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DISCUSSION OF STAFF DRAFT: RESEARCH INVOLVING PERSONS WITH MENTAL DISORDERS THAT MAY AFFECT DECISIONMAKING CAPACITY

DR. SHAPIRO: We hope the rest of our time today of course will be devoted to the capacity report. This is a report which I hope/believe that we ought to be able to issue this year very shortly. I think the report, even though there are some unanswered issues still, is really quite close to its completion. I think it is really our responsibility to finish this report and issue it this year. We should not allow time to go on any longer. I think weíre close enough to it and I think we ought to make the decisions we have to make and get on with it and get on to some other project.

Iím going to turn the Chair over to Jim, who will lead us through this project. I think there are a couple of issues at the beginning that we need to have some general discussion on regarding the scope and justifications of the report; Jim will talk to that in a moment, which need to be resolved. And then my proposal is that we go directly to the recommendations, which have been distributed to you. Thereís a follow-up memo that you all have which corrected some unfortunate slips at the end as we tried to put this thing together. And weíll go from there.

Let me turn the Chair over to Jim.

DR. CHILDRESS: Thanks. Let me start by thanking the number of people who gave public comments. I think we ended up with 87, is that right? Probably some came in after that total. These comments were very, very helpful. And weíre grateful to Randy Hull for providing a helpful analysis, and you received that analysis of the comments. As the comments were coming in along the way, it was possible to include points regarding those comments in memos, and some of those points got worked into the draft we currently have.

In addition, Iíd like to thank the staff, Eric Meslin and others, including Jack Schwartz, who has joined to help out with the discussion, in particular relating to the use of various kinds of advanced directives, but other parts as well, and Cathy Hollen, who has been serving as an editor on this.

As Harold mentioned, if we look back over the discussion weíve had here in meetings and the e-mail exchanges that have occurred, as well as the various conversations, two preliminary concerns perhaps need to be addressed before we look specifically at recommendations, and they certainly will have an impact on the recommendations. Those two concerns have to do with the scope of this reportóand we had some exceedingly helpful comments on the e-mail, I found myself changing my mind after reading one and moving to the next oneóand then the justification for the report. So if the Commissioners agree, letís start there and then move to the recommendations.

I would note that youíve received memos that address the issue particularly of scope, and Iíll just connect the justification issue with that. Some of the changes that are incorporated into the current draft try to focus a bit more why we have chosen the direction we have chosen here and what implications that might have. But I would note that this was a matter of particular concern to the respondents and that 52 of the 87 respondents addressed the question of scope; thatís 20 more than addressed any other topic. So it is something that we do need to make sure that weíre clear about and that we can offer an appropriate defense for.

Let me just make a couple other comments and then letís see where we want to go with it. We initially started out as I recall by looking at a decision on cognitively-impaired or decision-impaired research subjects. But throughout, the focus has been on a particular population. I think in the e-mail exchanges that occurred from, say, mid-August on, there may be more agreement than might at first glance appear. Let me just throw that out and let me offer two different ways in which one might approach this matter.

One is what I might call a build-up strategy. You might start in the report from those with mental disorders, and Iíll just use that as a shorthand expression rather than going through "that may affect decisionmaking capacity," et cetera, that are the subject of research, and this is where the report currently moves, I think. But then to indicate, perhaps even more than we do here, although we do have some suggestions along these lines, that these principles and guidelines apply to others who are decision impaired or cognitively impaired as well.

So thatís a kind of a build-up. You start from focus on this particular population and then you move from the particular to the more general, and you can say more or less about that. There might be a variety of reasons, some of which we include in the report, historical reasons, social reasons, concerns about vulnerability in the context of research and so forth, for concentrating on this particular population. That would be the build-up strategy.

And we could have a build-down strategy, which was suggested in some e-mail messages, that would start from the principles and guidelines and say these are the things that apply across the board, but there may be particular concerns with the population we address in this report, and we will look at this population for illustrative purposes.

Now those would be two different ways, and I think I sensed both of those in the e-mail exchanges. What I want to emphasize is that they end up, I think, pretty much at the same place but with a difference in emphasis. That is to say, one can give a variety of historical and other reasons for concentrating on this population, but we still have the question of the general applicability. It seems to me one of the big issues is how weíre going to balance those two matters.

The second point, and there are others as well, about focus would have to do with mental disorders versus some other formulations, or whether to include brain disorders and the like. But letís start with the first one and then see where we want to go.

DR. SHAPIRO: Okay. Letís focus on this before we get to the recommendations.

Bernie?

DR. LO: First, I want to thank Jim and Eric and the staff for really doing an awful lot since our last meeting to sort of collateó

DR. CHILDRESS: And Harold who agreed to everything all the time.

DR. LO: And Harold, going through this responses, trying to make sense of them, sort of taking a lead in suggesting language and responses. And I agree with Jim. As I read through most of that thick stack, I was really struck with how many of our respondents had very strong concerns about the focus, the title of our report. I think it really goes beyond that because many of our recommendations are phrased as "for persons with mental disorders that may affect decisionmaking." We single them out in the recommendations.

I was very concerned at the feeling among many respondents that by singling people out in this way weíre actually doing them a disservice. That the very group we were trying to help might end up being stigmatized as a result of a possible reading of the report that says that if you have a label of mental disorder attached to you, somehow your decisionmaking capacity will be suspect in the research context and all these "protections" we put on you.

But actually, it stigmatizes you in the sense of really singling you out on the basis of a categorization, not on first cut on an individualized assessment, particularly in the context of we know there are many, many other conditions that are not usually thought of as mental disorders that impair decisionmaking capacity in a research context. And as I thought about that, I was really persuaded that our emphasis on mental disorders was not necessarily the best approach and that we really are talking about persons with decisionmaking incapacity in a research context. Mental disorders is just one pathway by which you may arrive at that.

So I would just like to say I really want to rethink our focus on the mental disorders and am concerned about the responses we got with regard to singling out people and perhaps stigmatizing them.

DR. SHAPIRO: Alta?

MS. CHARO: When I began to work through this I also became persuaded from the comments that it would make more sense to work from generalizable principles that apply to all people with impaired decisionmaking, although I fully understood why it might make sense to urge IRBs as they begin to implement these recommendations on a voluntary basis to perhaps focus their efforts on those people within that population who have impaired decisionmaking capacity who seem to be most likely to be subject to inappropriate enrollment and use as human subjects. That might well be the population of people not with all mental illnesses, but with just certain mental illnesses that are particularly problematic in terms of interaction with others.

One of the reasons that I felt this to be true is that as an ethics body, it is valuable I think to recognize the logical extension of principles. And the principles here are really based upon the respect for people who cannot consent consistently over time for themselves, and under what circumstances can they be drafted into medical research.

The second is something that comes from an analogy to the world of epidemiology and public health law. I was very impressed once by an author named Wendy Parmett who talked about democratic versus undemocratic illnesses. That when one divides up a population into special subgroups and begins to make rules for themófor the poor, for the disabled, for immigrants, for people who are ethic and racial minoritiesóthere is a tendency by the majority to not see their own interests implicated and to be more draconian in one fashion or another. But when rules are drafted in a way thatís going to apply to everybody, one tends to take a more balanced view because you might be the recipient or the enforcer of the rules.

Now in the world of impaired decisionmaking, we have classic, very difficult debates over other scenarios. The granting of a waiver from the consent requirement for people who are in need of emergency medical care is a wonderful example. In that particular area there was the argument that without being able to do unconsented research on these people, important research would not take place. And this was fought out over years, and the decision in the end was to permit it only when there was a situation in which the experimental protocol was possibly of direct benefit and, at worst, was neutral because there was not standard therapy that was working. In other words, they were working through the same kinds of principles.

What I fear, if we were to focus on those with mental illness and then try to build up from there, is that we might find ourselves developing a set of rules that as they build up turn out to be somewhat inconsistent with the rules that are also being developed for other populations of people with impaired decisionmaking. That we might be safer testing every one of the rules that weíre proposing here against a whole variety of populations and asking are we willing to live with it for all populations, even if weíre only going to start by applying it to one population, and in that way get a nice balanced view at the end.

DR. SHAPIRO: Laurie?

MS. FLYNN: Iím very heartened to hear this discussion. This has been an issue even within those of us who deal around advocacy for individuals with mental disorders on a daily basis and, in fact, has been one of the most fervently debated points amongst members of my organization. Indeed, I think we have come to feel that the points that Alta and Bernie made are persuasive. That we do not want to, by virtue of a diagnostic label, make some assumptions and lay some particular and special categories of protection that really may not in the end be helpful.

So I think weíd do best to broaden the scope as we focus the report, recognize that decisional impairments affect a larger group than just those with specific mental disorders and yet pay attention, as indeed I think we have throughout our deliberations, pay attention to the particular vulnerabilities that we have learned are particularly attended to certain of these disorders. So I would favor us moving in the build-down strategy, as you described it, rather than the build-up strategy.

DR. SHAPIRO: Larry?

DR. MIIKE: I clearly disagree, and you know I disagree. This is kind of late to be talking about expanding beyond the people who have impaired decisionmaking because of mental illness, because that has been the whole focus of our almost two-year discussion. Why this comes up now at a critical time or toward the end is beyond my comprehension.

DR. SHAPIRO: Other comments?

Diane?

DR. SCOTT-JONES: As I reread our justification for this report and I listen to the comments about how it is important not to stigmatize any group of people, I agree with that. But I suppose when it comes down to getting this report done, I would have to agree with Larry that we made a decision a long time ago and I donít see how we can change this easily in the time thatís remaining to us. We would need to change the whole justification for the report.

DR. SHAPIRO: Rhetaugh?

DR. DUMAS: I have always seen this project as having very broad implications for people who impaired decisionmaking capacity, and I have seen the choice of the case in point as people who have mental illness because this is a population that has been seen as being particularly vulnerable. So I donít see these two concerns as being necessarily oppositional.

I believe that there is value in targeting the mentally ill because of the cases that we reviewed earlier because of the concerns that people have had. But I do think that we can make statements early on, if we havenít done it already, that this is a special case. What weíre really talking about is people who have decisionmaking incapacities. And I donít see anything in the report that is not applicable across a wide range of diagnoses.

DR. SHAPIRO: Eric?

DR. CASSELL: Everybody knows how I feel about it. But I would like to ask people who think we ought to focus on other conditions, would they tell me what other things that afflict the human condition; affect decisional capacity; wax and wane over long periods of time; are accompanied by defects of judgment secondary to misperceptions of the world, which also wax and wane over time; and which are susceptible to treatment to remove those two defects. If they can tell me anything else that dosnít come under what weíve discussed here that fits that category, Iíd like to hear what it is.

DR. SHAPIRO: Iím not going to answer that question, while I have some views on all this. But let me go to the Commissioners first.

Professor Capron: I would support Rhetaughís basic approach here. And it seems to me also that it isnít inconsistent. And what I would ask, in response to Alta and Bernie, is that as we look at the recommendations we ask ourselves is there anything said here that we would only say of a person who had a diagnosed mental disorder or disease or would we say it also of a person who because of some other problem was unable to make a particular decision? And if we get to something of that sort, then ask ourselves why are we separating out this group.

But the basic notion that we have studied this area, come to conclusions, and then could say these same considerations ought to be taken into account by IRBs as they review protocols that involve subjects who lack decisionmaking capacity for other reasons, I think that is a better approach rather than trying to rewrite the whole report now.

It is not this report that is going to stigmatize people with mental disorders. We are dealing with this issue precisely because that stigma exists, the system doesnít deal well, our country doesnít deal terribly well with people in this condition and they have been vulnerable to a level of problems in research which I donít think has been matched by many other categories of research. And I think if it were matched by other categories, weíd be looking at those categories. If cancer patients, it turned out, were suffering as many harms to which they werenít consenting and were sort of locked out of view for a good deal of the research, I think we would address cancer patients, yet we wouldnít say weíre stigmatizing cancer patients by that special concern.

DR. SHAPIRO: Diane?

DR. SCOTT-JONES: I would ask that we look at the other populations that have been singled out in the regulations, and theyíre footnoted on page 9: pregnant women, prisoners, children. I think the case of children in particular is instructive because that category includes adolescents, many of whom have decisionmaking capacity approaching that of adults and we still consider them a special category in general needing special considerations. Thatís not to say that there is never a child who cannot make a good decision about research participation, but that, on balance, it is helpful to have children as a special category.

I think we can say the same to justify our treatment of persons with mental disorders here. It is not to stigmatize them, but to say that, in general, we need special considerations and we might recognize that these regulations might not be needed for specific persons in that category, the same way specific persons whom we categorize as children might not need the special regulations.

DR. SHAPIRO: Bernie?

DR. LO: Let me just try and respond quickly to some of the points others made. I think there are other conditions that wax and wane that affect decisionmaking capacity.

DR. CASSELL: Give me one.

DR. LO: Delirium in acutely hospitalized patients.

DR. CASSELL: Over years? Itís transient.

DR. LO: Itís transient, but if you do research on them and they are delirious at the time, youíre in exactly the same situation as if you had relapsed from...

DR. CASSELL: Itís unarguable. Something in these regs will protect that. Theyíll be protected also.

DR. LO: But my concern is that when you read our recommendation, it says people with mental disorders, not people with other disorders that also have a very high likelihood of impairing decisionmaking capacity.

I think in response to Diane, I want to say children are different. The presumption with children is that youíre not competent and adolescents are an exception to the rule for children, so weíre going to treat them like adults. Thatís different from the way we treat most people. Adults, the starting presumption is that youíre competent. Now by virtue of having certain conditions, mental disorders is just one of a number of conditions, we may have good reason to question that.

But once you single someone out and say weíre questioning your decisionmaking capacity because you have this, this, or that, we are singling them out. And it could be for very good reasons, but it could also be singling them out in ways that are maybe not so desirable. And I think of all the things that could cause decisionmaking impairment, in our recommendation to single mental disorders out from all the others singles them out in a way which I donít think is fair. Weíre not treating similarly situated persons similarly.

DR. SHAPIRO: Rhetaugh? Excuse me, Alta first, then Rhetaugh.

MS. CHARO: Let her go.

DR. SHAPIRO: Okay. Rhetaugh?

DR. DUMAS: I think that we need to be careful about our wording so that what you just said, Bernie, is not the interpretation. Because certainly it is not my view that we are saying that people who are mentally ill are ipso facto incapacitated to make decisions. What weíre saying is that those people who are mentally ill who have incapacities need extra protection. And weíre also saying that efforts should be made to ensure that this assessment is appropriate and expertly done.

So it could be anybody who is ill who may have problems in making decisions and judgment. I think we need to make clear in our report that we are not saying that all people who are mentally ill have difficulty in making decisions. That is not our intent. And if that is the interpretation, then we need to do whatever is necessary to avoid that interpretation.

DR. SHAPIRO: Alta?

MS. CHARO: I believe, Larry, that the reason why this came up at this particular late moment is because the public comments were taken seriously and they raised this issue and suddenly everybody began grappling with it. And I think that is exactly what ought to happen as a result of the public comment period. So Iím not disturbed by the late arrival of this issue again.

For me, a central problem in medical research is about its underlying justification. And Iíve used the phrase "medical draft" many times, which some people might think of as being extreme, but I do think of the enrollment of people who cannot volunteer for themselves as a form of a draft for the public good and, occasionally, for their own personal benefit. And thatís extremely problematic and needs to be approached very cautiously.

So I find that to not address the situation with regard to the general population of people with decisional impairments, even if transient, because I never understood this report only to apply to people whose capacity fluctuates over multiple years, I understood it simply to apply to people who had decisional impairments, although in this case with mental illness. I find that it is important for us to emphasize that unconsented research that poses no prospect of direct benefit to the subject and is more than minimal risk should not be imposed on people. People should not be exposed to this without their consent. Prior consent, fine. Elaborate use of surrogates that have been appointed to make these decisions for them, fine, because those are all ways in which people essentially have said Iím volunteering in one fashion or another. But to simply ignore the fundamental principle that people should not be exposed to more than minimal risk for no benefit to themselves without their personal involvement in that I think is simply a hard line that I would encourage we drop. And I donít want to see us draw it only around the population of people whose impairments arise from mental illness. I think itís really more basic as a human rights question.

On the other hand, to conclude because I know Iím going on too long, Iím not suggesting, however, that we rewrite the entire report. I am suggesting specifically that the recommendations be written without reference to mental illness, that the report emphasize that as IRBs begin to implement this that they might quite appropriately focus, as we did, on the population of people with mental illness, for two reasons. One, the frequency of impaired decisionmaking is going to be higher in this population than in the general population of patients as a whole because of the nature of the disorders. It wonít be universal, but the frequency will be higher so youíll be seeing it more often. And second, because thereís a special history here that adds to the prospect that that impaired capacity will be taken advantage of in some fashion, deliberately or not.

So we donít have to change the entire report. We may need to change the first couple of pages and the actual wording of the recommendations, and in every other respect the report can stay the same, in which mental illness is the running example of a broader problem.

DR. SHAPIRO: Trish, Larry, Steve, Eric, Jim, and then I have a lot to say about this. Letís see, who is first? Trish.

MS. BACKLAR: Actually, Alta, thank you because now I donít need to say a great deal. What I was really hearing there was an argument between speed and content. I think that Alta has kind of put those both together and taken us off the hook. I do think that her suggestions are very good.

DR. SHAPIRO: Steve.

MR. HOLTZMAN: I was just going to observe that Iím hearing two very, very different strands of thought here. The one that Alta just articulated has to do with whether or not we should be making recommendationsóthe class of people to whom the recommendations should apply, and Iíll come back to that in a second. That seems to me very different from the question if in choosing a class we thereby stigmatize and therefore we ought not choose a class. I think we should run those two arguments together.

If weíre going to follow Altaís procedure, I think the way you have to do it is what Alex recommended. In your way, I think the way weíve articulated, is we took a case study, if you will, for good reasons, weíve reached conclusions, and now you want to apply those conclusions beyond the case study.

The only way to do that is to look at each one of your conclusions and ask would there be any reason why I wouldnít apply this more broadly. And after youíve asked that, youíre going to say have I really thought through all of those other cases so as to be able now to generalize, or does it take another year and a half to feel the same confidence with respect to that broader application that we needed the year and a half to get to this smaller group.

DR. SHAPIRO: Eric.

DR. CASSELL: Well, I think thatís a very good comment. I donít think anything in these recommendations does not apply to people who have lost decisionmaking capacity for other reasons. Nothing.

I personally think it stigmatizes people not to allow them to be who they are. And that in the whole current business of people who are decisionally challenged and vertically challenged and optically challenged, an attempt not to be what you are is a kind of negative stigmatization. And Iím not the only person to say that. Lots of people do and for good reason. In fact, there arenít other disorders that produce this particular problem, the particular population that has been punished by not being protected, singled out for many reasons but all of them leading to nonprotection. To focus on the decisional capacity is to focus away from the special protection that a population needs because of the trouble they have.

You donít want to call it mental disorders, call it trouble, call it anything, but it is a special population and itís a painful population for themselves and for others. We set out to do this, they were excluded from previous protections, and thatís what we should do.

On the other hand, I absolutely agree we should never permit research done on people who have no decisional capacity without protections. And these will take care of that. But I donít think we should hide from a special population because weíre afraid that the name is bad.

DR. SHAPIRO: Jim.

DR. CHILDRESS: This has been a very helpful discussion, and I know itís not over yet, thereís more to come. But it does seem to me that we have in the suggestions that have been offered a plausible way to go and that certainly Alexís suggestion is I think a very good one, that after we feel comfortable we have all the issues out on the table that we need to keep in mind about scope and justification, then the exercise of going through the recommendations and really seeing what we have with this question in mind as to whether what we have here applies merely to the population weíve focused on or whether it does have a great generalizability. So I think Alexís suggestion is an excellent one.

DR. SHAPIRO: Larry.

DR. MIIKE: Well, youíve already heard my opinion. But I just want to comment on Alta saying that the reason that this discussion is going on is because of the public comments. It depends on how one reacts responsibly to the public comments. It doesnít mean that you go and change your whole assumptions and all the work that weíve done. You try to allay the kinds of fears that have arisen that weíre singling out.

I would violently disagree that just because weíre looking at this issue because it arose in the area of mental illness and fluctuating capacity or varying capacity that we, therefore, stigmatize them. I donít accept that premise. I think that there are other ways of dealing with that public criticism than just wholesale transformation of our report. People are saying it applies to a whole lot of areas. But weíve never had that discussion. Weíve always focused basically on the people with mental illness. We have not had that wide discussion over this period. And to leap to a report that all of a sudden changes that is something I canít agree on.

DR. SHAPIRO: Diane.

DR. SCOTT-JONES: I agree with what Larry just said about how we should respond to public criticism. It isnít to completely change our goal in this report, but to be mindful of what might happen when people read and interpret what weíve written. I think it means that we need to reread our sections in the beginning, where we justify why weíve chosen this population and I think we can make a strong and convincing case. I think Altaís suggestions for focusing on frequency of impairment and the history of the way this population has fared are excellent ways to emphasize that we had a reason.

But weíre not saying that every person who fits in this category is the same. No matter how you break down categories you always will be subject to the criticism that the way you draw the boundaries isnít quite right. Thatís just the nature of categorizing individual human beings. You will have some variability and you will have some fuzziness at the boundaries of that category and people who donít fit that category.

So I think our strategy should be just to reread and make sure that weíve crafted the language as carefully as possible not to permit misinterpretations of what weíre about.

DR. SHAPIRO: I strongly agree with what Diane and Larry have said. I think we have to go back to the beginning here before we lose track and put ourselves at sea totally. Itís very interesting to me that of the long years weíve been working on this and the public comment we received, that issue never arose before except at this table, where it arose right at the beginning when we asked ourselves this exact question. Because immediately at this table the issue came up: What about other people whose decisionmaking power is impaired? And we discussed that and made a decision about it. And we have spent a year and a half or so thinking as carefully as we can about this issue.

It is not at all clear to me if you go through our recommendations that we can possibly, in the time we have reasonably available, understand whether it applies to everybody who ever has a decisionmaking impairment. I completely agree with Altaís commitment, as we all do, that people in that situation should not without some protections be drafted, as you say. I completely agree with that. But we looked at this issue and we took a particular branch. It may or may not have been the right one. I think, myself, it is a perfectly defensible one.

Of course, whenever you talk about a special population you are guaranteed to get this response. Thatís just the nature of public rhetoric today. And if you donít talk about it, youíll get the other response. And you can be sure that if we had broadened this and took the opposite view, we would now be getting comments, perfectly respectable, thoughtful, and from people of good will and knowledge, that, in fact, we had missed the boat because within that group of occasionally decisionally impaired, transiently decisionally impaired, permanently decisionally impaired people there is a special group whom we havenít taken the bother to notice.

Now I think it would be quite inappropriate for us to try now to expand this to include another worthy subjectóthis is a worthy subject, other people who are decisionally impairedóto expand this to include them. Thatís not what we focused on. Thatís not what we have asked. After all, we have had public comment not only at the end, but we had public comment every time we have met, and we have had people meeting before us at virtually every meeting on this issue, none of which raised that because they understood what we were dealing with. And I interpret the public process weíre involved in, it would be not quite within our contract to expand at this stage. Thereís a whole series of people out there who may have wished to address this if we were doing the broader thing.

So I think, however, that there are important ways, indeed, we have a responsibility to respond to the very thoughtful public comment we got at the end, and I think we have to find ways to include that in the language of our report, make it clear. This report, if you read it from the beginning, goes even at the current time to great lengths to try to make the point that having a mental illness is not per se ipso facto meaning youíre decisionally impaired, particularly with respect to your decision to participate in a research protocol. That has been on our minds right from the beginning in every draft that we have produced here, both the good ones and the ones that werenít so good.

And so I just think that short of remobilizing over a long period of time that we really donít have the option of the broader population. We could make that decision that we want to remobilize over a much longer period of time. I think thatís not a good strategy. We have too much on our agenda that we have to address.

Weíre about to do something useful and helpful and I think we should go ahead and do it and in as spectative way as possible. And if we think that there is another extremely important population which we have to deal with, we can add that to our agenda and, using this material, proceed to make additional recommendations. None of that should prevent us from making sure the language here is appropriate and is as responsive as possible. None of that should prevent us if we think we have a particular recommendation that need not mention or at least doesnít benefit from singling out a population (like people with mental disorders), then we could always not phrase it that way. But the idea that we could on the fly remobilize ourselves to deal with a much broader population, which has a whole series of issues weíve never even discussed at this table in some cases seems to me too risky and not responsive, mainly not responsive.

And so that I think our choices areóI donít know, Jim, I havenít thought of it build-up/build-down analogy before. I think weíve just got to work as imaginatively as possible with the build-up strategy, if I understood what you were saying, and use the public comments, many of which were very thoughtfulóindeed, I learned a lot from reading themóin ways to improve what weíre saying and to make sure what weíre doing. I donít think any fair-minded person can read this report and accuse us of stigmatizing people. I just reject that accusation. It has to come for some other reason or not having read what we said carefully. But we need to try our best to even use language which avoids that as much as possible because it wasnít anyoneís intent here.

So while we can go back and say way back then we should have made a different decision, well thatís possible. I certainly wouldnít want to defend that more than that. But we made a very sensible decision even though there were other sensible decisions we could have made. And so I think our challenge is to make sure the language we use is as responsive as possible to these concerns, which are real and important concerns. I donít want to belittle those concerns in any way. Those are real and important concerns. But in terms of our agenda, you all know what projects we have in front of us are we just have to get on with it.

Weíre on the verge of doing something very useful and about which thereís a long literature that says, somebody should have done something about this twenty years ago and thirty years ago. And here we are about to do something about it and stand some chance here of getting distracted and pulling back from that. I think that would not be wise. Bernie?

DR. LO: Let me go back to the point that Steve raised, which I think is a very good one. Letís put aside for a minute the title, the framing, that sort of thing. Letís go back to the recommendations, which are really the core of what weíre doing. And taking account of what Harold just said, how do you all feel about looking at the recommendations and trying to see if we can make the recommendations without specific reference wherever possible to mental disorders?

Responding to Larryís concern and Dianeís concern, and Haroldís concern, we just havenít thought about how this would play out in other scenarios or situations where people may be likely to remain, in fact not have decisionmaking capacity, do we feel confident phrasing recommendations which are broadly worded enough to apply to other types of situations that we really, frankly, havenít thought about except that criticism?

But I just am concerned that it is accurate to phrase our recommendations in terms of people with mental illness because thatís what we thought about. But I think the question is do we single out our recommendations to apply only to them, or to all people belonging to a category that has a high potential for not having decisionmaking capacity, or to all people who, in fact, do not have decisionmaking capacity. Weíre struggling with a problem of are these three groups ethically similar in relevant ways. And if so, should we treat them the same, or should we treat them differently, or should we just say we never thought about it, so weíll just state it in terms of the narrowest framing that applies to what we did?

DR. SHAPIRO: If I could just interrupt, Jim. I think we should go to the recommendations very shortly and just see as we go through, as a result of this conversation, understanding, and see if we can improve the language in ways that we feel comfortable with thatís within our capacity and knowledge to deal with. And so Iíd like, Jim, if itís all right with you, in just a few moments to go directly to the recommendations, because we can talk a long time about all these issues because it is an important but inexhaustible source of discussion.

So I would like to go directly to the recommendations at least very shortly. Now I have three people on my list and I want ask them if itís all right if we do that, and itís Trish, Alta, and Steve. But if not, we can wait and you can say a few other things.

MS. BACKLAR: I can say what I have to say very quickly. One is, I feel like you yesterday, whoever speaks last, I am persuaded. But actually, I am very persuaded by your argument. And I am also actually persuaded by Alex, who I thought was the person that said that we should look at these recommendations as though weíre looking at the issue of capacity to consent. And I think that that is the issue. Thatís why weíre having so much trouble, because what this reportís about is peopleís capacity to be medically drafted or to make their own decisions about going into a research protocol.

And I think if we examineóI agree, if we examine the recommendations, we may find that weíve resolved in ways things that we can easily change what goes before and use what goes before as something of a paradigm, not as just this particular group. I think it would be quite easy to do that.

DR. SHAPIRO: Alta?

MS. CHARO: Far be it from me to not be persuaded by an argument about pragmatics. But my concern had not been about stigmatizing. And so I would like to urge as Plan B, if people donít object, Iíd like to urge that we have an extremely strong, simple to understand statement right up front that says "Risky research with no benefit on people who canít consent is morally suspect." Period. We are focusing on the mentally ill. Much of what we say is going to be applicable to others. I know itís there. It is not clear. You have to wade through 200 pages to find that concept in there. I would like that to be emphasized, not the stigma issue.

DR. SHAPIRO: Iíll turn to Jim. I have no problem with that.

DR. CASSELL: I think it actually says that in the first sentence of the second paragraph quite clearly.

DR. CHILDRESS: I think the revision does go more in that direction. But, again, I think we can easily go back andó

DR. SHAPIRO: We can meet that challenge.

Steve.

MR. HOLTZMAN: Just very quickly. I agree with that. I took Harold to be saying what I said to Bernie: that the methodology would be to examine the recommendations but that you couldnít without going back for a long time be confident in terms of the general applicability of those. So that we could certainly go through this exercise now, but there is no way I, for one, would feel confident in the generalizability without then asking the questions who else, and by putting it in that and engaging that. And I took that to be Haroldís argument.

DR. SHAPIRO: Thatís correct.

DR. DUMAS: There are some that are written there generally. Many of the recommendations do not have the words "mentally ill" in them.

DR. SHAPIRO: Weíll get to all of them momentarily.

Jim, how about taking us to the recommendations.

DR. CHILDRESS: All right. Ifó

DR. SHAPIRO: Excuse me. I apologize again for interrupting. You may also want to refer the Commission membersí attention to the memo that you addressed.

DR. CHILDRESS: Right. I thought we would go to the draft text and then Iíll refer you back to the memo for particular discussion.

So the first recommendation is about IRB membership. That appears on 139, our recommendation number one.

DR. SHAPIRO: Larry?

DR. MIIKE: Iím going to have to leave about 11:30 or 12:00. So if we donít get to the areas in which Iíd like to say some comments, I hope you will indulge me in interrupting.

DR. SHAPIRO: Okay.

DR. CHILDRESS: How much time would you need?

DR. MIIKE: Let me just raise the issue. If you look at recommendations 4, 9, and 10, and I believe itís the revised 12 and 13. I read that to understand thatóeven those without the actual personal capacity to consent could be enrolled in minimal-risk research. In more-than-minimal research, thereís a distinction between with benefit and without benefit. I think I raised this issue in some of our e-mails. I donít understand the distinction why. I see that at least for the area of "more than minimal risk with no direct benefit," thereís been a change. It effectively says people who will never have the capacity to consent can never participate in research with minimal risk and no benefit. I had some problems with the dichotomy that we had there, where before that was left in and then people with some fluctuating capacity could participate only if they had an advanced thing. That still remains in the "not greater than minimal risk/direct benefit" area. It puzzles me about the logic behind that.

DR. CHILDRESS: Right. And Alta has raised a similar point with relation to that specific recommendation. So we will make sure that thatís dealt with.

So weíll just go in order then.

DR. SHAPIRO: But youíve noted that down, Jim?

DR. CHILDRESS: Iíve noted that, and Alta has also raised it this morning privately with Trish and me.

Okay. The first recommendation has to do with IRB membership. We did get public comment on that and the staff recommendation was that we basically not make any change in this. Is there any discussion of recommendation number one on page 139?

DR. MIIKE: I guess the discussion also says thatóweíre only talking about IRBs that regularly deal with these kinds of research topics. But I think the text adequately addresses that concern because it just depends on a particular situation, and IRBs that donít regularly deal with these will not have those members. The numbers are a toss-up. You can never agree on those specific numbers.

DR. CHILDRESS: And I should just note here that at times weíve actually had the rest of the paragraph following the boldfaced Recommendation 1; weíve sometimes had that as actually part of the recommendation. Here it is presented as text. But it has been at some times part of the formal recommendation.

DR. SHAPIRO: Bernie? Jim, why donít you recognize people so we arenít confused.

DR. LO: I have two concerns about this recommendation. I think they both can be fixed. One is that I think weíre under-inclusive. Iím actually very concerned about IRBs that donít regularly consider these sorts of proposals but get one handed to them. I think I would like to have something there to say that in that situation we strongly encourage an IRB to go out and get special expertise and discuss withó

DR. CHILDRESS: We do say that. Itís in the text but weíve sometimes had that whole first paragraph as a bold recommendation.

Professor Capron: What is this language that is indented as a paragraph and it stops being bold?

DR. CHILDRESS: I would prefer we go back to the way weíve had it in the past, which is this is all recommendation number one. That whole paragraph.

DR. MESLIN: Up to line two on page 140.

DR. CHILDRESS: Right. And that I think would take care of Bernieís concern here.

DR. LO: Yes. Iím just concerned that it be part of the bold recommendations. Thatís one.

The second concern has to do with the generalizability question we were discussing earlier. Could we put in a paragraph in the text saying IRBs that regularly deal with proposals with other classes of people that are likely to have impaired decisionmaking capacity consider getting input aboutóbecause youíre singling out...

DR. CASSELL: Who are they? They are a clinician, Bernie.

DR. LO: Eric, in my hospital and your hospital there are a lot of drug studies for pharmacokinetics on hospitalized patients, many of whom are not competent to consent, the consent form is signed and they have no idea what theyíre getting into.

DR. CASSELL: Bernie, thatís covered, clearly covered under existing regulations. They are not permitted to be included in research because they canít give consent. Now if in your hospital they are doing that, what are we going to do?

DR. CHILDRESS: Alta?

MS. CHARO: Eric, I beg to differ. Thatís exactly the problem. They are being included routinely.

DR. CASSELL: Even though the regulations prohibit it?

MS. CHARO: Other people are consenting on their behalfóroutinelyóbut without any of the special limitations, protections, audits, and monitors that are being proposed here.

DR. CASSELL: Iím saved by my phone. Hello?

Professor Capron: This is all on the transcript, Eric.

DR. CHILDRESS: The question is would it be possible though to accommodate Bernieís concern by either a footnote or parenthetical comment or separate paragraph?

DR. LO: Let me just say something. Steve and I had a side conversation. The category here, I think it would be good idea to have an IRB have someone who is not just a lay member but someone who has insight into what it means to be in the hospital, a former patient, a relative of a patient, a relative of an ICU patient is another category. What Iím concerned about here is people saying shouldnít we also have similar consideration. And I would say, yes. And we donít have to state it because we havenít thought it through, as Harold has so nicely argued, state it as a recommendation, but say IRBs ought to at least consider it so that we keep the issue out there.

DR. CHILDRESS: Diane?

DR. SCOTT-JONES: It seems to me that thatís already covered in the language that we have. On page 140, it states "It is for these reasons that the Common Rule directs those IRBs that frequently review research involving a vulnerable subject group to consider having as reviewers persons knowledgeable about and experienced with working with the relevant subject group." It is already in there to cover other groups.

DR. LO: But we had a small conversation before about membership on the IRB with voting rights and sort of being an ongoing for the process is different than being a reviewer. I just think that weíre not losing anything by putting that in and it signals that weíre aware that there are other groups that you can identify by group category that share many, if not all, of the characteristics of people with mental disorders.

DR. CHILDRESS: Mr. Chair, if it would be permissible. One possibility here would be actually to get Bernie to draft such a paragraph or a few sentences, not necessarily right now, so that we could then decide whether it was something that we could comfortably include.

DR. LO: Sure.

MR. HOLTZMAN: Bernie, I, for one, and I think most people would agree with the spirit of what you want to accomplish. The question is can we possibly do it here and is here the right place to do it? In general, if an IRB sees a lot of AIDS cases, it would be useful to have representation. If they hardly ever see them and they have one, they should get someone from the outside. The question is in the context of this report are we going to end up footnoting everything we say by saying one should consider the generalizability of this for all similar, where similar is so wide open? Thatís the concern I would have. And at the end of the day, we may have vitiated the impact of this for the problem weíre trying to address.

DR. CHILDRESS: Eric just mentioned, and I was on the same wavelength, that this might be exactly the sort of thing that the White Paper could well address.

Harold?

DR. SHAPIRO: One alternative, Bernie, to this situation, which doesnít address this particular one but as we go through this, as Steve says, if we try to accumulate one more paragraph after another here, it may be difficult. One alternative is to go to the area we have here somewhere called "Guidance to IRBs" or something like that and try to lay out much more carefully there how they, advise them that they should really look at this set of recommendations, think about other populations and consider.... I donít have the words, Iím sorry I canít get the words out right now. But that might be a way in which they might actually notice it more because it would be highlighted in one place and thought through carefully. Maybe that would be a good idea and would save us having to tailor-make it.

DR. LO: I like that suggestion better than my suggestion.

DR. CHILDRESS: Steve, a follow-up here, and then I have Rhetaugh, then Larry.

MR. HOLTZMAN: And also maybe we want to explicate right at the end, right out in bold, that in considering this, there are great lessons that have been learned that in fact are probably generalizable. And maybe we could specify there where we think the direction of thought should go.

DR. SHAPIRO: Give us a chance to do it in one place. And we can also do it more carefully. Give it more attention.

DR. LO: Thatís a good suggestion.

DR. CHILDRESS: Okay. Rhetaugh?

DR. DUMAS: Iíll be brief. I like the suggestion that just was made. Iím not in favor of changing the wording of recommendation one because I think it would dilute it or even confuse it. I think there are two suggestions that make a lot of sense to me, and that is to make a statement at the beginning in here, and also to treat the general issue in the White Paper. I thought that would be a good idea.

DR. CHILDRESS: Laurie?

MS. FLYNN: I wanted to make sure that we had some agreement. As I think you were indicating, Jim, that we would like to have the whole of that first paragraph become the recommendation. I wanted to support that and I didnít know if weíd come to some closure on that.

DR. CHILDRESS: Actually, let me emphasize, the whole has been the recommendation until this draft and then somehow only the first sentence became bold.

Anything else on this recommendation?

DR. SCOTT-JONES: And are we agreeing that we should move or strengthen the paragraph that says "additional guidance for IRBs" on page 157 that refers to the spirit and substance of these protections? Were we saying that we might consider moving that?

DR. CHILDRESS: Yes. We will do that. We will draft something.

Okay. Anything else on 1? Recommendation 2. Following public comment, the staff recommendation was for a more careful statement of the justification for this particular recommendation. The draft you have before youóthe text, I think, does go some distance toward providing stronger justification. It may not be there yet, but it will focus on the principle of fairness and on respect for persons in terms of informed consent as particular reasons.

Eric?

DR. CASSELL: Just a simple thing. Could we take the word "targeting" out? I donít think we want to target a population. I think we could just say "involving" persons.

DR. SHAPIRO: That was an issue we went over. I donít know about targeting or not. But what we were concerned about, as I recall, Jim, was we did not want to prevent people with mental disorders from participating if they are able in some research project just like any other person would. What we wanted to do was prevent those people being taken advantage of as a group, or thatís how I understood. Thatís where targeting came from. Iím quite willing to think of better words.

DR. CHILDRESS: I think I proposed it but it was just a way to get at exactly the point that Harold has made.

DR. SCOTT-JONES: Singling out, focusing on?

DR. DUMAS: A lot of people understand the word target, and so I would disagree with Eric. I think that in the general concepts in which weíre talking, the word target is appropriate. They understand what you mean when youíre talking about focusing on a particular group.

DR. CHILDRESS: At any rate, we will provide suggestions and weíll see what will work here.

Larry?

DR. MIIKE: I think part of the reason for the objections that we have received was that mistaken notion that if they were heart disease, period, weíre saying they canít participate. So I think on page 142, the lines 20 and down should be more prominent. It is sort of buried down there. I think we should make it clear that weíre not saying that they should not participate in research in these non-mental health areas if they are related to the condition that they have.

DR. CHILDRESS: Okay. Weíll work on strengthening that part then.

Any other comments on Recommendation 2? Okay. If thereís no objection, weíll turn to Recommendation 3. Recommendation 3 on assessing potential subjectsí capacity is the one that received the second-most public comment; 32 of the 87 addressed this. Here Iíd refer you to the memorandum of 9-15, page 1. This is the one from Harold, Eric, and myself, dated September 15, Supplemental Materials. Here there is an effortóif everyone locates that, it was at everyoneís table yesterdayóitís an effort to deal with this in part by going back to what had been a part of our discussion earlier but then got lost in part because of the location of this. This was really limited to research involving greater than minimal risk. That was the trigger for this kind of systematic assessment of competence of subjects, not that competence is not assessed in other settings, but this is a requirement for the systematic examination.

So that is the major change that is recommended on page 1. And, again, it goes back to our written and oral tradition here, but that doesnít mean that that resolves anything.

DR. MIIKE: Jim, I think the placement is what confuses people, too. It should be later on.

DR. CHILDRESS: I think thatís right and I actually have recommended that we consider doing that. One of the things in looking back over the materials leading up to this is we had, in addition to the flow chart appendix, we also had another appendix that just summarized the recommendations. And in that particular one we had it clearly targeted earlier in a different location: what would be appropriate for greater than minimal risk research. That may be a way to handle this to avoid the confusion. Because it was confusion that came up in our discussions with some other groups when they said, but look, this is going to be terrible in the research area, and we responded, but look, weíre only talking about greater than minimal risk research for some of these things at this point.

Eric?

DR. CASSELL: I understand that, and I understand the objections investigators have that this would be time consuming and expensive. There is an implication, however, when the method is specifically stated otherwise that this is one of those places that you can enroll people in research without being able to make consent. If we say you only have to assess when itís greater than minimal risk, the implication is you donít have to be that careful when it isnít there. I think we ought to say that ability to consentóto understandóis necessary for all research, however....

DR. CHILDRESS: Okay. Bernie?

DR. LO: I want to continue that line. I think you always need to assess the capacity of your potential subject to consent. I think what weíre talking about here is a formal assessment using some kind of validated instrument, and youíve thought about why that instrument rather than some otheróanother strand. I agree with the notion that that level of more formal assessment only kicks in on the greater than minimal risk.

And then thereís a third strand here, which is the independent assessment by someone other than the researcher on the project. Iíd like to seek that out a bit because thatís a really big change weíre recommending. Iíd like to talk and think a little more about what the implications of that. I know where it comes from. I think itís a well-meaning and an appropriate attempt to address the serious problems of conflicts of interest when you want to enroll your subjects; and subconsciously or otherwise, kind of deem them competent even using a formal capacity assessment.

DR. CHILDRESS: Harold?

DR. SHAPIRO: Iím just asking a question for clarification here. I agree with what I believe Eric and others have said here, that this ought not to be phrased as a way of saying here is a place, a big wide loophole, so to speak, where you can go without consent. That wasnít what was intended here but itís not clear, I think, from the way itís written. And so I do think that we need to rewrite this to reflect what Bernie and Eric both have said. We still have to worry about this, itís just you donít have to have this formalized instrument dealt with unless itís greater than minimal risk. So I think some rewording here is necessary. And I think placing it somewhere else, Jim, as you suggested, is also a good idea.

DR. CHILDRESS: Okay. I assume thereís general agreement about doing something along those lines just to make sure that we donít get off the hook too easily.

I have Trish, Alex, and then I think Bernie, and then Laurie.

DR. BACKLAR: What is interesting to me about this particular recommendation, Iím thinking of psychosocial research and I think of any protocol that goes through NIMH is going to be scrutinized on the human subject section, and anybody that I know of who is doing psychosocial research is going to be very careful that their potential subjects have capacity for consent, and thereís a whole lot of different pathways that one goes through this. I think this alerts us again to the terrific problem of that kind of research that goes on in this country which doesnít go through Federal funding in some way. And I just want to alert you and your paper to looking at this because this is a very good example.

Weíve read many different reports. I donít want to refer to it because I canít think of the precise reference, but different reports where we have found that people are doing research with subjects whose capacity for decisionmaking may be somewhat impaired who are not going through those funding streams where we watch them. So thatís all, just to alert to that.

DR. CHILDRESS: Alex.

Professor Capron: In light of Trishís comment and Ericís, I want to be clear about why we are limiting this to greater than minimal risk. If one has a subject with potential lack of capacity, and the thought is, well, we do an assessment, Bernie says, we donít have to use an instrument that meets as high a standard as this paragraph would require, we donít have to use an outside expert, we can do it ourselves as researchers, and the thought is either that we will say a person has capacity and get consent from them when they donít really have the capacity, or, conversely, we will say that they donít have capacity when they do and weíll get consent from someone else, which weíre permitted to do because it is less than minimal risk. Am I correct in understanding that? That in a certain ironic way the risk of exploitation, although probably not the risk of physical harm, is at least as pronounced in so-called minimal risk research as it is here.

If that is the case, I donít understand the reason for the revision that is proposed in your memo which limits it to the more-than-minimal-risk setting.

DR. CHILDRESS: First of all, I would emphasize that itís a revision only in the textual sense. We look back at the way weíve treated it all along, I think itís not a revision, itís actually capturing what we had suggested. But that doesnít get at your other important point. I guess in a number of these areas we are having to make certain assumptions about reliability, trustworthiness, et cetera of investigators.

I think the concern here, as I recall our discussion, would be the fact that if youíre going to have an appropriate method, validated, et cetera, and the independent expert, weíre talking about a very strong, heavy, and costly procedure many would say for certain kinds of minimal risk research of the sort that Trish mentioned. And the question would be whether thatís the sort of thing we want to require here.

I happen to agree with you about the risk of exploitation. I think we want to be very attentive to that. But, in part, itís a question of what we hope to accomplish, what sorts of things we want to protect at different points. Thatís the way I would interpret what weíre doing.

Professor Capron: Do we have any evidence that people conducting one category of research or another, minimal- or more-than-minimal-risk research, are more likely either intentionally or unintentionally to make errors in assessing capacity?

DR. CHILDRESS: I donít think we have that. I think it is the risk of harm.

Professor Capron: So itís the risk of harm rather than the risk of exploitation; that is to say, being used without your consent. Yet a few moments ago Alta said that the report should begin with a clear statement that people are not to be used in research without their consent, were not to be drafted, and we all shook our heads and said, yes, thatís a basic thing that we all agree with.

I actually, thinking as a member of an IRB, would think that the risk is certainly there that an IRB facing what is described and what they think already can be called less than minimal risk will be precisely more likely not to think hard about "is the method of assessment a good one, is there enough independence, or are we going to get, as I say, either people canít consent being called people who can, or people who can being called people who canít so that their surrogates can be asked and give permission for them?"

MS. BACKLAR: May I say something?

DR. CHILDRESS: Before I respond to that, letís go over here.

MS. BACKLAR: I think that we have to sort of think about the kinds of studies that I might be alluding to, where there are interviews or questionnaires. And if somebody canít consent, theyíre not going to be stabilized enough, theyíre not going to be able to go through the interview process, theyíre not going to be able to answer the questionnaires. And often these studies are involved in looking at outcomes over a period of time. Iím thinking about my psychiatric advanced directive studies, where I couldnít bring people in that didnít have capacity to consent in the beginning because I wouldnít be able to start off with that.

Professor Capron: So for that group itís a self-correcting process.

MS. BACKLAR: Absolutely. And I think thatís what many people were referring to, they are very concerned. There are a lot of epidemiological studies; these kinds of studies that go on across the country and they are very important in terms of the benefits that may occur, not necessarily in the study itself, in following this group of people.

DR. CHILDRESS: Letís see, I have Diane.

DR. SCOTT-JONES: I have a concern thatís a little bit different from what has just been discussed, and that is that I think the recommendation should reflect a little bit the language on page 71, that discusses the difficulty in evaluating decisional capacity and also points out the capacity performance distinction that one is always only assessing performance at a given point in time. So I would suggest that the recommendation lead investigators to employ an appropriate method carefully specified and justified to reflect the language on page 71, that points out that capacity assessment is not at all easy or straightforward.

DR. CHILDRESS: Laurie?

MS. FLYNN: Iím not sure I understood exactly what Trish was trying to say. But I am very happy with the way this recommendation has developed and feel that the addition is an appropriate one, or the inclusion of making this focus on research that is of greater than minimal risk. I think to try to impose this kind of requirement in all research, basically of any category, not only creates an enormous additional burden in research that weíve not seen any demonstrationóor Iíve not seen any convincing evidenceóthat it is necessary or is ameliorating a problem.

But I think, again, it tends to reinforce the notion that it is this category of people regardless of anything other than their illness label that we have to have these extraordinary additional kinds of supports for regardless of the risk involved in the research. So I was comfortable with the way we brought it forward here.

DR. CHILDRESS: Okay. Eric wants to get on, and I have Alta, then Bernie.

DR. MESLIN: I was just going to indicate this may be another place where the Guidance to IRB section, which may become a very useful and expanded section in this report, could profitably recommend the distinction Bernie was trying to make between formal capacity assessment and those areas where IRBs may wish on their own accord, we do mention that in the document, to take this up if they see fit.

DR. CHILDRESS: It may be useful to have it here as further explanation of the recommendation for the kinds of concerns that Alex and Bernie have mentioned.

Professor Capron: If we had non-bolded language as a paragraph following this that said that, what Trish just said, that in many of the circumstances of minimal risk or less the concern is self-correcting because you canít do a questionnaire with a person who lacks decisionmaking capacity, they wonít be able to answer the questions. Iím not clear that thatís the case, but Iíll accept your view that that must be the case. But alert the IRB that there may still be some "less than minimal" where they may need to have some additional assurance from the investigator as to the quality of the assessment process.

DR. CHILDRESS: Trish wants to respond.

MS. BACKLAR: I just want to amplify that. Itís capacity for the task at hand and thatís very much how we usually assess capacity anyway. So if you canít do it, you canít do it.

DR. CHILDRESS: Alta?

MS. CHARO: Two things. First, do I understand correctly that any expression of dissent on the part of the subject will be honored in both minimal and greater than minimal risk?

DR. CHILDRESS: Yes. And weíll come to that.

MS. CHARO: Okay. In that case, one of the harms that Alex had suggested, which is that inappropriate finding of incapacity yielding a loss of autonomy on the part of the subject and a third party being able to make decisions and enroll the subject is also ameliorated because the subject still can dissent and that will be honored. So thatís a second correction you might want the note to clarify.

Part and parcel of all of this was a slight concern on my part that the wording of the recommendation now is slightly at odds with the text that follows on the topic of presumption of capacity versus presumption of incapacity, because recommendation number three as written in the memo says that it shouldnít approve these research protocols unless the investigators employ appropriate methods. It strikes me that somehow that raises the inference; itís not clear, but when I read it it raised the inference that every time a greater-than-minimal-risk protocol, or perhaps amended here any protocol greater than minimal risk, or striking the IRB as unusual comes before them that the immediate thing theyíre going to do is require formal capacity assessments for every subject. And I believe that your intent is probably reflected more in your discussion, which is that the IRB is simply supposed to be looking at each of these and asking is there any reason here why we need a more formal assessment than we usually have? I thought you might want to think about rewording the recommendation to say the IRB should scrutinize the protocols, as opposed to automatically requiring...

DR. LO: I wanted to shift the discussion a little bit away from the using of an appropriate method for assessing capacity to administer by an expert independent of the research team. And I think clearly that this recommendation comes out of some of the individual cases weíve heard; for example, discontinuation of medicines for schizophrenia, where in that situation the stakes are very high if you have a person entering a protocol as a result of a flawed assessment capacity, itís a terrible tragedy. But in our deliberations, in which we said, weíre going to only have two categories of risk, minimal risk and everything thatís not minimal risk. We kind of applied it, weíre applying this now to everything that is greater than minimal risk, including the very, very potentially risky things to the just a little bit above minimum risk. And I understand the reason for having two categories and thatís a good place to draw the line. But, Iím not sure that having, Iím not sure that requiring an independent assessment by someone on the research team is as valuable when it is only a little bit more than minimal risk, where itís clearly desirable and needed in the much greater than minimal risk category. Let me give you two examples. One is a research that involves not just questionnaires. Trish was talking about questionnaires that deal with sensitive subjects like drug abuse, which is often a crossover with mental illness. Many IRBs deem that greater than minimal risk because of legal implications and such, and I think rightly so regard it as more than minimal risk. But it seems to me itís a little more than minimal riskónot a whole lot moreóand there is again that self-correcting as an investigator who is told "youíve got to use a standard validated instrument, not just your clinical assessment." Thatís a good protection. Having it, and itís self-correcting. No investor is going to want to enroll people who arenít going to be able to give meaningful answers to the questionnaire, which overlaps to some extent with giving consent to the research. So, I think we may be overly broad there. I think that the other example I keep thinking about is research thatís more than minimal risk in a sense that it involves an MRI scan or a CAT scan in someone who may have mental illness, and the argument is that that is more than minimal risk for someone who may be more likely to get anxious or upset by the procedure. Again to remind ourselves that there are several other protections in that situation that have to deal with if they dissent at the time of enrollment, youíre not going to enroll them anyway and if they dissent at the time the procedureís being done, youíre going to have stop the procedure at the time. So again, the likelihood in that situation of someone being sort of being pushed into a study when they donít have the capacity to say no is not as broad as would justify this kind of recommendation for that class of research. I think that the final part of it is, I think that research is valuable research and needs to be done. If we donít do that kind of research youíre not going to get therapeutic benefits down the line, and I think we have to ask ourselves. We have a good intervention for a certain class of research that presents a very high likelihood of serious problems with entering a patient who doesnít have the capacity, but weíre now extending it to all research that is greater than minimal risk, and I think weíve taken a good idea and extended it too far.

DR. CASSELL: Could I address that directly? Iím confused because I heard earlier in the argument how the investigators in your institution enroll people in research who have no ability to consent and they do that regularly. And now I understand that you donít want to make it harder for them because this will make it difficult. I canít have the two. Either your investigators in your institution have to have their nose to the stone or they donít.

DR. LO: Well, Eric, yes. It depends on the clinical situation, okay? An investigator who has a study that involves MRI scans or patients with schizophrenia, by virtue of our other recommendations is not going to be able to enroll that subject if the patient says I donít want to do it, even if the investigator misses the fact. Also, if they balk at the time of the study, theyíre not going to enroll.

DR. CASSELL: How about the one that wants to please the investigator, really wants to make him happy because they want to make sure that they still get fed or that thereís a blanket on their bed so they want to do everything they can do to make, they happen to be incompetent at the time, but theyíre doing that. How about that person, never mind the one that dissents. How about the one that consents when they shouldnít consent? Remember it works both ways.

DR. LO: Okay, and the question Iím asking is, is requiring an independent assessment by someone not on the team for protocols that present only a little more than minimal risk worth all the effort that itís going to involve?

DR. CASSELL: Then you have to go and make another risk category because otherwise youíre going to have that same problem we had with this before. You get stuck in that risk thing.

DR. CHILDRESS: Okay, I have Carol, Steve and Alta.

DR. GREIDER: I just have one quick point. When Alta said a minute ago just to reiterate that dissent from participation in research is true across the board, whether itís minimal risk or greater than minimal risk. That brought up the fact that Recommendations 3 and 4 are now focusing on greater than minimal risk, and a dissent comes as Recommendation 5. Maybe the order should be switched so that itís clear the dissent comes before we start talking about greater than minimal risk.

DR. CHILDRESS: I think thatís an important point because, and Iíve been struggling with this myself, because the notification or termination of capacity to enroll in research can apply to a variety of settings, whether youíve done the formal, systematic, heavy-duty assessment or not. As you have determined it. And so itís, 4, as I would understand it, is broader than 3 in terms of the population reply to. And 5. So relocation of what is currently 3 would be, I think, important for clarifying that. Letís see, Steve?

MR. HOLTZMAN: Two comments. Iíve gotten a little bit confused as to what weíre recommending, so at least analytically, Iím trying to break it down into the following parts. I mean I think the sense is here that we want the bar to be higher in certain cases. So the first question is what constitutes the bar? I think it has two parts, a formal assessment and an outside expert. Okay, Iím simplifying. The second is when is that higher bar in play or potentially in play? Iíll come to that in a second, and I think it is when itís greater than minimal risk. All right? And then the third is it mandatorily in play or is it discretionary to the IRB? Like, for example, if you make it mandatory then youíre going to have Bernieís concern about minimal risk and that, on the other hand, the way to ameliorate that is by making it, I think this is what Alta might have been saying, by making it not mandatory but rather the IRB discretion and then take it into account. So I think it would be useful to sort of break down what it is that we are recommending in that. The only other comment I have, and then weíll come back to Recommendation 4, is that we just say "lack of capacity" and we donít modify it as a result of mental illness. And I think that we have to just generally come back to that.

DR. CHILDRESS: Well, as it currently reads, and this is under the part of the regulation, this would be mandatory, okay? And on the other issues we have to decide as to where we want to go. We could put this somewhere else, but at least to this point it has been treated as a regulatory requirement. Alta?

MS. CHARO: Iíd like to return to Bernieís comments. Bernie, I want to understand better something about your comments before; you can think about responding. Iíd like to understand whether what you are now questioning is the need for a particular methodology for assessing capacity; that is, a formal assessment with an independent auditor, or whether itís you are beginning to question the need to ensure genuine capacity to consent with regard to what you would call this class of research that is just a little bit more risky than minimal risk. I want to know if the objections to the methodology because itís cumbersome, or to the real need to consent, to get real consent.

DR. LO: No, itís to the former. I think, I agree with you. You need to give informed consent or else you have to make sure that any other path that enters the patient is an appropriate one. And I would separate out the using of a formal assessment tool versus having someone other than an investigator carry out that assessment. Because I think the implications of having someone else do it are very profound. We need to make sure that thatís what we want to do.

MS. CHARO: All right. There are people here who have better memories for what actually happened on the transcript than I, but I suspect that the reason why this got written up the way it did was because of a feeling that without a simple rule to apply, that too much discretion on the part of IRBs and too much deference to colleagues might reduce the number of times that there is an insistence on this cumbersome mechanism to a diminishing few. All right? And that in most cases even with risky research, IRBs and investigators would say that we know that thereís going to be a truly ethical assessment of capacity and we donít need all this rigamarole. And I guess then I would want to suggest that we focus the discussion on whether we need to constrain, whether we want to constrain IRB discretion through this kind of mandatory procedure or whether we simply want to write it with a strong suggestion to them. Keeping in mind that everything we do in here is advisory so theyíll only implement what they feel like implementing anyway, and if it ever gets to a regulatory stage, that the regulation writers will also be responding to the pressure to ratchet back a little from what might be, argued to be, an excessive degree of solicitous attention on our part.

DR. CHILDRESS: And again, Steveís identified the guiding lines here, but we are going to have to make some choices. But before I turn to Harold, though, itís important to keep in mind that weíre trying to reach as much consensus as we can. But Iím sure thereíll be places where several individuals will file a separate statement, personal statement, in which they say well, Iíd like to amplify this or we should have gone further there and that sort of thing. Keep that in mind. I think thatís something that the document will inevitably have given the kinds of divisions that exist on some of these important matters. Harold.

DR. SHAPIRO: I just want to clarify in my own mind, Bernie, your point. I think I understand it. The, see phrase, "administered by an expert who is independent of the research team." Now that phrase has two qualifiers. One, you have to be an expert. Two, you have to be independent of the research team, and itís the independent of the research team that you think is especially cumbersome, or both. Iím asking a question.

DR. LO: Iím more concerned with "independent of the research team." To go back to the conversation Eric and I were having, I really think weíve responded to some very awful stories weíve heard about, cases. And they were characterized by a lot of, they had a lot of qualities. They were institutionalized patients who were much more dependent and vulnerable, Eric. There were situations where the investigator was also the responsible physician in some sense, the personal physician of the patient, which really ups the ante for a conflict of interest, and the nature of the protocol was such that these were very sick patients who were going to have a very high chance of relapsing from their condition, either by natural history or by the intervention. And all those together create a scenario where I would say, yes, that IRB should have said letís make really sure these people have the capacity to consent as well as a whole lot of other things downstream, which weíll get to later in the report. But to take those protections, which are totally appropriate in that situation, and then say the IRB should also do it across the whole range, thatís what Iím questioning. The expert thing gives a lot of wiggle room because Iím not sure who an expert is. Is it a professor who specializes or is it a research associate trained, the way I would train a research associate to do anything else in a competent fashion. I donít know.

DR. CASSELL: Well, I think that the expert problem is a real problem, but by someone independent of the research using a validated instrument, or using an approved, an instrument of which the IRB approves, but it ought to be somebody independent of the research. But it doesnít have to be an expert. It doesnít have to be the guy who designed the instrument to come down and test everybody and find out if they passed his instrument or not. So anybody else could do that too. But the independent of the research is what makes it, is what protects the patient. Now the other issue to bring up is unarguable. The problem is, what is arguable is the minute you do that you now have more than two levels of risk, and weíre back to the argument about well, what is that risk level and if you say serious risk, you know we get into all those questions. So what youíre bringing up is very important and we once again, I wonder if weíll ever have a discussion here that doesnít come back to that minimal risk thing and risk that doesnít get us out of that. But thatís where we are, right? So you have to say to yourself, either put the qualification in a way that really works or you just have to accept this.

DR. CHILDRESS: Let Bernie respond and I have Trish and Steve.

DR. LO: Or have some other means of having some nuanced approaches rather than having an absolute, "it has to be this way." So either you can have an extra category for risk or you can have some, a little bit of discretion when they apply it. But the more you get simplicity, you also worsen the problems of this application of a general principle.

DR. CHILDRESS: And the issue, and Steve raised it nicely earlier in terms of kinds of decision points we have on this, again the reason this receives so much attention from public comment is that is did seem to be unduly burdensome. And by limiting it to greater than minimal risk we open it up a bit, but the other kinds of questions that are being raised, we are going to have to come to some decision on.

MR. HOLTZMAN: I think Ericís hit at the point; itís instead of casting it, do you believe there should be multiple categories, itís really if, with the best intentions to protect human subjects, we keep tightening down each element and then you take a step back and you say there is some research which is not going to take place which we really think is important. Then the question is where are you going to open it up and it, if you feel that way, I certainly donít want on each recommendation say we should change this recommendation. But I also believe that if you loosened every one of them, that wouldnít be right either. So where do you pinch it?

Professor Capron: We talked about a version of that yesterday, Steve, with valuable human materials which are, which a researcher would love to use but if we require certain things and they canít contact the person, they lose it. Weíre talking about something different here, it seems to me. Weíre talking about the extra costs with more-than-minimal-risk research of having a qualified professional, which is the term that I would substitute for an expert, a qualified professional, independent of the team, do the assessment. And what are we concerned about? Weíre concerned about a person being recruited in who doesnít have the capacity, and is said to have the capacity, or recruited in under somebody elseís say-so when they do have the capacity. Now if itís the former thatís the main concern, it seems to me that that is something which, as the example Eric gave of the person who doesnít dissent, who goes along, is something we should avoid. Having someone give consent to something which theyíre not capable giving consent to. And if there is some research which is made more difficult because you canít use that person, it is different than saying, we have a wasted resource where, whatís the real harm of using it, itís just some cells here and so forth. This is a person who will be involved in more-than-minimal-risk research on their "own" consent whereas a person independent of the team looking at it and applying about qualified instrument would so, no this person doesnít really have the capacity to make that judgment. That is a cardinal example of some person who shouldnít be in the research. Shouldnít be used on that basis. And so it is not a matter of preventing something good that should be happening, itís a matter of preventing something bad that shouldnít be happening. And I have no problem there toward the recommendation. My suggestion, however, would be that we actually have recommendations 3a and 3b, and 3a apply to everyone, not just, and that is that the investigator be asked always to use an appropriate method to assess the subject. In other words, rather than my curbstone sense that this person is fine. It doesnít seem to me that it is inappropriate for IRBs to be told that they should always have as part of protocol review, where the subject is potentially incapable of making decisions, a statement that their capacity to make the decision will be evaluated according to the following validated protocol, which takes five minutes to run through. But itís a checklist of questions you ask them and responses youíre looking for and if you think they donít make it they donít make it. Not by an independent person, if itís less than minimal risk, because the chance of getting someone in is apparently regarded as acceptable because theyíre, itís only minimal risk. I would prefer that we apply it across the board. I can see that that does not have majority support but I would at least say that as to the less than minimal risk, thereís no reason not to say you ought to have a protocol for doing it rather than just your curbstone sense. I canít understand what our objection to that is. In what sense is that an inappropriate burden to place on someone?

DR. CHILDRESS: Could I respond and then Harold, I think I passed him earlier when it was his turn and promised to come back. I guess one of the questions would be what sort of presumption we work with and what triggers the assessment. By going to the greater than minimal risk, weíre saying that here youíre going to have to do the formal assessment because itís greater than minimal risk. In other kinds of settings, what triggers what kind of assessment seems to me is the question, and whether youíre working with the presumption that all the people with mental disorders that may affect decisionmaking capacity are people who have to be examined carefully. Or whether other kinds of usual informal source of procedures serve as triggers.

Professor Capron: Well, my sense is that there, would be no harm in that other discussion we have of sort of IRBs ought to be thinking about this to say to IRBs, when youíre dealing with patients in the ICU or patients who are otherwise heavily burdened by illness and so forth, a question of are they, under the circumstances, able to make their own, to make judgments about going into research ought to be evaluated because their thinking may be clouded, to say nothing of their independence of their doctors and so forth and so on. So I have no problem saying this is again the case study and then weíre sort of thinking this may have generalizations but weíre not yet ready to write a requirement for all those other categories because we havenít looked at all of them. But IRBs could well think about this. So the notion that the research community as a general matter has not given enough attention to the assessment of peopleís real capacity to make judgments about going into research seems to me to be a perfectly valid thing to suggest that we ought to be more concerned about. The fact that it hasnít been done is not conclusive to me that it shouldnít be done, to put the point briefly.

MS. CHARO: It strikes me during the course of this discussion that on a related but tangential topic, maybe the part of the struggle here has to do with the way in which the recommendations are being organized. Theyíve been organized around the question of the audience, to whom are they directed, IRBs, government, States. It may be that if they were organized in a fashion that was more chronological, the process of working with people as this study population, that some of these problems may get a little easier to describe. So itís something to think about. Because doing it that way, one might go, people should be allowed to participate in research when theyíre able to consent. Next. Is there a reason to believe somebodyís consent is not valid because they lack capacity? And that, then we turn naturally into a recommendation in which IRBs are directed to look at every protocol for any sign that in this case, the subject population is likely to contain people who may not clearly be able to, may not have the capacity and where it may not be obvious, so that more careful assessment has to be made. Or, at the risk of stigmatization but in light of the kind of consequences of how we are doing this report to say, IRBs should whenever dealing with research protocols that involve people with mental illnesses that are implicated in decisionmaking processes. There are mental illnesses, like bulimia, that have nothing to do with your decision making with regard to ruling on an MRI study, but some forms of mental illness are associated with disorders of thinking. So where you as IRB see a disorder thatís associated, mental disorder associated with problems in thinking, hereís where we want you to stop and assess whether special evaluations need to be made and, as the risk goes above minimum, that scrutiny should happen more and more frequently. You should be erring on the side of using these methodologies but because weíre doing it chronologically, I think it gets a little bit easier to see it in some kind of context, and thatís also where you can emphasize that the availability of dissent is an automatic withdrawal. It took place with this. Itís a corrector on a failure to do this properly, and that that should be taken into an account but not used as an excuse to avoid any capacity assessment. Iím just wondering if this might help us kind of work through it in a more integrated fashion.

DR. CHILDRESS: I think thatís right, though, I think that we would still have to raise the question of whether we want to bullet some of these things and say yes, but youíre going to be required to do this. This is not some guidance. It seems to me that question that still comes into play.

MS. CHARO: You know, Iím beginning to feel like we would be better off if we were to direct attention strongly without creating mandatory impositions of requirements, because Iím always aware of how difficult it is to write generalizable rules that cover situations perfectly. Iím highly aware of the problem of IRBs doing work that seems to be inappropriate or investigators jumping hoops they think of being as inappropriate creating a disrespect for the entire system. Iím not persuaded that IRBs and investigators are untrustworthy enough that they canít actually implement this, but it would have to be very strongly worded with, and this is where my lawyer training comes, presumptions that. The presumption is that if it is more than minimal risk, youíre going to wind up using an instrument unless youíre pretty sure that you really donít, in this particular case. The presumption is that if youíve got particular kinds of disorders youíre going to wind up using an independent expert. And that gives people the wiggle room they need to exercise some discretion and not feel bound by rigid rules that make them do silly things.

DR. CHILDRESS: I think weíre going to need to wrap this up. But there are still several points we have not, I think, reached any consensus on and I thought Steve identified those well and now Altaís come back to the one about whether we want to make it mandatory or not. Each of those things will make a big difference so we will need to see if we can reach some general agreement, again knowing that there will be some dissent from this. Larry.

DR. MIIKE: Coming from Hawaii, I like to fish or cut bait. I think we should reach some decision but let me just mention two things. One about the issue about mandatory versus of leaving it up to the IRB to decide on an individual basis when the risk is of serious enough of level to require a more formalized procedure. I think thatís the choice that we should really decide on. The second part is to address Alexís concern about the adequacy and why not say that just in any kind of research involving people with impaired decisionmaking. That we should have a more direct approach to ensure that their consent is possible. I think one way to do that is when we, if we follow through with our most formalized assessment with people with greater than minimal risk either in a mandatory way or a discretionary way, I think what we should point out is that investigators, the research committee and the IRBs should take a look as that process goes forward about whether it raises questions about the more informal way in which theyíve assessed capacity to make decisions, and that that would be a way of saying hey, if itís really deficient that we got it, we have to take a second look at even though less than minimal risk. So itís sort of like built into the process, a self-correcting measure or an assessment of the occurring assumptions about the adequacy in the minimal risk area. But I think our current focus on greater than minimal risk is that we want to impose a burden commensurate with the risk. Thatís what weíre doing, and I think we would argue forever, Alex, about whether we want to impose that on a lower size. So as long as they build a process into, I think it can be self-corrected.

MR. HOLTZMAN: I very much agree with Altaís way of thinking, where we need some word in here about appropriate; that when dealing with putting aside stigmatization. Weíre dealing with the population where antennas should up in any research. Thatís the first step, because thereís the possibility of not genuine consent. And then weíre saying that when the risk goes up, we want to raise the bar higher. But what I would ask Alta to think about is the desire not to make it mandatory, because what youíre recognizing is the inelectable rule of judgment here. All right? But what we want to do is provide clear guidance as to where the judgment is being exercised. In other words, whether or not to use a formal capacity to assess an instrument in an outside expert. If you are saying that should be left to judgment, it should be because what youíre focused on there is in this judgment thatís not necessary. It shouldnít be because, well, itís only more than minimal risk. So what Iím afraid of is since all these pieces interlock, that we donít want to be opening up valves here and there where people make it the gemisch again. I fundamentally disagree with Alexís characterization of what I was saying. Iím not trying to squeak things through; I want us to be clear, so we give people clear guidance, and weíre trying to make something happen, or not make something happen. Letís just be clear about it in where it is, and where it is disagreements, we can articulate them. I donít want, if I believe that there are certain kinds of research that may get blocked by these recommendations, I donít want to squeak it through by making believe I have consent when I donít. Thatís not what Iím saying Alex. Okay?

DR. SHAPIRO: Am I correct then, Iím just trying to catalog in my sense, the concerns that are swirling around on this particular item. One is the issue, what happens when it is less, when it is minimal-risk research? What happens there? And there was some initial discussion here around the table that no matter what kind of research it is, somebody has to be responsible for some kind of assessment. You canít go ahead and knowingly use people. We sort of left that there and Alexís suggestion, as I understood it correctly, under Recommendation 3a, which specifically addresses that issue; that is, if you just have less, if you just have minimal risk research you are required some formalized assessment, characterized as simple but it was formal, it wasnít just the curbside judgments. And then, so thatís an issue, first, that we need to clarify. Do we want to, is it necessary and helpful to highlight what happens in minimal risk research regarding assessment of capacity? Then thereís the greater-than-minimal-risk research of what this supposedly addresses directly and there I think there are two issues that perhaps divide us. One is whether it ought to be by someone who is independent of the research team, and the other is the issue Alta raised, is that whether this is normally required or always required? Those two, Iím just trying to understand if those are the issues in front of us, and if they are, Jim, maybe we should just go at them one at a time. Letís start with the minimal risk research one and say what we want, if anything, at this point on this issue.

DR. CHILDRESS: I think thatís very helpful. Steve, does that fit pretty well with what you remarked the issues?

MR. HOLTZMAN: I think so. The one comment I make, Harold, you almost have a "step zero" there, though. Is there a fundamental presumption that the antennae should be up with respect to the issue of whether we have genuine consent with this population? Weíve written language here where we want to make weíre not stigmatizing and we say you know, youíre capable unless not. But I think the issue about whether more than curbside judgment in any and all casesódepending we could go much higheróonly arises if you start with the presumption that the antenna should be up on the issue of whether or not you have genuine consent, you have the capability. If you donít start with that presumption, all right? Thatís where our focus should be and then we raise the bar as a function of risk. Itís not risk that triggers that question.

DR. CHILDRESS: Okay, I think Haroldís proposal is a very good one and I think thatís one way to resolve it. If Trish also wants to address aspects of that so we could just go through the parts and see where we stand?

MS. BACKLAR: In terms of minimal risk, obviously one still must assess capacity to enter into a protocol because one would do that with any group of people. And so that I think, I donít disagree with that. I agree there must be some, not assessment, but certainly an informed consent process in which the person agrees or disagrees and when youíre going through that, youíre making some kind of assessment at that particular point anyway.

DR. CHILDRESS: Right. Bernie. Oh sorry, Alta?

MS. CHARO: I was going to try to answer Haroldís question.

DR. CHILDRESS: Okay, go ahead, go ahead. Bernie, Iím sorry, Iíve got to come back to you.

MS. CHARO: It seems to me that someone could answer your series of questions by taking it from the point of view of an IRB, and it would almost be like a checklist. Checklist item number 1, is there a population thatís going to be studied that raises our antennae about their capacity to consent? If the answer to that is yes, then has the investigator explained how he or she plans to make sure that the subjects genuinely can consent? Number 3, is the research more than minimal risk? If yes, has one challenged the investigator or explained why one wouldnít need to have an independent expert doing the capacity assessment, and in that fashion one could work through connection of these two factors. But this does use the presumption as opposed to the mandatory approach.

DR. SHAPIRO: One word changes that whole set of recommendations. I mean, you follow through the minimal risk and your checklist, and only at the endóyour last recommendationóhad the presumption rather than the mandatory.

MS. CHARO: Thatís correct. Thatís true.

DR. LO: Let me first say, I like Altaís suggestion. I think giving people visual flowsheet or decisionmaking....

DR. CHILDRESS: Well, put up the one that in color we have.

DR. LO: And I would just say to Alta, I think, I like the idea of presumptions but if we are really concerned to protect or preventing the egregious cases, I think we can say that there are a set of circumstances which, if they are all present, itís mandatory. So I think if youíre institutionalized, if the person who is the principal investigator is also a caregiver for you and if the nature of the research is such that itís not just a little more than minimal risk, itís substantially more, itís not a presumption, itís mandatory. Let me go back to the original question which was people with less than minimal risk, do we want a formal assessment of capacity? And I guess Iím maybe having trouble with understanding what people are really thinking about. As I understand things, if you really were concerned, probably the most extensively studied and best validated instruments is the MacCarther instrument. I know that Eric doesnít like this, thereís a lot of criticism but thatís the, I think, the best thing out there going. There are other ways of asking questions which are not quite as lengthy which probably, it seems to me, do the job as the screening instrument. I think appropriate is fine because it covers a lot of ground and it seems to me that the amount of attention you put in up front has to do with the research circumstances, and then what usually happens, as little red flags start going up as you answer a brief screen instrument, you say whoa, this is really much more serious than it first appeared, and now we have to do an even more formal, lengthy assessment. But to have everyone go through a long formal assessment from the onset, I think, itís sort of a cost- effectiveness question. So I agree with the principle that no one should be included in the study on the basis of without consent. But how it measures the efforts you make to really determine that seems to me will vary with the situation, and including the initial responses you get when you first start to make the assessment.

DR. SHAPIRO: I think one of the problems weíre having with this Recommendation 3 is unlike the other recommendations, it has no text beside it at all and that has, I think, and thatísóto look at the memo youíll see some text in there. I canít say I feel strongly on any of these issues. But my own view of this matter is that we ought to be putting teeth in our recommendation at the greater-than-minimal risk area. I am much readier to allow the presumptions to flow the other way in the less-than-minimal risk concerns. Try to make it, try to highlight in text the need to be thoughtful, careful. If Bernie were head of all the IRBs, I wouldnít need any regulations. We would all be in fine shape, but thatís not the way life works out so on the less-than-minimal risk, excuse me, in the minimal risk research, Iím quite prepared to allow the presumptions to go myself. You let the IRBs use judgment, let them to presume the investigators know what theyíre doing in this area and so on and get consent in a normal way. This doesnít eliminate the need to get consent, but when it gets to the greater than minimal risk, I do think we need to bring something like a more formalized assessment into play. And I know we donít, and one of the problems here and why we canít use words like validate is we donít have any really validated ones yet. And so we just have to mobilize peopleís best attention to the problem as opposed to, say, do this test or do that test because we donít have any yet. And in some sense, the issue about independence has been argued back and forth a lot. Thatís out there in the literature and youíll see a lot of it. In some sense, if there werenít conflicts of interest, a qualified professional would be enough to say, right? Someone who is qualified will do things that their profession requires them to do and so on. The cutting edge is the that the course that weíre on runs right into the conflict of interest question, which is what so much of this is all about. So Iíd be very interested to know where the committee feels on that issue. Bernie raised it and I think if we just focus on it for a moment now without trying to complicate it with other issues as to whether the independence is critical to this now in the greater than minimal researchóIíd just like to know how people feel about it so we can move ahead. Eric.

DR. CASSELL: I think thatís what makes it what it is. The minute you donít put independent in, then weíre back to the simple thing. Somebody on the team said he was okay and thatís okay. I donít, I think independent is necessary.

DR. SHAPIRO: Okay, how do others, other people feel?

DR. SHAPIRO: Letís just take a straw vote and then we have to start moving forward. How many really want us to stick with independence? Okay, thatís clearly the majority of the people here. So that, again, I want to remind you what Jim had said before. If there are issues which individual members here feel very strongly about as we get to the end of this report, there will be an opportunity for people to express themselves in that, in this or any other conference. Letís assume that the independent, I like Alexís wordingóacts as qualified professional. I think it is much more helpful, I think, than "expert," and also widens the possibilities for an appropriate reason.

Professor Capron: What happened to Altaís suggestion vis-a-vis the presumption, because I thought she was raising that in response to Bernieís concerns?

DR. SHAPIRO: Letís go to them. if the language of the recommendation were to read something like "for research protocols that present greater than minimal risk to persons with mental disorders," the presumption is that investigators will employ an appropriate method, and then an IRB should approve a protocol when the presumption is not met only when persuasive grounds exist. Weíre dispensing with this means of assessing the subjectís capacity. Thatís what you had in mind. Is that right?

Professor Capron: Right.

DR. SHAPIRO: Iím glad youóI meant to raise that. Iím glad you did. How do people feel about that issue so weíll know how to write the report?

DR. CASSELL: It allows them to exclude stable outpatients who have had no symptoms for a long period of time and something like that. Right. Is that what you mean?

Professor Capron: What the presumption is, and I thought that her language was responsive to Bernieís concern, that the person would say, okay, this is more than minimal risk but what it involves is x and that is a situation in which I will do a formal assessment but I shouldnít have to pay for an outside expert. And then the IRB would decide whether that was a persuasive ground for dispensing with that. But the presumption that they will be operating on is no. If it qualifies as more than minimal risk, youíve got to do it. Youíve got to do this. Now, I, I just wanted to get this out on the table again. Iím, Iím still, I like the basic approach of this is what the IRB should do. But I understand Altaís alternative to allow what Steve was referring to as the element of judgment to come in when an IRB says, in terms of proportionality, this is overkill for this particular research although, yes, it is "more than minimal risk." Because, for example, in Bernieís example, it involves a questionnaire that has to do with drug use and we call that more than minimal risk, but we really think that you donít need an outside expert. In other words, we are comfortable with the risk that someone would be enrolled in this who doesnít actually have the capacity that the investigator says they have.

DR. CHILDRESS: Go ahead, Alta. Then I know Larryís going to have to leave in just a few minutes. We want to get his final word.

MS. CHARO: Iíd like to emphasize that my purpose of proposing this was not, in fact, to make it easier to enroll people in protocols that wouldnít qualify as a minor increment over minimal risk. So that is not the scenario I had in mind, actually. My purpose was in allowing IRBs to exercise judgment where they thought that a capacity assessment could be made by something less strenuous than a formal independent assessment instrument, and that would be what you were suggesting. Somebodyís been stable for a long time. I was not hoping to see this used as a way for IRBs to differentiate among levels of risk in the category of more-than-minimal. I wanted it to be used as a way for them to not need to go through all these hoops where, despite the fact that the subject meets the technical description of a population at risk of impaired capacity, itís nonetheless quite straightforward to tell if they are competent or incompetent without all of this rigamarole.

Professor Capron: That kind of language, however, would in the end give flexibility for either?

MS. CHARO: No, I guess actually weíd want to change your suggested wording a little bit so that thereís a presumption that theyíd have an independent expert unless thereís persuasive evidence shown that the capacity assessment can be achieved, can be reliably achieved without those needs.

DR. CHILDRESS: Your comments focused more on the independent assessor, and thatís one I would go in the direction that Bernie suggestedóif youíre institutionalized a whole host of factors could play a role there. We might want to pull out the independence and distinguish that from the formal assessment. And your comments focus much more on the independence.

MS. CHARO: That was only incidentally, of course, I mean.

DR. CHILDRESS: But it seems to me that one actually could make a plausible case for that, and requiring the independence might be circumstance-dependent.

DR. SHAPIRO: So we have just decided that we liked the independence? Right? And so I think we ought to require that.

DR. CHILDRESS: But youíre opening up the door for the presumption. Thatís what weíre dealing with here because thereís ways to set presumptions that have to do with certain kinds of circumstances.

DR. SHAPIRO: If I understood what, not focusing on language, we could generate the language. But if I understood what Alta was saying was that yes, this is fine, but as the normal presumption about the way the IRB would operate and investigators would behave or would be required to behave. However, and leaving open the fact that we can anticipate and articulate all the various kind of issues that come up and the scenarios that come up and so on and leave it open for the IRB to not use this recommendation.

DR. CHILDRESS: But as weíve heard several times, if we go that way and canít give any concrete examples, canít give any real meat to what we might considered a persuasive grounds for not following the presumption then I think our report basically at that point...

MS. CHARO: Hereís the example Iím keeping in mind with Ericís help, okay? Youíve got somebody with schizophrenia, so thatís kind of a population that might fall into this "antennae go up" category. The research is more than minimal risk. And the presumption would be that youíd have to have an independent formal assessment of capacity to consent and the investigator says, Iím going to work with the population of people only who have been well controlled with no overt symptoms for over 2 years. And the research itself, although itís more than minimal risk, does not in any way alter their medical management in such a fashion as to threaten in any obvious way. Their continued stability. Therefore, I think itís okay if we, the investigators are to simply assess the person standing in front of us as competent to consent in the same way youíd assess anybody else as competent to consent without needing to bring in an independent expert. Thatís the kind of example I have in mind of an investigator coming back with a persuasive justification.

DR. CHILDRESS: And before we try to resolve this issue, I want to get Larry in but weíll come back, sorry Harold, weíll come back and actually decide whether they want to go the presumption route or the absolute requirement route. Larry, do you want to give some parting words on things we need to attend to?

DR. MIIKE: Itís just that issue that I brought up in the beginning where weíre looking at people with fluctuating capacity versus people with no capacity to give consent. I donít understand the logic of requiring that for those that fluctuate in capacity; the only time they can participate in research is if they consented while they were with the capacity. And yet in those without capacity we say for greater than minimal risk and would benefit, someone else could make a decision for them. And then the way that you dealt with the part where there is no benefit was to totally eliminate people without capacity to make decisions from participating in that research, where I would have preferred the other way, in which those with fluctuating capacity.... My understanding of the way you changed the 12 and 13, I believe, is that now those without capacity to consent cannot participate in any research with no benefit and greater than minimal risk. Isnít that right? In the revision of September 15th, I think you took that out.

DR. CHILDRESS: But it was replaced.

DR. MIIKE: I know but the way you split it off was that you eliminated that, that, maybe you havenít, but if thatís still in there, then there is no difference between with benefit or without, right? But my point is that I donít understand you would allow research for people not capable of making decisions if someone else has the power to do that, and then only allow research for those with fluctuating capacity if they have indicated beforehand. I think that in the latter case, about people with fluctuating capacity, that you have to honor their wishes if they had made a specific request not to participate. But it doesnít make sense to me that that you say if they didnít give that permission, then under no circumstance could they participate.

DR. CHILDRESS: Point well noted. Okay, anything else you want?

DR. MIIKE: No, I mean those, there are lots of little things, but those were the parts that just logically, I couldnít understand the logic of them.

DR. CHILDRESS: All right. I think there are problems at that point that we have not yet fully worked out yet. Thank you.

DR. SHAPIRO: If youíre not here this afternoon, weíll be conscious of your exhortation for us to get on with things.

DR. CHILDRESS: What Iíd like for us to do if we could is to decide if we want to whether we want to go the presumption route or the absolute route now that weíve already indicated that independence is an important standard for us.

DR. DUMAS: Are you talking about doing that now?

DR. CHILDRESS: Well, if you would get your comments in here now.

DR. DUMAS: Well, Iíve kind of lost track of the recommendations, and at one time we had a recommendation that in cases where there was more than minimal risk and no benefit to the person, that we would not, we donít think that they should be involved in the research. Now did that change?

DR. CHILDRESS: Weíve got the conditions for that and a that we have to come back to.

DR. DUMAS: So now they can be involved.

DR. CHILDRESS: Right. Weíll get to those later. And weíve spent a lot of time on this particular one but I think itís a very important one; again, itís one that we got a lot of public comment on.

DR. DUMAS: Thatís, I want to just for the record, the main thing, the position Iíve had all along. I donít think they should be involved in the research.

DR. CHILDRESS: Will you be here for the rest of the day?

DR. DUMAS: No. Iím going to have to leave early.

DR. CHILDRESS: Are you leaving before lunch?

DR. DUMAS: Iím leaving now.

DR. CHILDRESS: Oh, youíre leaving now, too. Okay. Anything else? Sorry I wasnít aware of that. I was aware of Larryís departure.

DR. DUMAS: Iím sorry. I didnít tell you but I told Eric.

DR. CHILDRESS: Okay. Anything else youíd like to make sure we that we attend to in this discussion?

DR. DUMAS: No, I think most of the things that I have had in mind about review, thatís been one that has been on again, off again, and one that I feel very strongly about.

DR. CHILDRESS: Good. Okay.

DR. SHAPIRO: Jim, weíre going to have to, Eric has a comment and weíll have to take that, but then you have public comments scheduled.

DR. CASSELL: Weíre on the issue of presumption at the moment right? And we have two alternatives. One is you canít get out of it no matter what and the other is there may be certain circumstances where the presumption is that the person has capacity because of a clinical situation. And, in other words, we could, the IRB could determine that if this particular population, although it is made up of persons who may, because of their disorder have decisional incapacity. The characteristics at this time suggest that they will not have decisional incapacity and therefore the IRB does not have to apply this test. Thatís one way to do it. Then the other way to do it is that it doesnít matter. Now Iím trying to think of the study and I think the example given of the questionnaire about drug usage is a good one. That would be more-than-minimal risk, but hereís the population that is out in the outpatient setting and the question is, are they using drugs? Do they have to, does everybody there have to be brought in and asked do they know who the President is and etcetera, you know.

DR. CHILDRESS: And by an independent...

DR. CASSELL: Iíd have trouble with that. I must say. I got hard-nosed about all of this because I also live in hospitals and know about all of this stuff. But this does go a little far. So I think that the IRB ought to be able to release them from the requirement that the presumption in a particular population at a particular time is that they have capacity.

DR. SHAPIRO: Okay. Do people want to talk anymore or feel like talking about the presumption issue? Because if we could take a kind of straw vote on that now, we can, and then go directly to public comments if not. Letís just see how many are convinced by Ericís or anyone elseís comments. Altaísóand weíll worry about language at a subsequent momentóthat we should build in some leeway here, really, however. How many people feel thatís a plus?