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Continued Discussion of the Staff Draft on Research Involving Persons with Mental Disorders Affecting Decisionmaking Capacity: James F. Childress, Ph.D., Jonathan Moreno, Ph.D., and Commissioners

DR. CHILDRESS: We had discussed all of the topics on page 2 down to referent population for risk assessment." So, why donít we start there, and then we have a few more on the next page, as well as Laurie Flynnís concern about the necessity requirement, and there may be some other points left over as well that I did not note. So, letís start with the discussion of the referent population for risk assessment. This appears on pages 99 and 100. If youíll glance at those pages, unless you recall them well from an earlier reading, weíll see if we can handle this particular topic fairly quickly.

Jonathan or Eric, is there anything you want to sift over? Oh, Alta, go ahead.

PROF. CHARO: Consistent with where we were yesterday, I think the simplest thing might be to use the same definition of minimal risk and referent population as is used in the Federal regulations; specifically, the general population is an average of sick people and well people, and that there be a reminder in whatever document we ultimately send to the IRBs that reminds them they are always welcomed and encouraged to look at the specific population in the study and ask would ordinary minimal risk items be of more than minimal risk for them in particular and to adjust their protections accordingly, but not to try to change the definition of minimal risk for the referent population just for this purpose.

PROF. CAPRON: Alta, I think I agree with the objective but I disagree with the description. Taking into account whatís going to be done in the research and then figuring out what risk that represents for the population is not a matter of altering or departing from the notion that the definition of minimal risk is in reference to the whole population. Itís two different issues. One is, what is that level of risk? Obviously, what one is doing is something that doesnít yield a number, it yields a lot of analogies; walking over here from the hotel has a one-in-a- million chance of sudden death or something. Thatís the risk of ordinary life. As frequently as I go to see the doctor in a year. I mean, these kinds of things.

Whether going into a PET scan is more risky for me or more risky for one of the people who is actually going to be researched isnít really relevant unless going into a PET scan is not one of those base line things. One does have to ask, what is the risk for the population compared to what? And the "compared to what" are the minimal level of risk encountered in ordinary life of the general population, including the well and the ill.

PROF. CHARO: I take your point. But Iím thinking more at the level of the routinization of these kinds of recommendations. Now, on my IRB, if something involves something like a venipuncture which is ordinarily considered minimal risk for typical study populations, it means that the IRB administrator assigns the protocol differently. The protocol is not distributed to everybody, only to the reviewers who report back in the meeting instead of having everybody read it, right? And so, for example, if I were the assigned reviewer, I might be one of only two people reading the entire protocol. And it would be the job of the IRB administrator to either determine that, based on this subject population, maybe we shouldnít treat it this way, or me, as the reviewer, to bring to the attention of the committee that maybe we shouldnít treat it this way.

But to ask the IRB administrator to apply a different standard to begin with in figuring out how to routinely manage the review of these things is what I would like to avoid. That, I think, is just an invitation for confusion. And to simply say weíre not going to deviate from the Federal regs, but to point out to IRBs they need to pay attention to the population, which is what I thought I said, accommodates this requirement that people will take into account who it is whoís being studied.

PROF. CAPRON: The phrase "they are always free to adjust" made me think you were addressing the metric, where is the bar, not where does this particular procedure ó

PROF. CHARO: No, no, no. Itís this particular procedure when they review this particular protocol.

DR. SHAPIRO: I think youíre both saying the same thing here. I want to ask a question on this, if I may, Jim. And that is, I think I raised it yesterday toward the end of the afternoon, whether we would want to caution the IRBs that after taking all these special considerations into account, they can never exceed the referent bar just because itís this group. That is, they canít talk themselves into going past this reference by ascribing special characteristics.

PROF. CHARO: In other words, they canít wind up putting these people at more risk because typically they have more medical interactions, et cetera.

DR. SHAPIRO: Correct. Thatís right.

PROF. CHARO: And this is a classic thing that happens not only with these people, cancer patients routinely have more interventions, et cetera.

DR. CHILDRESS: Okay. Thank you. Do we need further discussion of this particular topic? Are we satisfied?

DR. MESLIN: I donít want to hold the proceedings, but we did hear in written form from Laurie Flynn and I donít want to quickly leave the subject in the event that we want to make sure that we at least attended to some of the points that sheís raised, which we did discuss yesterday. And Iím hoping that Alta and Alexís agreement, so to speak, the description of what we think weíre saying, can be read in the spirit of some of the concerns that Laurie had.

Were she here, she would probably say them herself, but one of the worries that came up yesterday was if we go this route, will we be preventing research from going forward? Will we be limiting certain types of research?

PROF. CAPRON: And that was to be a question to the public, can you give us examples?

DR. MESLIN: Okay. I just wanted to bring us back.

PROF. CAPRON: You may want to see if there is a division of the house on this issue, because I gather Laurie is not alone in her view that we should have a different approach for that intermediate category, which does not lead to bottom points.

DR. CHILDRESS: Thatís my sense in talking to individuals as well, that there would be some division.

PROF. CAPRON: And I donít think thatís going to be affected by the description either.

DR. SHAPIRO: No, I donít think so.

PROF. CAPRON: The question is, should you be prepared for a statement at this point that the following Commissioners believe that the correct approach should be something else?

DR. SHAPIRO: Why donít we just see? I donít want to take a long time this morning. Clearly, I think weíre going to have some disagreement on this and there will be certainly opportunities for Commissioners to express their disagreement within the report, if they feel strongly about it. But let me just ask that question, this is what I call the two- versus-three categories problem; that is, whether weíre going to have the minor increment over minimal risk receive less protection than whatever is on the other side of that bar?

MS. KRAMER: Harold, have we given up on trying to accommodate Laurieís concerns other than having that category of three? Is there any other way that we could formulate ó

DR. SHAPIRO: Laurie would have to speak for herself, but I think from what sheís written it seems to me pretty clear that she and I are in different spots here and I donít know where the rest of the Commission is. Weíll have to see. She may change her mind or not, I just donít know.

Steve?

MR. HOLTZMAN: I think Iím in Laurieís camp but not necessarily requiring three different categories. Because from my reading of Laurie, the real issue if you go to our flow diagram, is where you go down to in light of the specific study population, does this research involve greater than minimal risk. And that in the case of the ó yes, there is one pathway in which the research canít be done at all. Right?

PROF. CHARO: Yes. If itís non-therapeutic and they canít give informed consent.

PROF. CAPRON: Secretarial approval.

PROF. CHARO: Right. Yes. But thatís realistically thatís not much of an out.

MR. HOLTZMAN: Thatís exactly right. So that if there was a pathway opened up to leave that research to be done, we need not have the third intermediary category. I read Laurie as creating that category so that thereís a pathway for that research to be done.

PROF. CAPRON: But I read Laurie as saying that she would agree that greater than minimal increment over minimal, greater than minor increment, is appropriate. So you donít fix that category by saying, well, we donít need secretarial review, we need OPRR review or division chief review or something.

DR. SHAPIRO: Bette?

MS. KRAMER: I would like to request the staff or whoever to try to find a way to incorporate Laurieís concerns within this flow diagram. I think that thereís nobody on the Commission whose life is so completely devoted to the protection of these people as Laurie is. And I, myself, would be loathe to sign off on any document that didnít incorporate a concern about which she feels so strongly.

DR. SHAPIRO: Well, Eric?

DR. CASSELL: I think thereís another way out of this, actually. When we make it three categories of risk like that, we get into whatís in that category. Right? But if we say that over, instead of having that category, when a protocol suggests this risk-taking procedure, spinal tap would be an example, or the one sheís concerned about, or certain kinds of PET scans, it ought to be so specified and acted on as that thing by the IRB; specifically, in this instance, with the protections that are in place for these patients, is that a permissible thing for them to do. So that we donít just open up the bag, but made it specific risk-by-risk thing.

And if, in fact, the IRB thinks that it is too risky for this population, then it goes on. But if they see, a spinal tap is a good example, that this is a population that has in the past had spinal taps and so forth, then that might be permissible. So weíre not making it open-ended anything in that group you can do, weíre making it risk-specific.

PROF. CHARO: Iíd like on this particular occasion to argue for a line in the sand. And I recognize exactly how difficult this is because this is exactly the issue on which this area of policy has floundered for 20 years. Itís about the very fundamental tension between protecting these people against the exploitation that we have seen happening for years and their inability to protect themselves as well as we would like them to be able to versus the fear of lost research in a population that wants very much the best advances.

You canít quantify an instinct, and, therefore, I canít be sure Iím right. Iíve only been serving on IRBs for a decade or so, but my impression from that decade is that there is never any lack of pressure to expand the boundaries of permissible research. That the dominant pressure is always to get more research done. That one has to erect bulwarks against that because it is extremely easy in the context of a particular protocol, as you were suggesting, to find reasons why you want to go ahead and permit it and, in an incremental way, to find yourselves at the end of the day in a situation in which basic civil rights or human rights in fact are being violated. And weíve seen it happen over and over.

I donít think human rights and civil rights can ever be achieved in a way that is efficient, nor do I think they can be achieved in a way that does not have some real cost to societal advances. We accept those costs because we think itís so important to in fact create this bulwark against exploitation. So this is based entirely on an instinct of protectionism from my observations. And I canít argue with people that Iím right, I can only report my observations from those reviews.

And for this reason, I still fundamentally disagree with Laurie. And I respect her involvement. I also respect the fact that we could have easily had somebody who takes exactly the opposite position in terms of protection of human subjects with an equally illustrious CV with regard to involvement in this area sitting on the Commission and then we would have watched them fight it out. And so I donít ó

DR. SHAPIRO: Let me say a few things about this because I think we do have to move on today. We canít resolve this whole thing here. One, I think itís fair to say that nobody on the Commission has any special status over anybody else in the Commission. We all have our judgments and thereís nobody on the Commission on any issue for whom we should defer, although we should respect all views on this.

Second of all, just speaking about this issue, Iím unconvinced myself either by the logic of the argument for three categories or the empirical statements that are made that this is going to have this and that effect. Now, there may be some data that would convince me, Iím open to it, but Iím really unconvinced. I think what we have here right now is a disagreement, and itís an understandable disagreement, reasonable people can disagree on this issue, and so I think for the purposes of moving ahead right now, we can just move ahead, we will flag this issue, weíll have to decide how we all come down on it and ó

MS. BACKLAR: I can say something? Hello. Yes. Harold, Iím very pleased to hear you say this because I really canít follow the argument because I canít hear most of it. But it is something that I am concerned about and I take the position that I know it is not aligned with Laurieís. And, therefore, as both of us are out of this discussion, I would hope that you would let us have a little more time where both of us can be involved in some way also. Because I donít have Laurieís paper in front of me and I certainly donít know what her arguments would be. I do know what her position is, and I just want to make it quite clear that I believe that it is better not to have three categories but only to have two.

DR. SHAPIRO: Thank you. Larry, and then Iím going to make an executive decision to move on here.

DR. MIIKE: A couple points on Laurieís paper. I guess if we drew the line at "minor incremental over minimal risk" rather than at "minimal risk," I wouldnít see much difference anyway and we would be arguing about some very specific things. So Iím for two categories.

She does raise a last one, which is this issue about excluding people altogether, except her example doesnít seem to match because sheís saying therapeutic research. To me, therapeutic research means that person is qualified. So I donít understand that. I see her raising the issue but the example that she uses doesnít support the argument.

DR. SHAPIRO: Well, look, weíre going to make a draft, weíre going to flag this issue for people to get feedback on and Commissioners can think carefully about where theyíre going to come out on this because I think we may very well end up disagreeing, and if we do, we do and weíll just generate a report which flags that disagreement for others to decide eventually.

Steve, and then weíll go on.

MR. HOLTZMAN: Procedural question. I think what you said was we donít have a good sense of how much research, what types of research might not be allowed to occur.

DR. SHAPIRO: That I donít have, correct.

MR. HOLTZMAN: Right. And I donít have it either. Itís a question I asked yesterday. If one is going to throw out bath water, one ought to know just how many babies and how large they are might be in there. And I think thatís a function of what is the research thatís likely to occur and what is going to be the interpretation of minimal risk. And I think we cannotóor I donít feel like I can decide this unless I can put my arms around that.

DR. SHAPIRO: Thatís fine. I donít know whether weíre going to be able to provide adequate data. You may not be able to get your arms around it, therefore. Therefore, I donít know where that will take you.

My own view as Iíve looked at these things, youíre left with those issues no matter what you decide. Whether youíre three or two, you still donít know where you are because I canít get people to fill in these boxes. But weíll give it a try. Yes, Bette?

MS. KRAMER: Would it be possible when we put this out on the web or when we solicit public comment to flag this issue and say that the Commission had certain questions about this particular issue?

DR. SHAPIRO: Yes. Thatís the intent.

DR. MESLIN: In fact, if Commissioners want to identify the very individuals or groups who they feel are best qualified to respond to this question, staff would be delighted to receive those suggestions so that we can direct the report to those individuals on this issue.

DR. SHAPIRO: Jim, I apologize. Weíll go on to the next aspect of this.

DR. CHILDRESS: I guess my sense is that finally however much data we get in this area, we are going to be left with a fundamental philosophical difference at this point whichever categories we use, as the Chair indicated, and that finally weíll have to vote and there will be perhaps a majority statement and a minority statement.

On IRB membership, the next topic, we saw a recommendation from the NIH Expert Panel report yesterday, which called for one representative. Weíve recommended two subject representatives, and weíve recommended this as a matter of regulation that such change should occur.

The question being raised here is whether we agree with the recommendation as it stands in the draft report, and whether we offer sufficient reason for that. The relevant pages are 169Ė170, and 150Ė155 in the document.

Is there discussion of this particular topic?

DR. SHAPIRO: Anybody have any concerns?

On the smaller issue, Jim, thereís a second question here, is the justification provided. There actually is an interesting justification, but it occurs elsewhere in the report when weíre on to some other issue. I canít put my finger on the page right now, but thereís a spot in the reportóyou may know Jonathanówhere you talk about the fact that training in this area is not widespread even for physicians and so on. Thereís some conversation about that early on in the report dealing not with this point, but itís directly relevant to this point. Iím sorry I canít give you the page reference, but you may try to just bring that forward again when you look at this particular recommendation.

DR. CHILDRESS: Okay. No discussion? All right. Letís turn to the dissent standard. We have in the report still the apparent dissent standard and itís discussed in several places, 116 and following, 157-58, 178. The question here, and we talked about this briefly at earlier meetings, is whether we want to retain the apparent dissent standard.

Is there discussion of this?

DR. SHAPIRO: Remember Jimís rule from yesterday, that is, silence means youíre all right with whatís here.

DR. CASSELL: Or you canít find the page, one or the other.

DR. SHAPIRO: Thatís only for older people like you and me, Eric.

DR. CASSELL: You gave the wrong page reference for that. Sorry.

DR. CHILDRESS: I gave you the right pages, 116 and following, 157-58, 178, and there may be others but at least those deal with it.

DR. SHAPIRO: All right. Letís go on.

DR. CHILDRESS: Anticipatory planning. We discussed this around 120 and following, and 163. This is also a topic that was discussed at considerable length in previous meetings. The question is whether the way itís now handled in the draft captures the kinds of concerns that people have raised earlier and whether what we have is now sufficient.

DR. CASSELL: What page? That is the pages listed or ó

DR. CHILDRESS: Those pages are accurate, right.

Then we have the additional recommendations listed below that I guess grew out of Commissioners talking with staff as possible additional points. These have not really been discussed very thoroughly. Some have been touched on in passing. So letís start with the assessment of prospects for loss of decisionmaking capacity. You see the statement here, and the question being raised is, is this a direction the commission would like to go?

Eric, do you want to comment?

DR. MESLIN: We talked about this yesterday with the second flowchart. The question was whether or not in addition to any assessment of capacity that is done as an entry point for recruitment, should there be built into our recommendations any additional assessment of capacity for those individuals who might prospectively lose it during the course of their participation in a study. We have not built that into the flowchart. Weíve been working with various ways to do that. But given the subject population and those for whom this is appropriate, we felt it was necessary to raise it for you. There isnít language for you to comment on, so it may need to just be discussed for a minute or so.

DR. CASSELL: Just so I understand what the topic is leading into what you have here. There are, in fact, persons who have the ability to consent at point A, but later on in the project they may lose their ability to comment correctly or lose their capacity, and we have no mention of that. We donít discuss that?

DR. MORENO: Well, in a way we do, because we do have this notion of anticipatory planning. The problem isóif you see it as a problemóthat thereís no device to sort of goose people to focus specifically on the problem of prospective loss of capacity, though one would hope that that would be part of the anticipatory planning process.

DR. SCOTT-JONES: I was just going to say that on page 163, I read that to mean what is listed here, it refers to the prospect of a loss of decisionmaking capacity during the study period. So what are you saying thatís different?

DR. MESLIN: First of all, we havenít decided about anticipatory planning. If we are comfortable with the protections that that provides, then this may be unnecessary. But the difference is if an individual has identified their preferences for a future time, weíre only asking whether there should be a mechanism that kicks in to determine whether or not they are fully capable, or, in fact, whether that anticipatory planning does, in fact, kick in, because it would only kick in if the individual is incapable. If they are capable, then one doesnít refer to their anticipatory planning preferences. So they are connected.

DR. CASSELL: Itís not unusualólet me go back a step. Many of these projects go on for a number of years. Itís not unusual during the course of a project for something to be added to the project using the same population because of whatís transpired. By that time or at that time, one of the subjects may no longer have the ability to consent.

As far as Iím concerned, when that happens, that person should be protected as though they hadnít gotten that ability from the beginning. Anticipatory planning may not solve that because they wonít know what is coming on the board, thatís number one. Number two, if they have family protecting them along the line, then weíve already got this covered. In other words, I donít think we can act as though once somebody has consented, thatís it, there in. Itís like going over Niagara Falls, once you get in the barrel, thatís it, youíre on your way.

DR. CHILDRESS: Further discussion?

Alta?

PROF. CHARO: You know, it occurs to me that good research, and youíre right about twigging people to do this, good research, when they first recruit people, would include this in the discussion. Itís going to become an issue only when weíre contemplating a change of the personís status; for example, theyíre participating and they now need or want or would have wanted to withdraw, or they werenít participating and now they suddenly want to be in. Thatís the kind of thing that when done properly would, in fact, happen at the time of the early enrollment. Because with this population, one of the things that will happen in that discussion ideally between the recruiter and the subject is, what do you want us to do if you get foggy during the course of this research? Do you want us to pull you out immediately, or do you want to have somebody else making decisions for you, or do you want to give us rules now to follow?

And youíre quite right that you might want to just flag that with this particular population, since this is such a high probability occurrence, that good recruitment practices would include some discussion to flag this for the subject.

DR. MORENO: Can I just add that, if this flow of conversation is finished, thereís another angle on this question that we also discussed and also comes out of this formulation. Many people would argue, and Laurie might be one of them, that there are lots of folks who have mental disorders who are not at high risk of loss of decisionmaking capacity and that itís unnecessary to invoke the apparatus that weíre recommending in this report for people like that. And for want of a good example, Iíll just think of sort of garden variety Upper West Side-style neurotics of whom I know more than one, some ó

DR. SHAPIRO: Thatís a New York job.

DR. MORENO: Some of them are our colleagues.

PROF. CHARO: Some of them are sitting at this table.

DR. MORENO: Right. Or from Brooklyn, I think that counts also. People whom you might say have a mental disorder but are not at risk of loss of decisionmaking capacity. And you might well want to study those folks if you work at Columbia and yet you see this very complex apparatus before you that seems irrelevant.

Now, this is a big question that I sort of want to put on the table at this point because it is a suggestion thatís come up in my conversations with various people in the last few weeks when Iíve shown them the draft and the chart that youíre all struggling to interpret. They say, this makes sense for many people, it doesnít make sense for a lot of people who could be construed as having mental disorders because theyíre really not, however you want to put it, at significant risk, substantial risk of loss of capacity.

This is perhaps another question that we might want to flag for the Web and Iíll just put it on the table at this point.

DR. CHILDRESS: Larry, and then Eric.

DR. MIIKE: But how in practice would one differentiate? It seems to me you would have to set up a protocol before the protocol to decide which people are in or out.

MS. BACKLAR: I canít hear what you want to flag. So I hope that somebody will E-mail me something about this.

DR. SHAPIRO: We will do so.

DR. CASSELL: Well, the number of disorders that have as part of them the loss of decisionmaking capacity is not endless and they do not constitute most of the people walking on both sides of Broadway. Itís the ones sitting on the bench in the middle, and they have diagnoses. Weíre not talking about just ordinary neurotics, weíre talking about people whose mentation or cognition becomes impaired by their disease. Thatís not an endless list of people. Also, those are the people who may, in the course of their disease, become impaired or become no longer impaired.

I think you canít act as though all of this happens at one point in time and then itís over. So that we have to have some mechanism of protecting somebody whose decisional capacity changes.

DR. SHAPIRO: It also seems to me that the apparatus is not cumbersome for that very population. Decisions can be made quickly and itís just not cumbersome for that population compared to the risks one would take on in trying to make two different sets and say one of you falls in this box, one another box. Thatís much harder it seems to me and maybe just as cumbersome.

DR. CHILDRESS: Diane, then Alta, and then Alex.

DR. SCOTT-JONES: I just wanted to be sure what the question is that weíre addressing. Are we saying that we should somehow decide which categories of persons should not be subject to this because theyíre not at risk for becoming incapacitated during the course of a study? Iím not sure what weíre addressing thatís different from whatís already in the draft on page 163.

DR. CHILDRESS: Eric, could you comment?

DR. MORENO: This notion I guess rests on the theory that one could assess a whole population rather than individuals. So letís say the whole population of garden- variety Upper West Side neurotics, weíd say, donít require the protections in this system, rather than individuals. Then weíd do a population-based assessment and weíd convince the IRB that that is the case and thatís valid. And then they would be treated like any other subject.

PROF. CHARO: I think that the structure of the interactions here may solve this for us, even if intellectually the problem is as you state. Look, Iím a researcher, I want to keep my subjects who have enrolled in my protocol so that I can finish out my study. That means that if I look at somebody and I think this person is at substantial risk of losing their ability to continue to be consenting and voluntarily participating, Iím going to have an incentive to have a conversation with them about some kind of advanced planning because if I donít do that and they do lose their ability to make decisions in the course of the study, Iím going to have to drop them out. You canít keep people enrolled when theyíre no longer capable of making a continuing personal decision to stay enrolled.

So as a PI, Iím going to have an incentive to aggressively seek out those who need this and to talk to them about it. And that may solve the problem without us having to have anything analytically down here.

DR. CHILDRESS: Alex, and then Eric.

PROF. CAPRON: I think Alta is correct that the question only arises as there is some decision point that one would reach. But I donít think, Alta, that it will necessarily be self-policing by the investigator. Because if we look on the chart, I think what weíre talking about is the box that begins with the word "approved," a box which I donít understand the way these two clauses or sentence or whatever it is go together. But itís at that point where weíre saying during the course, if itís a week long or month long or whatever study, and during the course of it a person with fluctuating capacity moves from capable to incapable, they might move, for example, if we were over on the left of those two identical boxes, to say yes, they were but not, no, they are not any longer capable of giving consent, so we need to notify them that weíve reached that conclusion, and then turn to their legal representative for the permission to take the next step in the study. And if they donít start kicking and screaming ó the real issue will arise when the person starts saying, "I donít want you to do this anymore." And the question is, is this a crazy personís reaction now that we disregard? And thatís why these fulcrums of "are you capable or not" is so important. And if itís minimal risk and it has some benefit for the person, the legal representative would be able to say, no, keep them in the study.

Youíve determined theyíre not competent. Iím going to disregard that unless we say the no apparent dissent rule applies. And if theyíre dissenting, then knock them out on that basis and it doesnít matter. But in that case, the advanced planning isnít going to help. Itís not as though Iím going to pull a certificate out and say you signed the certificate before saying you wanted to be in this, this is a Ulysses contract and weíre going to disregard your present dissent.

DR. CHILDRESS: Alta, do you want to respond, and then Eric?

PROF. CHARO: We did agree that the no apparent dissent standard is going to be the one weíre with for the moment, correct?

DR. CHILDRESS: Yes.

PROF. CHARO: So the situation weíre in now is only one where somebodyís continuing capacity to consent appears to have diminished and theyíre neither dissenting nor assenting, they are simply continuing to be used in the study. And the only question is whether or not there is a mechanism to identify that moment and perhaps invoke some other set of protections. I would hope that at the time that the protocol is originally reviewed by the IRB that the subject population is being looked at, and if it is a population in which you have the kind of fluctuating capacity youíve described, that the IRBís in fact in a position at that point to be thinking about this with the PI together. We know that it canít be made totally perfect without having monitors necessarily attached to everybody.

PROF. CAPRON: Right. I totally agree with that. But I thought you said we would know investigators would themselves always take care of this problem because it would be in their interest to make sure that everybody had made advance planning. And Iím just saying, no, if they can go to the legal representative, they donít care if you have advance planning or not.

And so I agree. I think the statement that we want in the report is that the personís capacity should be reassessed as appropriate and one can never rely on a prior assessment if there is reason to believe it no longer is valid.

DR. MIIKE: Alex, if you look at the flowchart, the left arm has no legal representative. Thatís the area that I guess weíre most concerned with. You look down the left of the chart, the left side.

PROF. CAPRON: Yes. The answer is, yes, the person still is capable, Larry.

DR. MIIKE: No, but fluctuating capacity, that left arm has no legal representative to look out for ó

PROF. CAPRON: Because you reassess them and theyíre still capable.

DR. MIIKE: But whatís the mechanism for that?

PROF. CHARO: Right. The problem here is if they lose capacity, thatís what everybody is agreeing about.

PROF. CAPRON: I agree. All Iím saying is I donít think it will be self-enforcing. I agree with your final statement, that it ought to be up to the IRB to say to the person, "Youíve got to reassess this."

DR. CHILDRESS: Okay. Eric, and then Rhetaugh.

DR. CASSELL: Well, I want to hypothesize a specific thing that happens. This study has been going on now for two years, a new kind of instrumentation comes on the scene which is able to trace exact thoughts as they march through the front of the brain. Itís irresistible. Itís also a little uncomfortable. And permission is going to be asked to do this. Itís not part of the original study.

Now somebody comes up, and you think itís to the investigatorís advantage to have ensured an advance directive? Impossible. Itís to their advantage to cheat and thatís precisely what theyíll do unless we have some mechanism of having it invoked that doesnít bring their study to a halt. If they have to start the whole complex mechanics again, it will really make a lot of problems. On the other hand, we have to protect those subjects. So we ought to have some mechanism by which either the IRB is brought back into it or some way monitoring is brought back on.

DR. CHILDRESS: I guess following Steveís rule yesterday, if thereís this much discussion, itís clear that we need to do something in the report to indicate how this is going to be handled.

DR. DUMAS: Well, we need to be clear about what it is weíre debating. What Iím hearing is that if a person is deemed to be capable of giving consent and does so and they are involved in a project, then it is assumed that they would continue in that project unless there is some reason to stop to reconsider the issue. Now, are we asking for reasons to stop in the course of a project to reconsider consent?

PROF. CAPRON: If there has been a change in the personís behavior or status in a way which ó

DR. DUMAS: Okay. Which raises some question. So that is the issue that I think weíre debating. The other thing that Iím hearing is that if the study changes, that is another indication to stop and get consent for the study change. But itís the former one that I think people are groping with.

PROF. CAPRON: For the latter, you may need a new IRB to review it.

DR. DUMAS: Yes. And I think we ought to make that clear, the difference between stopping to get IRB approval and stopping to really assess whether this patient is capable of continuing.

DR. CHILDRESS: Right. I think itís your second one that the discussion has most strongly emphasized and where there are issues perhaps still to be resolved.

DR. CASSELL: Remember, thatís what makes this the special population that it is. This kind of problem is what makes them the special population.

DR. CHILDRESS: Have we indicated enough for staff to continue to work on the text in this regard?

Diane?

DR. SCOTT-JONES: I have one comment. I would be helpful in these discussions if we referred to specific sections of the text as it is, because we should be debating that at this point instead of something more general than what weíve already written. So it would help enormously if we could refer to what weíve already stated so that it can be clear how weíre saying something different from what is already in the text.

DR. CHILDRESS: Right. Except this particular one is one that staff in consultation with Commissioners felt was not perhaps dealt within the text in a way. So thatís the reason for the discussion moving beyond it.

Eric?

DR. MESLIN: Maybe I could just make one what I would hope would be a final comment on this. If the issue is, should the capacity assessment discussion, which weíve already agreed is important, and begins on 72 and continues in other places, should it include mention along the lines that Alta. was proposing, that as part of the design and the recruitment strategy, consideration should be given to whether or not that capacity assessment activity should not only occur at the beginning of the study, but should be kicked in or should be alerted later on in the study under particular conditions.

If the answer is yes, something like that should occur, then itís easy to insert language as early as page 72. What we would need to hear is whether you think that that language should say yes, it should be kicked in in exactly the same way, or simply that investigators should be particularly aware of the possibility and build it in, or some other such combination at work.

DR. CHILDRESS: All right. Iíll take a couple more comments and then we need to move on so that we can get onto the other topics.

David?

DR. COX: Iím arguing here for simplicity. I think making a comment about this being a possibility to look at but not trying to micro manage it in terms of detailed regulations and flows, is the way to go. I think that this is only one of many such things that one might be able to think of. And here when we get public comment, if we donít have a million of those, Iíll be amazed. So that to have a class of things that we see as potential complications that we want to alert people that we see but that we canít lay out the detailed rule for all of them. And I see this as one such thing.

DR. CHILDRESS: All right. Have we had enough discussion? Are people satisfied with the direction of the discussion? Could we take five or four minutes to finish up, we hope, the remainder. I hope so. So with that time constraint looming over us, the evaluation question that emerges as a possible additional recommendation. Should we include among our recommendations that an appropriate oversight body will evaluate and report on the effects of these new requirements in three to five years? This is something, again, that is not in the text. Is this the direction the Commission would like to proceed?

DR. COX: Harold raised or queried yesterday whether we might consider auditing or other such things. I thought about that last night in my dreams and woke up ó

DR. SHAPIRO: Sorry to give you nightmares.

DR. COX: No, actually, it was a good dream, Harold. Iím very much in favor of this. In a number of the public testimonies that weíve had and testimonies from different experts, we raised questions about how often does this or that happen, and we donít have a clue. And I would prefer not to be in that situation five years from now and I donít think it requires tremendous bookkeeping to audit how many times a particular protocol gets rejected. So Iím very much in favor of not setting up a commission to just evaluate it, but to be able to have some ongoing collection of data that theyíll be able to look at.

PROF. CAPRON: This is very consistent with our other larger project about how this whole process will take place, not with these subjects.

DR. COX: I think itís one of the most useful things this Commission could do to have a way of ongoing collection of data that will be accurate to be able to know what the facts are. Because I think in this field, for myself, thatís one of the things we struggle with the most. We have lots of paper and we have no idea how well itís working.

DR. SHAPIRO: Jim, could I make a comment on this? As I think about this, I think the issue of encouraging the collection of more informationóso many of the questions we ask donít seem to have any answersóis actually more important in my view than whether we evaluate what we recommend. Because what we recommend, if implemented at all, will be very slowly implemented over a longer period of time. I donít know where weíre going to be in three to five years and Iím not sure that thatís, in my view, a high priority. In any case, the world will evaluate it out there whether we say so or not. But the issue of finding some way to articulate the need for more information on how the system is operating, and as Alex said, this relates to a report we should have out next year sometime, is I think quite important.

DR. CHILDRESS: Further discussion on the evaluation, the collection of information? Is there general agreement with the direction Harold is suggesting? All right. We mentioned it in passing already this morning, I think Larry raised it, but we do have Laurieís second point, page 3 of her memorandum, worrying about our recommendation that IRBs not approve research involving subjects with mental disorders that may affect decisionmaking capacity when that can be done with other subjects. She worries about this having an unintended effect of excluding individuals from experimental treatments which can be life-saving.

How do you respond to this concern? I know from talking to several of you that you think this is not as much of an issue as she indicated.

DR. DUMAS: Well, my feeling is that if it can be done with another population, I donít know that would deny people the outcomes of that research that might be lifesaving. So that rationale doesnít quite compute.

DR. CHILDRESS: Steve?

MR. HOLTZMAN: I was just thinking about this. In her example, the trial was an efficacy trial with ó

DR. SHAPIRO: Iím sorry, Steve, I canít hear you.

MR. HOLTZMAN: I was just thinking about Laurieís question, and I think it goes like this. In her example, the trial was an efficacy trial with potential therapeutic benefit. Hence, by definition, the subjects must be people with the disease; e.g., schizophrenics. It canít be done in a normal population. Thatís good as far as it goes. But Laurieís question is, among, for example, schizophrenics, there is a population capable of giving consent and a population not so capable of giving consent, and can we be read as suggesting in that case that it has to be done with those who are incapable of giving consent. Thatís why she says a potential inadvertent consequence.

DR. CHILDRESS: Thank you.

DR. DUMAS: That helps. Thank you.

DR. MORENO: Iím not sure if Iím understanding what Laurieís concern is. My recollection is that we dealt with this issue under the rubric of the compassionate exception. I donít know why weíre sort of reconsidering this question. Thereís no issue of discrimination for people who have schizophrenia, say, and also have cancer, if thereís a potentially lifesaving or life-extending research procedure for which they might otherwise qualify, then they could qualify under compassionate grounds without being on the study.

MR. HOLTZMAN: I think thatís a different issue.

DR. MORENO: Is that a different issue?

PROF. CAPRON: I think she answered it that where we are dealing with so-called potential benefit we donít have an exclusion of these individuals if their legal representative agrees that they should be enrolled as a subject and they donít dissent from that. So her premise, her starting premise is that the report could be read to exclude people from eligibility I believe is an inaccurate representation of what we said.

DR. DUMAS: No, not on this chart. In theory, can this research be done in principle with another population? And if the answer is yes, that does in fact eliminate that population.

PROF. CHARO: Yes, Rhetaugh, thatís true. So if you were looking at chemotherapy and you didnít need to use people who had a form of dementia, you would avoid using them. But if the chemotherapy was potentially lifesaving and no standard treatment existed, compassionate use protocols would allow a person who has a form of dementia to have access to that experimental drug off of that study. Thatís the compassionate use route by which for somebody for whom it genuinely is a therapeutic intervention, it is available on special application.

PROF. CAPRON: But you donít enroll them in the study.

PROF. CHARO: Right. You do your chem. trials with competent cancer patients, and if there is a study drug that is the only available therapy for people who are failing on all standard therapies, it can be made available on a compassionate use basis regardless of their mental status. So if itís a lifesaving issue for me, it doesnít matter whether Iíve got dementia.

PROF. CAPRON: Laurieís concern is something that isnít lifesaving but it is potentially therapeutic. I think the annals of medicine are strewn with examples of things that were believed that they would be beneficial and turned out to be either not beneficial or harmful, which is why you would usually want people to consent to be the study population.

DR. CHILDRESS: Steve, do you want to pick up?

MR. HOLTZMAN: Iíll repeat it once more. If you read what she says, itís specifically not dealing with the cancer trial on schizophrenics. Itís asking with respect to what we mean by a population if you have a treatment regimen, a trial for that disease, schizophrenia, can we be read as saying that among schizophrenics, if youíve got those capable of consenting and those who are not, are those two distinct populations, and this is being read potentially as saying you have to go with those who are capable of consenting. She says some of these individuals, e.g., schizophrenics, may lack decisionmaking capacity at the time they enter these protocols if exclusion from these protocols could be detrimental to their best interest. The exclusionary clause is what "population" means ó

DR. MIIKE: But the answer is in this protocol. But because that distinction is made further down the scheme.

MR. HOLTZMAN: Okay. So thatís clear. Everyoneís clear?

PROF. CAPRON: Where, Jonathan, is the language which corresponds, as Larry was just suggesting, to that box at the top of this chart as to the meaning of population? Is it schizophrenics versus non-schizophrenics, or capable schizophrenics versus incapacitated?

DR. MORENO: Well, that was made in the approval. In general, the population I gather is the population of persons with mental disorders.

PROF. CAPRON: Thatís how I was reading it. But where is the language here that would answer this question?

DR. DUMAS: The reason is that if this is a research project that is not specifically focused on mental disorders, then if the person has a mental disorder that can be done with somebody else, then they should not be included. Thatís the way Iím reading it.

PROF. CAPRON: Thatís why we should document this therapeutic section and capacity uses section. Do we know where the language is, Jonathan? Iím still looking for an answer.

DR. MORENO: The language is that which introduces the whole report. That is to say thatís the population that this report is about is about persons with mental disorders.

PROF. CAPRON: No. This report is about a compound population. People with mental disorders impairing their ability to consent, right?

DR. MORENO: Thatís right. This is the problem with having a chart, as you know.

PROF. CAPRON: Right. With the chart lost in the report.

DR. MORENO: Rather than attending text.

DR. CHILDRESS: Are you raising that as question? Are you raising that as a research question for Jonathan?

PROF. CAPRON: Yes.

DR. CHILDRESS: All right. Page 170 on limiting subjects.

PROF. CAPRON: That sounds to me as though Laurie is absolutely right. This seems to suggest a policy choice saying that among schizophrenics, our example ó

PROF. CAPRON: 170, lines 7 through 10. It says "An IRB," line 9, "An IRB should not approve research involving subjects with mental disorders that may affect decisionmaking capacity when such research can be done with other subjects." Now, our whole process here is to talk about individual subjects being assessed. So it isnít enough that youíre in the category of a disorder which affects some people one way or the other, you could still end up on this chart. Itís at least ambiguous. And it needs to be expanded to make clear whether we are saying schizophrenics or mental disorders.

DR. SHAPIRO: Jim, you have three or four minutes to finish this.

DR. CHILDRESS: All right, folks, three or four minutes and three or four speakers.

Jonathan, David, and Alta.

DR. MORENO: The point is taken and I understand the ambiguity. We can take care of it.

DR. CHILDRESS: Okay. Jonathan says weíll work on the ambiguity.

David?

DR. COX: What Iím going to do, and I really encourage the staff to do this, itís matching the text to the flow chart. The flow chart is what I used to figure out what the hellís going on here because itís hard reading the text to put this in context. Laurieís pointed out one thing I think on page 170 where itís confusing. And Iím going to spend time doing that. But I think that the staff really needs to spend time doing that because otherwise people will focus on these inconsistencies to obfuscate actually all the good work.

PROF. CHARO: Unfortunately, again I find myself in opposition to Laurieís point of view but Iíd like to argue for it. There are two aspects to this population that concern us. One is their historic positioning and the stigmatization, marginalization, et cetera. The second is, in fact, the incapacity to consent. Now I must confess Iíve always been reading this document to mean that even within disease groups, we have a preference for subjects who can consent, that we recruit among those who can consent before we recruit among those who canít unless we absolutely need to use those who canít. And I have always assumed thatís what this means.

I would urge us to take that position explicitly. That it is better to use subjects who can consent for themselves than it is to use subjects who have to have somebody else consenting for them. I think Laurie, in fact, would oppose this strongly. Thatís the point of her paragraph, youíre quite right, Steve. And I think weíve at least identified the nub of the debate here.

DR. CHILDRESS: Okay. We have three more comments and then weíll have to see where we are at that point and stop. We have our marching orders.

I have Eric, I have Carol, and then Rhetaugh.

DR. CASSELL: Well, just briefly, Alta, I disagree with you because that is not just a difference between ability to consent and ability not to consent, itís a difference in the population. They are not the same population, except one can consent and one canít consent. The fact of consent is a statement about that illness, and weíre talking at this moment in time anyway. So I would cast an opposite vote.

PROF. CHARO: But if you needed to work with people who canít consent because you needed to look at the illness in that form, thatís fine. Iím saying if you could look at the illness in either form equally validly, scientifically, you would prefer to use the ones who can consent.

DR. GREIDER: I just want to point out one thing about this debate, and that again I think we should keep in mind the idea of therapeutic misconception. Weíre talking here about research and mixing that with lifesaving drugs and the idea about having lifesaving drugs. We should always keep in mind that research is research and therapy is therapy.

DR. SHAPIRO: Jim, just to ó I find myself, I agree with Alta on this. Thatís the position I have. Undoubtedly, there is some cost to any position you take here, you pay something to somebody. But I really think on balance, the dangers are much greater the other way. So when we come down to this, if we vote on this, thatís the side I would be on.

DR. CHILDRESS: This will be the last point.

DR. DUMAS: Thatís where I would come down, too. I agree with Alta. But I think thereís another question, and that is the issue of use of people who are mentally ill in studies that can be done on other populations. I donít know whether we have addressed that, I donít know whether we need to, but that is something that gets confused when you talk about who should be included and who should be excluded.

DR. SHAPIRO: All right. Jim, weíre going to have to draw this part of our discussion to a close. I want to doubly apologize to our guests. Weíve delayed over an hour now, and I apologize. Thank you very much for being here. Weíll turn to the next subject in a moment.

PROF. CAPRON: Thereís another topic here, two more topics we havenít addressed at all on this report. One is very small, page 112 and 113, and thereís a confusion here between a data monitor and subject monitor, a fundamental mixing of the two. And I would urge that we separate those unless someone disagrees.

The second is, are we prepared to send ó

DR. SHAPIRO: Iím coming to that issue right now.

PROF. CAPRON: ó out before we have results of our research.

DR. CHILDRESS: Thatís the next question.

DR. SHAPIRO: Thatís precisely the issue I wanted to turn to now. And thank you for the other comment as well.

My proposal is that weíll have to produce, will produce within the next couple of weeks, a new draft responding to the various suggestions raised today and the Commissioners have made and I think weíll try to improve it as much as we can. I donít know in that period whether weíll get to the executive summary that was called for yesterday; we may or may not get that done in that time interval.

My proposal is that we generate a new draft which weíll send to the Commissioners roughly two weeks from now with a relatively short turnaround time for comments before we then put the report out as a Commission Draft for public comment. Now we havenít resolved all the issues, weíll be flagging some of the issues which are unresolved and for which we want some feedback. But I think it is time to get some public feedback on this. It will only be a draft report, itís not our final report.

Yes?

DR. CASSELL: Time, you mean time now before weíve incorporated what weíve discussed?

DR. SHAPIRO: No, after weíve incorporated todayís discussions.

DR. CASSELL: Yes, because it may be only a draft but itís the draft weíll get hung with if it has got too much in it thatís a problem.

DR. SHAPIRO: We will have another opportunity to see a draft and respond to it. But on a short deadline. Weíre going to have a short time line when we get to that. But what I want to tell the Commissioners is roughly two weeks from now weíll have a new draft, which incorporates the discussion of the last day or so and have a relatively short feedback time. And if thereís something in it that really offends you, thatís the time to start jumping up and down and get our attention and we could make another decision at that time.

But the intent would be that we go for public comment on this draft. I think it is time for a larger number of people to see this, see where weíre going, and get feedback, and we shouldnít feel at all uncomfortable if we change our minds because of the feedback we get. Thatís the whole point of it. And weíre a finite group and there are other people out there who know a lot about this that might have some insights which are of great benefit to us.

So thatís the time line on which we will go. So for those of you that are carefully managing your schedule, Eric, itís now, of course we have a Memorial Day weekend coming up, but roughly the end of the first week in June is when you could expect this draft. Weíll keep you informed by E-mail if that schedule changes any significant way.

DR. MESLIN: Just as a request, I know that commissioners have read through the draft. If you have comments of an organizational nature, obviously editorial nature, please send us your drafts with a fax copy or a photocopy rather for yourself. And if you have them with you, leave them with us now, get them to us as quickly as possible so that we can start to work on this immediately.

MR. HOLTZMAN: Is it possible to request that the next draft is redlined? Marked to show changes?

DR. MESLIN: Yes, you can request that.

PROF. CAPRON: And with a summary memo of what youíve taken away from here and where the changes have been made in light of that.

DR. MESLIN: Sure.

DR. CHILDRESS: At some point, and maybe do this later, Alta raised a question yesterday about whether we might prepare some sort of document for education and edification for IRBs. Perhaps we could come back to that at some point, not necessarily today, but as youíre developing this other draft because that may be a document that could be useful on its own.

DR. SHAPIRO: Thank you. The one thing I wanted to make sure to mention, I talked with Eric and Jim about it this morning, as the next draft comes out, weíll be quite clear on how we feel about regulations versus guidance and so on and so forth and what weíll try for. My own view of that matter is that where we do want to recommend changes in the regulations, we certainly ought to do so. But we ought to do so in a framework, in my judgment, which asks the IRBs to act now even on a voluntary basis pending any changes in regulations that might or might not take place.

With that, letís move on. Apologize to everyone for the fact that we have been running almost late since we started somehow yesterday. And I apologize for that.

But let me now turn to Tom, because weíre going to be discussing the material on the human biological materials report. Let me turn to Tom and weíll get in a very few minutes to our guests.

DR. MURRAY: Thank you, Harold. First, I need to respond to a question that many of our visitors have been asking. They want to know if the weather in Cleveland is like this year-round. And as local residents will attest, of course it is, flowers are always blooming and the sun is always shining.

With that as sort of the benchmark for truthfulness for the rest of the day...

DR. SHAPIRO: Thatís why we have research monitors.