DR. SHAPIRO: Assessment of people’s logistic arrangements leads me to believe that although I’ve apologized twice about the fact that I have to leave at 2:30, I don’t know if anyone else is going to be left here. A number of people have to leave by 3:00, so I think that we’re going to have to move on as quickly as we can because once we get below a certain number it’s really not helpful to make any major decisions. As a result, I have suggested to Jim or he suggested to me, I can’t remember which, that we focus our attention now not on 4 thru 8, which are issues, not to say there are no issues there, but begin by focusing on material that begins on 150 with research that presents greater than minimal risk and so on. That set of recommendations which Larry was concerned with, as was Rhetaugh and so, Chairman, if you could get us started on page 150, which is Recommendation 9, we could perhaps go through that set of recommendations in which the memo you received contains quite a bit of information. That would be helpful. Jim.

DR. CHILDRESS: Let’s, everyone should turn to that. We’ll consider Recommendations 9 thru 11. And look back at, looking back at a draft for a minute, there’s one important point on page 2 of our memo of 9/15 that refers to something, at the very end of that section and I’ll just mention it now as to how the consent is to be honored. The important parts to focus on here, concerns have already been raised by Alta and others, Larry and Rhetaugh, about this particular one and then the set of recommendations that follow the next heading of "greater-than-minimal-risk and no prospect of direct benefit to the subject." And this will, I think, bring together some of the things we’ve already talked about but now will force us to focus the discussion very very sharply. So let’s go into this and, Alta, do you want, well first let’s see if there’s anything about number 9, recommendation number 9 that people would like to raise. Questions have been raised about number 10 but anything about number 9?

DR. SHAPIRO: Comments, questions, concerns with step 9? Good, let’s go on.

DR. CHILDRESS: Alta, would you like to raise your issue which overlaps with some of the others that have already left?

Professor Charo: Recommendation 10 concerns, to coin a loose phrase, therapeutic, greater-than-minimal-risk research. My understanding of the policy that we have been adopting up until now is that therapeutic, greater-than-minimal-risk research would be allowed to continue if the subject could consent or if an appropriate third party could consent. Right? And the appropriate third party was one, in fact, that generally we’ve been talking about very loosely in the same way that we talk, whoever makes the clinical decisions for that incapacitated person could make these research decisions. And it was all because there was a therapeutic component here. When I read Recommendation 10 as it’s written, however, it’s far narrower than that and would shut down a great deal of this category of research as written. As stated, somebody who is currently incapable or is likely to become incapable could only be used in research if three conditions were all met. And they were most pertinent that when previously competent, this person had expressed an agreement to participate in research through one of these durable power of attorney documents. Now, that was different from what I understood. It’s a tremendous limitation because very few people execute durable powers even for clinical care. The chance they’re going to do it for research is even more remote and I understood that kind of advance planning to be something we thought as essential in non-therapeutic research, but I was surprised to find it showing up here. And I wasn’t sure, and this is inconsistent with the way the chart that’s on the screen and that is in the appendix presents the decision points. That chart would suggest that all you need for an incapable subject faced with a choice of therapeutic risky research is approval by an appropriate third party. So, I wasn’t, I wasn’t sure which way we’re trying to go anymore.

DR. SHAPIRO: Eric?

DR. MESLIN: Just very quickly and we, in discussing this both with Jack Swartz and with Jonathan Moreno, who could not be here today, it was thought that the point that Alta made was exactly correct and perhaps a useful modification which we didn’t put in this memo. We didn’t want to keep burdening you with more detail in the memo and preferred having it brought up for discussion, is to in line 20 of the text that you have from the actual report, it would read something like the following. Decision about participation in research: have previously expressed a wish to participate or their agreement to participate, and delete the document, delete the instrument. Now that’s just so for the purposes of the record, the expectation for this language is that it would not be dependent upon the completion of a very narrow instrument such as a durable power of attorney, but that there only be advance agreement, and that interpretation I have just provided is consistent with the overhead chart behind me, which perhaps the audience will also have available to them. Now the Commissioners may not feel that that’s appropriate but it was, again, a piece of drafting that was narrower than it had been intended.

DR. CHILDRESS: Let me just press that for a minute because it’s not clear that the overhead actually does that; it goes a lot further than this does.

DR. MESLIN: I’m just trying to narrow it and come back to this.

DR. CHILDRESS: But if you build it, it’s, I’m not sure, yeah that’s exactly the problem, I think. And if you go the direction of the overhead, with the legally authorized representative’s permission and no subject’s consent, then you basically get rid of this stuff. That’s where I think the concern is because it’s so limiting. Now that it seems to me that we have to decide as a group if that’s where we want to go. Other comments, Bernie?

DR. LO: Could I ask two questions first?

DR. CHILDRESS: I’m sorry, I’m sorry. I had told Eric I would come back to him first, I’m sorry.

DR. CASSELL: Well we now have two possible modifications. First of all, I think that Alta’s basic point is absolutely correct. The question is, for me, does the subject have to have known about the research in advance? And would they, had they expressed some opinion about agreeing to that kind of research? And I lean to that. Although on the other hand, what do you have a legally authorized representative for if it’s not to act on your best behalf?

DR. CHILDRESS: And whether is the prospect the right benefit?

DR. CASSELL: I’d like to hear something that would tell me that the subject doesn’t have to have said, oh I think that’s a good kind of research to do.

DR. CHILDRESS: Eric and then Laurie. I mean, Bernie. Sorry.

DR. LO: First a couple questions. Are we allowing this expression of preference to be oral or must it be written, and with what degree of documentation? And secondly, must the subject, while competent, have consented or agreed to this specific protocol or research of a certain ilk under which this now protocol falls? Again, that, those have tremendous have implications for how likely it is that the subject would be able to enroll in this kind of therapeutic, more-than-minimal-risk study.

MS. FLYNN: Just to follow up on on this point, I was wondering what kind of expression was going to be deemed acceptable and what degree of focus or specificity such an expression would need to have. Given that we’re talking about research that is beneficial, that that’s the role of the legally authorized representative, and unless there’s some clear dissent or expression of a lack of support for participating, and given the lack of clarity about that what that expression looks like, I’m having trouble with it. It’s also just in the real world of practicality, highly unlikely that individuals who are this symptomatic or having this much difficulty in making decisions are going to have had the kind of discussions that would yield some kind of real clarity in the minds of those who would be reviewing this. That this particular kind of research was acceptable and such expression had been made. I think the cognitive impairments and the ongoing disability that often characterizes people with fluctuating capacity would likely have mitigated against their being able to make a statement or express a wish that would be actually be useful.

DR. CHILDRESS: Tom.

DR. MURRAY: Laurie said much of what I wish to say. If someone has expressed a prior wish not to be involved in research, I think that’s dispositive and would probably say that in the recommendation. If on the other hand, as is more likely the case, someone has made no expression, then I would leave it up to the legally authorized representative, where in these cases, there is some possibility. Is that consistent with yours?

MS. FLYNN: Yes.

DR. CHILDRESS: I have Alta, Trish and then Steve.

Professor Charo: I, too, would like to argue for a situation in which a person’s surrogate, legally authorized representative, is given a free hand here in this one category. Absent express wish not to participate. First, everything having to do with advanced planning has been nightmarish because it has all the problems of informed consent exponentially increased by the uncertainties of what that consent means and what they’re consenting to over the course of years of unknown developments. I don’t like that business to begin with, but it’s been a kind of necessary evil in the non-therapeutic area. I don’t like it whether written or oral in its form of advanced planning. The second is that this is consistent with the way in which we’ve been approaching other situations with decisional impairments. Again, let me refer us to the example of research in an emergency context, where routinely if there’s somebody in the car who is a family member of the person who is now bleeding and lying on the ground, they’ve been allowed to make decisions to go ahead and try an experimental procedure if it were therapeutic, it had potential for some kind of therapeutic value. The controversy there that unconsented research was where there was no surrogate decisionmaker at all. And, third and finally, this is a particular population, and here I am referring to specifically those that are mentally ill, where there are very frequent drug trials looking at various variations in dosages, variations in administration, administration protocols, minor variations in drug formulations looking to tweak these drugs to make them work. Because you’re working in the drug area, it’s very unlikely you’re going to meet the minimal risk definition, but it is also very likely that the reason that people are going to be enrolled by their surrogates is because their current treatment is quite imperfect. It’s not that there’s no therapeutic option, but it’s quite imperfect. And if we insist on some degree of advanced planning, an unrealistic expectation, we will, I think, very much shut down not only biological new research but a valuable source of potential improvement for these people.

DR. CHILDRESS: I have Trish, Steve and Harold and Bernie.

MS. BACKLAR: I just want to ascertain the fact that when we talk here in Recommendation 10 and we said the potential subjects previously incapable of making decisions about participation in research have previously expressed their agreement to participate, and we are agreeing that legally authorized representatives may do that for them if they don’t have capacity at this particular point. That they will have actually appointed that person, that this is not somebody who will have been appointed for them.

DR. CHILDRESS: Which makes it even more restrictive then. In this case it goes the opposite direction from the comments to this point.

Professor Charo: A legally authorized representative is not necessarily somebody who has been appointed.

DR. CHILDRESS: And as we have been using the term in the rest of this document.

MS. BACKLAR: At this point, if these people have agreed to be in research and they haven’t agreed to be in research, we’re saying they’ve agreed.

DR. MURRAY: They haven’t said "I don’t want to be involved in research," and they have a legally authorized representative that says that given this trial which may confer some benefit, possibility of benefit, we leave it up to the legally authorized representative to say under these circumstances I will consent on behalf of my....

MS. BACKLAR: Well, I would like to say I’m very concerned about people being put into research in which they haven’t made any kind of choice at all other than that they’re not, that they haven’t made a dissent and that they haven’t appointed somebody that they would, who would be there to make that representation for them. That is what I’m trying to say.

MR. HOLTZMAN: So summarizing, a number of people around the table are effectively saying that 10 should read the same as 11. Trish is expressing a dissent to that. And the key distinction between the two is whether or not there has to be an expositive expression of agreement prior, and it’s an implication of the way this is written that that prior expression would have been made to a legally authorized representative who is appointed prior. Okay.

DR. SHAPIRO: I’m just asking for some help from some of the Commissioners who will understand this area better than I do. As I look at this and ask about planning and not planning and so on and obviously if you eliminate the planning part of this, it simplifies the whole thing a lot and then you don’t have to worry about what they agreed to exactly. Is it the nature of the research or the risks, or, it makes everything a lot simpler that’s certainly true. But I need some help with this. I think of some conditions where people have fluctuating capacity, where large parts of their life are spent, fortunately for them, in conditions which are really quite normal, if I could use such a word, of where they are perfectly capable, put it that way. And parts of their life are not and it’s, I understand, not easy to predict when these things occur. But for a person in that capacity, in that condition, it’s a little bit hard for me to say when they’re not well, someone they don’t know, never heard of, could be the State, could be someone from an IRB, could sort of contribute them to this. Now I need some help with that because I don’t think that anyone really believes that or is suggesting that, but maybe we are but that’s what this would seem to say. Because we talk about people right here who are fluctuating, I mean that’s one of the categories. How should I think through that problem?

DR. CHILDRESS: Controls would be at the point of how one understands "legally authorized representative" in the state and institution.

Professor Charo: Exactly. There are two things here. First, who is this person who’s suddenly being given the power to enroll somebody? It’s not the IRB and it’s not the State, it’s by custom or law, depending on where you are, it’s a series of members of the family and on rare occasions close friends. Few States do that, so it’s a fairly narrow circle. Now on what basis are they supposed to go ahead and enroll somebody? And there was some discussion about this at the public comment and in subsequent memos from the staff, and I wondered if that might be the origin of this particular change here. There’s a very rich literature about how it is that third parties should exercise the ability to choose for others, and the best kind of generalized wisdom here, and maybe Jim will give it more detail, is that they should start by trying to figure out what the person would do for himself if he could. And that there is a genuine duty to figure out, if you can, what they would do. And in that quest to figure out what they would do, you’re allowed to assume that most people act in their self-interest, so they try to protect themselves from harm. They try to grab at benefit but you might know something special about this person that makes them deviate from the "typical." And if you really can’t tell what that person would do, then the next best thing would be to act in what seems objectively to be their best interests. And it’s on this basis that these third parties make clinical decisions all the time when people are impaired. And the question that faced us early on was whether we ought to use exactly the same standard that’s used in clinical decisionmaking in the research context. And in general, the answer is no. Research is different but where there’s a prospect of therapeutic benefit it was murkier. And if you’re in a field, and this is actually one of the advantages in working only with a mentally ill population, if you’re in a field where the current therapies are so imperfect that the prospect of benefit through research looms large, then it strengthens the argument that this is a circumstance where the standards for clinical decisionmaking with third parties could apply in a very ethical fashion. But you have to be confident that the third parties will live up to their duties.

DR. CHILDRESS: Bernie, I suspect Trish will want to respond to this and then I have to propose that we actually move and so we can see where people stand on this particular one. Bernie.

DR. LO: Let me start out by saying that I support the idea of first of all making 10 and 11 consistent and certainly not making it harder for patients that tend to be enrolled in these types of studies than in 11. It seems to me that the reverse of protection you would want. So I agree with the thrust of what Alta was saying. With response to, in regard to what Harold said, again, I’d agree with Alta, that to the extent that we know what the patient would have wanted prior, through general statements or specific statements, the surrogate ought to follow those unless there’s a compelling reason not to. You can’t do that, you’d be substituting judgment based on everything I know about this person, what would he want me to, what would he decide in this situation? And if you say I just really can’t tell, what do I as his surrogate think is best for him or her under the circumstances? And I think there’s a caveat we need to put in saying that what empirical data we have leads us to doubt whether surrogates actually follow that sort of procedure. And so I think we need to put in here some text that’s been there before about how it’s important that the IRB make sure that the investigators put in the protocol a discussion with the surrogate that covers the points that it’s not what you think you would want but it’s what the patient, the subject would want. There are a couple minor points we I think we need to tidy up. One has to do with what we mean by legally authorized representative. And I think, Harold, your concern is, I take it, is that there’s a guardianship procedure and someone, I once had a patient whose guardian was Wells Fargo Bank and the person who picked up the phone at Wells Fargo Bank to conserve the estate, to conserve to consent, leaves you very, may lead you to more trouble. So to the extent, the person who’s the surrogate is not connected to the patient, doesn’t know the patient, doesn’t know what the patient would want and has no kind of ongoing ties of affection, responsibility and stuff, this starts to fall apart. Then the other point is, I agree with Alta totally, that there are going to be very, very few patients who fill out a research advance directive, but to the extent that someone takes the trouble to do that, I think that should probably be dispositive absent a really good reason. So I’d like to, my suggestion would be to make it an or rather than an at. That if you, in this type of research, either if you’ve given prior consent through an oral or written directive or if you haven’t expressed dissent, the appropriate legally appointed surrogate makes the decision for you based on the standards Alta went through with the caveat that if at any time during this you object, you’re withdrawn from the, at least that portion of the research.

DR. CHILDRESS: After Harold’s comeback, we might even be able to come back and get some sense of the body on that direction. Harold.

DR. SHAPIRO: I want to make a, it’s not a suggestion. It’s not well enough thought out to be a suggestion. And I’m ready for someone to tell me to backspace after this and I’ll forget I’ve even said it. If you just look ahead to Recommendation 11 which is, I guess, Steve pointed out, under certain circumstances 11 and say collapsed, which in itself is a nice, is a nice thing. I have always, I have always struggled over the word "never" in that recommendation because I had envisioned in my mind of someone who may have been ill thirty, forty, fifty years but not when they were born and so that never is always, I didn’t ever know how to quite think about it and I began as this discussion is going on this afternoon, I began thinking of another way of describing that. That is someone who, where the current diagnosis is that they will never recover the decisional capacity. That could be a current. I don’t know how to describe that well but I could imagine people in advanced Alzheimer’s, other kinds of things where they will never, and in that case, 11 seems fine to me. It seems like there is no other choice. But I am still bothered by this case where someone will recover. The diagnosis is that they will before very long recover. They’ll have episodes and so on, but that case still bothers me. Now I think what I’ve just said may make things more confused than helpful, I’m afraid.

MR. HOLTZMAN: No, I think. I was fascinated by your remark because what you were trying to get at was the sense that if someone had or periodically has sufficient capacity to exercise autonomy, the idea that someone else would take over that rule for you is troubling. You go to 11 and you say to yourself well, they never had so from, for many if not all things in their life they’re having, many things in their life they’re having to give that over to someone else. But at the next layer you should ask yourself, Harold, why shouldn’t I be equally troubled there? Why does that difference make you feel okay about 11? I could read your argument about feeling uncomfortable with 10 leading to an 11 which prohibits....

DR. SHAPIRO: Well, I just, the image, which I’m not going to say this again because I’m willing to be guided by the rest of the Committee because I think I don’t fully understand this well enough, but the image of someone who is waxing and waning, of them being volunteered so to speak when they’re in one of their difficult periods rather than waiting until that episode is over and they are better and one could discuss matters with them is something that bothers me a little. I don’t know quite how to take care of that concern.

DR. MURRAY: There’s a factual presupposition in what Harold just said which Laurie, I take it, thinks is probably, as usually, incorrect based on your discussion before about people that would fall under current Recommendation 10, are usually, have significant impairments in other realms that it would make it unlikely that you’d have a long conversation with them about.

MS. FLYNN: It would be challenged, could be challenged. It’s highly individual.

DR. MURRAY: But I have a different, I want to make a different kind of suggestion. It seems to me that it’s not so much whether about how to combine 10 and 11. It’s not so much whether somebody has never had the capacity to speak for themselves about their desire to participate or not. That’s not important. What’s important is do we have a statement on the record or a reasonably construed statement about their wishes with respect to them participating in research? That’s what matters. Not whether they never could doesn’t really matter. So you start with that. Do we have it or do we not? If they’ve said no at some point and we think it’s pertinent to the research at issue, that’s the end of it. That’s really the answer. If they said yes, we’re enthusiastic about it and we think its pertinent to the point of issue we may want to have other protections like the legally authorized representatives also consenting. We can say that and maybe we want to add a condition such that where someone’s capacity to consent is fluctuating and where if it would wait, if we would wait a little bit, we could ask them and get a morally meaningful answer. We would probably, an IRB should consider that or we could advise IRBs to wait and not embrace the inclusion of such individuals in such studies when there is a reasonable capacity, where there is a likelihood within the near future that they can in fact answer for themselves.

DR. CASSELL: Well, I’m trying to think of the group that we’re talking about. Here’s a group of persons who’s usual state around the time that we’re talking about, sick enough, so their usual state includes decisional incapacity. They’re sick and they’re not getting better, which is one of the reasons why they’re going to be enrolled in this particular protocol. If they don’t come in within the next six months, they’re out. That’s it. Now, and everything from the past tells you that their usual state is not going to change. That is a thing that happens to people. There are groups of patients who are like that. The question is, you could make an argument for saying well that’s the way it is. There’s no research that could be done on them. We cannot really represent them without taking a chance of making a mistake, and we’re precluded from doing research on them. On the other hand, to do that, I think, what would do harm to a group. The question is whether that harm is greater, the harm of not doing the research is a lesser harm than the harm of doing the research on the possibility that you’re not truly representing them correctly. That’s where we really are. Myself, I feel that there is such a thing as waxing and waning capacity and that you may not get this, that they won’t be better soon. That’s what their parents have been hoping for the last 23 years and they won’t be better soon. And the question is do you just feel that they’re exempt from research? How do you feel about that? Do you think they should be exempt from research? Remember their legally authorized representative, we can specify even more closely. Their legally authorized representative may be the parent that’s been their caretaker all this time.

DR. SHAPIRO: I want to think about that a bit. I’m not sure how I feel.

DR. LO: Eric, I think, posed the question very well and I would just respond that I would be concerned that they’d be able to answer the question, is anything going to benefit this group of patients because we never been able to do the research on that group. I just wanted to say that you can’t totally foreclose research on a group of patients on whom you have no good therapy at this point. That’s, you want to be able to do the research in a responsible way. To go back to Harold’s comments about waiting until you recover, I think where the nature of the study is that that is feasible, we should encourage that, but I’m thinking really of the therapeutic studies where you’re trying a new drug that may in fact create some clinical fruit but you don’t know until you test it. And so you can’t really wait until they recover because you don’t really expect them to recover. And fine, if we have to keep coming back to the idea even if someone never had, or doesn’t had, excuse me, never expressed a preference about the research protocol or research in general, if they dissent from the actual study as you’re carrying it out, that dissent is possible so that there is some protection for the preferences, whether they’re autonomous of the subject, regardless of the consent that was given by the legally authorized surrogate.

DR. SHAPIRO: I think dissent, honoring dissent, of course, is extremely important and we’ve all said that all along. That’s not controversial among us. You have to remember with the population which we are defining as to who might be on the subset of those. Part of them are decision-incapable. Certainly we have to honor dissent. We don’t know if they are capable of knowing their best interests. I think that’s a defense and a good one. We ought to keep it. I’m not sure how much, I know, I don’t give a lot of benefit to it all and I’m glad we have it. If one looked at this Recommendation 10 and 11, which I’m trying now to see if we can’t and if we talked simply about people who are currently incapable of a decision about participation and not worried about whether they have always been incapable or they at some future day be in some different status, because 9 already says when they are capable that we go ahead in the normal course of way and get informed consent in a normal way. And so what 10 and 11 are concerned perhaps with are people who are not currently capable and it doesn’t matter how long they’ve been in that, and one could take the view it doesn’t matter how long they’ve been in that condition. But during that period, if you put it that way, then you could go to something like 11 which says that their legally authorized representative can make the decision and what one has to worry about is that person or persons or class of persons that might qualify really do represent this person’s best interest. And while I think I’m prepared to go ahead and go along with that, it is sobering sometimes some of the evidence that surrounds the way these people make decisions and whether they, you know, as the stuff we’ve read, they often make decisions they themselves would never volunteer for, even decisions that they think the person they represent wouldn’t volunteer for. There’s always this kind of evidence. It’s not so comprehensive that we can rely on it, it’s just sort of anecdote. Given the importance of continuing to do work in this area for these people as a group and those fields as individuals and here there’s a prospect of therapeutic benefit, I guess I would be willing to go along with that.

DR. CHILDRESS: And I think with the addition which I don’t obviously have in the text, I think we’d do a better job with defining a legally authorized representative later with the material that Jack Swartz has added so some of this gets resolved a little bit later in the text. But, I, the point that’s already been made that we really need to indicate here, the basis of the legally authorized representative’s decision and actually give recommendations about what IRBs and investigators ought to be looking at in terms of the tier where you have the fluctuating and persons that express certain wishes and that sort of thing. That ought to be done and moving onto the best interest later. I have several who want to get in. I have Trish, Laurie, Alta and Tom. And then we may be at a point where we can actually take a straw vote.

MS. BACKLAR: So I would really like to ask a few questions actually. Are we proposing here to put people into research that’s above minimal risk that they have neither consented to the research, putting away the dissent aspect, putting that on the side. So they have neither consented nor have they made a choice, a clear choice about this and they, and neither have they chosen to speak for them. Is that correct?

DR. MURRAY: You left out a condition Trish. Research that offers the prospect of direct benefit.

MS. BACKLAR: I just put that aside. I said more than minimal risk. You would have in order to persuade me, you’d have to show me the kinds of research that might occur where it would be okay for somebody to be in a research protocol in which they had no personal choice about this. I’m very concerned about this.

MR. HOLTZMAN: Well the example was given. Someone has a condition, they fulfill everything you’ve just described and now there’s a new drug, right, so it’s more than minimal risk, which is believed capable of treating that condition.

MS. FLYNN: It’s vast numbers of people, Trish, who participated in the clozapine trials who were among the most ill of individuals with schizophrenia, many of whom were quite impaired for many years, for whom current standard therapies had very limited effect; who had not been truly capable of making those kinds of choices or even in some cases expressing those kinds of issues. Their surrogates in most cases were family members and those trials as we know have made an enormous difference in the quality of life and have encouraged even more to the point a whole new generation of clinical trials to come forward where we now have in schizophrenia a choice of 4 or 5 new neuroleptics where a decade ago we had none.

MS. BACKLAR: So in a sense you’re saying what Alta is saying about this. Alta is saying about emergency room research with people with stroke who come into an emergency room in which there is nothing that can be done except to try something and there’s no adequate standard of therapy that’s going to work for them unless you try something that is experimental. Is that correct? Is that what we’re talking about?

Professor Charo: I think you’re perhaps overstating it just slightly by saying that there’s no standard therapy. The prospect of therapeutic benefit, and I mean therapeutic benefits because we haven’t, excuse me I know I jumped, but we haven’t highlighted the fact that we need to clarify that the benefit here is not money, it’s not getting a chance to be in a new institute, right?

DR. CHILDRESS: It’s one I’ve suggested e-mail messages having at every single point.

Professor Charo: That there’s a therapeutic benefit that’s possible through this research specifically because the experimental treatment offers the prospect of being better than existing treatment, even if existing treatments are not useless. So it’s not quite as strong as what you said.

MS. BACKLAR: That’s what this person, for instance as Laurie described it, the existing treatments may be useless because we have classes of people in this group and this particular population we’re talking about, standard treatments do absolutely nothing.

Professor Charo: Sure, that’s just an even more dramatic example.

MS. BACKLAR: We are suggesting this in a situation where the person’s life at the moment is so bad that this will not make it worse and may improve it.

Professor Charo: It could make it worse. There’s a risk.

DR. CASSELL: We don’t know. They may have to. It may wipe their bone marrow out.

MS. BACKLAR: And so what kind, so what kind of safeguards would you, would you put in place by putting someone into a research protocol in which they have made no choices about this for themselves?

MS. FLYNN: They can dissent and their legally authorized representative presumably maintains contact, and if a such adverse circumstances are present presumably they are recontacted; one does have to trust that we do a good job of determining and defining a legally authorized representative.

DR. CHILDRESS: And I still have a list, I’ll come back to these but letting people respond to Trish’s questions here, I have Bernie and then I Alta responding to Trish.

DR. LO: You may have people who get therapeutic benefit with the current therapy but the side effects are intolerable and complicated. And the new drug may be a little more effective, but more importantly it’s a lot more tolerable to the patient. So, that’s another example. I would want to try and not exclude these people.

You asked a question I think is different than the consent question. There are problems with consent and I’ll come back to suggestions for that—you’re also pointing to issues of monitoring of what happens during the trial, which have nothing to do with whether—what kind of consent I get up front. It’s the fact that—.

MS. BACKLAR: I understand that. It’s a double-barrel question.

DR. LO: Right. I’m saying that some of your concerns won’t—will be addressed not through climbing up the initial enrollment process but making sure there’s adequate protection later on when you get to it.

MS. BACKLAR: Okay. That’s what I’m—what I’m saying. So, if you don’t have consent I want to go the next step, which is what are you going to do to make sure that harm—further harm is not going to come to this person.

DR. SHAPIRO: We will come back when all this is done and look at the set of things we have, as Steve has pointed out more than once for the past few days.

MS. BACKLAR: For instance, I could not vote. I could not vote on the consent issue without having explored the other issues.

DR. CHILDRESS: Alta will respond. I’m going down the list and then we’ll come back and get a straw vote on this.

Professor Charo: I think that the following four things at least are part of what keeps this from being abusive. And I say that as somebody who made this whole big thing about morally suspect. First is the fact that dissent will be acknowledged and will shut things down. Second is the narrow definition of "benefits." We’re really talking about benefits flowing from exposure to the experimental intervention—the research intervention. Third is, I think appropriately, a narrowing of our understanding of legally authorized representative, in which we come to something that says whatever is legally authorized under State law is the outer limit of it but—no. Let me back up, sorry—that friends, and to the extent permitted by State—sorry—family and to the extent permitted by State law, friends can act as the legally authorized representative. But we’re not looking for institutional. Your Wells Fargo example resonated. Fourth, Harold, that—as is done in other circumstances, at the first moment somebody regains their capacity to consent, they are reconsented. They are fresh—they’re freshly approached and they’re asked if they want to continue. That’s routinely done now because, remember, we’re narrowing a universe of things that are happening with third-party decisionmakers and good practice does that. And finally, it’s not specifically protection, but I think it’s a context we need to keep us in. Although it’s true that as a rule, research interventions are going to be riskier than clinical interventions. I think we need to keep in mind that’s not always the case. We comfortably allow third parties to make things efficient based on their best effort what people would do, in very risky clinical context, to make very big clinical decisions. But as soon as you put in as part of a systematic investigation—alright?—we’re going to draw back from that and I want to simply urge that we not be knee-jerk about that because risk levels are not necessarily varying with whether something’s in a research context or a clinical context, although there is a large overlap. Right?

The bottom line is that in general we know empirically most people do not volunteer for nontherapeutic research, so it’s hard to say what a third party could legitimately say. I am guessing that this person would not want to be enrolled in nontherapeutic research. But’s it’s therapeutic research. We’ve seen lots of examples of people wanting to enroll, and it’s much easier to imagine a third party legitimately saying, "I guess he would want to be in this trial."

DR. CASSELL: Can I clarify what she said?

DR. CHILDRESS: Okay. Clarification, right.

DR. CASSELL: The person has responded to treatment. They are now competent. And they—their first act is to stop their medication. They are now incompetent. What happens then?

DR. CHILDRESS: Alright. That’s a good casuistic case. And then I want to push to getting a straw vote after we get through these five comments. Bernie....

DR. LO: I want to go back again to Harold’s concern about a stranger surrogate making these decisions. I think you can put in that the IRB ought to put in some special monitoring of the consent by the surrogate in these situations and may want to have their consent monitored or something else to preclude these stranger surrogates who don’t know the patient at all and don’t have any ongoing relationship from consenting.

MS. BACKLAR: I think that you also, even if they’re not stranger surrogates, I think you need just as equally.

DR. LO: To make an optional additional protection....

DR. CHILDRESS: And I think a lot of things are emerging once we’re clear on which direction we’re going that can be helpfully added in both guidance and in the textual support for whatever we come up here. Some very important points have been made. Tom and then Carol and then Trish and then we’ll see if we can get a straw vote.

DR. MURRAY: Okay. Very quickly, I take it we are trying to function by the Bauhausian School of Commissioning; that is, only as complex as absolutely necessary to accomplish the task. So if we can go from Recommendation 10 and 11 to one recommendation that’s good, right? I think that’s where we’re headed. There will be cases where there’ll be no expression from the person about whether they want to be in research or not. And that’s what—we want to cover that. There’ll be cases where they say, "No, I don’t want to be," and we think that ends the—ends the inquiry. There will be cases where they say, "Yes, I’m interested." We want—I presume we want to take that as the kind of information that the legally authorized representative ought to take into account, but not in and of itself as dispositive. Am I right about that? We already dealt with the dissent. I’m talking about where they say, "No, I think research would be cool." Do we agree?

Someone has expressed an interest in participating in research prior to...Do we take that as positive evidence that they ought to be enrolled in research? I don’t think it would be rare that that would be the case. So it’s relative information to whom? To the legally authorized representative.

DR. CHILDRESS: We’re going to offer further guidance.

DR. MURRAY: Okay. Now, Harold had one other case that I’m not sure we responded to, and that is somebody who is wavering, do we today enroll them in the research, they’re just not able to give us a meaningful answer. And Harold said it seemed to him an affront to say let somebody else say he can be in the research when if we waited a short interval and they could make up their own mind.

DR. SHAPIRO: I—well, I have been convinced by others that there’s so much uncertainty in that case, and length of period often so long that we ought not to handle it within this recommendation. Although it did bother me, I’m satisfied, too, the way it’s going. It doesn’t quite feel that case, but that’s fine.

DR. CHILDRESS: Eric Meslin’s called my attention to something before I turn to Carol and Trish, that there are some materials earlier in the text—not in Chapter 6, in the recommendations. For example, on 104 and following "Protections to ensure that the LAR is an ethically valid surrogate for research decisionmaking." Now, in one sense it doesn’t help to have it—it helps in effect there for certain purposes but what we need to do is go through in order to strengthen the kind of argument we’re making now and pull out relevant summary points from that discussion to support what seems to be the direction that’s emerging here and I appreciate Eric reminding me of this in the text. Do you want to add anything to that before I get to Carol?

DR. MESLIN: Carol [INAUDIBLE]? The only other thing is that we do mention on 106, and depicted up in the recommendations, that ongoing evaluation of LARs is an important issue, that there isn’t enough evidence about their efficacy, so Commissioners may wish to revisit those pages as they continue to talk about the recommendation.

DR. GREIDER: I actually have a comment. I’m happy to wait until after the straw poll. It’s not directly relevant to how we vote on this, but it’s a comment about the text. It surrounds this whole area, and part of the issue is the box up there that reads "Does the research offer potential benefit to subject?" As the researcher thinking about experiments, it’s very difficult for me to think about research having benefit if the research isn’t completed yet. This whole issue about beneficial research—we’ve said it now a hundred times around this table today, and there is text on page 36 which deals with this, and I would really like to see that incorporated here as well as previous Recommendation 8 that we skipped over. Bottom of page 148. I think some of that language needs to go in. I understand how people are using this term, but I think it’s a very dangerous term because research means you don’t know if it’s therapeutic or not.

DR. CHILDRESS: So, in some cases—right, you don’t know whether there’s benefit, but you may be comparing two therapeutic agents, for instance.

DR. GREIDER: But you—a lot of this discussion is assuming that there’s a benefit to the people getting those drugs.

DR. CASSELL: Potential. The intent of the research.

DR. CHILDRESS: The intent is to generate the generalizable knowledge, but you’re doing it with therapeutic agents and thus offer the possibility of direct benefit to patients.

DR. MESLIN: I would just like to remind the Commission: We’ve had public comment on this, which drives to our attention the importance of this language, and the language that we crafted tries to track directly the language in the regulations which talks about research holding out the prospect of benefit. Now, a few Commissioners have been using the language of therapeutic benefit, and I think it would be important to state for the record that that’s a shorthand expression for the much longer regulatory phrase, where research may hold out the prospect of direct benefit or the research does not hold out the prospect of direct benefit.

DR. GREIDER: I’d just like to see that reflected in the final text.

MS. BACKLAR: I’m looking at Alta’s fifth point of what one might do in clinical treatment to try and help an individual with something that is hopefully going to be therapeutic. And I again want to point out the critical difference between the clinical treatment, where there is one person caring about one individual, one clinician looking at one individual in front of them, titrating things, trying quickly to make sure that something isn’t going to go wrong if something looks like it’s not doing so well; whereas when somebody is in a research protocol, it’s not quite like that. There’s not a clinician carefully focused on one individual. That individual is one of a group of individuals who is not being looked at and where the medication may not be titrated according to their particular needs because it’s part of a group need. And, so, that is the danger area, and it ties in exactly with your point and so I’m still exceedingly uncomfortable about this. That’s all.

DR. CHILDRESS: Maybe in the simplest form we should just see how people stand on basically combining 10 and 11, going in the direction of the legally authorized representative’s permission with all the other conditions we mentioned, then providing in the text guidance, reference to empirical studies and the whole host of things we’ve talked about. So, how many are in favor of going in the direction of combining—basically combining 10 and 11 into a recommendation about the legally authorized representative? Okay.

MS. BACKLAR: But that doesn’t mean that we agree with it. If we’re interested in combining it.

DR. CHILDRESS: We’re going in the direction of the legally authorized representative model. That’s what emerges. Okay. How many are opposed to that?

DR. CHILDRESS: Well, this is clearly going to have to be written up and we’re going to have to find the justification. This was just the starting point to see if people agree with that direction and then we have a lot of work to do on it. Steve....

MR. HOLTZMAN: Trish just raised some very persuasive argument about the difference between the clinical setting and the research setting, even with therapeutic or potentially therapeutic agents. I don’t personally remember a lot of discussion or any in this text sort of reflecting that kind of distinction. Is there?

MS. BACKLAR: A little bit...mostly reference to Applebaum’s therapeutic....

MR. HOLTZMAN: I’m not that familiar with the literature, but what I found was that was a nice explication of when one is thinking through the prospect for—what’s the language: prospect for benefit. That—sort of elucidating that a little bit, drawing that out. That just because it’s a drug agent doesn’t mean that the prospect is as great there as it would be if the individual physician is working with you on an off-label use and titrating, etc., etc.

DR. CHILDRESS: Nor does it mean it’s less.

DR. SHAPIRO: It’s really just a special example of a case why there are more conflicts buzzing in the research arena than there are in the clinical arena. That’s just an example.

DR. CHILDRESS: It’s a double agency problem here.

MS. BACKLAR: And a perfect example of this is this extraordinarily important medication that Laurie alluded to, which was clozapine, which my own son now is very successfully having a good life with. But people in that research protocol actually died, and if that had been my son that had died instead of his benefit now, which he did on other people’s deaths, make one somewhat concerned. So that one person’s death—many people may have succeeded and had a good life out of it. That one person—I’m concerned about that individual.

DR. CHILDRESS: Bernie, and then we’ll move onto the next recommendation.

DR. LO: There’s another side of this issue. I mean, I agree the double agency problem for principal investigators who are also doctors or patients—it’s a big one. But, on the other hand, good research protocols that do drug studies have visits that are fairly frequent with very intensive evaluation of a patient—frankly, much more thorough than the usual source of—of checkups that happen when someone’s on medication at physicians’ offices. Certainly in this context with people with mental illness, many of who go to drug monitoring clinics, drug therapy clinics where one physician is prescribing for a whole raft of—I’m not sure that, as a matter of empirical fact, there might not be protocols where you get more careful follow-up within a protocol than you do in center practices. The standard in practices is not very good, unfortunately, maybe particular to these people.

Finally, the fact that someone dies on a protocol does not necessarily mean that the study was unethical. A side effect of clozapine is that you get agranulocytosis. It’s a very—not always lethal, but it’s a very serious condition. It’s the price you pay for the therapeutic benefit. It’s a separate question whether they didn’t monitor those people in trial closely enough so they missed the early warning signs and made a small leukopenia much more serious. That’s a real serious issue of the protocol design. I think we have to be very careful not to go backwards in the fact that someone suffered an adverse event in a clinical trial to say, there was a problem with the ethics of the research design. There may have been, but I think we need to see that case worked out. In fact, responsible investigators will certainly.... Data safety monitoring commissions spend a lot of their time on just those cases going back over those unfortunate cases and say, "Does this mean we shut the whole trial down, does it mean we should modify the protocol dramatically to add exclusionary conditions," and so forth. So, you know, it’s always easy in retrospect. You go back and say, "We should have done t differently. But if we don’t do the research; we don’t now what we should be doing there.

And there are two kinds of monitoring. We’re interested in this report in the data safety monitoring board, as a whole, but also the individual subject monitoring, and we’ll come back to that in some later discussion. Okay. Let’s turn to a set of recommendations that fall under 12 and the revision that appears on the memorandum from September the 15th on page 3. I noted already, but let me just—at the point in the text on 152 there is an addition about dissent from page 2 of the September the 15th memorandum. Just note that. Eric. Jack’s is not here. Do you want to say anything about Recommendation 12 as revised?

DR. MESLIN: That suggestion was simply that first and foremost the original Recommendation 13, which appears on page 153, is inconsistent with Recommendation 12A to D, and the easiest way of resolving that—it was an oversight in drafting and we apologize—is to simply divide up what is now Recommendation 12A and call it Recommendation 12. And the following three parts—B, C, and D—of what is now Recommendation 12—make that Recommendation 13, with the altered language that you see in the memo. And for those who may not—does the audience have the memo? Okay, then I won’t go ahead and read it. The proposal is to make this more clear and then you would simply delete what is in the text as Recommendation 13, focusing on competent persons, and Recommendation 12 on those who currently lack capacity in the revised or proposed Recommendation 13.

DR. LO: Again, I have a couple of questions: In 13A a person is given consent for participation in specified future research. My question’s whether the specification is to a specific protocol to a sort of class or type of study. I would favor the second—and in B, we’re talking about patient—when competent, appointing someone as a surrogate specifically for research decisions. Does that appointment also have to specify the types of studies, or can I just appoint someone whom I trust and say, I’ll rely on that person when the study comes along that I’m eligible for to make the decision based on what they think is best given all they know about me. What if I have to have said I want to be included in certain types of protocols? The danger I see there is that I can’t anticipate what kind of research people are going to be doing in the future and I have to have said I’ll participate in that type of research, let alone the specific protocol.

DR. CHILDRESS: Does D go—it goes a little bit farther in dealing with the kind of case I think you have in mind, but it may still be too restrictive.

DR. MESLIN: I was going to say in answer to your question, Bernie, the intention in making the proposal in the way that it was in the—to you use your language, the former—it was not specific, not specifically designated protocols but to specify type or class. The word "class" is not there. That was the intention, but it’s obviously up to the Commission to discuss that.

Professor Charo: Okay. First I’ve got to say that it gave me a headache to try to read this. We need to simplify this. I’d like to not only add the two-comma rule; the two-semicolon rule. If you need more than two semicolons you make a list. Several things. First, we’ve gone around in part as a result of public comments a little bit about the nature of the prior set should be permitted, and much of what’s going on here in between the various commas and clauses is an attempt to specify how precisely somebody has to have anticipated the specific research protocols for which they might—in which they might be enrolled by a third party. I would like, once again, to simply put on the table a simpler alternative, which is that people indeed are allowed, if they want to, to go by this kind of layered approach we’ve been using in the tissue sample area. Some people may want to say, "I’m designating this person to enroll me in research related to my condition" period. Have at lease one simple option. This is only going to be used—I mean, again, I don’t want to spend too much time on it, but it’s only been used by about 11 people in the entire United States. But of those 11, at least 7 are going to wind up finding that the document is useless, that they weren’t able to write it correctly. But if they were able to simply say, "I want my mother to be able to do whatever she has to do that she thinks is right for me." I want people to be able to do that. I want people to be able to act they way actually act in real life.

MR. HOLTZMAN: This recommendation is the one which really brings home all of the real key issues—in many respects, that the hardest issue to grapple with—and I feel that we’re trying to finesse something here and it’s not working. I can very forcefully make the arguments why you should never do more than—do potential harm to someone if they can’t consent, and no one should be in a position to let them do that. I can make the arguments why we all know that it would be nice to have research which actually would help this class of people. To put in place a mechanism where I think the consensus is there will be next to no one who went up beforehand and provided a directive to someone that said, "Make sure I can get into any research including more than minimal risk or even just any research."

Once upon a time I was a professional engaged in counting angels on pinheads; I don’t do that anymore. Okay? So, I real—and then—and I’m not sure I understand the language because we introduced language then about substantial harm—which when I thought we were in a minimal—so we ratcheted on down, and now we say, "But now we’re not uncomfortable." So why don’t we call a spade a spade here. We should either say that research is off the table, okay? Just can’t be consented because—Alta’s explained it very well—pragmatically people don’t do these advance directives. And No. 2, most of us—most people can see how if we were to be interested in therapeutic research as opposed to nontherapeutic research, and therefore the legally authorized rep could be representing you. Or, we say—and that would be the cleanest way to do it, and then grapple with, if we’re uncomfortable with it, this—the continuum of risk. That’s why I keep focusing on the continuum risk, because I don’t want to screw around with consent process.

DR. CHILDRESS: Okay. Alta and then we’ll take a quick straw poll on this and see what is most interesting point.

Professor Charo: First I’ve got to tell you from the very beginning I was unhappy with the idea that even in minimal risk nontherapeutic research, you could be enrolled and was, you know, shot down on that. But I think it’s possible to say that people—it would be very easy to say that there’s presumption of people do not want to enrolled in nontherapeutic risky research.

And if somebody can come forward with whatever kinds of proof that’s appropriate to that IRB, which shows that in this case we’ve got somebody. And someone may come in with a durable power of attorney and others may come in with a tape recording, and if we can communicate to the IRB that they are to construe as narrowly as possible. We will have given the leeway we want to the few people that really have contemplated these things. We will have—make sure that it’s stringent, but we will not have to grapple with the details of what goes in, what goes out. Is it "written"; does it have to be witnessed? Did it have to be independent? I mean, it’s all going to be very situation-specific, and it would permit if somebody who very clearly has said, "So and so’s going to make all the decisions for me." The only thing we’d insist there is that they made clear that it was decisions in a research context as opposed to clinical. That’s all.

DR. CHILDRESS: Okay. I think we then have three options floating around. One is the direction we have here, and I haven’t heard a groundswell of support for this. And then we have directions like you were proposing, Steve, which wouldn’t go as far, I take it, as you put in the kind of presumption that Alta would—although you might.

MR. HOLTZMAN: No. Actually it’s completely consistent. Because I believe it is the case, the presumption is most people don’t want to get involved in research that’s potentially harmful and is not beneficial for the good of science in the world. Most of us don’t think that way. I believe the pure place to fight the fight on this one is over what is the class of research, how much risk? Let’s not confound it with consent issues.

DR. CHILDRESS: Are we in favor, then, of merging yours into Alta’s? Alta and Steve will say it for us.

Professor Charo: As a substitute for what now constitutes Recommendations 12 and 13—Recommendation 13 on the handout. Thank you. We would say that nobody can be be enrolled in greater-than-minimal research that offers no prospect of direct benefit unless the investigator who proposes to enroll them can persuade an IRB that there is—I don’t know what word we want to use but—that they overcome the presumption that nobody wants this through some evidence of prior wishes. Some expression of prior wishes either to be enrolled in research of this type or to allow a particular third party to make decisions concerning enrollment in research in general; furthermore, that the IRBs should be extremely cautious on this topic when reviewing those kinds of special pleadings. Something in that vein.

DR. CHILDRESS: Without worrying about, now, exact wording and the kind of justification we might offer, how many would be comfortable with that direction? How many would like for us to go that way?

DR. SHAPIRO: I could certainly understand just eliminating enrolling these people altogether. That’s very clear, and I think I could even support that because it’s—especially if all the claims being made around here—that there are 11 people. You know, it doesn’t become sort of moot in most ways and doesn’t, certainly, impact scientific research in any way if there are 11 people who are going to qualify. So that I can understand that. I’m having a little harder time understanding how we’re going to phrase in an effective way the capacity for the IRB to enroll nevertheless on the basis of some set of evidence, however described, that this person really wanted this. But, you know, perhaps it can be drafted in a way that would be helpful.

DR. LO: I want to say something that I think is going against the tide I’m hearing. I like Alta’s formulation very much. But then I really have concerns, reservations about making the cutoff minimal risk versus nonminimal risk.

Professor Charo: Well, I’m not going to argue with you because I’ve always thought that enrolling people in nontherapeutic research without their consent or third party—they’ve asked to do it.

DR. LO: No. I’m actually going the other way. I think there’s some research that’s not minimal risk but not a whole lot much more than minimal risk which.... I think that’s the point Steve was raising, isn’t it? That’s the locus of concern. We can either address it with the level of risk that kicks in these recommendations or the nature of the recommendations. I also would prefer to address it directly on the type of risk we’re willing to allow surrogates to enroll patients who lack decisionmaking capacity into. Rather than trying to say we’re calling it minimal, but it’s really more than minimal.

DR. SHAPIRO: One, I don’t think it’s helpful to go back and talk about the spectrums of risk. I have—I think I have a very strong argument that that’s a very bad idea at this time. Eric an excellent essay on that. I think in the end we really are fooling ourselves; we’re not helping ourselves is the point, but I’m not going to go over that now.

I think there are two ways to handle risk: One is to say you can have two, three, four, eight, ten categories—whatever number you pick—and start trying to titrate that out; or, you can write things which are normalized on a level of risk. If you’re trying to describe protocols, you don’t try to describe them as whether they’re images or not images—imaging protocols—but they are protocols which have a risk classification. And then you could try to normalize on that.

The Commission will have to decide, but I think that—I’m very, very worried about the categories they use in children’s research and the capacity to deal with that. I think, in fact, we think we’re dealing with something which is not being dealt with. You look at it carefully and you try to think of what the indexing policy requirements are for deciding between categories. It’s virtually an unsolvable problem, and so I think that’s a very bad direction to go in.

DR. GREIDER: I just would ask for some help—for somebody to tell me exactly what kind of research we’re talking about that would be no possibility of therapeutic benefit, greater-than-minimal-risk. I don’t have a clear idea in my head about it.

DR. LO: A patient with schizophrenia, depression, bipolar disorder in whom the research question is whether it’s possible to correlate certain imaging patterns or PET scans or MRI scans or whatever later technology follows with either clinical prognosis or response to medications or levels of hormones, receptors, or something drawn in a bloodstream test. The bloodstream test—I take that the venipuncture is minimal risk, yes, except if the patient freaks out. But we’ve said that—my understanding of the prior discussion is we don’t think MRI scans and PET scans are minimal risk for this population because they may well get anxious, agitated with those procedures. I just have to say that’s true, but remember we’re letting people say, "No, I don’t want to do it even though you don’t think I’m competent." If they don’t say that and the surrogate enrolls them and they go down to the PET scanner and they start to balk, it’s standard procedure at any scanner if a patient shows agitation you don’t just push them into the—whether they’re competent or not. You stop the procedure and you deal with that. So, I think the actual level of risk that people are going to be subjected to—we’re saying it’s not minimal, but I just don’t think this really is the same thing as giving someone a drug that’s going to wipe out their bone marrow. To collapse that all together is not very realistic.

DR. CHILDRESS: Carol and Steve respond, then Harold who has to leave would like to offer some comments.

DR. GREIDER: This gets back to my earlier comment about what it means to do research, and what Bernie just described to me I would not put in the category of no possibility of benefit. Because, that is a research protocol that’s designed to study the disease in the individual, which could—twelve months later, lead to the possibility of benefit for that patient. One person tell me why this is not beneficial to the....

Professor Charo: This person in the course of this study is not necessarily going to get any benefit. So that entirely changes the view in—my view of this, because I was thinking of, you know, an incapacitated patient in which you implant a tumor to see if it will grow. So, this not in my mind completely divorced from the treatment of the individual, because it’s a research related to the disease, and if we could capture the language of "related to the disease."

MR. HOLTZMAN: This is somewhat in response to Harold. I want to keep the issue of consent pure and I want to acknowledge that in reality risk is on a continuum. There’s just no way around that fact. But now when you start to direct the—see, I don’t think three categories is necessarily better than two categories, right? But the problem you’re now facing is if you say X cannot be done in the following situation, the category, that’s where you’ve run into the problem, because you swept in maybe more than you intended, right? And this desire for another category is to try to loosen that up a bit.

If you—you could take the position well, I’m willing to live with that—I’m willing to live with none of those PET scans; some of us find that unacceptable—we’re trying to find room for the PET scan but not the tumor implantation, and yet we’re not being given the latitude for it. Now, one of the ways it may play out in reality if we write it this way is that people will start to broaden the concept if what is minimal risk. And I think that’s anathema to what we’re actually trying to accomplish, which is we’re saying we want heightened scrutiny here; we want people to be sensitive to the fact that certain protocols might be more risky in this population. But if you write it in such a way that we’re writing it, I’m afraid a practical result is, again, you’ll get more winks and nods.

DR. SHAPIRO: Well, haven’t got time today, unfortunately, to think about that full issue. I actually favor a situation where sort of something equivalent to Common Law begins sharpening our understanding of minimal risk and it will float up and down and change as we understand it. I think, in fact, that you erect an extremely good argument. That’s a far preferable way to deal with it than an arbitrary number of classes and we can’t settle that today. I understand your point and I accept your point in part also.

Let me just say—I apologize, I have to leave but I do have to make a plane and I just apologize for it.

I just want to say a few words—not about this particular recommendation and so on, which Jim and others will go through and the Commission will decide how it would like to proceed. We will, of course, on the basis of all that’s decided today, produce a new draft. We absolutely require your attention to that material as soon as it’s ready, and your thoughtful responses to it, because we do have to move along here, do our best to get a report that is, in our view, a positive contribution to this area, and those of you who feel that somehow there’s an important issue that we were—either didn’t handle properly or you want to add something to it, of course there’ll be room in the final report to express that. But Jim has said that once; I think I’ve said it once before. But—so, I think we all understand that. But the critical thing now is going to be feedback—thoughtful feedback, and we may schedule—in fact, the meeting, as Eric said before, a conference call meeting, so that we can meet together without having to assemble together, because it’s very hard to get people from all over the country to an extra meeting. But that looks to me like more and more a likely possibility as we get down to these final stages. So, we’ll probably—I don’t know, Eric, what your feeling is, but it’ll probably be something like three weeks to get a new draft, so that’s going to put us in the middle of October. We’ll probably try to give Commissioners ten days, two weeks to respond back. We’ll have to have a conference call sometime. We’ll generate—and then we’re going to have to generate a final report and then allow some short period for any Commissioners who wish to add their own particular statement regarding any particular aspect of it. Obviously, the report is not going to be what any single one of us would have written if we had our way on everything. And we all have the areas where we would have gone somewhere else. But I think, and I believe on the basis of the discussion today, that we can get enough in agreement so we will have broad-scale agreement on most of the important issues—but perhaps not all. And, it’s my own view that absolute consensus is not necessarily a great thing; in fact, it hides information in some cases. Other people made that point many times.

So, Jim, I apologize once again and look forward to the next draft.

DR. LO: Harold, you’ve given us a lot of good thoughts and very penetrating questions. Could I ask you to tell us how you would stand on the example I gave of the PET scan? Would you allow a surrogate to consent to that in the absence of some indication from a patient?

DR. SHAPIRO: I’d have some concerns about that in a nontherapeutic case. This is not advanced planning. This is an actual procedure. But I’m always open to good arguments.

Professor Charo: You know, Bernie, one of the things that may happen as a result of this is that people will begin looking for ways to make that generally minimal risk. I mean, as somebody who needed to medicated before I could undergo my MRI because I’m claustrophobic, I was impressed that there were all sorts of things that people can do to minimize the problems, ranging from medication to massage to changing to the environment of the room to having a friend. There are all sorts of things that—where you have to figure it out. One of the classic things that happens in the law—in legal systems—is that you try to figure out where the pressure points are that will change behavior and move the system in the direction you want. It’s possible that this will help to take those things that are in the—what you would call minor increment, and make people creative in figuring out how to make genuinely minimal risk so that people can be enrolled without opening the door to things that are far riskier than what you’re describing.

DR. LO: If we say, great idea, Alta. In the protocol there’s this provision that if the patient gets agitated they are offered the option between stopping the study or being medicated. Is that now minimal risk?

Professor Charo: No. I’m not saying dissent makes it minimal.

DR. LO: No, that’s what I mean, that—well, are you going to routinely pre-medicate people who may not need it?

Professor Charo: I think you might routinely—you might change the way in which this is done. It doesn’t have to be medication. You may be able to assess people individually—my thing is simply you might be generating an initiative toward creatively trying to make this less potentially upsetting.

DR. CHILDRESS: Diane wants to get in on this, and I have also Bernie and Trish and Eric.

DR. SCOTT-JONES: I’d like to emphasize what Alta just said, because I think we have to keep in mind that science changes constantly, and as Alta has just said, there will be different ways to conduct studies. Science moves in order to be more ethical if you demand it, so I don’t think we have to assume that there will be no change in how science is conducted.

DR. CHILDRESS: Bernie, did you want to get in on this?

DR. LO: I absolutely agree that we should minimize risk and we should use creative ideas to avoid putting people at unnecessary risk and identifying people who are more likely to have an adverse effect and anticipate. But I think at some level I’d like us to acknowledge that some research is going to be more than minimal risk under the definitions we’ve been working with. Even after we’ve done everything that Alta noticed and suggests. And I’m saying that if that’s the cutoff for basically not allowing it, you’re precluding a lot of useful research on conditions that are going to lead to the therapeutic benefits that you’re hoping for. And it’s like what Eric pointed out yesterday, that’s the classic dilemma in doing research. It’s the long-term benefit to society as a whole versus the harms that people undertake in order to achieve that goal. And it’s that tension and where you put the fulcrum. At some point we’re going to lose some research no matter how hard we try to reduce the risk.

DR. CHILDRESS: Okay. Eric, Trish, and then Laurie.

DR. CASSELL: Boy, you talk about back and forth and back and forth—I was for it, I’m against it, I’m for it, I’m against it. I’m now convinced in fact that the problem is serious enough so a solution—we have to try and find a solution to it. It might be that we add—this is a point in which we add the responsible health care professional to monitor the procedures. And, so that there’s somebody protecting that person.

Professor Charo: I—you’re going to add that, but the person can’t be enrolled now at all.

DR. CASSELL: We enroll them knowing that there will be a responsible health care professional not part of the study.

Professor Charo: For all levels of risk? Only minor increase, something....

DR. CASSELL: No, I’m allowing—no, I don’t think you can do that. I don’t think you can specify—unless we—I mean I know that one of these days this Commission is going to decide we have to solve the risk problem. At the moment we haven’t, and consequently I’m trying to add in there some third party who is not part of the program, who is there, and you can’t minor above, little above—it doesn’t work. But you do have an IRB to understand that this is our problem. It’s a problematic area where maximum protection of the subject has to be exerted because of its problematic nature, and then the IRB acts in that regard.

DR. CHILDRESS: I have Trish and Laurie, and then I know that some people have to leave around three. So I’m going to push this and try to get a sense of direction here that is what we think—what the majority of the group would like to do—and then we’ll see if we can talk about a few other recommendations before we close.

MS. BACKLAR: I’m sorry—I’m going to go back to something we really don’t want to discuss, and Carol brought this up so I can blame her. This issue of benefit and therapeutic research. And I’m not sure if I’m pronouncing Robert Levine’s name right. I do wish in a sense we would invite him back because he certainly comes from this perspective that to use the word "beneficial," "of benefit," or "direct benefit" is a very peculiar word to use in research. And I would like to say there are clear research protocols which are minimal risk and under that, and then there are protocols which go on a kind of continuum—which one needs to explore, perhaps in a kind of casualistic fashion, of where you go from minimal risk up this way. And I think we have confused ourselves. This is a perfect example—of Bernie bringing up what you’re going to do if you’re going to put somebody in an MRI, which is very useful, or a PET scan or all of these things which we all agree is not really going to harm the person. It may frighten them and then we let them out. We don’t force them to do it and so on and so forth. But it’s certainly not something like a challenge study of the kind that we have been reading. And so we certainly don’t want to close the door on that. Therefore, I think we may have to seriously think through of making the categories we put here about benefit and try to describe the risk on some kind of a continuum. I don’t know how to do it. That’s all.

DR. CHILDRESS: Laurie....

MS. FLYNN: Well, I think I just would follow on to what Eric and Trish said. It’s completely unacceptable to cut off this much research, given the suffering that these folks endure, given the low level of therapeutic benefit that’s still available to them, given the basic sciences is where we have to be in terms of understanding the functioning and the mechanisms of the human brain. It’s just unacceptable to arbitrarily cut off all access without any other kind of ability to, as risk increases, to then increase protection. We would, as I think we heard earlier, not even be able to really compare what’s going on in the brains of individuals with bipolar disorder versus individuals with schizophrenia when there’s considerable suspicion now that in fact these may not be two separate orders but disorders on a continuum. There’s a lot of significant basic understandings of what’s going on in the human brain that I think we would simply say could not be done. And I find that unacceptable and I would recommend we think through some way to more carefully match risk with protection than what this does for us.

Professor Charo: I appreciate your frustration. And indeed I was expressing similar frustration on the last go-around on research that offers the prospect of direct benefit. But I also think it’s possible that we can overstate the research that’s going to get lost as well. So, if we’re going to be talking about what’s really at stake and are we willing to live with our decisions, I think it’s important to be even more precise. The research with PET scans and MRIs can all be done with people who are competent, even if only fluctuating, because either they can consent at the moment’s going to be done or those are the very people who can be approached and asked during your next episode, "Would it be okay if we did this to you?" Right? So that that is exactly where this kind of advanced planning is going to suddenly become the avenue people are using, or looking to use. Alright? And, as a result, I would welcome a description of those things that absolutely could not be done, a scale of those things, and the impossibility of reducing the risk that’s associated with these procedures to something that would genuinely match what is commonly understood—whatever that is—as minimal risk. So I understood really what’s at stake here if we were to live by this kind of simple two-party system.

DR. LO: I mean, I would like to get a request to someone at NIMH to answer Alta’s point directly, because I think that would be important to give s a sense of what would be giving up if we actually made these recommendations.

DR. GREIDER: Well, at the risk of being really heretical here, one of the responses to the issue that I raised, which is really two issues, it gets to my fundamental understanding of the term "research," was the reason that there’s a difference between therapeutic benefit and nontherapeutic benefit is because the regulations say that. The regulations say that if there’s a direct therapeutic benefit to these people, it’s different than if there’s a long-term—how I would characterize a possible long-term benefit. I wouldn’t draw the boxes that way at all, and I just want to point out that part of what we’re going around about here is because we’ve decided to put this in the current context under the current regulations. And I’m not sure why we have to adhere to a framework that was laid down ahead of time rather than coming up with what we think is a useful framework.

DR. CHILDRESS: We’re probably going to have enough problems making the changes we have to make.

DR. GREIDER: I realize I was raising all kinds of other problems.

DR. CHILDRESS: I challenge that. But any other general points to be made, because what I—it seems to me we have three options on the table and I’d like to get some sense of—one thing we certainly had a request for is to get more information about the sorts of things that would be lost. That could not be done. And so we will pursue that. We could get that probably within a week actually. With telephone calls and e-mail we can get at least some indication and give us some sense of the ballpark we’re talking about.

But we have—the model that we have here on page 3 we talked about—the consent in various ways in advanced planning—we had Harold’s no to this category of research, and we had the presumption model. Those are very brief and cryptically stated, or the three models it seems to me we have been talking about here. Is there anything missed, and is there something else—? One we have before us here, that was the first one. The second one is basically no, we don’t do greater-than-minimal risk research. It doesn’t offer the prospect of direct medical benefit unless we have direct immediate consent. Forget this advanced consent stuff. And then the third would be to work with the presumption against doing it, but then to allow it to be done when you could have evidence about the person’s prior wishes—that sort of thing.

DR. LO: I would like the recommendation to allow nontherapeutic research under the current understanding, taking into account Carol’s reservation. That’s slightly more than minimal risk. It should be done with the approval of a legally appointed surrogate subject to the kinds of protections which would include Eric’s suggestion that an independent physician monitor the patient in the course of the trial as the patient’s representative, and Alta’s previous suggestion that really rigorous, creative thought be taken to making sure that the risk really has been minimized.

Professor Charo: Bernie, from what I understand, the only two kinds of studies that have been mentioned to date that fall into what people are calling minor incremental minimal risk are MRI and PET scan. I’ve never heard a single other example of a study that people want to do that would fall into this mystery third category, right? So far. So what’s the advantage of creating—you are creating a third category. You’re creating an intermediate category with an intermediate set of protections that allows the research to go forward, more than—more protections than if it were offering the prospect of the direct benefit as commonly understood, but fewer prohibitions than if it were nontherapeutic entirely. What’s the benefit of creating a third category as opposed to issuing a list? Special dispensation. Which goes, you know, type of research by type of research or people can debate it over exactly what this research would offer and exactly how comfortable we are about drafting people without their consent into this research for the purpose of providing a benefit to society at large. We’re going to draft them just like we draft soldiers. Because they’re the only people who can do it for us. Only the people that have this disease can serve this societal purpose, so we’re going to draft them the way we draft soldiers. And let them debate it protocol by protocol for a special list.

DR. LO: My main concern is that we not effectively close all research like that. I don’t know enough about the fields to know what other types of studies are in that category, and that’s why I supported your suggestion to get more information on that. I’m not wedded to creating a third category, but I just want to find some way to make it reasonable for investigators to get that kind of study approved providing it’s done all the right things. I certainly think stimulating debate directly on that point, discussing, and so forth is really valuable, and, you know, we’ve talked about the views and the Common Law of understanding, things like that. I would support that. But my major concern right now is that we not totally preclude this kind of research in our regulation, in our recommendations—or force people to blatantly misinterpret the plain meaning of the words in the regulations by saying, "It really is minimal," when in fact, you know, it really wasn’t.

DR. CHILDRESS: We’re going to request additional information, but let me just see if anyone in the audience in two sentences, three sentences could give an example of something beyond what we’ve talked about that might be ruled out. Anyone? And if you’ll identify yourself for the record.

DR. SHORE: David Shore, National Institute of Mental Health. Certainly research involving spinal taps, looking at cerebrospinal fluid metabolites of neural transmitters, which may reflect treatment effects or predict treatment response for the next group of patients might be certainly within this category. We talked the last time about genetics studies in which you’re dealing with an affected sib pair, and if in the case of Alzheimer’s disease, by the time the younger sib develops the disorder, the older sib is almost invariable not competent to consent, and since this involves genetic research this group has tended to see that it is greater than minimal risk. Arguably the most dramatic medical progress in neuropsychiatry has been the discovery of four or five genes which directly increase vulnerability to Alzheimer’s disease in specific individuals. If you were not to allow research involving the elder sib with severe dementia, we simply could not have found those genes. We simply could not be developing mouse models. We simply could not be determining which drugs or interventions might prevent the development of that illness. We could not predict which patients with other types of mood disorders or schizophrenia would respond to treatment. There are numerous answers to that question. However, based on—I mean, the fact that you have a letter from Mr. Aller and the fact that Freedom of Information requests have been used in the past to tar some of our investigators, I would like to find a way to provide information to NBAC in such a way that investigators who have conducted such studies would not find themselves the victim of media assassination or lawsuits.

DR. CHILDRESS: I think the information we’re requesting need not be tied with specific studies but rather can be generic in nature, and what you’ve just provided is helpful but it would be helpful for you and your colleagues to provide fairly concrete examples that may not be specific to particular protocols. Eric. Thank you. Eric.

DR. CASSELL: Where we are now is there is a general feeling that there are kinds of research that must go on but that do represent some risk but of no benefit to the individual subject. We are worried that giving advanced directives of any kind and the surrogate might put somebody at really great risk. We’re worried that that could happen, but we’re not so much worried about this PET scan with cautions and so forth. So, I don’t see why we cannot specify the protections that we’ve already talked about, including the neutral observer—neutral medical observer—and provide a set of examples that might be acceptable if the IRB—remember, this is—we’re not speci—say yes or no in IRB. It might be acceptable to the IRB if they understand what the problem is. And so we’re trying to keep from free rein. You can do anything you want. That’s the thing we’re trying to stop. We don’t "anything you want." So, with examples, but not with people because the day after tomorrow there’ll be a new procedure, and if we could do that, I don’t, myself, find that objectionable. I can accept that.

Professor Charo: I’d like to take the examples that were given and kind of work through them. Why not, right?

DR. SHORE: This is only a partial list.

Professor Charo: It’s only a partial list, I understand. One has to do with genetic studies, and the example of why this would be undoable was premised on the assumption that it would be found to be nonminimal risk. If it were found to be minimal risk, it’s no obstacle. And on the assumption that it was not possible, or at least not easy to get prior planned consent—because that also would make it possible, right?

DR. SHORE: Well, again, based on your discussion from this morning as compared to yesterday afternoon, if you’re going to say that every subject who’s competency must be questionable needs to provide informed consent, and the consent cannot be waived, then you have in fact made the issue of minimal risk irrelevant and you’re treating all research as greater than minimal risk.

Professor Charo: Actually, no. First, we’ve never said that you can’t waive in these circumstances under the same criteria in which you can waive consent generally. But more importantly, if it’s minimal risk, then according to the recommendations we’ve been debating so far, a third party could volunteer this person as a subject without any real complication.

DR. SHORE: Well, as Mr. Holtzman noticed in a previous meeting of this very Commission, that many IRBs, because of the kinds of risks to ensure ability, confidentiality, etc., routinely considered genetic studies to exceed greater-than-minimal-risk. So I think until this issue is resolved, I think there is a strong possibility that local IRBs are going to judge research on the genetic basis of these disorders to exceed minimal risk, and therefore the older sibling who will be unable to consent—and the research will certainly not benefit that older sibling—it might benefit his or her children, but that’s irrelevant for this purpose.

Professor Charo: Right. So, actually we could generalize it to pedigree studies in which somebody—I’m sorry.

DR. CHILDRESS: Three people are going to have to leave by three or shortly thereafter. So what I’d like to is actually for us to carry on this with some written examples and try to elaborate that. And what we need to do if we can is get some sense of where you’d most like to go of these five options. Do we consider Eric’s list as a modification of Bernie’s, or as a fifth option rather than just sort of list exceptions. Rather than simply say, "We’re going the direction of slightly more than minimal use," carve out very specific exceptions. But if we could get—and we may not be able to do it, and that’s understandable if you can’t, but it would be helpful if we could—of these possibilities, what we have here, and I’ve heard a lot of reservations about that—Harold’s view of saying no to this kind of research, if it’s great than minimal risk, nontherapeutic, no potential, no prospect of potential—direct medical benefit—and presumption against the research but aligned for the possibility that there might be some, perhaps even given these examples, more than eleven, who would go through the next planning process and authorize either a proxy or some other way of participating in the research. Bernie’s proposal of nontherapeutic, slightly more than minimal risk, and then Eric’s list approach. Let me just run through it and see, quickly, where your sympathies are.

DR. GREIDER: Can we combine four and five?

DR. CHILDRESS: They are different. I think it’s—if you open the door, I think that the—we can combine them, that’d be fine but I think it’s one thing to carve out some very, very specific exceptions. Another thing to say—.

DR. SCOTT-JONES: Then we have to have two rounds of voting.

MS. BACKLAR: I thought you said that what we have here is five has become three. Correct? Dissent has become the third one.

DR. CHILDRESS: Let me let you go through it one by one. How many are in favor of going the direction we have on page 3 for the revised recommendation 13, which is the—well, as in the document of 9/15? Okay. How many would go Eric’s—Harold’s direction of saying no to a nontherapeutic research greater than minimal risk? How many of you would be in favor of what I—our version of what Alta suggested in earlier point, a presumption—

it’s a recommendation what to do with nontherapeutic research greater than minimal risk. How many would be in favor of a nontherapeutic research greater than minimal risk? How many would be in favor of a presumption against that, but recognizing the possibility that some might engage in advance planning so rather than saying no, rather than basing everything on a model of a consent in advance through either specifying the research or designated proxy, when we just work with the presumption but allow the door open. Now, the problem with this one is it doesn’t really open to the risk side and that’s what some are wanting to do. On the next one or two—

Professor Charo: So they’re not mutually exclusive.

MR. HOLTZMANN: Can I ask for clarification from Alta when she thinks about that one? Suppose we’ve got one of those eleven people who said, "It’s fine with me to do nontherapeutic research that’s more than minimal risk. So, you’ve got that advanced planning. Now we’re looking at a protocol that is absolutely dangerous. Is it okay? Or, is what you have in mind—.

Professor Charo: No. If the IRB has passed on its reasonableness of risk versus—you know, risk in relation to the size of the question? And if the person’s statement really clearly seems to accomplish this, sure. I mean, I’d be glad to hear what they had said. That’s the whole point of having a case-by-case review of what somebody’s said or done.

DR. CHILDRESS: And as someone noted, these—one could vote for three and also vote for A or B. Any in favor in this direction?

Professor Charo: So they don’t want either the current or the revision. They don’t want anything. So we’re voting on No. 3 now.

DR. CHILDRESS: We’re moving ahead now. So let’s keep going. Have you voted yes? Okay. How many would vote for the presumption against, recognizing the kind of research, but opening the door for the advanced planning for the few who did it?

DR. MURRAY: Wait a minute—opening the door for what?

DR. CHILDRESS: For the advanced planning. What we’re doing is getting a direction of where people want to go with the revision. We don’t have the formulated options here other than what we have in the text.

Okay, a little support for that. We have nontherapeutic research with slightly more than minimal risk—Bernie’s proposal. How many are in favor of going in that direction.

Professor Charo: What are you going to do, create a list?

DR. MURRAY: Does this—wait, is this the list or does this acknowledge that we will—we are creating the third category as slightly more than minimal.

DR. CHILDRESS: How many are in favor of going in that direction. Okay. How many in favor of—we’ll call it 4B since they’re similar in many ways, but how many would be in favor of Eric’s direction with a specified list of exceptions but without the kind of flexibility?

MR. HOLTZMANN: Wait, I need clarification. I also heard you say, I believe—of course we won’t have a complete list, so—but if it—did you envisage that the list would be—these would be the exceptions: A, B, C, D. Or did it say "and others of this type"?

DR. CHILDRESS: Yes. So therefore it is no different.

DR. CASSELL: It’s different because it specifies for this purpose only. We don’t say "We now have a new category called greater than minimal risk." We specify "such as." Now, that’s a common thing in—.

MR. HOLTZMAN: But, okay, now, but what’s the organizing principle by which you’re going to put things on that list and also say "and others like them in the future that are similar"?

DR. CASSELL: Wait a minute. What makes it different? Because it does not give official credence to a third category. It specifies for this purpose and this purpose only interventions "such as."

DR. CHILDRESS: Or, put differently and perhaps less charitably, "it smuggles the third integer"—.

DR. CASSELL: But it does have—but you see, if you start putting that in, then we’re back into that whole risk thing, everything.

DR. MURRAY: Let me suggest a different analogy. The IRB—the whole—the Federal rule requires that there must be a whole IRB review except when it fills one of the categories for exception. I think you’re looking for us to build something analogous of the category of research which is exempt from the whole issue, or research which is eligible for expedited review. That list, research A, B, C, D.

DR. CASSELL: There’s another part to my proposal, and that is with the added protection.

DR. CHILDRESS: But that would be included.

MR. HOLTZMAN: I’m genuinely confused, okay? I understand what it means to specify something. I also understand what it means to give the extension of a concept through substantiations. But if you’re allowing that there can be more, you’ll have to specify the intention of the concept to provide guidance for what else will go onto the list.

DR. MURRAY: Steve’s right. You can’t say "and stuff like this."

DR. CHILDRESS: Okay. Alta, and then those people having to leave. I want to run that proposed—is that—Bernie, we will look forward to hearing from you with a concrete proposal on this. Eric, the same from you, and quickly in the next few days. Write out something. Give us direction here, and let’s—because we can’t resolve it today and we do need some—and we’ll also be getting further information about the kinds of things that will be lost if we went one of the other directions. Okay?

Since people are having to leave, what else do we need to talk about in the recommendations? Where else do you want to focus in the few minutes we have before we lose our quorum, whatever that is? Other problem areas? Still have no problems with our notification discussion? We had suggested—this is No. 4—we had suggestions about how notification would occur—or could occur—and it’s important, I think, to build that into the discussion, which hasn’t happened yet. But I think it was general agreement that that was important. But anything else about notification?

Professor Charo: Oh, no. No. I’m sorry. I was on to the legal authorized representative option.

DR. CHILDRESS: Okay. Let me just see if there’s anything about dissent—you know, the change that’s been made there. I’m looking away from no apparent dissent. Okay? I guess one proposal I would make, if you’re with me on 145 for a moment, I think it makes no sense to have Recommendation 6 as a separate recommendation. It’s really a qualification of 5 and I would strongly propose that we just include that as the last sentence of 5.

Anything else you want to focus on? Let’s look at the legally authorized representative issue.

Professor Charo: It’s the end of the memo that was handed out with a long separate memo from Jack Swartz. You know, I think in the context of responding to the comments, there was some draft text that we distributed on e-mail that would have limited the legally authorized representative to family members. I know I must—I was one. I don’t know if there were others who wrote back and said that they seem to deliberately exclude friends and that this may not be appropriate. It’s a special concern to people who are homosexual because they’re not allowed to marry in the United States. It’s a concern generally for people that really are very close to their friends and not with their families. And then it showed up again as a possible recommendation of how States can change their laws about what constitutes a legally authorized representative, which I think was a pendulum swing that went way in the other direction. And there’s a perfectly sensible recommendation—potential Recommendation 15 that says simply we should understand that legally authorized representative includes people who, under the law of the State where research is conducted, can serve as proxy decisionmakers. That means those states that had thought to put in "friends." Friends would not be excluded by our recommendations. Those States that have not thought to include friends will struggle along with that issue in the clinical context where it’s more frequently raised.

DR. MESLIN: So you like the memo’s version of Recommendation 15.

Professor Charo: Yes.

DR. CHILDRESS: Okay. That’s page 4 of the 9/15 memo.

MR. HOLTZMAN: I agree with that, Alta. I have a question to you since you raised it in the e-mail. States will do what they want to do. It’s part of the purview of this Commission to note that there are States where those statutes would not include the potential for friends and it’s therefore worth their thinking about changing some of the contents?

Professor Charo: I think it’s perfectly—I think it’s worth our while to note that the exclusion of friends has problems, and that it has special impact on certain sub-populations in the U.S. I think that making a recommendation that States change their laws on this point is probably more than we need to do. They’ll do with it what they wish.

DR. CHILDRESS: Jack has joined us—and, Jack, feel free to add to any of this discussion. Bernie....

DR. LO: Before people break up, I can’t find it now in the chapter but when I read it through before I was concerned about a recommendation, which now I can’t find, that IRBs be responsible for monitoring untoward side effects or something?

DR. CHILDRESS: I hope that was eliminated.

DR. LO: But I think it would be reasonable for IRBs to require in cases that are a lot more than minimal risk, without creating a need for a third or fourth category, to make sure the protocol has in place—a system to monitor individuals in a study for adverse side effects—for example, through the appointment of a physician, whatever, dedicated to that person, who is different from the principal investigator of the study if that’s—the patient’s treating physician. So, I think—you know, I think the concept is good. I just don’t think the IRBs should do it themselves. They should make sure the investigators put in the protocol a way to do it.

DR. CHILDRESS: And by the way, on all these points—I haven’t talked to Eric, but I’m hopeful that we can get a transcript very, very quickly on—that meeting is today, so we can actually use that as we’re thinking further about the revised draft.

Professor Charo: We’re getting close to closing? I would like to propose an experiment to people as they leave here today. I’d like each person here to imagine when they get on their very planes to go home—and I apologize, Trish, for you—I want you to imagine that unbeknownst to you somebody volunteered you and the other people on your plane for a special experiment in how scary it is to have an emergency. And suddenly an announcement goes on telling everybody that the plane is at risk of crashing, that you should get your shoes off, get your glasses, that you grab your knees, you should get your life vest, read the thing, and it goes on for 10 minutes. And then at the end of that they say, "Actually, you know, this was just a test to see how people react because we need to understand how to make it possible for flight attendants to handle the panic in a plane. It’s crucial, because in a plane you can’t have panic that goes riot." And it wasn’t that you volunteered for it. Somebody volunteered you for it. As a thought experiment, you’ll appreciate what’s at issue in volunteering people for things that are not harmful—it’s only going to frighten them—where it’s not possible necessarily with a mere dissent to eliminate all of the frightening aspects of this experience. Just so that we can have some empathy with what’s going on as we figure out if it’s worth it to do this.

DR. MURRAY: And on the way my plane, upon landing, it suddenly geared up. The shuttle pilot came on two minutes later and explained there was another plane on the runway.

DR. CASSELL: The problem with that is that my colleague on the left just told me that a list is not like an analogy and since you gave a case example so that we could use it as a thought experiment, so I find that unpersuasive. But the much thing—much different than that is these are not people who are being volunteered out of the blue—healthy volunteers. They have no relationship to the thing that happened at all. Not only that, the person who volunteered these people had no knowledge of their mind, no knowledge of what’s bothered them in the past, and so forth. This is a totally different situation. It’s the difference between sickness and health.

DR. CHILDRESS: It looks like this is deteriorating rapidly, but before we close, are there are any other recommendations you want to call our attention to and staff’s attention to or you think we need to do further work? In general are you comfortable with the other recommendations? Going once, going twice—.

DR. CASSELL: With one caveat. There are differences in the way the thing is described in various places in the document. For example, the neutral health care professional. That makes them not the same each time and I think we have to be very careful about that.

DR. CHILDRESS: And if you have—thank you for that general point, but if there are very specific things, would you call it to our attention.

MS. BACKLAR: Well, like I’m sorry for harping on the same thing, and I’m grateful for Carol for bringing it up. I think that we are—I think we have been put into a box by the direct benefits, and that if we want to have minimal risk and greater-than-minimal-risk, we have to get ourselves out of this box and find some other way of describing researches against riskier and riskier and what we do and don’t agree to. That’s all. And I think that—I understand your point, we can’t change everything. But we may find out that we have done very little good by staying in a box that has been given to us, which really is no longer making sense; which is again—I would like to have some advice from Robert Levine, who has thought about this a great deal and may in fact have some good suggestions for us.

Professor Charo: You know, it’s possible that we’re thinking about this problem the wrong way. The box isn’t created by the regulations. We’ve created the box in the following fashion. Everybody recognizes the difference between direct and indirect benefit. What you were describing, Carol, is a long-term consequence of participating in these studies would classically be described as an indirect benefit. If the studies yield advances, this person may well be one of the many people who will benefit from those advances. They’re not benefitting from this intervention so much as the long-term knowledge that’s gained from it. It was earlier in the day that we said that we were limiting the notion of research that offers the prospect of benefit and therefore allows for easy volunteering to situations where it’s direct benefit. It’s not that the regulations put us in the box; it’s that we chose to be very narrow, and so it is not a matter of changing the regs—it’s up to us. If you want to say that the prospect of indirect benefit is enough to volunteer people, we can argue that out. But that is now opening up the door to like a gazillion things that may pan out in the distant future, so it’s a slippery slope here, and my initial problem was that people were assuming in the research with possible direct benefit—people just slip in the mindset that that is going to benefit people, when in fact there’s a high probability that none of those people will benefit at all. So if we think about the probabilities, even in that category that we’re calling benefit, there’s no guarantee that there’s going to be any benefit at all there, and it’s exactly the same thing true for experimental studies—PET scans, whatever—on the same disease probably have overlapping probabilities about whether they’re going to benefit that person or not.

DR. GREIDER: Well, no, because the second category is zero prospect.

Professor Charo: No, it’s not. It’s not.

DR. GREIDER: There’s a probability that there will be some experiment done with venipuncture or a PET scan or whatever, and they’ll find out. They can then turn around and treat those same patients that went into that research protocol. So I see it as a realm of probability of benefit out the patient if it’s directly related to their illness. And one of those probabilities is in this box, and the other one overlaps in this box. And I see that it is completely arbitrary to break those into two different categories if it’s directly studying the disease that the person has. So that’s the box I think we’ve put ourselves in.

DR. CHILDRESS: Okay. You have at your desk—you received after lunch the statement Alex submitted to revise No. 3. Is there any comment on that before we break? Everyone should have it.

MS. FLYNN: I need to find it; I already put it away. But I think that it should still have some language that doesn’t make it seem that capacity assessment is fairly straightforward, because it isn’t. Capacity assessment may or may not actually reveal the person’s capacity, so I think we need some language, and I had suggested this earlier, that would be something like, you know, the researcher would need to provide some justification for the method used or something like that because capacity assessment is not easy, and part of having decisionmaking capacity depends not only on your internal capacity but on how well the researcher explains research to you—I just find it problematic.

DR. CHILDRESS: Could you offer, of course, a revision; and second—even if we stick with this language, for instance, after further reflection and proposed revision, it would still be helpful for you to provide material for the text. That is, part of what you’re suggesting, it seems to me, is something that would be very important for interpreting this, even if it is not incorporated into the recommendation itself. But if you could think about that and submit that to Eric. Getting down to the final comment or two—Bernie...?

MS. FLYNN: Okay.

DR. LO: Just a comment on Alex’s amendment. Again, I still have my concerns about do we need this for all protocols or particularly for ones where the principal investigator has a dual role as also patient’s primary physician. I was just wondering, would the approval of the patient’s primary physician fit as appropriate assessment of capacity? The goal here is to avoid situations where the—Eric, you brought this up earlier—where the principal investigator is—it’s going to be very hard for the patient to say no to the principal investigator for a whole lot of reasons. The doctor may be the private physician providing ongoing care; the patient may be institutionalized involuntarily and really dependent in that sense. And in some of those situations I very strongly agree. We need some independent research team who’s qualified to do it. But if you’re in a situation—well, one of my patients was just admitted on a involuntary hold for relapse of his bipolar disorder. Now, he’s not on a research protocol, but if he were to be on a research protocol, he and his wife would call me and say, "Do you think this is a good idea?" And If I said—if I was asked by the investigators, "Do you think he is competent to—has the capacity to consent at this time?" and I went and talked to, without learning MacArthur protocol—which I don’t know—would that—but I know this guy over time. We’ve talked, not about this, but life in general. Would that be permitted? I mean, I think we’re looking for protection, and I’m not sure there aren’t other ways to get protection that aren’t covered by....

MS. BACKLAR: It’s interesting, of course, because in minimal risk research—psychosocial minimal risk research, often that is exactly what is done. It’s before somebody is brought into a recent protocol. It is ascertained from their clinician whether or not this person could be approached even.

DR. LO: If he can be approached do you think he’s capable of consent?

MS. BACKLAR: Right. And in fact the reason you’re asking if he can be approached is because they’re asking is this person going to be capable of consenting.

DR. LO: I’m talking about independent assessment so that someone’s not sort of pushed into a study against their better judgment without necessarily having some independent qualified professional assess them.

DR. CHILDRESS: But again, this is a presumption that’s a rebuttable one. That’s the reason for going this way. Okay? It’s only a presumption, and you’ve offered persuasive grounds for using a less formal means of assessing somebody’s capacity. It seems to me that’s what this allows. That may still go to far for you, but it’s different from what we had before. It opens the door in a way the other one did not.

Diane....

DR. SCOTT-JONES: I think what Bernie said is related to the point that I was making, that we’re not in a position to endorse a way of assessing capacity, that what Bernie said he would do might be as good as some of those methods that we’ve outlined in the text of assessing decisionmaking capacity.

DR. CHILDRESS: Well, we’re not recommending that particular one. This says "only an appropriate method which the IRB has to make a judgment about." "Administered by a qualified professional who is independent of the research team."

DR. SCOTT-JONES: But I think when people read the report and they read that, they’ll go back to the section where we go through the methods of assessing capacity and they’ll figure that we believe....

DR. CHILDRESS: I think we’re very clear there, as a matter of fact; and if not, we should be, so when you look back over it and you think we’re not—and I don’t expect everyone to have read this draft through and carefully and every word this time. I didn’t. But this has changed a lot, and it’s changed a lot in relation to the kinds of concerns that people have expressed. I think Eric did read through it all, probably word for word. I think the draft as a whole is a much better draft. I think we still have a lot of problems with the recommendation and in connecting, then, appropriate text with the recommendations and pulling out things from earlier in the text that were made that were very, very important. But I think the discussion in the text is much more—is much clearer and much more nuance actually than it was at an earlier point. However, one question was raised and I’d love to get a—Trish has forgotten she told me to remind her if she hasn’t mentioned it, and that is a question as to whether it would be good actually to put the second chapter in an appendix. It’s the history of regulatory efforts and it, in a way, does break the flow. One could add a few sentences about what it’s done there up in the first chapter when we’re setting a context for the work in the report, but Trish, do you want to say more?

MS. BACKLAR: Yes, I thought that perhaps that could go in the appendix because that really is background material and I think when people come into read this, they’re going to really want to know what it is that we’re asking them to think about and to do. And I think that then they might like to go back and see what that background material—how it has affected the way we have come to this. But I’m just concerned that it will still be off-putting right at the beginning in there, sort of trying to get information out. That’s all. It wasn’t that I didn’t think that the chapter was useful; I actually thought it was very interesting and very useful.

DR. CHILDRESS: It’s only about 15 pages long, so we could make an appropriate appendix with a few of the points drawn into the first chapter as appropriate. But any sense of that? In general, it could appropriately go into the appendix rather than into the text. And then you would have pretty nice flow from setting up the research in Chapter 1 to informed consent to assent/dissent, etc., to risk potential benefit, and our concluding chapter. I think it would make a neater report.

Any last comments?

MS. BACKLAR: I only want to say again I’m very concerned about putting people into research where they haven’t made any choices at all, even about their legally authorized representatives.

DR. MESLIN: We have important writing assignments for those who have already indicated that they would prepare something. But all the rest of us, if there are things that we want to work on and want to see in a different form, then we need to provide that material in writing. Let me thank all of you for your very hard work today. I think we reached the end of our productive labors. And let me see if Eric has any concluding words. Thank you all very much.

DR. CASSELL: Only to remind you that our intention is to turn a draft around within the next two to three weeks. We are scheduled to meet, again, on the 20th of October unless that, for any number of reasons which relate to fiscal year in the government, could change. But we are intending here in Washington, D.C., on the 20th. The reason we haven’t given you the exact location is we’ve been prevented from doing that in a sense. But we’ll work extremely hard on staff to turn a draft around. The way that we can do that is if Commissioners will give us their written comments that have written on their drafts. Either leave them with us or Federal Express your packages to us. It’s much easier to have it quicker than to ask you for it later. And, as I say, we will attempt to get all of the information that you have asked us for and to make the transcripts available as quickly as they are available. And I would like to thank the public who came out the meeting and has been so attentive and so helpful, as well as those who gave public testimony today. Thank you very much.

DR. CHILDRESS: Second all that, and thank the staff very much for the continuing important labors. Thank you.

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