DR. MORENO: I think that what people were telling me was that what we had been thinking of as an advanced directive was a semantic error and that, in fact, what we’re really talking about is planning...in the informed consent context for a specific study or a kind of study. So, that’s why the term "advanced directive" would seem to people to be inappropriately hauled in from the clinical context and so forth got taken out.

PROFESSOR CHARO: Right, okay. But some provision for somebody to give prospective consent...to have somebody else make the decision to enroll them, even in non-beneficial stuff, is on the table? Yes?

DR. MORENO: I think—I think it’s in the rubric here.

MS. FLYNN: I didn’t see it and it’s part of my concern that I think we’ve created a box and it’s very hard to get out of it.

PROFESSOR CHARO: Right. But, remember, though, that if it’s true most—that a large number of these people are capable of consent, that we have still not shut down research in this area, right?

MS. FLYNN: Yes and no. That large numbers of people are capable of consent much of the time. But the kind of research that is most critical, the kind of research where we want to look at individuals, do PET scans—I’m talking about the problem we created when we took away the category of minor-increase-over-minimal risk and made everything a big risk. When we want to do PET scans on people who are actively psychotic, it’s really good to know what the brain looks like and how it’s functioning and what’s working and not when it’s actively psychotic. It could help us a great deal. I don’t see how we can do that. We cannot get their consent when they’re actively psychotic.

PROFESSOR CAPRON: That’s true. Advanced planning.

MS. FLYNN: That’s nice for lawyers to talk about, but the reality is that almost nobody—we know and you all pointed out in earlier discussions, in other parts of medicine we’re not seeing this. There are lots and lots of challenges to it. It’s going to be very difficult to get it. And for a population that is characterized by Medicaid eligibility, long-term poverty, it’s going to be hard for us to imagine—I mean, members of my organization might be able to get with their relatives, but the kinds of research that we need, we’re not going to be able to get the very people who could benefit the most, and I think it’s not going to happen.

PROFESSOR CHARO: I’m just going to give you the last thing on my list so that I can move the chart over to the next person.

MS. FLYNN: I don’t mean immediate benefits. I mean as a—.

PROFESSOR CHARO: The last thing on my list so I can give up my turn to somebody else. Appendix 1 in your definitions, "necessary use"—this is page 148—"necessary use" means that the IRB should not approve research when such research can be done with other subjects. Just to remind you, something that turned up that you’ll find in the transcript—Tom Murray noted that there may be circumstances where people who have these kinds of disorders also have other kinds of conditions; for example, an advanced cancer for which they would very much like to be enrolled in research and that we need to craft this language, and this is a mea culpa because Eric actually asked me to help with this and I couldn’t remember what he wanted me to write about—I never wrote anything. But we need to somehow craft into this that when there is a serious condition for which enrollment would be potentially beneficial and existing therapies are not adequate, that we shouldn’t be excluding people just because we have some problem with the—just because we tried to set up a presumption against the enrollment of people.

DR. MORENO: I think this is what you and I had our E-mail conversation about. What I don’t understand about that suggestion is, wouldn’t those people be covered under a compassionate-use exception? You don’t want them in the research project. You don’t want them to be counted in the numbers.

PROFESSOR CAPRON: You want to be able to give them the benefit but not exploit their decision-making problems to make them research subjects.

PROFESSOR CHARO: That’s actually a good solution. It didn’t come up at the discussion in Los Angeles.

DR. SHAPIRO: Larry, you’re next.

DR. MIIKE: I don’t want anybody to comment on my comments. I know it’s hard, but I’m just going to say my main issue is around this prohibition without informed consent, without beneficial research, and my problem is as follows: I sent an E-mail message, I think in January, raising this issue, and I said that if you read the body of the report it had a whole range of other safeguards that were not considered before we reached this rather drastic conclusion and one of them was the Secretary’s type of thing. But there are more than that. Number one, on the consent side, we just had a discussion yesterday and today that advanced the records of general consent documents, or their general consent. They’re not specific. So I don’t see how an advanced directive can replace the specific consent around a specific project. So I would not agree that advanced directives help by making it more available. I don’t think it’s the same thing as informed consent. If we stick to the issue about benefits, what we have is the following: There is the discussion about direct benefits and indirect benefits, but there is no parallel statement in this recommendation about what benefits we’re talking about. And, if we’re going to be talking about benefits—if we keep it this way and I want direct benefits that arise specifically around the intervention and not this thing about they get free medical care, etc., etc., then, the other part is that this is going to lead to disingenuous statements. They are going to try to find the benefit rather than face the issue directly about how we have safeguards. So, it’s too much of a slippery area for me and I would rather have a very tightly crafted allowance with enough safeguards in there. But there are lots of things around this particular area, which I think can be done; for example, there are other statements that you’ll not use such a person if other classes of people can be used in those particular—so, it seems to me that this will be such a narrow exception, and it will be so scrutinized, and I would rather have that than have a blanket prohibition.

My last comment is on the recommendation about State legislation. What I worry about that is that we’ve got 50 States, and if you start having the standards of the State legislative statutorily defined surrogate decision maker or someone that stands in place, it'll place in turmoil those areas where we do not have a clear State statute, and this is such a narrow, small area that I don’t think too many States are going to even bother with a stand-in person, particularly for the research area in an advanced directive site. So, I think that that might sound good to offer up, but it’s just going to complicate the situation and may actually—it may actually impede the use of a surrogate or decision maker in this particular area that's, I believe, on page 140—140, so it's not going to improve the situation; it’s going to make it worse.

DR. SHAPIRO: Larry, thank you. Let me make a comment that I wanted to make before. You will, of course, have the transcript of the meeting and that’ll be very helpful for those of us who are going to continue drafting. It would be even more help for any issues on which people quite strongly if they would try to submit some language and where you think it might help and so on that really would enable us to reflect your review much more faithfully and not allow us, as we probably sometimes do, to forget them or don’t completely take account of them. So, if we come across views that are mutually inconsistent, we’ll have to argue those out at a meeting. But, that would really be extraordinarily helpful because there have been very thoughtful things said here today—I’m sure there will be more thoughtful things. And if any one of you feels strongly about them, which I think you do, please give us a chance and—to reflect that feeling, and if you put it in writing that’ll be a big help, although we will look—we’ll use the transcript to help us. The next person I have on the list is Jim.

DR. CHILDRESS: I very much appreciate the kinds of concerns that Laurie’s raised. I think this draft actually does a pretty good job at reducing the number of external people involved, and let me just note what is required or what we say may be recommended by IRBs. Obviously, the competence assessment is one where we involve someone. But we understand the legally authorized representative basically to be legal recognition of the kinds of parties who are already usually the ones who’d be involved and the kinds of ones who Laurie’s most concerned about. And then for the independent health care professional monitor, we require that in greater-than-minimal-risk nonpotentially beneficial research and then say only that the IRB may—may—not required to, but may require it in the potentially beneficial research area where there’s greater than minimal risk. And, we say the IRB may require a consent monitor. So I’m not sure that we end up with the kind of rigid requirement here of a variety of external parties that would go very far beyond what Laurie’s proposal already included. But I’m sure there’s still room for a fair amount of debate about that, and I agree with Harold—I very much hope that people will get their views in so that we can take them into account, even perhaps present alternative wording in the next draft so that people can make some choice then about which way they want to go.

DR. SHAPIRO: Thank you. Trish.

MS. BACKLAR: I’m hoping that we could have a discussion about minimal—that we could start to clarify what we mean about minimal risk, because I think there’s a lot of discussion about what we’re putting in place that we can’t get to until we have some agreement as a group on what we’re going to mean as minimal risk and how we’re going to look at what happens when it’s whatever it is above minimal risk.

DR. SHAPIRO: Okay. We’ll try to get back to that as soon as we can. Eric, have you—still have something you want to say? No. Alex?

PROFESSOR CAPRON: Trying to focus on the language of the report, Arturo raised an issue which we’ve looked at several times in the past, and he raised it to Laurie and I was very confused by the answer. And I’m not trying to encourage the dialogues that apparently are not a good idea among Commissioners talking to each other, but the language that we use in the report, now, is "persons with disorders that affects decision making capacity." That’s the definition. I don’t now from this discussion whether either Arturo or Laurie thinks that that’s the wrong category. I don’t know whether Eric, by his example of the fact that mental conditions are not the only thing that affects decision-making capacity, means to say we shouldn’t use that language because medical conditions are in that category. It seems to me that that is the absolute trigger of the entire report, and if we are not clear about that then it’s not just recommendation no. 3 where that language is, but throughout—after the last meeting I sent in a lot of material to Jonathan in which I tried to synthesize what I thought was the discussion and most of that is reflected here in this latest draft. And, we used that language. That’s the language that triggers having an IRB with diverse membership. Can have a decision about that? I don’t understand, since Laurie’s comments followed my last comments, whether she thinks that I was in the category with the person who was saying that we shouldn’t listen to mental patients who say this is the decision I want to come to, or she thought Eric was taking that position. I simply wanted to be clear that any time that we don’t listen to a person and we say either your capacity isn’t there or we don’t like the judgment you’ve made, we’re overriding it, and we may override it in a way which is very defensible. It may even be necessary to do so. But let’s be clear that is what we’re doing. And let’s be clear the interests that are given up, including, Laurie, as you say, a lot of people who are offended. Patients in that category say, "I should be able to make—I can make my decisions. Why are you stepping in for me?" Among my schizophrenic relatives it is often the notion that the relatives are the last people they want to have involved. They are the relatives of the people they distrust the most compared to others. So, you’re following that with the comment about the value of having family decision makers in the process. I suppose, in the ordinary course, if I’m going in to see my doctor about something and I bring my wife along, that’s my choice to do so. But if I don’t bring my wife along, no one says I have to have my wife there to help me make the decision. So, I—I’m not clear whether this is a comment about something that may be helpful if the patient wants it, or something that an IRB should require or want to have.

On the legally authorized representative, I would ask that we would have staff very quickly and easily, themselves or talking to someone like Judy or somebody who’s followed this, just to tell us what is the status now of State laws. The common-law tradition was that next-of-kin stepped in to make medical decisions. There was in fact no actual common-law decision making basis—I mean, the decisions, the judicial decisions—basis for that. It was as dictums set by judges. Well, of course you reveal the information and get the consent of the next of kin, but it was never the issue in cases. It was just a practice that everybody did. Now, many states—I don’t know if it’s roughly thirty-some today, and that’s what you could advise on—have adopted family decisionmaking statutes of one sort or another where, for mostly growing out of the end-of-life care issues, they actually say, "Here’s the priority order of people who are supposed to decide." If most all States have done that, then the phrase "legally authorized representative" is defined by those statutes, and we’re just meshing with State laws. I don’t think this is an area—and I don’t know if Larry meant to say this—is where we’d have Federal preemption and we would say that the right—. So we’re going to be stuck with State laws, and all our language in here now says, with which I agree, is the State legislatures should attend to this issue. Now, many of them won’t read this report, but if there are only two or three states that haven’t addressed it, maybe it’s not a big issue.

Finally, I don’t think that anything we’re doing in here prohibits research. We had a recommendation to prohibit cloning. That was a recommendation. A time-limited moratorium. There’s nothing in here that says subjects should not be used if they have mental disorders or certain categories of research should never be done. We have a process by which the subjects, the researchers, and the IRBs, and maybe the Secretary or maybe somebody else would be involved in deciding who should be in that research and when it can go forward. We don’t have prohibitions, and I think unless there’s language in here that says we have a prohibition, I don’t think we should attack the report for instituting a prohibition.

DR. SHAPIRO: Thank you. Laurie, and then I want to come back to one or two of the comments Alex made, then Larry and Trish.

MS. FLYNN: I may actually have to have a back-and-forth with Alex for a minute, just so I can understand what he’s saying.

DR. SHAPIRO: What I said was not that we shouldn’t do it, but if you could avoid it whenever you got a chance it would be helpful—but not you shouldn’t if it’s necessary.

MS. FLYNN: Then we can do more later. You made some reference to the concern about family and whether or not family should automatically be involved in referencing the—. Very often individuals with schizophrenia are suspicious of their family. That’s the last person they want involved. And I would simply point out (a) that’s characteristic of the disorder. It’s quite painful for families, but it’s quite characteristic of the disorder and one needs to understand it for what it is. It’s a symptom of the disorder, particularly when it’s not treated or not well treated. Nonetheless, families—particularly of people with schizophrenia—are enormously on the line as caregivers. A recent study—going to be released in March by the Agency for Health Care Policy and Research, a five-year study of practices in schizophrenia and looking at actual care—will show that more than 70 percent of individuals in the study rely on their family, are in contact with their family, and in more half the cases live in the same place with their family. So, all I’m asserting is that ought to count for something, that those folks have demonstrated, and I think we’ve heard in various testimonies, a long-term, often difficult-to-maintain commitment and that it ought to be respected, and I was concerned, as I expressed, about what looked to me like a cumbersome legal authorization as though they had to demonstrate their bona fides once again. We need to understand what these disorders are like and we need to recognize in balance what that means.

PROFESSOR CAPRON: Could you offer language?

MS. FLYNN: Yes, I'll be glad to offer some language up. I wanted to just repeat again that a lot of the concerns that I have, and I continue to believe that we are going to make it if not prohibitive, almost impossible, to do research with certain subjects on whom we need research—with whom we need research because of the way we structured these recommendations. I could be made very much happier, and I think we would all perhaps find a way through this, if we could reexamine the issue of categories of risk. To have only minimal risk and every other kind of risk, and then to assign fairly simple procedures to that, creates enormous problems in neuroscience research. And so I think we could get out of that box by rethinking that issue. I'm not sure if there was another third thing. I thought there was a third thing you raised with me, but those are the two I remember.

DR. SHAPIRO: Okay, Larry....

DR. MIIKE: Yeah. Just on the last point that Alex raised about the State statutes. What I’m reading is this, that States should legislate a definition of legally authorized representatives in research. That’s what I’m objecting to. If you’re saying that States which have not defined what a legally authorized representative is or any kind of competency matters should do so, I don’t have any problems with that. But the way I read this was that there was a recommendation that there be, specifically in the research area, and all I’m saying is that when you look at 50 States, they are not going to be that many that are going to be interested in this as a very big issue for the legislation.

PROFESSOR CAPRON: This is not a challenge to that, I just think we need to look at the statutes and see which of them are restrictive and would not include a decision about a person in research.

DR. MIIKE: If that’s the case, then that’s fine. But all I was responding to was this specific recommendation.

DR. SHAPIRO: No, I think that’s a point well taken and Alex has made some helpful comments. We do need to clarify and rewrite that in some way that meets some of the concerns that people have. I think that’s pretty clear, and so we'll attempt to do that. Laurie, do you have anything else right now?

MS. FLYNN: No.

DR. SHAPIRO: Thank you, Trish.

MS. BACKLAR: Alta brought up the fact that we seem to have dropped research advance directives out of the document, and in fact I think we have and that we were starting to call it, as somebody else noted, anticipatory planning. It isn’t that I disagree with you, Laurie, about the importance of families being involved, because you certainly know that I feel very strongly about this, but there are many people, for instance, who do have these disorders, who do become estranged from their family because of the disease, and if one had some mechanism of anticipatory planning for people who have fluctuating decision making capacity or prospective decision making capacity like dementia or in their early stage of Alzheimer’s—if they didn’t have family members that they felt they could call upon, if you had some mechanism for the procedure, the process of that anticipatory planning, people could appoint a friend, somebody that they trust. And, that’s why I don’t want to see the whole anticipatory planning mechanism be dropped out of this.

MS. FLYNN: Can I ask a question? Because I may be the only one—in general, I would agree with what Trish said. I think any time we can create mechanisms that enable individuals who may have cognitive impairments to exercise control, to state their wishes, and to thereby help to direct their future, that that’s an important thing and we should do it. What I think I’ve been hearing and what I think I’ve been reading is that while we may do that, we are bound almost to do it in a very generalized way that will not hold up, in fact, in the test of the specific study down the road, that we may not be able to see that through to actual implementation, and that’s the only concern that I’ve heard that is at all persuasive to me, that we may set people up to think we’ve gotten them this thing, but down the road, depending upon the study, it may or may not in fact be true that that wish could be carried through. And, if there’s a way to handle that—.

PROFESSOR CAPRON: You’ve been hearing that from researchers. Or do you mean like you’ve been hearing it here?

MS. FLYNN: I've been hearing that here as well as other things that I’ve read and as well as from researchers, that in fact if there were any challenge, if there were any question, or if there was just a heightened awareness of all of these issues that we and others are bringing, that that would not be seen as in fact strong enough and that it is therefore not very widely viewed as an actual implementable tool.

MS. BACKLAR: I want to go back to—oh, I’m sorry, I’m not allowed to.

DR. SHAPIRO: Go ahead, Trish, take most of the day—you’ve got some extra credits.

MS. BACKLAR: I think that we need to be very careful not to muddle this up with, and I’ve said this before, advance directives for end-of-life care. This is something that is quite different, and that’s why I think Jonathan and I drew back from our earlier language because people were confused by the terminology. It doesn’t mean that we have to throw the baby out with the bath water. I think that these kinds of mechanisms will work if we tie it to the informed consent process. And, of course we cannot be assured that anything that we recommend will be followed anyway. But that doesn’t mean that we shouldn’t make our best attempts to recommend things that might both advantage the subject and the researcher and advantage the trust that the community will have in the research process.

DR. SHAPIRO: The other—on this big issue—the other issue that came up in our last discussion was assertions and/or forecasts, but how many people would take advantage of such instruments given the asserting empirical evidence, which may be right—I just haven’t reviewed it—that even though people overwhelmingly they would like to have something that deals with issues regarding around the end of life, they don’t actually execute the documents. That may be true, but I don’t know. But that was asserted, and the claim was that that was another aspect of this, which might—.

PROFESSOR CAPRON: Apples and oranges.

DR. SHAPIRO: Yes, well—and that came up, too. But I just wanted to reflect back, because that was an issue that came up. Okay, Steve. No? Alta?

PROFESSOR CHARO: I’d like to address the question of minor increment over minimal risk, because it’s come up several times. I think it’s possible that for the purpose of a draft going out for public comment, we may choose to write this up as something that’s an option and ask for reactions. It may be that if there’s no agreement among members of the commission that the appropriate thing to do is to lay out the options. My instinct, again seemingly constantly at odds with Laurie, is not to go down this road for the following reason: The IRBs currently are having a tremendous amount of difficulty just dealing with minimal risk versus all other. And, there’s new guidance that’s being developed for them at this time. I fear that creating a new category called "minor increment" that applies only to a subset of protocols that most IRBs will see only on occasion because it’s not going to be a generic category being added to all research just for this population. It’s going to mean that we’re creating a category that will be difficult to interpret—subject to misinterpretation based on whether people are hoping to do the experiment or not. My experience is IRBs usually are hoping to be able to approve the research. And that they won’t have enough experience to check themselves. And, this might be an opening for abuse of a real sort. Finally, it’s very difficult to write generic language here. Now, the fact that there is the option of the Secretary’s waiver means that one can turn to that mechanism for individualized and very specific consideration of, for example, a proposal that says, "I have a subpopulation of people who are psychotic that can never give consent and I want to do a PET scan, which is not minimal risk and so by definition nobody could ever do this research unless you give me this waiver and now people can evaluate, the Secretary can evaluate, and people can comment on the very specifics of that particular risk and that particular benefit. And, the only question I have about the workability of that suggestion, which otherwise provides exactly the escape hatch we need, is how frequently that waiver has been sought and granted, and I think I remember we got that information once but I don’t remember what the answer was.

DR. SHAPIRO: Once.

PROFESSOR CHARO: Once. Is it possible that that might be used more frequently and successfully, or is there some institutional problem in its use?

DR. SHAPIRO: I don’t know the answer to that but when I read that particular proposal, it struck me that anything that requires the Secretary to approve something is going to happen very seldom.

PROFESSOR CHARO: Is it, in fact, the Secretary who approves it, or is it in fact OPRR with a bunch of signatures that come automatically after that?

DR. SHAPIRO: I don’t know.

MS. FLYNN: May I ask an informational question?

DR. SHAPIRO: Yes. Laurie....

MS. FLYNN: Because I’m interested in what I think I heard you saying. Is it correct that we are moving to an understanding of the categories in research that IRBs will have only these categories?

DR. SHAPIRO: IRBs only now have "minimal risk" and "non-minimal risk." That’s all they currently have.

MS. FLYNN: But there has been in fact in practice the use of this subset of "minor increment over minimal risk." I mean, it’s been out there. I’m not sure why, but it’s been out there and must have been seen as useful. Maybe someone can enlighten us as to why it was there if it’s not an officially authorized category and why it’s not going to be there any longer if what you’re saying is that it’s no longer going to be a way in which we can accommodate what are clearly gradations. There’s a big difference between what we’ve seen as examples of minor, or minimal, risk and everything else. I mean, the next is such a huge and undifferentiated step.

DR. SHAPIRO: Okay, Jim.

DR. CHILDRESS: I’d be glad to yield to someone else. I think Alex wanted to respond to that...to clarify that issue and then I’d like to get a point in.

PROFESSOR CAPRON: Alta, I think it would be useful to have an alternative language here. Because as I understand it, Laurie’s objection—if you look on page 143 under 7, there are the examples of minimal risk and greater than minimal risk, and your objection, which I credit, is that some of these things that are called greater than minimal risk are, in your view, in this minor increment.

MS. FLYNN: Right.

PROFESSOR CAPRON: And, so substantively, one way of dealing with this would be to have those spelled out as being in this intermediate class and I would like to know then how they get treated. In other words, do they get treated just like the minimal risk or just like the more than minimal risk...or is there somehow a third path, and to have that available for comment, available for us all to look at, and then have it be part of what goes out in the staff draft for public commentary to us. I think it would be very helpful because you make very strong points about why it would be hard on researchers to have something like a PET scan be only allowed with the requirements that we now have for the greater-than-minimal risk. I’d like to know what’s in the category and what are the procedures that would apply.

MS. FLYNN: Okay.

DR. SHAPIRO: Jim.

DR. CHILDRESS: That actually is the direction I was going, to, Alex, but a couple of other points on it. It doesn’t mean that the points have been raised really—and I agree with Alta that we ought to get a public comment on it. And I’d like, Alex, I want to know what kinds of procedures and standards then of evaluation will occur for that intermediate step. But I want to know something else, too, from both Laurie and Larry—if we are able to carve out a category of "slightly more than minimal risk" and can work out some acceptable procedures and standards for dealing with that, would you then have any objection to what we do with the box? On 150, the last box, which would be then for greater than--substantially greater than—greater than minimal risk, whatever—and not potentially beneficial; that is to say, would that?

MS. FLYNN: That would take care of my problem.

DR. CHILDRESS: So if we can just carve out this intermediate category from your standpoint, though, it’d be okay.

DR. MIIKE: If I understand the question, I don’t think we should have a blanket prohibition. I think we should have lots of hurdles to overcome before you can do something, but to have a blanket prohibition—.

PROFESSOR CAPRON: We don’t have any.

DR. MIIKE: Yes we do, right now. Right now we have a blanket prohibition.

DR. CASSELL: Greater than minimal risk.

PROFESSOR CAPRON: No, it’s not! You do it if you have the following things.

DR. MIIKE: Yes, but if you don’t have informed consent you don’t get anywhere.

PROFESSOR CAPRON: It’s not a blanket prohibition; it says use people from whom you can get—.

DR. CHILDRESS: My question, then, is you wouldn’t accept that, then, as a category even if we’ve already pulled out "slightly more than minimal risk, non-beneficial research" ... and develop procedures for that, and then you wouldn’t be satisfied with this as the category for the maximal risk, the—.

DR. MIIKE: I'll write you my suggested option, but let’s not forget the benefit side. There’s no discussion about what we mean by beneficial research except for that section that talks about direct and indirect benefits. It does not say in the policy side what we mean and what qualifies. We need that. Because there’s such a—I mean, all the focus has been on the risk side but we need the benefit side. Otherwise, many things are going to slip in on the benefits side to avoid having to meet the requirements on the risk side.

DR. CHILDRESS: That’s true.

MS. KRAMER: I just want to go back to the matter of advance directives. I think as a practical matter that it would be shame to drop that terminology, because given the fact that people don’t like to plan, why introduce another concept? At least you’ve got that one concept out there that people in the medical field are fighting for, so combine your efforts with it. I think that the plan, that the words, ought to be reintroduced.

DR. SHAPIRO: Eric.

DR. MESLIN: Not to interrupt the flow, but at previous meetings Commissioners expressed an interest to staff to start to work up an analysis of some of these categories of risk following from materials which we received from the FDA and others, and we were intending to distribute this analysis, complete with some very nice graphics, but there are a couple of glitches in it and we didn’t want to distribute something that wasn’t entirely accurate. It’s 95 percent done, and it describes both what HHS requires with respect to the children’s regs and distinguishes between the four categories of not greater than minimal risk, more than minimal risk with the prospect of direct benefit, more than minimal risk with no prospect of direct benefit—all of which are incremental categories—and then the Secretary’s waiver category, which is a fourth. And we’ve also looked at the FDA’s protections in device studies and done the same kind of analysis given that that’s material we received from them at the last meeting, which included their interesting categories of nonsignificant and significant risk. And, I don’t want to confuse you with that terminology, but there are some existing Federal regulations that address these categories in a variety of ways, and although there was a movement two meetings ago to lump rather than split our categories of risk, staff would be more than delighted to provide you with this updated analysis so that you might be able then—sort of Alta’s suggestion—to compare two different categories or two different frameworks, if you will. I won’t attempt to prejudge for you whether it makes sense to harmonize our recommendations with existing regs for children or FDA regs for devices, but you do have those options available to you, and, as I say, staff would be more than delighted to circulate that material within 48 hours of you leaving this meeting. I’m trying to at least allow you the luxury of knowing that some of us have given this some thought and you might not have to deliberate more.

DR. MIIKE: Can I ask Jim a question to clarify? Jim, I guess I did not quite ask that question. I can live with an exclusion as long as there is something that you can appeal on a specific project basis like the Secretary’s, so I guess it’s a matter of semantics to me—what I’m concerned about is that there’s a process—an in-depth process—there’s a total exclusion without an appeal on a particular case. So, if we’re talking about an appeal on a particular—I can live with that.

DR. SHAPIRO: Jim.

DR. CHILDRESS: Basically, if we would just glance for a moment to make sure I know where you are, Larry, in your thinking. If we were to look at 150 and if we, at the bottom of the page, were now to insert a box, another box, that would say slightly more than minimal risk, a nonpotentially beneficial research, and work out the appropriate kinds of procedures for that, we would still be left with this possibly large category of something that goes beyond that in terms of risk and nonpotentially beneficial research, and I guess what I’m asking you is whether for that leftover category you’d be willing to accept the kinds of requirements that are listed here. Or would that go too far—and of course we can talk about the exceptional—.

DR. MIIKE: Again, as I say, if there is something like an appeal to the Secretary—.

DR. CHILDRESS: Then you would, okay. Thanks.

DR. SHAPIRO: Okay, Alta, you’re next. Then Trish, then Rhetaugh.

PROFESSOR CHARO: Do I have a hand up? I give my turn away.

DR. SHAPIRO: Trish.

MS. BACKLAR: Have we agreed that minimal risk is that experienced by the population being studied in their everyday life that—have we agreed on what we mean by minimal risk?

DR. SHAPIRO: Alta.

PROFESSOR CHARO: Jonathan’s been asking on E-mail over and over for people to respond to this and I’d just like to share...

MS. BACKLAR: And I did respond.

PROFESSOR CHARO: ...and I’d like to share for the record what I told him privately, which is that after having ducked several times, my vote for the moment is that the definition of minimal risk should stay the same for everybody, which is the daily risks experienced by the general population. Again, for very pragmatic reasons, IRBs already are dealing with many subjective factors and I would love to keep the number of hairsplitting moments to a minimum there—there are plenty of them already—and so a consistent definition across all populations seems better than special definitions for special populations.

MS. BACKLAR: Does that mean that minimal risk means those risks experienced by healthy people in their everyday life—is that what you mean?

PROFESSOR CHARO: Yes.

MS. BACKLAR: So, then, for a population like people with schizophrenia, their risk is so much higher, so how are you going to measure minimal risk? Their minimal risk is very, very different...

PROFESSOR CHARO: No. When an IRB gets a protocol and has to deal with it, it could qualify for minimal risk treatment but that doesn’t tell you what their final judgment’s going to be about the acceptability of the protocol. A procedure like a blood draw is presumably minimal risk, but they always exercise judgment and say, "But you know, in this particular protocol you’re dealing with people who might get very excited and upset at being stuck with a needle so we think there’s still a problem with this protocol even though a blood draw is usually treated as minimal risk." I mean, IRBs do exercise that judgment. The minimal risk determination is only about the procedures the IRB is now required or not required to follow in terms of who has to be there in subcommittees and things like that.

DR. SHAPIRO: Let me make a suggestion on this set of issues dealing with definition of risk and how many categories of risk that we’re going to deal with. As Eric indicated, the staff has prepared some analysis of this. Let’s get that finished and out so we can discuss it. It’s a very important issue, just how we define it, so I don’t want—it’s extremely important, and I think, in fact, what decisions we make there could interrelate with other aspects of the analysis and not exactly—may not be an independent thing. So, I think we should carry on further discussion of that once we receive some initial suggestions from our staff on this issue. I take it from the Commissioners' conversation that there is some concern about whether we have enough categories—that is, whether we should have minimal risk, minor increase over minimal risk, and something more than that, and then how we define those categories. So, let’s take a look at what work we can put together on that and make at least some initial recommendations on this and then we can have I think a somewhat more informed discussion. Yes, Rhetaugh . . .

DR. DUMAS: I am satisfied with the categories that we have. I’d be happy to see the information that comes out, but I feel very strongly that if the procedure is going to have risks by the subject and there’s no way to obtain consent, then it should only be done if there’s a legally authorized person who can make decisions on the behalf of that other person. I think that whatever we come out with should improve the situation and we know that there are certain populations of people who have been exploited and we have case examples, and I think that we have to be very careful how we formulate our recommendations such that we can make some improvements rather than perpetuating a situation that we’re trying to amend. And I think that when you get into splitting hairs about whether it’s slightly more than minimal, it just encourages people to push forward, and I don’t want to feel that anybody is going to be forced to participate in a research project that’s not going to benefit them at all and they can’t consent.

DR. SHAPIRO: I propose to the Commission that we could take two points of view: Here’s what it would look like if you only had two categories of risk; here’s what it would like if you had three categories of risk. No matter how many categories you have, you’re going to have tough cases. We’re not going to be able to define all those tough cases, and all of a sudden, the IRBs are going to have to struggle with those regardless of the number of categories we have. And as far as getting science done, there are two ways to—at least two ways—to does it. One could change the definition of minimal risk to a category where you’d be uncomfortable having any other category beyond lots of risk. Or, you could—and, you know, whether you put that bar up or down changes it a lot whether you want to have a third category. So, let’s try to think this through systematically if we can and provide some suggestions—some alternative suggestions that we can discuss. Eric?

DR. CASSELL: At the moment I haven't heard a way to go by it, and I'm hoping that what Eric distributes to us will at least give us an idea that—if we can only get by this problem, and of course one of the ways is we give the IRBs more latitude but we’re nervous about doing that, so I just want to come up with some useful suggestions in this regard.

PROFESSOR CAPRON: Can we have a discussion on this question of what disorders—?

DR. SHAPIRO: Yes, that’s where I want to go next. I really wanted to get back to Alex’s issue, which is a substantive focusing on the title of our document. Now, that title’s gone through a number of evolutions over time as we’ve tried not to make sure that we weren’t stigmatizing people, treating people in some inappropriate way or—and therefore we came up eventually with this particular title and Eric began this meeting, or began part of this meeting, by suggesting that this includes just about everybody who’s sick. I think it’s more or less what you said. And, that’s certainly not the intention of this report. We’re not trying to rewrite all of the regs and guidelines here; we’re trying to deal with regs and guidelines for a population which I think we all have a clear idea who they are and now the question is Alex’s question: What’s the domain? I took the domain to use another word which perhaps is got its own problems. It’d be people with mental disorders of one kind or another, and not include people who have very serious diseases of other kinds and therefore are upset and their minds are not as acute as they might be. I was not thinking of those people. That was my interpretation.

DR. CASSELL: But you were thinking of people who are very sick with their mental disorders.

DR. SHAPIRO: Yes, of course.

DR. CASSELL: And there’s no difference in some ways between them and people who are physically—.

DR. SHAPIRO: I understand that, but we really need to decide whether the domain—I had assumed people with mental disorders of one type or another—is really what we’re talking about here. Yes?

DR. BRITO: Yes, I raised this issue a little bit earlier about that in the context of the first recommendation...and I think the title is fine, but I think somewhere in the body of the paper we do have to define that. But, even if you just limit it to people with defined mental disorders, I think there’s a problem there, too. For instance, this morning the public comment was brought up, even though it was a child study, still children that are aggressive—well, all the public testimony we’ve heard is about, for the most part, schizophrenia and manic depressives, etc., but what do you do if you have an adult population that is impulsive? That’s considered a mental disorder. ADHD in adults is considered a mental disorder. Are we talking about them, too? Do they have the capacity to make a decision in some situations? Probably not. In some situations? Yes. Or, most situations, yes. So the point is that that’s where it’s confusing to me when we say "this population." So, somewhere in the context we have to talk about that we’re just saying—and that’s where I was asking Laurie and the rest of the people—the rest of the Commission, all right when we’re saying "this population," without stigmatizing anyone are we going to limit it to schizophrenic individuals, manic depressives—where does it start and where does it end? Because even, you know, we’ve heard today that 50 percent of schizophrenics can make their own decisions. That might be more than in other mental health disorder we haven’t even talked about. So, that’s where my concern is in here.

MS. BACKLAR: On page 10 we have a list that Paul Appelbaum put together for us. Very clearly set out the nature of disorders that affect decision making capacity. When I spoke about 50 percent of people with schizophrenia being able, that was in a particular study that I was alluding to that Paul Appelbaum was doing in terms of other people. I don’t want people to walk out of this room and think that I just made a blanket statement.

DR. BRITO: Nobody’s going to think that. That’s not the point of that.

MS. BACKLAR: Okay. But on page 10 Paul talks about dementia, delirium, depression, schizophrenia, other disorders.

DR. BRITO: Okay, Trish, that’s my question. Are we limiting this population to mean the mental health disorders described in this introductory chapter—this first chapter? Are we saying this paper talking about disorders affecting decision making capacity is going to be just these disorders and this is where the extra provisions are going to be required?

MS. BACKLAR: As I understood it, we are trying to fill a gap that is in 45 CFR, and that gap was left because it was a document put together in the late 1970s by the national commission called something like Institutionally Mentally Infirm—I can’t remember—Recommendations. And that looked at a group of people who I believe are described by Paul Appelbaum in our introductory chapter, and that’s what we want to do. Our intention is to fill that gap. Am I wrong?

PROFESSOR CAPRON: Well, you’re only wrong to the extent that that group was a little easier to define because those were institutionalized as mentally infirm—and even there, of course, that report never was able to gather enough consensus in the relevant competing communities to be translated into regulations, which is why we had this lacuna in the present regulation. So, it's one thing, it seems to me, to say that we know we’re talking about mental disorders here, but if someone challenges you and says, "Well, why are you talking about mental disorders that affect decision making capacity if"—suppose Eric Cassell's research were not something that was orally reported here but had been replicated and peer-reviewed and it was now widely believed that all medical patients with serious illnesses have disorders affecting their decision making capacity, and indeed it was very hard to distinguish between the effects of those disorders on many decisions that they made and these mental patients. Would it be that we would still want to have a separate set of rules, and we would want to, in fact, put the word "mental disorders" into our--which is not now here—but put it in because we think that this is a more vulnerable group, this is a group whose mental condition, whose disorder is of a chronic nature—either it’s progressive or it’s fluctuating—I mean, is there some reason for treating them differently than patients who have cancer and who will be enrolled in cancer research despite the fact that Eric’s study would show that they have problems with their judgment for which some supplemental process or something else is going to be necessary before we can have reasonable confidence that they’re making the judgments that Eric would regard as authentic or something, or autonomous.

DR. SHAPIRO: I have an answer to that, but I’ll let Tom and then Trish—.

DR. MURRAY: Life is full of continua and you can’t solve all problems at once. With those two principles, let me just speculate a little bit. Suppose—.

DR. CASSELL: We’ll solve this ’cause it’s not tissue. [GROUP LAUGHTER]

DR. MURRAY: Right. I wish I could make your life harder. It looks like you’re doing it for me. No, actually, I think I’d like to try to make it easier. Let’s suppose that the study was of cancer patients, but what we were particularly interested in was, because your hypothesis was that at least a certain population of advanced cancer patients were suffering very severe cognitive disorders, disorientation. That was your assumption going in. Would you want those subjects—"subjects" covered by this rule? And I think the answer is yes, you probably do. And so you might end up with a description that looks something like this. The words are by no means ideal, but, if you’re investigating persons with a disorder, whatever the mantra is, or persons who might be regarded as having—that’s not good at all, but basically people with a diagnosis of one of the listed cognitive disorders, disorders affecting cognitive function, or people whom you have reason to believe might have disorders in their cognitive function, even if they don’t meet this diagnosis. Now, you don’t want to have every patient listed in an oncology trial to be included in that category, I think—do you?

DR. CASSELL: No. But there are some of them who are cognitively impaired and then they should be protected.

DR. MURRAY: Yes, and there should be ways of solving that problem, too, particularly if—.

DR. CASSELL: There are.

DR. SHAPIRO: Trish?

MS. BACKLAR: Well, very early on in our discussions I remember trying to put these into various categories so there was prospective incapacity and fluctuating incapacity and so on and so forth. Oddly enough, it seems to me that our recommendations may be useful beyond what was our intended filling of a gap, and I don’t think that’s all bad. We never talked about these wraparound studies at the end of the paper and I’m concerned about that. I was planning to discuss it with you afterwards, but I don’t think it’s fair because maybe we should discuss it now. I'm worried about the therapeutic misconception; I’m worried about the way they’re not thought out very well; and I think that we need to have some discussion if not today another time. I have a whole long list of other things, but that seems rather important.

DR. SHAPIRO: My own, at least initial, response to this issue I think is similar to what Trish just said, and namely that this is a set of recommendations designed for a particular population. We have to think of the right way to describe them. They may very well have application elsewhere. But our attempt here is to fill a gap, and maybe the next step, if that seems reasonable, is to look at the broader issue for people with other kinds of disease which also affect the cognitive fascia. I think there are, as you were suggesting, Alex, in your remarks, some additional reasons than just filling a gap, which I think distinguishes some of these cases—I wouldn’t say in every case, but it’s the recurring nature of chronic—it’s not the only chronic disease, of course—but I think there are, if we thought about them, some distinguishing characteristics, which helps a little bit.

PROFESSOR CAPRON: But that’s not what our report says now, because our report now, in talking about delirium, for example, cites studies in the intensive care unit and says the patients in the intensive care unit may have a temporary but severe impairment of the decision making capacity. So suppose that the agencies involved in the common rule were to take our report and say put it out for comment, and then when the comment was done decide that the language we had suggested should become part of a special subpart describing this, and they just used that language. Now, someone would say, well what did they mean? They would go back to our report, and in our report a conscientious IRB would find this discussion of delirium, which arises in intensive care unit patients. In that case they would say, "Now when you come in to study surgery or various other forms of treatment for patients in the intensive care unit, you need to have this process." Now, if we don’t mean that, then having discussed that we’re going to say, "Although there are common similarities, we are now going to limit ourselves to those conditions usually thought of as mental disorders because of certain characteristics of the patients in this population—marginalization—you know, difficulties relating to their community and their families, often institutionalization, etc., etc., etc., and so we’re going to treat them differently," although, as Tom says, there’s a range and you don’t attack everything at once. But we should be clear because...

DR. SHAPIRO: I agree with you, exactly with what you said. As a matter of fact, one of the more modest concerns I have of the draft as a whole is I would like, as we go ahead, to substitute more of our examples from the restricted population, so to speak, than from the broader population, because I think all the examples are pertinent, at least not that, but I think that some of them, a number of them, just don’t come from the population we originally started out to think about. And, so, I would like to sort of enrich us. In part we’ll do that through these protocols that we’ll look at and bring those examples in. But, I agree with you that we have to change some of the language in here and the structure to accommodate that.

PROFESSOR CAPRON: I mean, our protocol search is not looking in intensive care units.

DR. SHAPIRO: No.

PROFESSOR CAPRON: It’s only looking at mental disorders.

DR. SHAPIRO: That’s right. Exactly. But it will give us examples, exactly, that’ll substitute one for the other. Other comments or questions? I recognize it’s the end of a long day, but comments are helpful.

PROFESSOR CHARO: Just a correction for the record, because I misspoke before on the definition of minimal risk. And the question was, "With reference to whom?" and I said, "The general population." Somebody said, "You mean healthy people," and I said, "Yes." The answer should be "No." The general population, which is healthy people and sick people, so that’s a slightly lower threshold. Okay? That’s all.

DR. SHAPIRO: Thank you. Jim....

DR. CHILDRESS: If you’re moving, Mr. Chair, toward adjournment...

DR. SHAPIRO: Yes.

DR. CHILDRESS: ...maybe one question we could think about is whether we think with the incorporation of the kinds of changes that have been proposed here, including in some cases, presenting alternatives that go this way and go this way, and with Jonathan, Eric, myself, and anyone else who would like to volunteer or would be willing—not necessarily willing, but—to join us to put something in shape over the next two or three weeks to deal with these issues, then whether you’d think we’re at a point where it’d be good to get public comment. I think that—I have a couple of reasons for thinking it might be good to go that direction. I mentioned that at the very outset of our discussion this afternoon. One is, there is the time consideration. We’re not meeting again until May and then after that until July and so forth, and it’d be good to get some input, I think, well before then. Second, I think that it will be easier for us to sustain our personal and vigorous investment involvement in this process if we get some outside input, and—because we’ve spent a lot of time going over particular parts and I think it would be helpful, so I guess my proposal would be, if it’s all right, Mr. Chair, that we consider going that direction and going ahead and getting public comment sooner rather than later, but stating very carefully that this is a draft report and we’re going to use language now that Harold has suggested and draft a report for the Commission rather than of the Commission and thus we’re not signing off on it any way. We’re getting input on some matters that we’re continuing to reflect on and will continue to work on.

PROFESSOR CAPRON: And if you do that at a time when it’s a draft which hasn’t yet been before us and it’s being circulated publicly prior to our next meeting for comment, then it is in truth something that no one could say is the Commission draft because we won’t have seen it in the point that it’s put out for comment.

DR. SHAPIRO: Some of us are still members of the public or something. But, in any case. I very much favor getting it out for comment. There are a lot of people out there who I think, once they see it and know a document is available, will in fact go arrest their attention and we’ll get valuable feedback, and I can’t see any downside to it, as a matter of fact.

DR. CHILDRESS: And my hope would be, if I might add to it, that if we’re able to do that in a timely fashion, allow a month, say, for feedback, there might, as information as responses are coming in, we might have to staff begin to analyze those and, say, if we have a cutoff date of—of, say, April the 20^th or whatever, that we then put those in final shape and kind of an analysis of the major types of objections that are occurring and so forth and try to sort some of those out, and then at the May meeting talk about how, given what we’re hearing from people who are responding, we might want to revise the draft that will have been circulated. That's the kind of direction I would have proposed.

DR. SHAPIRO: That sounds quite fine. I hope there’s nobody that has any objection. So, first of all, let me in closing thank all Commissioners for a lot of very useful conversation that we’ve had in the last day and a half and to—we’re now on a new schedule, so to speak—we’re meeting every two months. I will, for purposes of assisting our colleagues on the West Coast—we will try to schedule the meetings where possible where we go a day then half a day as opposed to the reverse—half a day, then a day. But we’ll just have to see—we’re going to try to schedule it that way as much as we can. So thank everyone. I want to thank the staff for their assistance and help, and we look forward to hearing from you all. I said before that we would be making some assignments regarding the tissue report for two or three people who worked rather intensively on that. We will do the same in this support. I’ve not yet talked to Jim about it, but we will do the same. I think that’s necessary to get this into shape. So, thank you all very much.

ADJOURNMENT, 4:59 p.m.