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

DR. CHILDRESS: Thanks, and let me just echo Harold's expression of appreciation to Jonathan for all of his work on this document. Also, other members of the staff and the Commissioners had a lot of input. And that's always been very, very valuable, and we're always amazed how much input Harold is able to provide on this for different drafts. We wonder when he sleeps. The schedule, as I understand it—and I'll get Eric Meslin to amplify this, would be that we do have the document from July 1 on the website. It's been sent out also for comments, and the staff will analyze the input and take—we'll take that into account, along with our own discussion today and social developments when we look at this again. The protocol review also is under way, and the analysis will be provided by staff. Staff will be working on the Maryland report. We have sent copies out before, and the final draft came out recently, and the interstate report, which we finished soon. And all of these will be things that will play a role in our preparation of the final draft. And then we would try to incorporate—deal with those materials the best we can, and based on staff analysis in September, try to develop a revised draft as soon as possible, and the hope is that we could sign off on this in November. Is that correct? I just wanted that to be before us, so that helps us clarify our marching orders for today and over the next several weeks. You have a memo prepared by staff on remaining issues. And I think this is a very helpful memo. There will be some other issues that Commissioners will want to raise for discussion. So, what I would propose is that we go through these issues, think about them in relation to the text, and then come back to a number of questions and comments, and proposals that they will have that go beyond the ones that are identified here. If that's satisfactory, then we'll just proceed that way. The first one shouldn't take very long, although saying that sometimes opens the door to—. The use of the words "subjects," that proposal poses no problem for people, I hope.

MR. CAPRON: Yes, it does. I believe we should continue to use the word "person." We are talking about people here, who may or may not become subjects of research. And I think the phrase, "subject," here is a way of classifying people already and deemphasizing them, their personhood. The choice is not between subjects and patients. Obviously, where that issue comes up, subjects is preferable to reminding people that although people are, perhaps, receiving medical care, they are, for the purpose of study, a subject. I would prefer staying with the word "persons."

DR. CHILDRESS: I think you've made a good case. I don't have strong feelings about it. Diane.

DR. SCOTT-JONES: I prefer using "persons" also, where appropriate. And I prefer using "participants," instead of subjects when we're talking about people actually involved in study.

MS. BACKLAR: I agree. But, also, I'm wondering in the title if we should not say, "Research Involving Persons with Mental Disorders that May Affect Their Decisionmaking Capacity."

DR. CHILDRESS: That we'll come to in a moment, as the second issue I think in the title itself. So let's do the studies part first, because I think that we do use language that may affect throughout. And sometimes we cannot get with their decisionmaking capacity; sometimes we don't. But in the title, if we're focusing on—and we'll come back in just a moment. So, let's do the subjects part first.

MS. CHARO: I may offer a compromise—at least accommodate this all. Until people have actually been enrolled, they are clearly persons. Sometimes they are patients, depending upon the phrasing. At the moment at which they are enrolled, they are subjects participating in research. Is that a way of getting everybody's points included?

DR. CHILDRESS: That is. But how will that help us with the title?

MS. CHARO: I'm sorry. I thought you said you were still working on subjects.

DR. CHILDRESS: Well, as it relates to the title part, as well.

MS. CHARO: Excuse me. I was a step behind you.

DR. CHILDRESS: But it's both. It's the title, the part having to do with subjects, but then it's also why we use it throughout. Larry.

DR. MIIKE: I would just go with "persons." If we're talking about subjects, we should be talking about human subjects versus animal subjects, versus other subjects. But "persons" would be the way to go.

DR. CHILDRESS: I hear a consensus that we go with—back to the original formulation of persons. And I think we'll need to look very carefully, actually, in the text. Because in some cases in the text, I think it will be more appropriate—to use subjects. And sometimes participants, Diane, will be more appropriate. But we also do have to tie in with the regulations. And so, we want to keep the subjects in mind for—in places where it would appropriate to do so. But with the staff alerted to this need to be flexible throughout, then will that be sufficient, Bernie?

MR. CAPRON: Well, to put a sense to what you're saying. Although the language of subjects is used in the regulations, some connotations are not ones we like, and participants may more sum up the sort of the ethical relationship. . . .

DR. CHILDRESS: Good. Duly noted. Any objection to that change in the title, and then careful attention to this throughout the text? Okay. The second part on how we think about may affect decisionmaking capacity. And, sometimes, we're talking about this generally, in terms of mental disorders, that affect decisionmaking capacity, or affecting decisionmaking capacity, where we want to indicate that sometimes, perhaps, even often there maybe that kind of effect, but leaving it open in particular cases.

MR. CAPRON: I thought she just wanted to put a pronoun in there?

MS. BACKLAR: I did. I just wanted to identify that this was their issue. They're a decisionmaking capacity, that mental disorders may affect them. I'm not saying that you said may effect them, but that's why I wanted to put their decision there. I want to make it very clear that it's going to effect them. That's all.

DR. CHILDRESS: Okay. Any objection? Sorry I misunderstood. Okay. Two categories of risk. We have discussed this before. Is Laurie available? Is she going to be?

DR. MESLIN: We've made an attempt. We're going to try again. We tried to get in touch with her. We haven't been able to.

DR. CHILDRESS: Why don't we just skip over this, and see if she can get involved with us, since this is something that she's been very interested in. Let's go to the dissent point, number three. And I'm missing some lines in my draft, so it's confusing.

MS. BACKLAR: If there was something at the bottom of the page that then went to the top of the next one.

DR. CHILDRESS: Right. So it's not clear, but that's the point. Is it—the National Commission had a complete review on this, relating to overt objection. We've gone in the direction of no apparent dissent. And the question is we don't—do we give enough justification for departing from the National Commission's standard, and are we satisfied with a departure.

DR. SCOTT-JONES: Jim, did you reference the pages where that is discussed?

MR. CAPRON: 111 is a discussion of the National Commission's view and following. And then our recommendations. We come to this statement, as well as in the special protections in research.

DR. CHILDRESS: Actually, I'm not sure. I think we could go ahead and discuss the topic, because the issue, whatever wording is there, is whether we want to depart from it in the direction that we have already taken, namely, no apparent dissent. Are you satisfied with our standard no apparent dissent?

DR. MIIKE: That is stronger or?

DR. CHILDRESS: It will exclude a lot more people from the research.

DR. LO: I would like to see more explanation of what the differences mean. Because, frankly, I'm not clear what implications of changes there are. I think it would be nice to have a justification for why we're moving away from what up to now has been the accepted line on the subject. And we've made it pretty strong, in that, it does—it is apparent dissent is in level with risks and of any level of benefit to the subject. So it's—and apparent dissent can cover a variety of options resembling sort of waving one's hands, "no, no, no," would be quite sufficient to stop the research. So, this it's strong standard. Let me give it a try.

MR. CAPRON: I don't think we should have this discussion without Laurie. Because it seems to me again that she was bothered by that and talked about it, the notion that an incapable subject, not fully comprehending something that's being done, but it would say, "No, no, no." And if you—that was her view that you shouldn't necessarily halt the research, as I recall her discussion.

DR. CHILDRESS: Okay, I have several, Jonathan, Diane, Bernie, and then Trish.

DR. MORENO: Well, in response to Bernie's request for rationale. I think that the rationale would be that these are people, first of all, who are in a dependent relationship with the researchers and the institution. I think that the rationale would be that these are people who are in a dependent relationship with the institution and often the researchers, and that the image that they would be, in some fashion, forcibly required to go to a room and continue to be part of a—perhaps, an imaging study, or that they would be forced to accept an injection or the placement of a line, an intravenous line so repulsive that even if they didn't understand the underlying, perhaps, benign—and certainly benign motivation, that the atmosphere that would be created, and the statement would be made by such activity, would in the long run be a much greater harm than any expected benefit to science from this kind of participation.

DR. SHAPIRO: That was exactly the reason we used last time. We—and I'm not speaking for Laurie, of course, who may have a different view. And that's a good point. We ought to check and see what her views on these are. But that was—as I recall this discussion quite well. And that's exactly, at least speaking for myself, convinced me they didn't want to recommend anything which would force that scene. That's just my view.

DR. SCOTT-JONES: I agree with the position that we've taken. And I just wanted to point out that the National Commission's sentences reflect what's ordinarily done in research with children; that is, that if there is some direct benefit they can be forced, even though they don't assent. And I also looked at the document that we got from the—from Jack Schwartz regarding Maryland's recommendation. And I believe, if I'm interpreting correctly, they take the same position that we do regarding assent, that the potential research participant can, if they withhold assent, they cannot be enrolled in the research, and there is no provision made for an exception, and there is direct benefit. So, I think what they have decided is in keeping with the position that we've taken.

DR. LO: I just want to say, the other thing that I would say is that in clinical practice there are presumably—there is a known benefit, as opposed to potential direct benefit. It's very troubling for forced treatment on a non-assenting patient. And I think we cite the Canadian Task Force for that. But I think that's another reason I would put in in support of the position.

MS. BACKLAR: I'm just back this up. I just can only imagine being ushered in to have an MRI, for instance, if you were—and you maybe were afraid, and nobody was going to listen to you. That's all. I just you know—just have a visual image of how that would effect the subject.

MR. CAPRON: Well, I just—this is a recommendation. It appears on page 162. And what we're really talking about is where in Chapter 5, and how explicitly we provide the rationale. As I understand it, there really—there are two issues, which we've collapsed a little bit in this discussion. One is the issue of whether you need to do—there is a difference between any objection and no overt objection. And the other is what is the status of the individual? Because the National Commission certainly looked at capability of assent, depending upon the person's ability to appreciate what was involved in the research, and, so forth, even if they didn't have the ability, the full ability, to do legally binding consent, as I understand it. And so, we're really taking a stricter view on both of those points. Is that correct? And I think we need to explain the justification quite fully. I agree with the conclusion, but it does mean that we need to say that since we're not talking about consent, this is an issue which can be revisited with the individual after further discussion, or at a time when the person is calmer, and so forth. Because we don't—if someone says—when you participate in a research and someone says, "No, I will not." The idea of constantly going back to them and battering them, as it were, badgering them, rather, for it is wrong. But on the other hand, if consent has been given, and then at that moment the persons says, "No, no, no, I don't want them doing that, too, right now." You sort of say, "Okay. We're dealing with a situation where they're fearful. We can sit down. We can go through whatever methods work, if any do, in taking a person, and giving—raising their level of comfort with this, and then saying, now, can we do it?" And they don't object now, or they continue to, whatever the outcome is. But it seems to me we need to indicate, this isn't sort of a cut-off of the research forever. It's just that it would be wrong to force a screaming person into a tube to do something you know is benign, but they don't find it benign.

DR. CHILDRESS: So you would agree with the line of—

MR. CAPRON: I agree.

DR. CHILDRESS: Because if you're dealing with someone who really doesn't have the ability to give assent, what you're doing is you're placing their—the interaction, quite correctly, takes predominance, even though it's like a two-year-old child or something, in terms of their ability to actually make an intelligent decision about this. And we're just saying it's still wrong to do it to them at this moment. So, we'll add that, presumably, in the discussion, although we're talking about the National Commission's view, but also at the point in our framework and special protections.

MR. CAPRON: Well, I'm not clear about that. It would seem to me that when we get to the recommendation—are you saying at 162, where we give the recommendation? Because I thought that the way those recommendations usually—

DR. CHILDRESS: No, I said the framework of special protections, which is the chapter within which the recommendations fall. And it would seem to me that that would be an appropriate place for it. Because there we have a more extensive discussion of what we ended up with in the recommendations themselves. It's really 149, following. And that a bit of it's already there, but needs to be I think fleshed out along the lines that have just been indicated. Is everyone in agreement with the two—the direction that several mentioned? One comment. On 162, are we going to have trouble when we qualify the word "dissent" by a parent? That seems pretty big standard.

DR. MIIKE: But that's the Commission talked about overt. We're talking basically about dissent. But if we see an apparent dissent, that—it should be a lot more in the opposite direction.

DR. CHILDRESS: Any form of resistance. For example, going to an MRI. So, it is—it's much broader. We capture a lot more people that way.

DR. MIIKE: Well, I'm just a little worried of how full and apparent as the qualifier of what he said.

DR. CHILDRESS: And we've had some discussion about it. Jonathan, do you want to say anything about this?

DR. MORENO: To use the phrase "apparent dissent" places a much heavier burden on the member of the research team to show that there is no apparent; that there is no reason to suspect that this person doesn't want to continue or start the study. If one were to say, "no dissent," then clearly one could construe that in a much stricter fashion. Dissent means for us such and such. It means calling one's lawyer, insisting that the one be able to rip up the original consent form, setting chapter and verse of the regulations, and so forth.

DR. MIIKE: Instead of apparent, could we say expression of dissent? An apparent, one gets to be very subject, in terms of what one—an expression can be an expression, verbal, nonverbal, etc. Anyway just consider that. To me apparent is so vague, that it's just wide open.

MS. LEVINSON: But maybe one would want to put in "expression," and then parentheses, verbal or nonverbal. It makes it more specific.

DR. CHILDRESS: Harold has mentioned that indication is a possibility, no indication of dissent, which would be another way to go.

MS. CHARO: It strikes me that the discussion is, in a sense, really about the deeper issue that troubles us I think, which is that what you'd like is to honor all authentic dissent, and in this and every other—transient thing. And the fear is really that if there is any discretion in the interpretation of the expression indication, whatever, of dissent, that there will be a tendency to interpret away many expressions as nonauthentic. And that returns us over and over again to the degree of confidence we have in the research community in this particular area. And so, although I—you know you can use the indication or expression, or whatever. Actually, Larry, I found "apparent" to be a word that seemed to reduce the discretion of the research community as much as possible at the cost of excluding many people who were not authentically dissenting. It was an extremely protective standard. And so, really, in some ways, whether you pick that word or not, the question is do you want to have this extremely protective standard, or do you want to have more discretion and interpretation on the part of the researchers?

MS. BACKLAR: I am trying to think of the kinds of people who might have great difficulty in expressing something, somebody with dementia. I mean I'm listening to what you're saying, and I'm very concerned about the discretion of the researcher, with somebody who has dementia or Alzheimer's. I'm less worried about some other situations; people with schizophrenia in this particular situation, or people with bipolar disorders, and, so forth, that I'm very concerned about that group of people who may not have a very clear way of expressing their fears, except that you can certainly see it. So, and indeed that's what you're seeing may need to be retained.

DR. LO: I think that we should try to hear what you're trying to do this morning. It would be very helpful I think if we gave some examples of the kind of things that counted as expressions of dissent, or indications of dissent or apparent dissent. Because the way 160—lost my page here—162, I think it is. It's very theoretical and abstract, sort of a philosophical discussion. I think the IRBs and investigators really help. What are we talking about here? A person says, "No, I don't want it." Okay. That's fairly clear. Folds the arm, so you can't do the I.V. I think that's—you shouldn't sort of force the arm. I think some examples of what we mean would help flesh this out. It's a said kind of a de facto standard.

DR. CHILDRESS: And I think that a good place to do that is 149 and 50, where we do have—get into a discussion of the rationale for this position. Okay. Other points to be made?

MR. CAPRON: I just want to state that I understand what Larry was saying about the use of the word "apparent." But the more I hear the conversation going on, I really think it is important to keep it somewhat—well, it somewhat may be left open to interpretation, because it does put the onus on the researcher. And I would be more comfortable with leaving it as, "any apparent dissent," than even putting indication in dissent. Because then the researcher can say, "Well, they didn't say they didn't want to do this," or they can interpret it and say, "Well, they're not—you know they're mentally ill, they don't know what they're talking about," or something like that. And in the practical day-to-day research, I can see how this would be left open to more interpretation. I just like using the word "any apparent dissent." So, I'm in favor of leaving it as it is.

DR. CHILDRESS: Well, there was no apparent dissent, an indication, an expression, and, obviously, the need to amplify this, in terms of examples. I don't know whether you want to push it to a resolution of the word today, or whether we actually would prefer to have examples, and then sort of see what we think makes the most sense, in terms of that.

MS. BACKLAR: Make sure that we indicate both verbal and nonverbal.

DR. CHILDRESS: Right. I think the feeling of the Commission is really pretty straightforward here; that we do want to be restrictive. We have to give some examples to give it some light, as Bernie as suggested. But let's not worry today about preparing for a syndication versus something else, whatever we settle on there will be—if we have good examples, it will be true and clear.

MS. CHARO: I just want to respond to the possibility that this may be excessively protectionist, regarding the participant's rights. And it clearly states that halting the research intervention with the subject at that time, so it doesn't mean that the person discontinues participation entirely, just at that time.

DR. SHAPIRO: And Alex's elaboration of that I thought was very helpful in getting in something we really need to include.

DR. CHILDRESS: Okay. Is that—if there is no apparent dissent, we'll move on to the next. Okay. Independent and professional support for subjects and surrogates. This is a question, in part, as—and this actually comes up in some areas, too, that when you look very carefully out in the framework of special protections, and in the recommendations, were sometimes not clear that we are actually applying certain things only to greater than minimal risk research. And I think one way we can clarify this is actually to have appropriate statements in the framework of special protections about what we're doing with minimal risk research. So, we don't really—as I look back over this, we don't really say that. We do have a little box on the chart, if you're—if you look at our chart. And, Bernie, I do find the chart useful. This is on page 173. We do have—if you look over the next to the last line, vertical line, that's where there is minimal risk research. And we say a no apparent dissent is required. But it might be a lot better if we actually spelled that out in the text, as to exactly what we're doing with minimal risk research. And I think that that will help people interpret our document. But that having been said, what do we need to say about independent professional support and the categories for which we are applying it? The recommendation here is that we limit that to only greater than minimal risk research. But then, you have a lot of discretion of IRBs, in terms of—I mean the scope of the involvement of such persons. So, let's open that to discussion. Jonathan, anything you want to add?

DR. MORENO: It seems to me that its use is limited to the greater than minimal risk research. I think I feel pretty comfortable with that. Involvement in this particular group we're talking about; allowing the IRBs, of course, to acquire it if they choose to. In any other research project they're dealing with, if it somehow seems appropriate to them in the situation.

DR. CHILDRESS: I also think the issue here is, even in saying it, the independent professional should be involved for both subjects and surrogates, as appropriate. The question of what that involvement details, what's the scope of it? What's—what exactly that would include? It's something, perhaps, we ought to discuss very clearly. Perhaps, there is something we want to leave open to IRBs will it determine.

MS. BACKLAR: But what is the section where we describe? I thought that you just—that it is starting to make sense in this particular draft.

DR. CHILDRESS: Where we dissent, those page numbers are accurate. And first of all, on 134, we have the extensive discussion of independent pressures for—

DR. MORENO: And then the recommendation on 156. And then there is—probably is also a section in the special protections as well. I don't see it just now. On page 156, there is a paragraph that gives it during the course of the study. Maybe I'd just add that in thinking, trying to think this through, Trish, I found it difficult to express in detail for a vast range of studies and circumstances, exactly what role the individual would have. I think we have to work, to some degree, at least, on the confidence in people's professionalism; that once—that the positions that I know, once one of them would be identified for this role, they would take it very seriously. And they would see that they're on the line, as well as the investigators and officers that are involved in the institution with the research, so that one would think that they would be quite responsible in their execution of this role. And I don't think that it's possible to go much further than that, frankly.

MS. BACKLAR: I actually thought on page 134, the top of 135, I thought it was—and then when you referred to the British Law Commission, I think that's very well done, and probably as good as you can.

DR. MORENO: Not that I'm not willing to hear your suggestions. Of course, I'd be delighted to hear suggestions to elaborate this.

DR. LO: I wanted to go back to the flow chart on 173, because I keep in my mind coming back to it to try and pull this all together. And I guess one thing that isn't clear to me—I mean it is. It's not clear to me why we choose the bottom lines as we do, rather than other bottom lines. So, I think it makes sense to say that subjects cannot do informed consent. They need more protection than when they can, if it's you know greater minimal risk and no direct potential benefit. But why we put two things in the box, rather than three, or why those two, we don't really go through. And I think it would helpful to get IRBs and investigators to use this, not just why we think there should be more protection, but why those specific protections are called issues and not others. So, I think that's what I'd like to see more of throughout you know this draft, just to make it more useful. And then I had some other questions about the way the outline runs in 173. Are subjects likely to be capable of giving full consent? I'm not sure that's the operational question. Isn't it whether they are capable? Because if they're likely to be capable, but in fact not really capable, then this particular situation doesn't make much sense to talk about getting informed consent. So, I was confused about that.

DR. MORENO: The problem we run into here, Bernie, is that the state in which the IRB is making these judgments, the specific likely participants may not be known. And so, to a great extent, at least, this, in the initial stage of reviewing the proposal, the IRB members have to make a judgment based on what is known about the population from which participants are going to be drawn. This is a real—this has been a terrible problem.

DR. LO: But then what happens—I mean it's something of a protocol to say I do this. I get IRB approval, then I go on this subject that she is not capable, according to the guidelines I spelled out in section 1B of my protocol with whatever independent monitoring. Then what do I do with that?

DR. MORENO: Right, the investigator, the onus is on the investigator to make it clear what arrangements are going to be made under those circumstances. But shouldn't we, by the extent of our logic, say you can't use that subject if they can't give an informed consent?

DR. LO: I think that actually—and this comes up in some other issues of what we talked about today, too, that we're sometimes confused I think of what the IRB has to consider in thinking about the group and what a particular individual may be—whether a particular individual may be enrolled or not, and the kinds of qualities or limitations.

DR. CHILDRESS: I would agree with your direction here.

DR. LO: Look at the protocol and make sure there is an adequate branch in the protocol of individual subjects or persons to decide what happens if in fact they aren't capable.

DR. SHAPIRO: My understanding of the process, I have not—I think maybe that some elaboration of this is really a very good idea, is that if you go down that route and you're wrong, they can't give informed consent. Then it's over.

DR. CHILDRESS: I think that needs clarification, but I think the point he's suggesting is the one that I think is found in the text, but the other elements are present, too. We need to just clarify that.

DR. MORENO: Well, in some defense of the explanation that's in the current draft, we do make it clear if you look at the boxes at the bottom of 173, where informed consent is required, or where it is an alternative. So I do think that we do explain, if not perhaps in sufficient enough length, we do indicate in the draft where it is required and where people would simply have to be thrown out as candidates for participation if they didn't have capacity consent. But we need to revisit that and make it clear perhaps earlier.

DR. CHILDRESS: I agree, affirming Bernie's point though about beneath, or, perhaps, more elaboration, the reasons for choosing some of the particular requirements for each of these boxes. Okay. Other points about independent protectional support, as we move from that to a more general consideration about the way in which we argue for different requirements for different boxes. Do you know the points? I take it then that there is agreement that the scope which would need to be determined by our leads, and that's something that has to be worked out in relation to particular protocols. It's the scope of the involvement. Okay? Okay. Another issue has to do with consent monitor, and this is addressed on page 148. The—why this recommendation is being made here is a staff-prepared memo, is that we really need to distinguish why we do not in the current text in that one particular paragraph on lines 10 to 14. There is a concrete proposal for the way that we write that. Any objection to that? Okay, good. Now we move into—

DR. LO: Who are you expecting to pay for this consent monitoring? Page 148 suggests that an IRB member, or an Ethics Committee member is going to do it. This is a lot of work. And you know are we expecting investigators to compensate people for this? That should be—I don't know—a fundable part of your grant. Because I'm afraid that if we say something that's really impractical, people are going to say, what is this guy thinking?

DR. MORENO: There does seem to be, Bernie, at least one institution that operates through overhead. It pays the salary out of their research nurse, who goes around following a consent process two or three days later, and essentially reinterviews the subjects in that room. That is one option. Other institutions may choose to do it differently.

MS. CHARO: Bernie, I wonder if it would be sufficient if we simply take note of the fact that it has to be paid for by somebody, and that institutions may vary. Those that do a lot a of this research may have an institutional response; others may leave it up to the PI to incorporate that in the cost of the grant, and not for us to try to decide who pays for it.

DR. KING: As a researcher in the field, could I ask that whenever your recommendations will lead to substantial additional expense, that you please note that in your view these are expenses that NIH needs to consider supporting for those of us that write—that support all of us off of IR-1's, so that we can put in our human subject sections of our grants, in order to be able to follow NBAC's recommendation that such and such, we have added a 20 percent type of position for the research, or 20 percent type of position for a genetics counselor. Otherwise, study sections who do not include, typically, large numbers of people working with you and subjects in the field well funded and will be stuck.

DR. CHILDRESS: And also, that it probably can't come out of indirect under current interpretation.

DR. KING: It wouldn't come out of the indirect anywhere.

DR. CHILDRESS: You know let's see. If I'm not mistaken, we are offering—correct me if I'm wrong. This is only under the heading of guidance for IRBs, and not in terms the requirement, right? That changes a bit, in terms of the kind of discretions. Am I right about that? Okay.

DR. SHAPIRO: The point is well taken. There are a number of recommendations here and in other reports, which we discussed earlier this morning, which are in that character. But by recommending simply as guidance, then for IRBs we are allowed a lot more room, where they are considered a variety of factors, including the cost elements.

DR. CHILDRESS: Okay. Anything else? Okay. Let's turn then to the point raised on 161, 162, the recommendation to, which is also discussed in different ways on 170 and 149. And this seems to me to be another place where we may be jumping back and forth between the group and the individual. Because there are two points that we're concerned with; one is that we not exploit a particular group or class of potential subjects. And that's the reason we are requiring that the research can be done with another group or class, so be done. And there never is the issue of consent for particular individuals and what surrounds that. But we do have this specific point here, and a question being raised about whether the recommendation we have would prevent individuals who have mental disorders and who can consent from participating in research studies and directly relating mental disorder and an example was given.

DR. SHAPIRO: I guess I'm not sure that what we recommend—I guess I'm not sure if we would exclude that. I think it would—I think it allows that. Well, at the very least, we could articulate exactly what it is we'd want to say here.

DR. CHILDRESS: And make sure that—and then satisfy ourselves this report says or doesn't say it. But I guess we'd have to hear what people think we all want to be the result. Right now, it's the result of one person's interpretation and just to get the discussion going. Diane.

DR. SCOTT-JONES: As I reflect on the pages 161 and 162, it does not seem to me that what precludes the study that's given in the example on page 2 of the memo, that is, that there would be a genetic study examining the relationship between cardiovascular disease and Alzheimer's disease. What we have already written says that—only says that you would—I'm sorry—that you would exclude the participant if the research could be done with other subjects. And that clearly isn't the case with the example. You couldn't study the relationship between cardiovascular disease and Alzheimer's disease without using Alzheimer's patients. So, it seems that we have already taken care of this in what we've written.

DR. CHILDRESS: That's my sense also. Other thoughts? Okay. Just to make sure, let's assume that is right and we just want to make sure Commissioners feel that's the right position to be in. I'm satisfied with that position, certainly, but I want to make others are, as well. Okay. Further discussion? Larry.

DR. MIIKE: But are we talking about research that's unrelated totally to their mental incapacity? So the example that Diane gave is one that related to the group of people in capacity. So, I think we need to make it clear. This—

DR. SHAPIRO: What do you propose then?

DR. MIIKE: A clarification.

DR. CHILDRESS: Okay. You have language to suggest, or just recommending, as we've been recommending IRBs just do it?

DR. SHAPIRO: Well, I understood Larry to say that there is—that maybe the use of an example here, which might involve this population, you want an example where they weren't involved in something that was specifically related to a mental disorder. Is that right?

DR. MIIKE: As long as they have the capacity to consent.

DR. SHAPIRO: Right. Okay. Diane, did you want to say something further about that?

DR. SCOTT-JONES: I just wasn't sure what Larry was saying. That isn't already covered. I'm not sure what your comments are.

DR. MIIKE: Well, the way that it says, subjects with mental disorder, any—if we're talking about research, involving subject with mental disorders that may affect decisionmaking. That's the all-encompassing. It talks about any research. It's not limited to research that is related to their mental disorder. So I'm saying that if you read this and I, as a person covered by this, developed cancer and suffered a particular cancer that is of interest to researchers and they had the capacity to say yes, this would say they can't participate in that protocol, and I don't think that's what it means. As long as they have the capacity to consent to that. That's what you're getting at, right?

DR. CHILDRESS: This is moving between the group and individual in class.

DR. SHAPIRO: I need some clarification here myself, and I apologize. Maybe I'm just confusing a few things. One of the decisions we made early on was that this population should not be used if it wasn't necessary. If the research could be carried on with other populations perfectly well, then that's what people should do. We have that recommendations somewhere here. And now we have an example, an interesting example, which Larry brings up. Namely, what if we want to do genetic studies of one kind or another that are unrelated to the disorder that these people have? Which means they don't need these people to carry on the study. But the question is do we still want them to be able to participate? Because the issue that your question raises in my mind. . . .

DR. MIIKE: Well, I think I was going on the assumption that the earlier discussions were something like Phase I trial, where you're talking about the physiology of a particular medication, where this is a totally different issue.

DR. SHAPIRO: Correct. I agree with that. And I think that if we're going to—if that's what we want, I don't have myself any objection to it, to have a capacity consent, just as you've said.

DR. CHILDRESS: We need to look at 145 and 146 before this is discussed and the framework of discussion reflections. We've just been just looking at the recommendation. And, in particular, look at 146. And I think there is some problem in that first—I think the first part of the sentence doesn't work well. We need to probably work it out. But it says that, "An individual with impaired decisionmaking classes on 15, 14, may have a life-threatening condition for which there is no satisfactory treatment. When the intervention is designed to potentially cure a life-threatening condition, then under current regulations these individuals may obtain investigational treatment outside the closed study on compassionate grounds as a matter of justice, etc." I don't think that fully addresses your concern, Larry, but this is at least one place in the text where they're trying to talk about something close to it. Eric?

DR. MESLIN: It may help just to clarify one point. Perhaps, the case example is not the best example. The reason that it was put in was to try and ensure that we would not be discriminating those individuals, who, by dint of having a mental disorder, that perhaps coincidentally can be mapped on to another physiologic disease. They might be able to participate in that research. Do we want to discriminate against them just because they have a mental disorder? Larry's question is really—asks whether the consent issue renders that movement you can consent, and the fact that you have a mental disorder shouldn't disqualify you from consenting to any kind of research that comes along down the pike. It only becomes a problem when there is some impairment to your capacity.

DR. CHILDRESS: Again, I think we're just not clear in the document about the effort to avoid exploitation of a group or class. And the issue of particular individual consent. And I'm not sure I have a good way to get those two together. But I don't use them unless the research is necessary, never to avoid exploitation of this population as a group. Then for particular individuals of consent, why shouldn't they be allowed to enter other kinds of protocols that are not directed at them as a group? And that seems to me to be the way to think about it. For that direction, if it's a protocol in cancer research, and this particular individual who has a mental disorder that may affect his or her decisionmaking capacity, could consent to that, then that person should—we should be moved to protect. Does that make sense?

DR. SCOTT-JONES: I think is covered very well in the Belmont Report. It says explicitly when research is proposed that involves risks and does not include a therapeutic component, other less-burdened classes of persons should be called upon first to accept these risks of research, except where the research is directly related to the specific conditions of the class involved. I think it includes the therapeutic component, which is captured in the example on page 146. And it was excluded—I think Larry's example, a researcher is studying cancer and could use any person as the participant. There is no need to use persons who have Alzheimer's to be in that research, even if they can consent. That's different from when there is a therapeutic component, as in the example on page 146.

MS. BACKLAR: The kind of person I'm thinking of protecting, who would want to be in such a protocol, would be for instance somebody, a very high functioning person with a bipolar disorder, that you wouldn't want to stop them from being in another kind of protocol that has nothing to do with bipolar disease.

DR. KING: I would point out a practical case from our experience, in which in large kindreds with inherited susceptibility to breast cancer, there are from time-to-time people with bipolar disorder, or schizophrenia, or Alzheimer's, and those persons sometimes wish to participate in these studies. They're not treatment trials. They're research projects. But if the person is capable of—if it is possible to obtain legitimate consent from the person we certainly wouldn't want to exclude them. So, it isn't only treatment. I think that's the point.

DR. SHAPIRO: All right. At this moment, we have three or four people signed up for public comments today. I just want to remind everyone that the rules of the Commission are five minutes, in order to give everyone a chance to say what they'd like before the Commission. Anybody, of course, who would like to give us written material is always welcome and it will be distributed to the entire Commission. So, let me just proceed immediately to those people here for public comments. Let me turn to Dr. Ted Falk, first.