Research Involving Persons with Mental Disorders That May Affect Decisionmaking Capacity

DR. SHAPIRO: But let's go to the recommendations themselves. Jim, if it's all right with you, we'll just begin by going to Recommendation 1. Is that all right? This has to do with the IRB membership issue, if anybody wants to recall what that's about. It is on page 121 in chapter 5. And for each one of these, I think, I will ask Eric to just remind the Commission what we have heard or what issues have come up during the public comments just in case you want to know about them. We haven't gone back to Recommendation 1 in quite a while. Do any of the Commissioners have any concerns or comments they want to make regarding Recommendation 1? This is what I call the IRB membership issue, but however you want to describe it.

DR. CHILDRESS: I might just add this is one we, by and large, received positive response to, though I think many of those who favor the recommendation would be happier if it were a matter of guidance rather than a regulatory requirement. But I think the substance of this particular one seems to generate a positive response.

DR. SHAPIRO: All right. Then I'll assume that Recommendation 1 is something we'll just go ahead with. Again, any editorial or other comments regarding just how this is described in the text and so on, please pass on to the staff.

PROF. CAPRON: Could I, Mr. Chair?

DR. SHAPIRO: Yes, certainly.

PROF. CAPRON: Steve turned to me as you were making your opening remarks and asked vis-a-vis the one remark that was the most delphic what was going on. So let me put my own question before you. Whether the question is principally that the psychiatric community is unhappy with the report. And the reason it comes up with Recommendation 1 is that I believe that some of the objection that we heard early on was that any singling out of people with any particular disease category and saying that they are in need of extra protection here by being made members of the IRB is a form of stigmatization of that group. So it's a compound question, Mr. Chair.

DR. SHAPIRO: Delphic is my own remark.

PROF. CAPRON: Is the objection that keeps us from being able to progress to conclusion on this, other than the absence of the one recommendation that you mentioned that we need to address about minimal risk research, is it that we have got to refine or revise in light of objections from the research community? And if so, what about this first recommendation, is it not subject to the same objection? Or did I entirely misread your delphic—

DR. SHAPIRO: My delphic remarks come from all sides of the issue; that is, it is not confined to any one community. I wouldn't want to characterize any community as having any uniform views on these matters. But it came from all sides; that is, some people thought we were being nowhere near demanding enough, and others who thought—and it didn't relate to this recommendation. I will highlight any recommendation it relates to. It did not relate to this one as far as I'm aware.

PROF. CAPRON: I understand it did not. But I should say, because I believe we have to be open about these matters, that I was approached by several members of the psychiatric research community at a meeting I was at last week who described to me a process of addressing with the Commission, both out of the National Institute of Mental Health and out of leaders from the psychiatric research community, their unhappiness with this and, in particular, some views attributed to me which they thought made me a good candidate for their services. And since we hadn't had those views from those people ever in writing or in public comment before, I was not surprised to know that they were being voiced to us rather strongly.

But it seemed to me that the logic that I was hearing from them was that any attempt to single out a group of subjects and treat them differently bordered on stigmatization because it took at view that this was a vulnerable group needing protection of some sort and that that's an old-fashioned view that buys into all the prejudices about mental illness.

DR. SHAPIRO: That view has certainly been expressed. We discussed it last time we were together when we discussed the scope of this report. That wasn't the one that was especially on my mind.

PROF. CAPRON: And their further statement is that there is no objection that we know of to the insistence that IRBs that regularly review would always have and have present at their meetings where they deliberate on such protocols this sort of representation.

DR. SHAPIRO: That's correct.


DR. CHILDRESS: Well, on your distinction between guidance and regulation, I think there's very little objection to this being offered as guidance. There is objection to it being offered as a regulatory requirement.

PROF. CAPRON: But I said the substance doesn't seem to be as problematic as what kind of form is this recommendation going to take.

DR. CHILDRESS: That's just one person's impression having looked at the comments and talked to a lot of people. Maybe Eric has a response as well.

MS. FLYNN: Could I offer a comment here because this recommendation, which I'm very, very pleased with, is very similar to a recommendation that my organization adopted as policy in 1995 and forwarded to all academic institutions' departments of psychiatry that were actively engaged in research. At least while there are many other parts of this report that some members of the research community may have concerns about, Alex, I think I'm fairly confident in saying that I don't think this is one of them.

The feedback I've received as recently at a meeting of biological psychiatry a couple of weeks ago is that this is really in fact a linchpin of ongoing support and protection for vulnerable human subjects. Putting representatives in the room on the IRBs when such protocols are developed and discussed I think is accepted very broadly in the research community. I've had literally no one in that community come up to me and complain about this one.

I have had, interestingly, a colleague who is active in breast cancer research, and you do hear from folks who move to the issue of will we have the balkanization of IRBs, we will have a drive to include subject representatives in a variety of areas. And I suspect we will and I don't necessarily think it's a bad thing to consider those issues for other potentially vulnerable or high-risk populations.

DR. SHAPIRO: Thank you.

PROF. CAPRON: What I wonder then is if the recommendation has generally in your experience met with such a good reception in the community, and given the fact that for all the reasons that we talk about in the report the subject population has vulnerabilities which may not characterize all other balkanized different disease populations, as it were, why is it that we do stop short of saying that this is a change that the OPRR should insist upon as it has insisted in cases in which it has found problems to exist? In other words, why not regard this as something that is prophylactic in its effect and not wait for another institution to have the sorts of problems that arose, for example, at UCLA?

Would you like me to move that we make this a stronger recommendation? I'm not sure what—

DR. SHAPIRO: That's right. If you think—

MS. FLYNN: I would support it.

PROF. CAPRON: Then I would so move that our understanding of "should" here or whatever changes in language are necessary to make that the case, that this become a recommendation for action rather than for advice.

DR. CHILDRESS: It is a recommendation for regulation.

MS. FLYNN: Yes, I do not read it as offering a choice.

PROF. CAPRON: I had, too, but then I thought I was being corrected by you earlier.

DR. CHILDRESS: No, no. I've said the agreement has to do largely with substance. But there's a lot of disagreement about whether this should be offered as a recommendation for regulation versus guidance.

PROF. CAPRON: But the shoulds and the shalls mean that if—

DR. CHILDRESS: We're offering this for regulation. It's clearly in the regulation section.

MS. FLYNN: We've already taken the stronger stand on that.

PROF. CAPRON: Well, that was my understanding and I thought from your comment, Jim, that I had simply misread it. We didn't say "OPRR shall require that..." but that we were somehow saying this is the ideal world. Then I have no problem with it.

DR. SHAPIRO: Any other comments on this?

Let's go on then to our second recommendation which I call, perhaps unkindly, the targeting regulation. This is so short I can read it to everyone. "An IRB should not approve research targeting persons with mental disorders as subjects when such research can be done with other subjects."

Any concerns regarding that recommendation?

MS. FLYNN: I believe I read in this one some clarity that I think we had wanted, that this does not preclude individuals with mental disorders from participating in such research on other health conditions that they may be afflicted with by virtue of their having a mental disorder. I felt good about the way this came through clearly.

DR. SHAPIRO: That's exactly right. Thank you for mentioning that again. I think it was the reason why the word "targeting" got into this phrase as opposed to its original draft.

Okay. Let's move on to Recommendation 3, subjects' refusal to participate, et cetera. This is too long for me to read, besides which all of you have read it. I think in the last times we've discussed this there seemed amongst the Commissioners to be little concern about this, nor did I pick up any serious concern about this reading the public comments.

DR. DUMAS: My only concern is that it's rather long and there's a vague statement at the bottom having to do with reapproaching previously dissenting persons. There's some concern about how many times people should be approached and when it borders on coercion.


DR. MESLIN: Just to remind the Commissioners, in the previous draft these two items had been separate recommendations. The Commission requested that they be brought together since reapproaching someone who has previously dissented is not inappropriate if done in a sensitive way. And the language which I think was attempting to be faithful to your concern, Rhetaugh, is around page 127, lines 7 to 10. There have not been any public comments that describe how many times one would approach and would make it too much.

DR. DUMAS: I am very sensitive to this because I am in the process of reviewing some documents where there are questions about how often interviewers have approached people who are reluctant to agree to participate in a project and it is alleged that some interviewers have approached people as many as 14 times.

DR. SHAPIRO: I think that concern is entirely appropriate. However, I do think the language here, which I agree doesn't give us an upper limit like a number seven or a number three or something, but with appropriate care and sensitivity, I think that's pretty straightforward.

DR. DUMAS: The thing that bothers me is the care and sensitivity. I don't know what I would substitute for those words. I'm not suggesting that we ought to say how many times they should. But I think there should be some statement to the point that there is concern that beyond a certain level of contact or what have you people might feel coerced. I don't know exactly how to say that at this moment; I'll think more about that.

DR. SHAPIRO: Larry, then Eric.

DR. MIIKE: But I think that you've just explained the practical way you do it. You felt uncomfortable about it, and as an IRB member you would say it's not appropriate and sensitive to ask 14 times. I don't think we should be giving any guidance more specific than what we are.

DR. CASSELL: That has to be addressed and, of course, is the issue of are they going to pummel some poor person into saying yes again? So I don't think anything you say is going to change that. But care and sensitivity in regard to coercion, if you want to put the word "coercion" in there.

DR. SHAPIRO: Well, I think we all agree on the issue here, I don't think there's any disagreement amongst us. But Rhetaugh, if you could just think about that during the morning sometime and provide us with some language either to put in the recommendation, which you point out is already a little long, but perhaps it could be in the language below it, whichever you think is best. And if you could just provide us directly with that language, I think there's no disagreement amongst us on the issue.

DR. DUMAS: Okay.

PROF. CAPRON: Just to respond to one comment that Larry just made. I don't think there's any reason to believe that the IRB is going to be particularly aware of this. This would have to be advice that in effect governs the conduct of the researchers. Because I think what we're talking about is a situation which is below the level of visibility in all situations unless there is a companion to the researcher from the IRB walking around with the researcher any time he has contact with a subject.

I did have one other substantive question, which is the meaning of the phrase "at the point of notification." Jim or Eric, can you—

DR. SHAPIRO: That's in line 7?

PROF. CAPRON: Excuse me, in line 7, that's right.

DR. MESLIN: The notification will refer rather to recommendations regarding informing them or approaching them to participate. So it's the notification regarding participation. I think that's perhaps a little unclear.

DR. SHAPIRO: I agree with that.

PROF. CAPRON: And there's also the unique spelling of "incapable."

DR. SHAPIRO: Trying to save space. Leave out a few syllables here and there.

I think the idea here in my mind is straightforward; namely, the subject's refusal to participate or continue to participate at any time must be honored, period. And everything else is just commentary. Maybe that's the way we should— "A subject's refusal to participate or continue to participate in research must be honored." Then go on to say whatever it is we want. I think that was our sentiment here.

Any other comments regarding this? Thank you. Let's go on to Recommendation 4, which has to do with providing thorough justification, et cetera, and see what kind of comments.


DR. LO: Two comments. One, I was a little confused as to which of these recommendations were calls for regulatory change or guidance for IRBs. And this, in particular, it seems this and number 5 are really just restatements of what is already required in any research, whether it's on persons with mental disorders or not. So if we could somehow flag in the way these recommendations are worded which are the ones that require recommendations—

DR. CHILDRESS: These are all under, go back to 120, recommendations directed at the regulation of IRBs. That continues, as I understand what we've done, till we get to 147 where we offer additional guidance for IRBs. So as I understand the way this text has evolved, that's the distinction. So everything we're working with up to 147 would be a part of our recommendation for regulatory change.

MR. HOLTZMAN: Jim, I had the same confusion reading it before I saw that. It gets lost in the formatting, because right after you get that title you then say we will distinguish what we're talking about.

DR. CHILDRESS: I agree, I think there's confusion with that, too.

DR. SHAPIRO: If I could interrupt, I apologize, Jim. I think Bernie is raising what I think to be a substantive issue here; namely, if I could state it this way, it would just suggest that 4 and 5, however they get to be worded eventually, belong under "guidance" rather than here?

DR. LO: I guess my point is that I think right now any investigator is required to justify the research design they would use to the IRB and to provide a justification of why the benefit-to-risk ratio is acceptable to proceed with the research.

PROF. CAPRON: This goes beyond that. This says it not only must be acceptable, the risk side must be minimized. That's how I read it.

DR. LO: Isn't that in the current Federal regulations?

DR. MESLIN: Protections in the research—I'm sorry.

DR. SHAPIRO: Go ahead.

DR. MESLIN: I was going to say the Recommendation 4 is not explicitly in regulation now. There is no requirement that one provide to an IRB, requirement that one provide a justification in selection of a design, including those that you were describing at the top of 128. I think you're right by implication that as part of a protocol submission one provides a justification for what one is doing, including an assessment of risk and benefit, a description thereof. But I think, if I can recall the Commission's deliberations on this, it was to make explicit that, because of concerns about certain types of designs, investigators should be expected to provide justifications for those.


MR. HOLTZMAN: So is the issue one of wording again? I mean is the recommendation specifically directed to that set of types of protocols? And if so, should we get that up in the front of the sentence? "Provide a thorough justification of the research design involving..." that—

DR. MESLIN: It sounds like you just volunteered to write something.

DR. SHAPIRO: Well, the issue there I don't know that we should put in a recommendation. I'll have to think about it, Steve.

MR. HOLTZMAN: But which is it?

DR. SHAPIRO: I would prefer the broader definition, not the narrower definition. I think these are examples we have before us, there may be other examples, and I don't think there's any reason to draw a recommendation focused just on two or three research designs that happen to be controversial now. There might be others that come along. Diane?

DR. SCOTT-JONES: If we're really only putting them in as examples, then I guess I would have to go back to what Bernie said, researchers are already expected to do this. And I thought the point of this recommendation was to note that these designs at this time are especially controversial and might need special attention.


DR. CASSELL: What I want to emphasize—I wouldn't say they're controversial, these are designs which may produce harm and they have been brought before us specifically and they're not going to go away.

DR. SHAPIRO: I think we all agree on that part of it. The question is whether we should draw the recommendation solely for those particular designs or as including those designs.

DR. CASSELL: "Including" is fine.

DR. SHAPIRO: That's my view also. And so we would meet our responsibilities regarding things that are brought before us and we believe need some attention.

MS. FLYNN: But we wouldn't preclude.

DR. SHAPIRO: We wouldn't preclude other things that may fall under this category sometime, that may indeed today fall under these categories, we just haven't focused on.

Any other comments? Arturo?

DR. BRITO: Yes, I have a comment about page 130, following this recommendation, the very last line where we talk about possible grounds for excluding subjects from particular studies. I think the language in number 3 there, "standard therapy is generally considered effective," needs to be a little bit stronger and more direct to where I think the standard therapy should be "is previously proven to be scientifically effective." The reason for that is I think it leaves too much room for interpretation there.

DR. SHAPIRO: That's a helpful suggestion. And other suggestions like that, please get them before us. But to the extent you can write them down, it's a very big help to us.


MS. BACKLAR: Thank you. I think one could get into a problem with the words "standard therapy," for instance, with a disease like schizophrenia. One of the arguments going on now is what is standard therapy? So I have exactly the opposite reaction to that. And I don't mean to add to the problems, so I'll talk to you about it afterwards.

I did want to say that usually, on page 130, line 8, nowadays one would refer to this medication as anti-psychotic.

DR. SHAPIRO: Thank you.

Let's go on to Recommendation 5 which has to do with assessment of risks.


MS. FLYNN: I know this is contained somewhere in the text, but one of the things that we've talked about and I think there was broad agreement on is that we wanted, particularly in studies where we had some concerns about the vulnerability of the subject population or the potential benefit-risk ratio, we wanted to be sure there was linkage to community care for subjects who withdrew or who were dropped from the study. I think there's text about this somewhere in the document but it does not appear here. I would suggest that this is an important protection particularly given the concerns we've heard around relapse and the problems of some of these studies that have been laid before the Commission.

I would be interested in comments from Commissioners as to whether we might strengthen this in some way by adding a requirement that for this subject population, there be that obligation to assure that when they leave the study they are linked up to care in the community.

MS. BACKLAR: There's something about this on page 129, I think, following Recommendation 4. But it may not be enough and I don't know that it does actually say "aftercare."

MS.FLYNN: It's not very specific. I see it there and I think it's trying to reference—

MS. BACKLAR: Starting around line 10, it starts at 9 actually.

DR. CASSELL: But that's a wraparound provision. This is a broader provision than wraparound.

MS. FLYNN: I think some of the cases that we've heard about that were most troubling to us involved this very problem, that people left the research and were not connected. It is a critical problem if we accept up front that these are vulnerable folks and that they are going to be perhaps placed in greater potential vulnerability by virtue of being involved in the research. And when they leave the research, for whatever reason, it seems to me there's some obligation to assure a connection to care.

DR. SHAPIRO: I want to think about that a little more. I think I understand, Laurie, the point you're making. I want to be cautious about participating in research entitling you to a whole series of benefits which no one else in the society has access to.

MS. FLYNN: Obviously, we can't assure that they're going to continue in the care, that the care is going to be good enough, all those things we can't know. But there would at least be an obligation to link them to the care providers in the community to make that connection, such as one makes when there is a discharge from a hospital. We don't just discharge people from a hospital and say "good luck." We discharge them from a hospital and we provide connection to their community care provider.

DR. SHAPIRO: Let's see how others feel about it.


DR. MESLIN: I was just going to draw the Commission's attention to page 146, where it is further down the road than where you're referring to, Laurie, 146, lines 4 to 11, and specifically lines 8 to 11, "The research team must also make adequate provision for...." That may be where you were referring to elsewhere in the text.


DR. MESLIN: My understanding of Recommendation 5 was that it was still at the protocol review portion and that risks and benefits being described for the intervention itself rather than the risks of premature stopping and follow-up. But that's where it is also mentioned in the report. It can be moved, obviously.

DR. SHAPIRO: We'll certainly think about that further. And if you have any additional language that would be helpful to us, we'd be very happy to receive it. Go ahead, Trish.

MS. BACKLAR: When we were reviewing some of the protocols, Alex, remember we discussed this, Jim, in terms of the protocols that we were concerned about that people were not being provided with aftercare, and I had said something which you asked to be put into the text. And I can't remember precisely what it was but it was rather similar to what Laurie was bringing up.

DR. SHAPIRO: We will pursue that. Let's go on then to Recommendation 6. I'm sorry, Jim.

DR. CHILDRESS: On 6, I had some difficulties bringing our text together with our recommendation. And this may, in part, have to do with what Harold has already noted, that we really haven't spelled out what we expect to be involved in minimal risk research, what kind of assessment of competence and so forth would occur.

In terms of what Recommendation 6 itself states, I'm quite comfortable with that, as well as with number 7. But then when we try to explain what's involved, beginning at the bottom of 134, in both 6 and 7, it seems to me that we're introducing a second trigger for capacity assessment.

In our Recommendation 6, we're saying that for greater than minimal risk research we're presuming, and this is language that Alex and others worked out last time and I think it's very helpful, presuming an appropriate method and so forth, though a less formal method could be permitted if there are persuasive grounds for doing so. But then when we move on in the text, on 135, the first couple of lines and midway down, the other trigger has to do with when potential subjects are believed to be incapable of deciding. And believed by whom, under what circumstances and so forth, that triggers an assessment. Now it may be that we're thinking about that in relation to minimal risk. At any rate, we really do need to be clear as we try to explain this recommendation exactly what's going on, what will trigger what level of assessment of capacity.

DR. SHAPIRO: Alta, excuse me, I'm sorry I didn't see you.

PROF. CHARO: That's all right. Jim, I think that your concern can be addressed in a pretty straightforward way. If any person involved in enrolling a subject or working with a subject has reason to believe the subject has not got capacity to consent or to continually make decisions about whether or not to withdraw, at that moment an assessment should be made. And that is for all research and that's just the norm currently today as well.

In addition, at the moment at which an IRB is reviewing a protocol that involves greater than minimal risk research, it should look at the population to be studied. If it falls within these recommendations and if the research is greater than minimal risk, it should proceed on the assumption that capacity assessments will be needed unless the investigator can explain why they will not. So there are, in fact, two separate triggers.

DR. SHAPIRO: Alta, could I just ask a question? I'm just trying to make sure I understand what you've said, because if I do understand what you've said, it corresponds with my notion of what we were doing, although that's up for further discussion. That would mean that in minimal risk research, any time an investigator or anyone associated with the project feels there's some question about someone's capacity to look out for their own interests, that ought to trigger some kind of an assessment. That's in minimal risk research. And maybe we need to be clear about that, if that's what we believe, in the text.

However, this recommendation here deals with greater than minimal risk research where, if I understood what you said, the presumption is that an assessment would be required unless, as you put it, this last sentence holds, I don't want to repeat it. Is that consistent with what you said?

PROF. CHARO: Yes. The only clarification I'd make is that these are not mutually exclusive categories. Perhaps the easiest thing is to think about them chronologically. The protocol first comes to the IRB. If it's minimal risk and the IRB thinks that these people are not going to have capacity to consent, they may require a competency assessment or not. That's their usual job. If it's greater than minimal risk, we ask that they assume you're going to need it unless shown otherwise. That's the first step of the chronology.

The second step is, regardless of the level of risk and regardless of the IRB's actions, at any point along the way in the actual implementation of the research, if an investigator or somebody enrolling the person or another person working with the subject says I think this person has lost their capacity to be an effective partner in the research, we need to stop and make an assessment here about this person's capabilities.

DR. SHAPIRO: Other comments?


MS. FLYNN: I just want to understand this one because I certainly generally support the thrust of it. I believe we've determined that greater than minimal risk research would include most, if not all, clinical trials of new medications. Would this then mean that people who are showing up to participate in a clinical trial for a new anxiety medication, people who are not likely to be by definition folks who would necessarily have their competency questioned, would now be subjected to this kind of thing? That this would be an assumption being made that—

DR. SHAPIRO: If I understand it, Laurie, just to try to answer your question directly, tell me if I've misunderstood, Alta, is that at the IRB approval level when it is initially approved, if the IRB feels that this is a population for which this problem doesn't arise, then they can waive that requirement. If they feel this is a population where that's an open issue, then they may not waive the requirement. But the IRB could make that decision. That's the purpose, as I understand it, of lines 6 through 8 of Recommendation 6.


DR. LO: Let me inject another issue here with regard to Recommendation 6, which is the requirement that the capacity assessment be done by someone independent of the research team qualified in an appropriate manner. It seems to me in a lot of situations, particularly for minimal risk research, many protocols will try to meet this requirement by saying we will go to the personal physician of the patient who is not a member of our research team and ask that personal physician whether the potential subject has capacity or not. One question is often those are not very formal assessments and it seems to me it would be unusual for the personal doctor to then say, okay, come into my office, schedule a 20-minute appointment, let's go through a standard protocol to determine the person's capacity. Are we comfortable with the doctor just saying let me think about that, yes, I think this person does have capacity, or are we really requiring a much more formalized assessment?

Secondly, I would like to see in the accompanying text some justification, which I didn't find in this section, for having the person be independent of the research team. I think it's elsewhere in the report. I think we need to acknowledge that this will be a substantial change in the way the protocol is run and could be a substantial burden on some studies to have someone, presumably they would have to be—I'm not sure how this would be done and I think there are real practical issues of is this going to be covered in the cost of doing the study—having an outside person independent of the team conduct a capacity assessment? If I weren't sure, I would not want to pay for a separate office visit to determine one's capacity to consent to a research.

So I think there are a lot of issues here that we at least need to acknowledge. My sense is that many researchers feel that this recommendation will shut off a lot of research.


DR. CASSELL: Well, the recommendation requires the employment of an appropriate method. It doesn't just say a qualified professional can just say he is or she is, so forth; it requires a methodology. The methodology should be specified and the IRB should cover that. But, yes, this is going to be a substantial burden for people doing this kind of research. But it also prevents probably the central abuse, that the investigator who has an interest in going ahead also does the assessment of capacity. That's how we got into this in the first place.

So I think we just have to accept the fact that this particular issue is one that's going to be a problem for investigators, and rightly so, because these are people who have an interest in the research going forward that may preclude their doing the best assessment possible. We just know that. And you want that spelled out in it that there's a "double agent" problem here, then that might be necessary to spell that out. But I personally don't think it is necessary to spell that out.

DR. SHAPIRO: Rhetaugh?

DR. DUMAS: I'd just like to point out that this is one of the areas where some of my colleagues in the psychiatric field are taking exception to the idea that someone other than a member of the research team would be involved in making that decision.


PROF. CHARO: I'd like to speak in support of the current approach here. My experience working with health care professionals in several institutions has been that competency is only questioned, in that large gray zone, competency is only questioned when people want to do something that the health care professional disapproves of. When people want to do what the doctor or the nurse or the other professional wants them to do, rarely in these ambiguous cases do people stop and say, gee, I wonder if this person can really consent?

DR. LO: That's absolutely right.

PROF. CHARO: And the disagreement or unwillingness or obstinacy is usually used as the first sign the person is probably incompetent because they're not going along with the recommended course of action. And I truly, truly, truly do not believe that this is motivated by evil intentions. I think it is genuinely motivated by people who are embedded in a situation in which they're trying to do what they think is right and they look at somebody who seems to be making decisions that are all wrong and there's got to be an explanation. And it's going to be a lack of competency.

I find it hard to believe that some of that same dynamic does not exist as well in the research context. Which is why I think that in those circumstances, where you genuinely need to make this assessment in a serious fashion, that the independence of the assessor is very valuable because it removes some of that embedded context problem that I've seen so frequently.

DR. SHAPIRO: Laurie?

MS. FLYNN: I want to endorse this recommendation strongly. Again, this recommendation is very, very similar language to policy we adopted in my organization in 1995 for precisely the reason that Eric points out, that this is a very appropriate safeguard, it will be a burden in the research arena, but it's an appropriate way to make certain that as people enter studies we know that they have had an independent assessment. So we feel strongly that this is an important protection and, although it is indeed a burden, that it can be handled and should be seen as part of the price that one pays in a research institution for the privilege of doing research with these individuals.

DR. SHAPIRO: Bernie?

DR. LO: I think if we're going to keep this independent requirement, I would want us to make a recommendation somewhere that NIH and other funders of research need to write that in as part of the legitimate cost of doing the research.

DR. SHAPIRO: I think we will get in the final report some general comments about it. This is not the only place where that comes up. It comes up in a lot of places, virtually everywhere where we're asking for additional efforts.


PROF. CAPRON: I agree with Alta's observation. I want to add, however, that the review of the protocols that we engaged in, indicated the need for exactly this kind of a recommendation, because in none of those protocols that we reviewed was there any indication of any attempt to assess the capacity of subjects, some of whom were enrolled precisely because they had major disorders, and all of the protocols we were looking at were ones in which their published descriptions involved more than minimal risk.

I think this is one of those recommendations which may be onerous but is not something that comes out of the blue. It is based upon experience in this field.

DR. SHAPIRO: Okay. If I could just make a recommendation. I think that the Commission probably is in support of this. We will have to write our recommendations regarding minimal risk which relates to assessment in that case, and that will have to come before us and that will give us a chance to look at it altogether when we do look at that. And we'll have to clarify, Jim, the language that you pointed to on page 135, if I remember correctly. So we will certainly do that. But I think there is broad support for this. But we will need to clarify and bring together our recommendations regarding minimal risk.

PROF. CAPRON: Mr. Chairman, there are two points in the commentary that seem confusing to me. The first occurs on page 135 at line 1, the statement carrying over from the previous page is "the capacity assessment should only be required," et cetera, et cetera.

DR. SHAPIRO: That does have to be clarified. I agree with you.

PROF. CAPRON: Okay. And I have a suggestion there.

The other is on the top of page 136, the justification that is given for value of this capacity assessment is that, by finding the subject incapable, investigators would then be obligated to approach a third party to make a decision on behalf of the person. It seems to me that that obliges the real value, which is that people will not be enrolled in research until a person who is capable of making a judgment about their participation is called upon to make that judgement. And I'll give you language because it doesn't seem, if people agree with that, it doesn't spell out really the justification very well.

DR. CHILDRESS: I think you're quite right. I'd actually changed it in my text. I assume that rather than value we probably meant the effect; that is, it describes an effect rather than—

PROF. CAPRON: I think it would be fine to describe the value of it.

DR. CHILDRESS: Right. But we would need something very different from this. I agree with your suggestion.

DR. SHAPIRO: Alex, can you give us language on both of those because both of those need some language.

PROF. CAPRON: Do you want me to read a sentence and see if it works, just very quickly?

DR. SHAPIRO: Why don't we do that since we there right now.

PROF. CAPRON: "Capacity assessment," this is the thing on the top of 135, "Capacity assessments are usually required only when there are reasons to believe potential subjects may be incapable of deciding about their participation." And then as we work down from there, we get to the point we say, "Our presumption is that for studies involving greater than minimal risk IRBs will always expect...." So it changes the first to descriptive and then goes from there. Is that satisfactory?

DR. SHAPIRO: That's helpful. Thank you.

Let's go on then to Recommendation 7.

DR. CASSELL: Just to clarify that. That leaves that sentence, "Our presumption is that for studies involving...." that stays in?

PROF. CAPRON: Sure. No change at all there.

DR. CHILDRESS: Yes, no change in that.

DR. CASSELL: So it isn't a question of, it's that circular thing that says if you don't think they have capacity, you have to measure their capacity.


DR. SHAPIRO: Thank you.

Recommendation 7 is what I call the notification recommendation. Any comments regarding that particular recommendation?

DR. MURRAY: I have a comment in the text that follows.

DR. SHAPIRO: That was just the text we were working on. Do you want to make the comment now?


DR. SHAPIRO: Fine. Go ahead.

DR. MURRAY: Lines end of 12 through 15, that statement. The current sentence reads, "Studies involving non-invasive interventions which satisfy the conditions of minimal risk defined in the Common Rule," et cetera, "would probably not result in IRBs expecting such an assessment to occur." Now I can't tell if we are giving a simple description there and we're going to build an argument from that, or if we are actually prescribing to IRBs that they ought not to expect such an assessment to occur. It's just I found that ambiguous and I'd just like to be clear which it is we're saying. Is it descriptive or prescriptive?


DR. MESLIN: It was attempting to be a statement that shows that the presumption would not be in favor of requiring this in all instances because the assumption is that a capacity assessment would not be needed.

PROF. CAPRON: I move to strike that sentence.

DR. SHAPIRO: It doesn't add a lot. I agree with that.

DR. CHILDRESS: I agree. This is another indication of why we need to state, as Harold suggested, exactly what we expect to go on in the area of minimal risk research.

PROF. CAPRON: And part of the reason that I move to strike it, just to be clear, is there is no necessary connection at all between minimal risk and more than minimal risk as to this assessment issue. You don't want to enroll incapable subjects in either case. It's just that the probable harm is less when you make a mistake in one case than in the other. And so I think that leaving that sentence out doesn't put us on the side of seeming to suggest that the two are linked.


MR. HOLTZMAN: I'm just wondering if some ambiguity doesn't arise here from the word "assessment." Are we referring to assessment, per se, or to the formal process of assessment being recommended? Alta's comments about assessing, that you never enroll someone that you feel incapable of assessing, I agree, regardless of the minimal risk.

DR. SHAPIRO: Let me suggest, I think that really we do need, in order to really resolve this carefully, we do need to have our recommendations regarding minimal risk and I think it will be easier to do the language here. I really do sense an agreement amongst us on this, but we'll have to get the language and make sure that that's correct. We will try to do that part before we leave here today.

Let me ask a question then about Recommendation 7, which is the notification, as I said before, any comments regarding that? Okay. Eric, there are two issues, before we continue on with the recommendations, there are two issues I think it might be useful to interject now and then we can take a break and take a stretch or something and then go on with some of the other recommendations. One is minimal risk. We've already talked about that. Do you want to say anything further, or we'll just go to the drafting board? We might take a break which will give us a chance to draft some material here.

DR. MESLIN: I'd only like to point out an issue that has arisen in the public comments that we received that are reflected in the flow chart in appendix 3 but are not reflected explicitly in the text since we do not have a recommendation relating to minimal risk. That comment referred to the assumption that IRBs can utilize a waiver of informed consent; they can waive informed consent in minimal risk research if the conditions within the Common Rule have been satisfied. There's no difference for minimal risk research, so goes the argument. Now we have had this implied in the text but it has never been made explicit.

Two points follow from that. If the Commission agrees that that is appropriate, because by implication you've been saying it all along, then I would suggest that that explicitly be created in the text. And secondly, it would be very useful if a single recommendation regarding minimal risk were constructed that included both that provision as well as provisions regarding assent and dissent, how those are acceptable and when they are not, and the capacity assessment issue which we've just described.

So I raise those for you. I think the first is noncontroversial, but I wanted to make sure that you were aware that there have been public comments on this. In fact, at the last meeting in Alexandria there was a public statement asking the Commission whether we would, in fact, be making that clear. It's not explicit in the text but is implied.

DR. SHAPIRO: So is there any—I don't see how there could be any objection to drafting a proposal, so I don't want to ask that question. But I think that's a proposal we perhaps could draft relatively quickly because I think it's straightforward. Then we could see whether you found it straightforward when you looked at it or not. So I'm going to propose that when we break in a few minutes that we'll assign two or three of us to actually draft that proposal and present us something on that later on this morning.

Let's now also take up the issue which I flagged before when I was making my introductory remarks regarding health care professionals. Let me see where it is dealt with first. If I remember, it's page 86 where we make certain statements. I'm going to turn to Eric to just describe the issues as I see them. It's really all at page 86, forgetting the lines 5 through 16 or something which really refers to someone else's views of this matter.

Eric, why don't I turn to you because I do think we need to have some discussion and resolve where we stand on this issue.

DR. MESLIN: I'll just briefly remind the Commissioners, it turns out that we begin the discussion on line 6 of page 85 where the discussion of independent professional support for subjects and surrogates begins. It continues from that page all the way up to line 4 of 86. And then there is a continuation of that discussion in the guidance section of the report on page 151. All that is said on 151, and as you turn to it you'll see it yourself, is that IRBs may wish to consider recommending that an independent clinician be available to counsel the subjects, a responsible health care professional.

There is, in short, a confusion about the number of individuals who we are calling health care professionals and what their roles and responsibilities are. My understanding in relating to you what the public comments have said...are first, it would be excessively burdensome to require that every person who participates in research must always have available to them a health care professional to counsel them, plus or minus counsel of their legally authorized representative. That's one issue. The second issue is whether, in cases of greater than minimal risk research, without the prospect of direct medical benefits to the subject, where the subjects might be incapable—I apologize for the three parts of that recommendation. You are currently describing the role of the legally authorized representative as allowing patients to continue or withdrawing them, but not to enroll them. And here, the role of the health care professional would rear his or her head. Is it required that when the legally authorized representative decides part way through a study, that it would be appropriate to withdraw someone, that they could do that only upon consultation with a health care professional, or is it simply that someone should be available should they seek to obtain that counsel? It is a very simple problem that I believe the text has confused.

DR. SHAPIRO: I think that we might focus on the issue of when they are required, because obviously anyone could always make use of it and so on. But it would be required when a patient lacked capacity to decide and so, no. So the real issue is—I'm somewhat confused myself as to how the Commission feels about this. That is, when you feel this extra assistance is required as opposed to when it should be considered. I would just like some help on what the Commission is thinking on this issue. Eric?

DR. CASSELL: Well, I think that if we required it for everybody, or really put a requirement in, that is very burdensome. On the other hand, it ought to be mandated that a research team understands that the legally authorized representative or the patient can request such a person. They can request it under any circumstance, but it's not required under any circumstance. When there is risk, regular to minimal risk, I think whether there's benefit or not, there should be an identified health care professional out there.

DR. SHAPIRO: Well, in that case Eric—I'm just trying to clear it up in my mind what your thinking is. In that case, if it's greater than minimal risk and they know there's a health care professional available if they want, must they use them?

DR. CASSELL: No, I don't think you must use anything.

DR. SHAPIRO: I'm just asking.

DR. CASSELL: No, I think it should be available, but they do not have to use them.

DR. SHAPIRO: So the distinction you've drawn, if I understand it correctly again—I apologize if I'm repeating myself—and that is unless the minimal risk research patients and/or other representatives, I don't understand, that they may request that.


DR. SHAPRIO: And in greater than minimal risk research, they need to be informed that someone is available if they want it.


DR. SHAPIRO: That's your view. Let's just see how that feels to the rest of the Commission. Thank you very much. How do other Commissioners feel about that? Bernie?

DR. LO: Let me follow up with the greater than minimal risk. Someone ought to be designated as being available. Could that person be the personal physician of the patient? Because there's language at some point saying that you had to have another professional advising the health care professional.

DR. CASSELL That's the team approach.

DR. LO: So what you're saying, Eric, is that the patient should be notified that either their personal physician or so and so who has been formally invited by the study to serve in this role is available to them.

DR. CASSELL: And we don't require yet another specialist to advise the sub-specialist and so forth.

DR. SHAPIRO: Let me just ask the obvious question here so just I can be clear in my mind. What if the personal physician is the investigator on this subject? I just want to make sure I understand.

PROF. CAPRON: And don't we need to, again, vis-a-vis Bernie's comments about research grants being made adequate to fund our proposal, be clear that available means paid for by someone? Because it may not be regarded as reimbursable treatment cost.

DR. LO: Now let me ask the next question. There are some protocols that are much riskier than others, such as symptom provocation, withdrawal patients, randomizing where there's a known effective. What we want to throw out is in that situation, do you want to have a mandatory discussion with an advisor as opposed to making him available. The issue is that they really are on different levels of benefits or risk involved.

DR. LO: Let's follow it through. Let's suppose we mandated it. And the subject comes through and says "I don't care what my advisor ..."—and we get into that kind of ... I think people have to have a choice in this. If they have the capacity to consent....

DR. SHAPIRO: My own thought on that, and I think that's right and I think there are other kinds of studies we can suggest which are even riskier and so on and the IRB always has options to make requests. I think that I'm satisfied here that they must perform if something is available. As a subject is competent or incompetent, we have to rely on competency somewhere along the line here or this whole thing sort of doesn't add up. I would be satisfied, just speaking to myself now—the way that Eric phrased it, although we need to get language together so we can look at it. All right. We will try to draft some language on the health care professional consistent with this kind of approach. I would like to suggest, we've gone for about an hour and a half now. I would like to suggest that we take a break, but I'm going to make some arbitrary announcements here regarding drafting material. And Eric, I wonder if you and Alta and anyone else who wants to participate, providing there are not more than two others—can draft something on the minimal risk side. The other thing that I think we have to do is clarify just what we want to do along the lines of the talk about the health care professionals. And Jim, I was going to ask you if you and Eric can get together with anyone else who might want to participate and we could try to get back here by 10:00, which will give us a half hour of drafting time and let's see what we have. Is that acceptable? Thank you very much. We're recessed for half an hour.

DR. SHAPIRO: I'd like to return to some subjects we raised earlier and ask our colleagues if they drafted some language that we could at least consider. We will, of course, incorporate this into the document as appropriate. Let me first go to Eric, who was working with a group. If you recall, this had to do the role of the health care professional, just to say it in summary form. Eric?

DR. CASSELL: There are two clauses. The first clause is for any research subjects or their legally authorized representatives to be informed that they may request the opinion of an independent health care professional about their participation in their research. Investigators must make available any information or access to the subject or research site that the independent health care professional requests in relationship to the investigation. Clause two. For greater than minimal risk research, whether or not benefit is anticipated, an independent health care professional must be identified in advance of the start of the research. The subjects or their legally authorized representatives may or may not request the opinion of the independent health care professional if they wish. The investigators must make available any information or aspect of the patient or research that the independent health care professional requests. Thank you. These are comments.

DR. CHILDRESS: I think one of the big questions that emerges out of the first question is that for regulation, really guidance for our IRBs takes on quite a different tone.

PROF. CAPRON: Certainly the funding issue.

DR. SHAPIRO: Quite aside from the funding issue, it's a different kind of issue which we can come back to. The issue as I understand it is whether or not we think that Eric has captured the intent of our discussion, namely to try just feed it back. There are two aspects of your recommendation. One is the fact that if the patient or subject and/or their legally authorized representatives requests the use of the health care professional for advice or assistance, then investigators must yield the appropriate information—must be informed. You've said it explicitly, but I don't know what it would mean if that weren't the case, if they only got some of the information. So that seems to me—I just highlight it because it wasn't mentioned before, but it seems very straightforward to me. So that part of it seems straightforward. Now with the issue of minimal risk research, they may request the use of someone.

DR. CASSELL: But we don't have to identify in advance.

DR. SHAPIRO: That's right. And they may not. That's just something that the patient or their legally authorized representative does: request it, it has to be provided. In greater than minimal risk research, they must identify someone and patients and/or their legally authorized representative may request. Just so I understand. Do people have any concerns? I'll come back to the issue of where it goes in the report in a moment. Yes, Bernie?

DR. LO: I have two suggested modifications. One when you say independent health care professional. At least once I'd like to suggest we change it to be "health care professional independent of the research team." Because independence to some may mean independent of the institution or hospital.

DR. CASSELL: I actually was going to say be the super, because we have a whole set of paragraphs about independent professional support.

DR. LO: And then I didn't quite catch the sentences about what information must be provided. It seems to me that what you would want is information about the protocol, the risks and benefits. But if that person would say "well, show me your preliminary results, I want to see them." It seems to me that would not be legitimate.

DR. CASSELL: I don't have that in here. I have "to the subject or research site, subject protocol or research site."

DR. LO: So the information is about the protocol, the research. I didn't understand.

PROF. CAPRON: Do you think it is illegitimate, Bernie, for a subject to say "show me you preliminary results?"

DR. LO: I think they may ask, but I think it may be part of the design where there's blinding and there's concern about taking preliminary looks. If that's part of the protocol and explained as such—the subject may ask and they may be dissatisfied with the explanation, but I don't think there should be any obligation on the researcher to disclose preliminary information which would undermine the research program.

PROF. CAPRON: But obviously, anything that a research subject would have access to would be available to the advisor.

DR. SHAPIRO: I actually think that's a neat and summary way to put it. And so if the protocol didn't allow the subject to access it, then of course others couldn't have access. Okay. I think you've captured—

PROF. CAPRON: Could I ask one other question? Back on page 87, which is where the descriptive part in chapter 3 about this independent professional comes in. At the end of line 4 or following line 4, I wonder if it would be desirable there to tie together the notion that the person who we say had been previously acquainted with the potential subject would therefore potentially be the person who was their treater previously. If we had language of this sort in another sentence, when as is usually desirable, the researcher is not the health care professional who has been providing services to the subject as patient, this independent advice can come from that person. In other words, tying the two thoughts together that we've talked about. The advisability that we not have as a routine matter physicians and others caring for patients turn around and ask them to be subjects. And the fact that we're saying that there should be an independent person and all the better if he knows the subject. Would a sentence of that sort be acceptable there?

DR. SHAPIRO: Is the idea—I just want to make sure I understand what you're getting it—is the idea being that when someone who is serving as the caregiver in this case, the physician in this case for this person, if they are not involved with research, they would ideal for this kind of position.

PROF. CAPRON: We already say that in each instance. And so this is just tying that thought back to our previous thoughts about the desirability of not having the caregiver turn around and becoming the researcher.

MS. FLYNN: Isn't that captured on page 85, lines 13, 14, 15, 16, right in there? Don't we say it right in there? I'm not sure why we need to say it again.

PROF. CAPRON: No, I don't think it is. This refers to an independent and properly skilled person available to be the advisor. We then go and say "in each instance, this advisor should, whenever possible, have been previously acquainted with the potential subject." And I'm just trying to close the circle and tie it into our previous recommendation and say "when, as is usually desirable, the researcher is not the health care professional who has taken care of the patient previously." That person would be the ideal person to play this role of independent advisor, to take on the role of independent advisor. Or that person is available to play this role.

DR. SHAPIRO: I think I agree with you, but I'd like you to write out the sentence and I'd like to look at it. I think it actually may be helpful. It doesn't introduce anything new, any new idea, but it might be helpful. And so if you can just do that, I would appreciate it. Okay. We will have to deal with where this discussion regarding health care professional comes in now. Currently it's only in under "Guidance." And if I understand the recommendation here, it's not really guidance we're asking for here, we're asking for changes in behavior. I don't know exactly where it will go, but it will have to find its way into that list. We'll work that out. Okay. Let's go on now. There's another group that was looking at the issue of minimal risk. Let me turn to Eric. This is a question, just to remind everybody, of wanting to state what is consistent with our ongoing text here, what our views are on minimal risk research. And that also will have to find its way to the appropriate spot.

DR. MESLIN: I'm reading what Alta Charo has principally drafted with some modification; It's in two parts. First, research that presents minimal risk, whether or not it offers the prospect of direct medical benefit to the subject—this is the italicized version—the recommendation reads as follows. An IRB may approve protocols in this category if a) the potential subject consents or b) the potential subject's legally authorized representative gives—and I'm going to edit on the fly if you don't mind—authorizes or gives permission, since we have agreed that third parties cannot consent directly. Additionally, when the legally authorized representative gives this permission, a subject's assent should be sought and, of course, dissent would need to be honored as well. That's working language. There is a second part to this recommendation, which is that nothing in these recommendations is intended to limit the use of current regulations to approve expedited IRB review and waivers of the usual consent requirement. I know that Alex may have had some comments on this. My only point would be that we have mentioned assent and dissent in this recommendation because we have described it in the text earlier in the report and we have attempted to make clear what the public comment was requesting. And we've already indicated this in a flow chart about consent waivers.

DR. SHAPIRO: Comments, questions regarding this? Jim?

DR. CHILDRESS: I just have one question. Even though we talk about assent as well as dissent in the text, we don't really anywhere in the recommendations bring in a fuller notion of assent. It seems to me if we do that, then we're going to need to amplify things quite a bit more. And that's not necessarily to argue against it, it's just that we've taken the notion of dissent to allow the opting out under any circumstances. And if you want to make a stronger role for assent, then I think we'll probably have to go back and rework some of this.

PROF. CAPRON: In a way, to second what Jim says, I think if the point is to develop a recommendation around assent, then that makes sense to me. If the language that you read is not further elaborated, it seems to me that it is more appropriate as commentary around Recommendations 8 and 9. The thought being that we introduce this whole section on page 121, I guess or 122-120, excuse me—by saying that these are recommendations for regulatory reform. And the language of what you are saying here, particularly the language about nothing here is intended to alter the usual rules, none of what's there really sounds to me as though it's intended to alter the usual rules around minimal risk. And I think as a matter of logic, we ought to explain what our view is on the minimal risk or less research and then say that with research of more than minimal risk, that we are recommending changes in regulatory reform. Rather than trying now to craft language that rises to the level of a recommendation, where I think the need for precision certainly greater than if it's merely commentary. So I would favor. Now if you come up with some language which you believe would involve a real notion of assent which is different than the present regulations provide for, then obviously such a recommendation should come before us as a recommendation.

DR. MESLIN: I'd just like to make an observation. On page 60, there is a short paragraph that I think the Chair agrees requires some more careful rewording. This is a paragraph that describes what the national commissions use on assent and dissent work. I'm taking from what you said, Alex, that by moving in the direction away from it being a recommendation as a commentary, that it might be appropriate both in the text of page 60 to amplify that issue and then, if necessary, somewhere around 120—around recommendation 8 on 130, somewhere around 134. That would be some other commentary, prior to the greater than minimal risk section.

DR. SHAPIRO: I think the notion that we have to say what it is we support with respect to minimal risk, it ought to come first rather than an afterthought to this. I think it does make sense. And I also think—I've forgotten the page number now—but where we do discuss assent and dissent, we don't make anything of it in the report currently there. We don't know why this is discussed or why it's in there, and it does relate at the end to deciding whether assent is sufficient in some cases to go ahead and enroll people. And that we deal with directly here. So we just have to beef up that explanation, why it is we're raising these issues. But I think other than that, this seems to me something that we can put in our next draft. Any other comments, questions? Okay. Let's go back. I want to thank all those who did some drafting in the interim and let's go back to considering some of the recommendations that we have before us and what our views and so on are. Now we can go to Recommendations 8 and 9. I think the recommendations that we are about to go through now, 8, 9, 10, 11 and then 12 and 13 are where, of the ones that we haven't dealt with so far today, are the ones that have generated the most comment and reactions. So we ought to take care as we go through these. We have recommendations, I think we can take Recommendations 8, and 9 together. This is now dealing with research that presents greater than minimal risk and offers the prospect of direct medical benefit to the subject. In the recommendation itself, 8 I think, is relatively straightforward. It simply says that informed consent, that's what is required and I think it's self-explanatory. Nine, of course, deals with a case of potential subjects who are currently incapable of making decisions. I would just make two comments and then we can just turn to see what further discussions there are. Maybe I'll turn to Eric, also to see what some of the public comments on this have been. My own view currently on 9—I won't have anything further to say about 8—I really have two views. One, I think c)—this ought to be broken up into two different—you ought to have c) and d) rather than c). C) attempts to get two different ideas across in one sentence and it makes more sense to try to try to break it into two. That's a relatively small issue, no substantive issue there. And under a) and b) under 9, under a), you go talk about expressed willingness to participate. And my own view, participation in research is, I think what the intent was, in this type of research as opposed to research overall. But we can come back and discuss that in a few moments. But Eric, do you want to talk about the public comments? You can't characterize them all, obviously—we don't have time. But what do you think some of the highlights are?

DR. MESLIN: I think the only thing that has come up may have been confusion on the part of some of the public comments that took the Commission to be saying that the research that offers the prospect of direct medical benefit, even if it has a greater than minimal risk threshold, that we would be imposing a strict standard of advance consent. Some kind of documentation of that advance consent and a burdensome requirement with respect to legally authorized representatives. I don't think that that's what Recommendation 9 is saying. I think it is saying that for research that involves the prospect of direct benefit, these are the ways it can occur and it provides ample opportunity for that to go forward. Not much more to add to that.

MS. BACKLAR: Then how would you know that somebody had expressed their willingness to participate if you don't have some documentation of some sort? I'm asking.

PROF. CHARO: I think we are walking the same kind of fine line here that we do in a clinical context where family members—that's most typically what we're talking about here, because we have excluded from this institutional representatives, right? We walk a fine line where family members make decisions on behalf of people who have lost capacity to make decisions for themselves. And we have chosen on the clinical context not to limit family members to making decision that have been previously documented in writing. We give them far more leeway. And the question has been whether we should mimic that degree of leeway here, or whether we should narrow it specifically because it's a research context. Now because this research, although not at the same level of certainty and benefit as standard therapy frequently is, is nonetheless research that offers the prospect of benefit. I understood us to be trying to parallel the rules for clinical decisionmaking and basically placing a fair amount of trust in the representatives, typically family members, who are making decisions in this context. I appreciate that in the context of research without benefit, the equation might be a little bit different. The degree of decisionmaking authority one might want to grant is different. But I understood this to be one that was paralleling clinical decisionmaking privileges by family members. That we understand that we've relied on that language in this particular instance. Because I think it raises a problem of why is it adequate in one place and not in the other, and that is the discretion of the family based on their knowledge of the person and informal as opposed to unsubstantiated willingness or expressions of willingness.

DR. SHAPIRO: Is there language for Alta's suggestion?

PROF. CHARO: No, no.

DR. LO: A couple points about inconsistencies between the recommendation and the text that follows. It wasn't clear to me in the language of the recommendation, potential subjects had made it in this type of research as opposed to this specific protocol. The example given on page 139 suggests a specific protocol to which they'd expressed a willingness to participate and I think that's way too narrow. I think that we should allow families, we should allow for previous statements to participate in a certain class or type of research, not to a specific protocol. And then secondly, I just want to flag a problem that I think is on page 138, from paragraph 12 to 17.

DR. SHAPIRO: Unfortunately, I think one of the things where either the word processing or something else has run wild is on most of 38 and top of 39. It just needs to be reassigned or rewritten. We just have to ignore it for the moment. It will either come out or it will go somewhere more appropriate. Larry?

DR. MIIKE: Since a) and b) is an alternative to c) and d), I don't understand why we have such loose language about consent when you're expressing a willingness to participate. Whereas if you asked me, you're not going to enroll me in a research project simply on the basis that I expressed a willingness to consent. You have to get my consent. So if you can enroll someone without capacity under a) and b), the way it's written right now, isn't it too loose? You're just taking somebody's word? Shouldn't that just be straight consent, consent previously expressed and documented?

DR. SHAPIRO: I'd like to respond to that and secondly, I'd just like to see if there are other comments. Because I think this is an important issue. First of all, on the issue Bernie raised—or at least one of the issues he raised. On the question of whether it's a particular protocol or type. My view is that it ought to be parallel to what's on this c) and d) or c) right now which deals with a type of or nature of research. It's appropriate language, it doesn't tie it to a specific protocol. That's my own view. As I recall, that's what it says under c) or I would like it to say, put it that way. I don't know whether it says that right now. Let me tell you what I've rewritten here just so as not to take the language. Let me go to c) and d) first and I'll come back up to a). What I did is I took c) and I wrote "the subject's legally authorized representative is given permission for the subject to be enrolled in the study." That's c). And both c) and d) would have to be satisfied. And d) I wrote—and this is a little informal, but I'll tell you what I've written—"the subject has not expressed ..." gosh, I'd better work on this. But the substance of it is that I want to tie it, my view, to a category of researcher, type of research, and that's my own view. Because i think it is too narrow. And I'll get back to Larry's point in just a second. Diane?

DR. SCOTT-JONES: I just wanted to say that on page 140, the language is, as you're saying now, Harold, where it does refer to a type of study and it says "agree to participate." Whereas the one we are on now, on page 137, just says "expressed willingness." So the language is very different on page 140 and it should be probably be more consistent.

DR. SHAPIRO: I agree with that. And I think—Jim, and then I want to get back to Larry.

DR. CHILDRESS: I would just like to connect this with Larry's, or build on it, at any rate. It seems to me the way we have this worded on 137 now, that the a) and b) extending along as providing the basis for enrolling someone in research, that that is too vague. And that really what we want there, it seems to me, is the LAR being the person who interprets the person's previous wishes or willingness to participate if we take that very broadly in understanding. Because we do have to ask the question of a) and b), who is going to be providing this information? Simply the investigator or the physician, etc.? I don't think this could really stand alone. So I don't see a) and b) as totally separate from the other if we're going to word a) and b) as loosely as we do here. Now if we move into a much more specific direction, then we do get closer to something like advanced planning that is much more direct and perhaps even includes something like informed consent. So I think we need to work on these components together and if we stay with these loose ones for a) and b), then I think we really do need to make it "and the LAR's permission." I don't think what we have in a) and b) is sufficient, would be sufficient by itself to enroll.

DR. MIIKE: But if you follow that line, then it makes it much more restrictive. That the LAR can only approve if there has been a previously expressed ... If these are combined, then why bother with including that? If the LAR can give permission with or without some previous indication by the potential enrollee in the program, why list that in this if you're going to combine them? I'm only responding to Jim's suggestion. I still have problem with it or the way it's written.

DR. LO: Let me carry on with the discussion that Larry and Jim were having. It seems to me the reason for having an a) and b) or c) and d) is that there may be some people who don't have someone they feel comfortable appointing as a legally authorized representative, but may have a strong willingness to participate in certain types of research and want to express that willingness to participate in advance. It seems to me that in a clinical situation, you want to have one mechanism by which patients can give prior consent, if that's the right word, without having a third party involved. And the other track is for people who may not have just thought about the issue or made specific statements, but have a legally authorized representative who they trust or is willing to make a determination, based not on what the individuals had said about willingness to participate, but just on the basis of asking them to.

DR. SHAPIRO: I think that one of the key issues we have to resolve here before we're going to straighten this out, and has been pointed to by a number of you, is the issue of willingness. That is, whether that really is informative enough. First of all, will people understand what we mean? Do we understand what we mean? The alternative, which I guess that language was selected with the idea of not having required previous consent, and the question I think we have to face directly is whether we feel in the case of greater than minimal risk research, which offers some potential direct benefit, that a person who is currently incapable really can be enrolled—let's take the top one—only if they've had previously given their consent or not. If we put consent in there, that's what that would mean. And we need to address that issue. Steve?

MR. HOLTZMAN: It may be that we really want to roll these all together. Because if you look at b), isn't it the case that if you move down to c) and d), you'd still want b) to apply?

DR. SHAPIRO: Right. That's what d) was in my case, although I got the wording here wrong. It's really a version of b).

MR. HOLTZMAN: No, because d) has to do with the previously who didn't say they were against it. B) has to do with the notification of the assessment. And I think to Larry's point, if a) is something short of written documentation of consent of this type of research, you're turning to someone. And if that someone is saying well, they were in favor of it or even if they weren't in favor of it, I still think it's a good idea. It kind of rolls together, at least pragmatically. So maybe there's a way of doing this where either there's written evidence of documented previous consent. In the absence of that, then you have the LAR who says it's okay. The subject has been notified of the assessment—I can try writing it if you want, combine them all.

DR. SHAPIRO: I appreciate the offer, but let me just see where we are in the substance of the issue, particularly in regards to willingness, or do we want something stronger than that. Bette?

MS. KRAMER: That's the problem I'm having, is that I don't know what we mean by an expressed willingness to participate. Is it going to require a formal document? Will it be sufficient for the LAR, for the family member to come forward and say "I had a specific conversation with this person." Or, failing that, would it be sufficient for that LAR or family person to say "I knew this person intimately. These were the kinds of values that this person had. This is how this person would have responded could he or she respond to the question now."

DR. SHAPIRO: How do you feel about it?

MS. KRAMER: How do I feel about it? I think that I personally am comfortable with the clinical model. I think that when a person who has known the individual intimately comes forward and says "it's my strong feeling on the basis of what I knew of this person and the kinds of values he or she expressed that he or she would want to be enrolled." I'm comfortable with that.

MS. BACKLAR: There are lots of little problems here and one of them we really haven't put out on the table, which may make something of a difference to what I'm thinking about. And that is who this LAR is. Is it somebody, as Bernie says, that the persons have chosen themselves? Or is it somebody who now is appointed to make these decisions? And I don't think that we've made that clear and that would make a very big difference in terms of Alta's suggestion of using the clinical model. But there's another problem here which we seem to have forgotten about. The clinical model is okay because the person is a patient and the provider cares about the well-being of that patient in front of them. This is very different, even if there is benefit, because now no longer is that person going to be looked at directly in terms of their own well-being. What is wanted by that person in a research protocol is generalizable knowledge. And if you switch around with that person's care because they're not doing so well, you're going to ruin your research protocol. So I think we have to be very careful at every stage to remember what it is we are talking about. My question still goes back. I want to know about the LAR.

PROF. CAPRON: It seems to me that several of these comments are tending in the same direction, which is that the difference is not between a legally authorized representative and a patient's advance document, but it's among types of representatives and the basis on which they are deciding. That the representative who knows the patient and is deciding based upon the patient's own prior expression of precise wishes or more generalized wishes is in a different category than a legally authorized representative who doesn't know the patient. And that either of those people is in a different category when they are making this so-called best interest judgment. That is to say that the benefits here, the prospect of benefits, are sufficient to justify even without knowing that the person would have chosen this based upon solid evidence that they would have chosen this. And that that really is the difference. A further comment is I don't think we need to have b) or d) here at all. We have Recommendation 7. Recommendation 7 already says you have to notify and if they dissent from participating in research, you have to respect that dissent. I think that kind of extra language here is going to keep us from addressing what is really the issue here, which is partially driven by what Trish says, with which I agree. That the pure use of the clinical model at least as to be addressed as to why it would be suitable in a research setting and why we don't need to insist upon something more for this setting. But if we're going to have a)s and b)s and c)s and make differences, I would make the contrast between what a person does when they're choosing, as a person who knows well, as Bette says, versus the person who simply says "well, it seems to me, not knowing this person at all, I'm now appointed as their conservator. It's in their best interest to be in this."

PROF. CHARO: I take Larry's point. I think he actually stumbled on what would might have been—

DR. MIIKE: I never stumble.

PROF. CHARO: Strode forcefully upon what I think was a confusion—captured eloquently—a confusion between our goals in this section and our goals in the section with non-beneficial research. I think that the discussion about the role of the LAR actually is quite revealing because the issue of willingness to participate and other kinds of less formal expressions are all rolled into the legitimacy of the LAR's decision to enroll an incompetent subject into research. Because that is supposed to be premised upon a best estimation of what that person would have done for himself or herself if still competent. So I think it's entirely possible to redraft 8 and 9, as Steve was suggesting, together to simply say that these protocols can be approved if the potential subject consents at the time of enrollment. Or the potential subject has consented, as you would say, genuinely consented in the past while capable of informed consent. Or c), is being enrolled by a LAR who is acting appropriately. And appropriately is acting as one assumes that this person would have acted for himself or herself. I don't recall if we've got a separate section that speaks directly to the kind of decisionmaking tree for LARs and how it is that they are supposed to start with what the person would have wanted to do and only move secondly to a kind of best interest analysis. But if that's not there, we could either create that as a separate section or we could try to roll in here. I think it may be best to—

PROF. CAPRON: But you would allow it, the best interest judgment. I don't know this person, but on balance it looks like it would in be the best interest.

PROF. CHARO: No, no. First, my understanding, I think it's very important that we keep in mind that the LARs are not going to be strangers. They are not going to be court-appointed strangers and they are not going to be institutions. Second, that the LAR's role as a surrogate decisionmaker is to do what the person would have done for himself or herself. That means first, you start with what they've expressed in the past, which can encompass things that are idiosyncratic. And if they've not expressed things in the past, then I think that friends and family are entitled to make assumptions that people would act generally in their own best interest because most people do. So you start with what people have actually said or indicated, and if it's really vague on that, you can, I think, empirically safely assume that they would act in their own best interest. And that's why you've got a hierarchy. You start with what they've said, and then you move to kind of best interests only secondarily. And this thoroughly allows them for all of these situations, consent, prior consent, or LAR permission, to incorporate the notion of seeking assent where it's appropriate, respecting dissent at all times. And as an integrated model, I think it gets away from this problem. Finally, I think the question about the language about willingness to participate in that vague language I think is going to become very important in the next section of non-beneficial research. That's where, I think, it's going to become a subject of real discussion where we assume that there's been no prior consent and the question is on what degree of knowledge of the person is necessary to enroll them in research that has no prospect of direct medical benefit. And maybe that's the place to take up that discussion, what degree of formality is needed.

DR. MIIKE: Let me just state it real simply. The only difference that should be, in my mind, in this area where there's either benefit or not in this greater than minimal research is the ability of somebody else to consent for the subject. So therefore, in this area and in the following area, the proof of a subject consenting directly should be exactly the same. And we should use the language that I believe is on 10. Because in 10, it lays out very explicitly what's proof of a subject and then it says nothing about LARs being able to approve. So the only difference between this one and the next one should be the discussion around the LAR. Because if we get into the kind of discussion we're getting into now, we're talking about a different type of LAR for this area from the other side.

DR. SHAPIRO: I think this has been a very helpful discussion and clarified a number of issues. Just to reinforce the strategy I want to use today, I'd like to ask at the next break that Steve, Larry and Alta take a shot at this and another version of Recommendation 9. Steve, I'll put you in charge so you have to mobilize this at our next break. Okay. Let's now go on and at least have an initial discussion and see how far that takes us with respect to Recommendations 10 and 11 which are, in some sense, parallel to 8 and 9, only dealing with the situation of greater than minimal risk that does not offer the prospect of direct medical benefit. Trish?

MS. BACKLAR: Just before you move on. I just wanted to make sure that we've agreed that this LAR is somebody who has been chosen by the subject. Is that correct? We're not moving to the next recommendation, the recommendation we were just talking about.

PROF. CHARO: I did not choose my mother as my legally authorized representative but, under many State laws, she would be because I'm not married.

MS. BACKLAR: So you have children of an Alzheimer's patient who are anxious to get this person off their backs.

MS. FLYNN: I have to object to that, I really do. I think that there is a tone that runs through this that assumes that family members in this situation are not going to be acting in the best interest of their relatives. And I think that everything we know tells us that that's not the case. And we should assume that, as we do in all clinical situations, that people who are involved in long-term caregiving with a chronically ill person care about that person and not assume that they don't. There certainly are cases, of course, but we don't want to build a whole structure around exceptions and assume that this is supportive of good decisionmaking.

DR. DUMAS: But you also don't want to avoid making provisions for certain controls in cases where that might not be, in situations where that might not be the case. So I think the point that we're making is that we believe that this category of people need to have added protections and the emphasis is on the added protection. I don't think we should ignore the possibility that even a family member might not be as objective as would be warranted in that situation. That's not to assume that all family members would not be, but I don't think we ought to go to the opposite extreme, either.

MS. FLYNN: Well, this will just be a place where we'll disagree. Here we're talking again about research that is expecting to be of benefit to the patient.

DR. DUMAS: Yes, but consider that—I don't conceive of this argument as being about whether or not the patient should participate in research that is potentially beneficial. Our argument has to do with when the person can't make their own decision, what kind of safeguards need to be provided in order that people who do make the decision do so in the best interest of the person?

MS. FLYNN: And again, I'm stating that I believe in that circumstance, we can and we should trust families. That patients can dissent, that there are other protections we've built in earlier and that families who are legally authorized representatives in almost all cases should and can be trusted to make good decisions. And that there's very limited risk involved in research here that is seen as having direct medical benefit.

PROF. CAPRON: I have a question, since there seems to be such disagreement about what we're talking about. Not just the wisdom of it, but what we're talking about. In the discussion around page 81, about the legally authorized rep, I don't see anything there that says the legally authorized representative as a family member necessarily was involved in caretaking for the patient. It may simply be in the view that Alta expressed that the relative is usually turned to. Although it isn't true in most States unless they have a statute that says this that any adult is automatically the legally authorized rep. It's the custom to turn to a spouse or a parent, but there's no common law in that at all except for minors, that I know of. But this discussion, the legally authorized rep, is all around the person who, as Trish was assuming, is appointed in some fashion. And the questions that we raise about that are how much documentation is necessary, how much clarity is necessary. That the person you're choosing could make this or that decision about you. The kinds of things which now exist in durable power of attorney for health care statutes, where they have to very clear. You're giving this person permission basically to decide about life and death for you. And all of that suggests that the legally authorized representative means authorized by the subject. But the reaction to which I don't think we have any recommendation that clarifies this, was no, that it would include people who are placed in that role by custom or because they've gone to court, I guess, and had their informal status formally recognized. Those are very different relationships, it seems to me. And I agree with Laurie that it is very likely that most family members who have been in a caring relationship know their subject better than others and are motivated to see the subject get whatever benefit research could offer. But we don't here require that there be any, as it were, assessment of that or even any requirement that the person have been an active caretaker. As opposed to Mrs. Jones, you were listed on the form as Steven Jones' mother, you are his mother—that's right. You haven't seen him for awhile, but we want to enroll him in research which we think will be beneficial to him. Will you give us permission? Yes, I will. That would also fit within this. And that relative may be a loving person or may be neglectful. May be knowledgeable about the person's wishes, or may not be. And we don't differentiate that.

MS. BACKLAR: I agree with Laurie that families are usually the best people to go to. But for instance, I just wanted to say that I have a very large family and there are people in that family who I would trust to care for me when I no longer have the capacity to do so, and there are people in my family who I would say "I love you dearly, but I don't think you're going to be the person to do this." So this blanket, saying people are all right is what concerns me. That's really what I'm after.

MS. FLYNN: But I don't see how we can parse this out effectively unless we start giving psychological tests to family members. Unless we start credentialing people in terms of the most recent time that they spent more than an hour with the individual. I mean, either families generally have the welfare of their kin in mind, or don't. Certainly the closeness of the relationship often speaks to that level of dedication, but not always. And certainly caregiving often speaks to the closeness of connection to the person's wishes, but not always. We either believe, as we do in clinical settings, that families ultimately care enough about their relatives to sort out their personal wishes from what they believe to be the good of the person who is incapacitated. We permit this in a clinical setting. We recognize the extraordinary reliance of the individuals we are most concerned about on family members for many aspects of their ability to live in the community. And yet we're not so sure we can rely on them to enroll subjects who are incapacitated in research that may benefit them. I'm having trouble understanding why.

DR. SHAPIRO: There are a number of people who want to speak, and then we're going to move on until we get a new look at this recommendation. Larry, Alta, Jim, Eric and Arturo.

DR. MIIKE: This discussion seems to me to be around a real simple issue, whether the LAR must be appointed by the subject or not. If we limit it to just an LAR that the subject thought capable appointed, I think we're really going to be cutting back on the research. So are we just going to make a decision of whether we particularize an LAR? You can have the clearer notion that what we're talking about is... we have LAR. I'm not simply limited to one designated by the person himself or herself. I guess one question, though, that arises for me, and that I have a way to deal with the kinds of exceptional cases as they've been called, there are ways to disqualify LARs. LARs may not be competent, for instance, to make decisions. LARs may not be, may have given evidence that they're acting against the best interests of the person and so forth. Now, some of those, some State statutes, and I'll have to let the lawyers in the group tell me if it's right or not, presumably have some of those things that we're doing certainly about competence. But part of what we're talking about here would be there may be situations where we'd want investigators, and this may be a matter of advice rather than of something we could recommend for regulation, we'd be attending to those sorts of issues. So that even though we start with a presumption, given that by the legal structure as well, in favor of the legally authorized representative as structured by that legal context. There may be situations in which basically we seek to disqualify the LAR.

DR. CASSELL: I just want to briefly lend my voice to Arturo and Laurie. It's generally and for the most part, the question isn't are families nice or not nice. It's the alternative. Generally and for the most part, is a stranger or a family member more likely to be beneficent in regard to the person? And I think that the family members are. And that's just the way it is. The fact that some people screw you is just also the way it is, but—.

DR. BRITO: I agree with Alta about the similarities between the clinical arena and research. But I do feel uncomfortable with the parallels, or extending them too far. In a clinical arena, when a physician or healthcare provider has, in the best interests of that patient, they are usually resorting to new trials of medication when they're really a last resort. But in research, okay, in research that there is hope, that there is direct medical benefit. You could be putting the patient at risk, and making their—especially when we're talking about greater than minimal risk—you'd be putting that patient at risk that is subject to making their life worse after the research. I just don't feel real comfortable with these parallels. Because I think that there's a big distinction between clinical work and research. And maybe Alta you could explain what—I wouldn't feel comfortable saying—and this goes along with the LARs. If an LAR is told by a physician that there is a chance, there is a chance that by placing their, who they're representing, at greater than minimal risk, with some sort of prospect, they, even if they have the best interests of that patient, which would be in most situations, I agree with that, they could still be, they may not be as objective as they would in a clinical arena. I'm not explaining this very well, but I just don't feel real comfortable with that parallel and using that here. I don't know.

DR. MURRAY: I want to address two points. In the discussion about whether to give a kind of specialist's moral status to legally authorized representatives chosen by the subject, that we should admit the possibility that prospective subjects wouldn't always choose wisely. Or even the personally chosen LARs would always act out of, you know, for the best interests of the subject. Granted, it may be there's maybe somewhat, you may be a little bit more confident if they're hand-picked, but we shouldn't be entirely confident. So it's not a matter of either/or, it's really a matter of degree. Second point is, as I think about the purpose of the document we'll be writing, it has primarily on researchers and on the people who are regulating the actions of researchers, rather than on the behavior of subjects or their representatives. That is, our document, if the recommendations are implemented, ought to prevent researchers from performing research on people with impaired decisional capacity. That might be harmful to those people, or otherwise not in their interest. And we would want to prevent researchers from doing this either out of ignorance or insensitivity, out of indifference, or certainly out of malice. Which we don't expect researchers to show. Insofar as the document we write will bear on the families, the legally authorized representatives, we can certainly help prevent them from agreeing to research based on ignorance by insuring that they are informed properly. It's not clear to me that anything we could do could check an LAR out of indifference or malice. I mean, the most we can try to do is alert researchers and others involved to be sensitive to that, and if they see that happening, obviously, to try to be responsive to it.

DR. SHAPIRO: Now let's listen to Bernie, and then we're going to stop discussion on this now. You'll have more chances later.

PROF. CAPRON: It is certainly true that a representative who is making a poor decision, either because they're incapable or because they don't seem to be taking the interest of the subject into account, could be disqualified. But for the reasons that Arturo and Trish have focussed on, we should recognize that the incentives in the case of a person providing clinical care, to institutes, such a disqualification are very different than in the research setting. And I don't think it is, as Tom just said, any assumption that researchers would be operating out of any malice or evil thought. They are operating and motivated by the desire to prove that some treatment is going to work. But that isn't the same as being focussed only on the welfare of the patient. And therefore, I think that the assurance that you suggest that we can be pretty comfortable because people who aren't deciding the right way will be knocked out of the picture. It's just the other way around here. The person who objects to the subject being used might be found to be the person who, well, why are we listing to this person? Let's get somebody else in here who will understand the benefits of what we're talking about more.

DR. LO: Let me take a crack at trying to find some common ground here. I think we're all recognizing that we can set a general presumption or assumption, but we have to take into account the fact that there are going to be some families, legally or authorized representatives, who don't act the way we would hope and want to act. I agree with Alta and Eric and Laurie that we should start from the generality that legally authorized representatives will follow the patients' wishes and act in their best interests. Then how do we take into account the fact that some won't? And Arturo and Pat very rightly point out that in the clinical setting, there are some automatic safeguards built in. Let's look at those safeguards. What we can't capture in these regulations is the face-to-face discussions. In a clinical arena, it's the doctor talking with the family or the representative, trying to explain, making sure they understand. Sort of probing, you know, what their motives are, how close they've been, things like that. We can't regulate that. And I agree that in the research setting, the assumptions about the stance of the researcher have to be somewhat different than the assumptions we make about the treating physician in a clinical setting. But I think that there are other tools that we have for providing safeguards. And we've talked about them elsewhere in the report. Consent monitors to make sure that when this legally authorized representative consents, someone else is there to listen in on the discussion. Make sure that the way they make decisions fits with this model, following the patient's previous statements or best interest. I think trying to involve an independent physician who is not part of the research team to talk with the legally authorized representative to try to make sure they've informed and not under a therapeutic misconception is something else we've talked about. But I'm not sure I'd put it in the regulation, but there are certainly are other things that we've already laid out that IRBs may choose to do for certain protocols, certain types of studies that would, it seems to me, go a long way toward affording the protections that Alex and Pat and Arturo are rather concerned about, where the analogy with the clinical situation backs down. I think again you have to look at the alternative. Is the alternative to make it so restrictive that basically a lot of people are going to be closed off from participating in this category of research?

DR. SHAPIRO:I'm sorry, we're going to have to stop discussion of this now. But let me just remind you, for those of you who will be writing, Steve, the head of the group and Alta and Larry and Eric, to rework this to try to incorporate some of the very interesting and useful comments that have come out here. And I'd like to do that so we could turn back to that early, right after lunch at 1:00 we could come back to this. And Trish, I know you have other things to say. You're welcome to join this group, incidentally, and maybe that's an effective way. But also, you could bring it up at 1:00 when we get back and discuss this. So I'm sorry—I just want to move on. Let me just remind the Commission that in roughly 10 minutes from now, even a little less than that, we do have public comments and that's really an important part of our day today. So we'll be turning to that very shortly. Let's see if we can't have at least an initial discussion of what are, in some sense or another, a parallel set of recommendations that are in here, but this time dealing with greater than minimal risk research that does not offer the possibility of direct medical benefits to the subject. And I'm not going to attempt to describe Recommendation 10 for you—it's parallel to 8. Recommendation 11 is different but parallel, in some sense, to Recommendation 9. Maybe we could have at least a few initial comments no this as to how the Commissioners feel about 10 and 11. We could put 10 to bed if you like. Let's talk about 10, first of all. Diane?

DR. SCOTT-JONES: I just have a question about the way it is worded, especially compared to Recommendation 8. It states that an IRB may approve, if the person with the capacity to give informed consent to participation, has done so. It reads that the consent would have been given before going to—

DR. SHAPIRO: I agree with that. That's a problem with 8, too. Any other comments on 8? Let's see if there are some initial comments on 11, which requires 3 conditions to be fulfilled. Any comments, questions—Larry?

DR. MIIKE: Only that I think this should also be the test of 10 with the "with benefit" and the "greater than minimal risk." That this is what I think should be used in place of that willingness to participate.

DR. SHAPIRO: You'll have a chance with Steve to work all that out after the break. Any other comments on 11? Bernie?

DR. LO: Well, I think maybe we could first ask if anyone thinks that if conditions a), b) and c) are fulfilled, the person may not be enrolled in the study. So my concern isn't that I would object to someone who fills a), b) and c) being enrolled. The question I have is that the only way you may enroll a subject in this type of study? But maybe just to start we should see if there are even things that even if this were met, you wouldn't permit this type of research for this. So I think we have to get to 12 a) and b). In my mind, I don't have a problem with 11 as long as I know what the alternatives are.

DR. SHAPIRO: That's a useful initial comment and we do have to allow some discussion when we get to 12. I should mention in general that there are, as many have noted already, interrelationships some times between these proposals. So when we go through a proposal, that doesn't mean we can't come back to it if, on the basis of what we do later, either it changes it or it doesn't look quite right. And so we have a package at the end which has to be looked at in its own right. So that's something that is really quite important so thank you for mentioning it. Diane?

DR. SCOTT-JONES: I have a question about what we mean by this type of study. And also, in other places in the recommendations when we say this category of study, does it refer only to what's laid out in the heading? And the category would be studies that present greater than minimal risk and do not offer the prospect of direct benefit. That's what's meant by type of study. It isn't meant to be type of study in a substantive research sense. It's that heading there.

MR. HOLTZMAN: Category refers to the italics, type refers to the type of research.

DR. SHAPIRO:I can tell you how I interpret it, type. I think it's really important we use this vocabulary appropriately, as Steve has indicated. I had thought not of the whole category of research, greater than minimal risk, no potential benefit. That's not what I thought type referred to. I thought it referred to a class of research not completely easy to define which was similar, let's say imaging studies of various kinds and that's what type meant. So you wouldn't have to insist on having it down to a single research protocol, but a type that had roughly the same kind of procedures involved, roughly the same levels of risk and benefit without being able to define it exactly. But in my view, it didn't refer to everything under this category, which is any research project that was grater than minimal risk with no potential benefit. That's just how I interpret it, but this is open for discussion. Bette?

MS. KRAMER: Then would your understanding preclude a person who has just expressed a willingness to participate in a prospectively beneficial research period, or would they had to have specified the type?

DR. SHAPIRO: This is not prospectively beneficial.

MS. KRAMER: Excuse me, I didn't use the language properly. I didn't mean beneficial to the individual. In an otherwise approved research. In other words, how specific would a person's expression of willingness have had to be to qualify within your understanding?

DR. SHAPIRO: In my understanding, I can't draw the boundaries exactly, that would be up for the IRBs to look at more carefully. But it's a kind of protocol that is roughly similar kinds of procedures, similar kinds of risks and so on that would be available so you'd have some basis on which the consent was granted. I don't want this to be, or at least my interpretation was, it was not a blank check for everything in this category.

MS. KRAMER: Would that presuppose a fairly sophisticated understanding of what research might look like down the road?

DR. SHAPIRO: Well, if it changes very dramatically, then a) doesn't hold, the way I interpret it. Because you have a dramatically different type of research then you wouldn't be covered by this. This is just the way that I interpret it and that's why this table is open for discussion. Larry then Alta, then we're going to have to break. We'll come back to this, obviously.

DR. MIIKE: Actually now I'm having problems with this. What I'm comparing this is to, say, I'm being asked to enroll in a research project that has nothing to do with mental illness or behavioral research. And they say "well, we're going to be doing a series of studies and it's going to involve a bone scan." And I say "yes, that sounds great." That would never stand up as my consent when we actually get into the study. So it seems that I would rather have these cleanly defined. Because everything in b) and c), it follows that we're not talking about this type of study. How can we talk about this type of study if we also we've said that there's no material change in the major research protocol, etc.? So it seems to me that the simplest way to do it, as long as we have the discussion around 12 about exceptions to the general rule. It seems to me that to be clean, both Recommendation 11 and 9, there needs to be a consent to that particular study contemplated. Because in prior discussions over the past year or so, we have been talking about—it had to be really close to the time of the study that that person became incapacitated. We couldn't talk about 1 or 2 years before that and they would generally say "oh, I wouldn't mind participating in MRI studies" or whatever. I thought we had come to the conclusion at that time that that was too far removed. So I'm looking at this and saying that this type of study is not really satisfactory to me. It's really got to be consent to a particular protocol, the research we're talking about.

PROF. CHARO: Just to give you an idea of how troublesome this is going to be after lunch, I'd like to argue for the far end of the spectrum, away from where Larry is. I'd like to argue for the blank check approach. I'd like to argue for those few people who actually bother to express their wishes prospectively, being able to say "I want to be used." And if they want to make limitations based on levels of pain or variations of interventions, they are free to. But they also should be allowed to say "I want to be used." And that there needs to be in here, actually, a stronger statement about the role of the representative in giving permission consistent with that prior expression of wishes. Because I find the possibility of specific consent to specific protocols to be so rarely usable that it eviscerates this provision. And I think that if there's any hope for integrating this discussion into the larger discussion about exactly how protective we're going to be of people who've made no expression of wish, then I think we need to be as expansive as possible about people who would like to express their willingness in general to altruistically serve as a research subject. So they are very much related to the afternoon discussion.

DR. SHAPIRO: Trish was bursting before and is still bursting ...

MS. BACKLAR: Actually, it's because I agree and it affects what I wanted to say before. I think if the people make a choice, then it's their choice. And if it's clearly made, they may make it as they wish as long as they're not going to harm somebody else. But the same concept applies in terms of choosing somebody to speak for you. And I just wanted to say that this "Being Researched" by Greg Sachs on people who, in fact, may already have dementia but are capable of saying "this is a person who I trust and they can make the kinds of decisions that I'm now no longer capable of making." That's all. The choice is what counts.