correct?

DR. CHILDRESS: That's right, it ties back to the top of page 3. Okay, we've...basically is right...we've been skipping...the middle's organized in a confusing way. But this part on individuals who can consent, on the middle of page 3 to the top of page 4 really is a matter to be handled editorially. What we're really talking about is this first paragraph on the top of page 3 and the part that Larry directed us for at the bottom of page 4, right? Those are the two connected passages and basically what we want to say about the requirement of consent for participation and research involving greater than minimal risk, that it does not offer the prospective direct benefit. And what we want to say about Secretarial approval.

DR. LO: Right. Now, Larry's question, then, I thought somebody said this box down here should read either Secretarial approval, is it an prior consent in advance of the...


DR. MIIKE: No, that box is okay, Bernie, because the left side of the box would say that there was consent obtained. So it mirrors the box, it's either/or. Neither consent was obtained or consent was not obtained, Secretarial approval was.

MS. BACKLAR: Okay, okay, all right. This is not as confusing as we have made it.

MS. CHARO: All the people here who are fuzzy after meeting too long raise their hands.

DR. CHILDRESS: We're reaching the end of the day. Yes, any other points that need to be made about this. And obviously we will have to continue some of the discussion.

MS. BACKLAR: I think I need a surrogate to make some decisions for me.

DR. CHILDRESS: And need to listen very carefully to Laurie's arguments, it may well be we'll end up obviously with individuals filing dissents to different parts of the part after we've gone through. Are there other points that need to be made about 3, pages 3 and 4? I have just a couple other points I'd like to raise, and I'm sure other Commissioners do to about the draft and then ... other points about 3 and 4? Let me offer just a few observations. Again, I think we've made real progress on this draft, and thanks to all those who've been involved in it. One thing that I think may not have adequately reflected in our recommendations and in our special protections is something that came up, comes up in the report earlier, and something we've talked about before. And that has to do with the contextual elements that the IRB might consider. We don't bring in, for instance, consideration of institutionalized versus noninstitutionalized. Some of these contextual factors I don't think we really worked in very well even to our guidance to IRBs, and that's one thing we might try to do. Then a few other points I have may appear to be editorial in nature but I think they're not. I think they're actually more conceptual than they are editorial, and I'd like to make them and get them out on the table because they affect the way we think about the structure of the report. If you look at the table of contents, I feel very strongly that we ought to reverse the order of Chapter 4 and 5. Because we have Chapter 3, and I'm going to argue for retitling that, that really focuses on voluntary informed choice. And we have Chapter 5 that deals with advanced planning, surrogate decisionmaking, and the like. And we have in between those two a chapter on risk and benefit. And it seems to me that five really follows from three and that's a structural matter we ought to take care of. So it's more than editorial, it really is conceptual matter, how you can see the project. I think that connected with that that we really need to retitle Chapters 3 and 5, because we've got a criticism of the draft that focused on the fact that we don't really deal with informed consent, but actually Chapter 3 is on informed consent and the limitations of informed consent. But that's not really reflected in the title, so we need something like—and I'm just throw these out, these are hardly well-thought through—but something like "Informed Consent and Limitations on Decisionmaking Capacity." Because that, first of all, what it means is you've got voluntary informed consent, and then looking at the limitations because of decisional impairment and the like. Or in Chapter 5, which I would suggest would be now Chapter 4, we need something like "Assent, Dissent, Advance Planning and Surrogate Decisionmaking" because even though you can't tell from the table of contents we have here, the whole first part of that is on assent and dissent. And that's where we bring their argument and discussion in the text about how we relate to the National Commission. I think those are...I'd like to propose those unless there are strong objections that could be taken account of when we make the next revision. Those are some of the thoughts I had, what other points would you like to raise about the draft, the recommendations, the framework of protections?

DR. LO: I'd like to readdress the issue of IRBs. As I read through the report, it seems that one of the crucial things we're doing is asking the IRBs to play a more active role in protecting persons with possible impairments in decisionmaking capacity. We really are asking them to do a lot of different things. To put them all in one place, special scrutiny to protocols that intentionally cause harm, identifying problematic study designs, scrutinizing the procedures for evaluating decisionmaking capacity, evaluating the scientific merit of the proposal, determining which supplemental protections are warranted in particular cases. That's a lot of responsibility. And I think I want to put that in the context of a lot of growing concern now that IRBs simply don't have the resources, and may not have the expertise to do this. And even taking into account the recommendations to add additional members and to perhaps the audit, which I'm not sure of, I think I have concerns about making so many of our recommendations hinge on a process, a technique, that is of questionable effectiveness doing what it is now supposed to do for a whole host of reasons. And I know we're planning to do a separate report that addresses that, but it seems to me that as part of this report, we need to try and address some of the fissures because frankly an IRB is not going to be able to handle this. I mean they're stretched to the limit. And unless they get a lot of extra funding to do this, I think we're not...the protections we're hoping for are not going to materialize without a very robust, active, IRB at major institutions. So I'm concerned about making the implication realistic—work in the real world. And there're going to be real costs, we talked earlier this day about monetary costs. I mean we're really talking about asking institutions to make a substantial commitment to our views. That's just not there now.

DR. SCOTT-JONES: Bernie, I see your point about IRBs and the fact that they're overburdened, but what would be your alternative for recommendations that we could make in this report? If we don't make the IRB central in this process, what could we do instead that would be helpful?

DR. LO: Well, I'm not sure I would quite answer it that way. I would say what do we need to say in our report to make the IRBs really capable of taking all these additional tasks. And to really explicitly spell out we understand that IRBs are being asked to do increasing amounts of work; they're dependent on volunteers; don't have enough administrative support. These are things, they may not be trained to think about some of these issues. These are the things that we suggest need to be implemented to make this really feasible.

DR. SHAPIRO: I actually have a lot of sympathy for that. I think that we should find a place in the report to acknowledge the increased burden, the increased set of requirements, and acknowledge the fact that the system as a whole has to find institutions and better support the IRBs themselves. I thought a lot about whether there is an alternative arrangement. It's not easy to think that with an alternative arrangement that would be anywhere near as effective. And despite all the limitations, and genuine ones that you have pointed to, I think if we can say something now about the need in this context, at least, to strengthen these institutions in various ways, that would be very helpful and then when we follow that up next year with a report that has more to say about this. So I'm sympathetic to acknowledging this and not pretending that this could be just put on their plate without any ...they'll just do it. I think there's enormous variability in institutions regarding how our IRBs work, how much institutional support they get, how well organized they are and so on. But nevertheless, your point is well taken, I'm sympathetic.

MS. BACKLAR: And there's a section in the report where that could fit in very well because you've started a section, the reason there are extra costs and why one will have to pay for this.

DR. MORENO: I had the opportunity about two months ago to present the draft recommendations to an FDA-OPRR workshop in Albuquerque. And I said at the beginning of the talk that I was afraid they wouldn't like me very much when I got to the end. These were, of course, all IRB people. And I was surprised at the benign response. Now that might be because a lot of these IRBs work with people from Native American communities who already have a high monitoring and reconsenting and so forth in place. Another case, an individual from a very large, research nurse, from a very large academic medical center, said they had already a liaison as I mentioned before who does much of what I've been talking about. And she wasn't put off at all. So this leads me to a practical suggestion. Perhaps what NBAC might want to consider is after this report comes out, is sponsoring a conference, perhaps with another organization, perhaps OPRR, where individuals from some of these institutions could model their work, could model the arrangements that they have already, and give a very practical indication of what kind of institutional vestment it has met. Because I think although many of the larger IRBs, we also knew from the Belmont Report, that about 10 percent of IRBs do 48 percent of the protocols. So there's a small number, they are very stressed. There could be a specifically identified effort to help them make the arrangements they need to make with an assessment of how much it would cost them.

MS. CHARO: First I second the suggestion about a conference; I think it's actually a very nice way of disseminating. I'd like to perhaps even encourage us to take one step beyond what Bernie and Harold have suggested on this text. In the Executive Summary and in the Introduction to the recommendations and whatever short version comes out as well as in the main text, I'd love to see us emphasize that after much deliberation it was only a nuanced, scaled, complex approach to a range of protections that emerged as a realistic way of managing this problem. But no other solution really seemed to present itself, and that we were perforce required to send this kind of work somewhere, and that the current system either has to be massively changed or massively improved in order to accommodate this work. And to do the same thing in the biological materials report, and to also note in both of them that the structure of human subjects protection in the federal government makes it difficult to make these changes in a regulatory fashion because of not only the decentralized IRB system, but the decentralized authority over human subjects protection in the U.S. government. And in this way truly use these reports to build a record towards next year's report on the human subjects system. Use these very deliberately to introduce some of the difficulties as inevitable unless there is change. Because we already know the system needs to be changed, it's already been stressed beyond its capacities and it's not been enough. So maybe the addition of these, which are our conclusions of what you absolutely have to have to do it right and yet is now a straw on the camel's back will be enough to perhaps get some attention to the need to change the system.

DR. LO: I'd also like to urge us to list out some of the directions we think things need to go. And we have some of this within the report. I mean, inclusion of a meaningful number of persons who have some knowledge of their condition and how to fix potential subjects, increase in staff, particularly for like things like consent monitoring. I'd like to say, you know, for IRBs that routinely see a fair number of protocols that deal with population, there should be some mandatory training for at least some of the people in the IRB to familiarize themselves with what's in this report, and it's not just reading the report.

MS. CHARO: I suspect that when we get the public comments back that a lot of them are going to have a kind of bifurcated look. Nifty ideas, wonderful thoughts, some of them will hate us, you know, but nifty ideas, wonderful thoughts, can't possibly be done because we need X, Y, and Z, and that we should be quoting from those letters, right. Remarks from the field about exactly what makes it...what is necessary to make this possible, I think that would be the most persuasive evidence we could provide. And they'll give it to us.

DR. LO: Great. But I think ... what am I trying to say here...I guess, to present a solution that we know has a lot of practical difficulties without also taking the lead and suggesting how to overcome difficulties, sort of undermines our report. I think if we just say these are the things that we recommend, yes a lot of this is more for the IRBs, yes, we know it's tough, and please address the situation. That's not going to be as powerful a report as ...and these are some of the things that we recommend that institutions and the federal government do, and this is something simple like allowing extra indirect costs for NIH grants to cover some of this would be a tremendous boon to big research institutions. And I think unless we make some recommendations that really are going to make this happen, it's going to make us look naive.

MS. CHARO: You're not suggesting, though, that we try to actually debate out to the point of consensus specific recommendations on the change of the entire standards we want them to enforce. That they are integrated and you can't separate them. And we all said intellectually that makes perfectly good sense. But as a practical matter we can't manage to figure out how to write a report that covers everything because it's a 10,000-page report that will take 15 years and we will have gone out of existence before we get there. So we were stuck with this practical problem of how to tackle jungles. And I'm wondering if we can avoid the need to try to debate out specific recommendations. If it's enough to say we've gotten evidence from the people who commented that these are the kinds of things that we're bound to wind up recommending eventually, which is better staffing, better financial support, increased representation on the membership of the IRBs, perhaps some possibilities about performance standards or certifications or licensing or some other kind of quality assurance in this system, but we have not yet gotten to that point but we promise you we will by the turn of the century.

DR. MIIKE: My suggestion, Bernie, is that we can all write individual comments on these reports, so if you feel strongly about reemphasizing that point, it's something you can write. But I agree with Alta. We're recommending policy, not operational changes. I don't think we can do both in reports of this.

DR. CHILDRESS: Other points you'd like to make about the draft to guide staff as we try to again go through the several steps we need to produce another version for September?

MS. BACKLAR: I want to make sure that we understand, I want to go back to the legally authorized representative, and I'm not certain if that's still a little confused. Where we are clear, where it is the person who's the subject who picks that, appoints, chooses a person they trust, and it seemed to me, I found places where it was slipped was imposed upon them, and I'm a little concerned about that confusion.

DR. CHILDRESS: We have both. But the prior would be the individual selection and then in the absence of that the legally authorized representative according to state laws. I think we have both in the report. But there is a priority, there is a ranking.

MS. BACKLAR: Right, I want to make sure that we're very clear about when which happens because one wants the person choosing in every instance where one can have it. And as we know from Greg Sachs' research, people even in certain stages of dementia can still choose people that they trust.

DR. CHILDRESS: Jonathan, any comment?

DR. MORENO: I think it's mainly an editorial matter at this point, Trish. I really think we're pretty clear about that.

MS. BACKLAR: I have marked pages where I find it confusing and we could e-mail about that.

DR. CHILDRESS: Other points? Mr. Chair, it looks as though we're talked out on this subject. Well thank you everyone.

DR. SHAPIRO: Okay, just looking over these issues, I think we've gotten some very good suggestions today which will certainly help us improve this. I think the issue of increment over minimal risk is not going to go away, we're going to have to resolve that. We'll have to see how we can work with it but that's going to be a decision that's still in front of us. I don't see that we came to a conclusion on that today. We didn't force ourselves to vote on just what it is, but I think that's something we ought to pay very careful attention to, and each of us try to think through whether this is really a distinction worth making. And in my view it's because different, as Bernie has suggested, different protections would flow in, i.e., not have to go to the Secretary under certain circumstances or not. And it's really that question we should ask ourselves and see where we all stand on that. And let's try to exchange ideas on that over the next weeks by e-mail and so on so I don't think it's sufficient to leave it to September. We have to sort of...we'll formulate some ideas and then we have to start working with each other on it.

DR. MESLIN: If I could just make a request couched as a plea, if you have marked-up copies of either of the reports, please give them to any one of the staff members or put them in an envelope and send them back to us. We are engaging an editor so all of the comments of either an editorial nature or conceptual nature will be incorporated into the next draft. Where there are issues of disagreement, I would certainly propose that we use our NBAC e-mail list and that if not just a one-to-one exchange that you share it with everyone on the list, everyone can see what your views are; if you would like to join in the conversation I think that would be most productive to staff. And the sooner, obviously, the better. And we will inform you on an ongoing basis as we receive public comments, not every single one, but as we develop a small critical mass we will share any of those with you in whole or in part. Please feel free to ask, but you will be getting notification of it anyway. We'll also be letting you know about the two consultation activities, the protocol review activity that Trish and Alex and Jim have agreed to assist with. And the other activity is relating to conversations with the Maryland Attorney General's office, the New York Department of Health, and officials at NIH and NIMH as we all begin to review each of the drafts in progress to see where overlap is and gaps may exist. So we'll keep you as up-to-date, and obviously please communicate with us as regularly as you can.

DR. SHAPIRO: Okay, other comments on this? Because if not, what I ... depending on the will of the Committee, I would suggest a short break and then we go back and see if we can pick up some of the material from the materials report, so to speak, because we hadn't gone through that whole memo and there may be other issues as well. And we have some time here this afternoon, I think we should try to get a little further. Why don't's now about seven or eight minutes after three, why don't we try to be back at 3:20.