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DISCUSSION OF STAFF DRAFT: THE USE OF HUMAN BIOLOGICAL MATERIALS IN RESEARCH

DR. SHAPIRO: Any questions for Eric on any of the issues he has raised? Okay, why donít we proceed with the consideration of the draft material that we have before us. Commissioners have received a number of materials over the past two months since our Portland meeting including a revised Chapter 5, which includes summary recommendations of others. Many Commissioners have offered comments and input, and what you now have before you is a complete revision of the staff draft, and we will be discussing it this morning. Dr. Hanna and the research staff have done, I think, a very admirable job of bringing this draft forward and Iíd like to turn it over to Kathi to lead our discussion and then when Tom Murray joins us, heís coming in on an early flight this morning, he can join in as well.

DR. HANNA: Thank you, Eric. You can see from Chapter 5 that it has grown in length and I hope that itís beginning to reflect the discussions in Commission. Iím sorry it was not at the Portland meeting but I listened very carefully to the transcripts, and I think a lot of progress was made there, and I hope itís reflected.

DR. MESLIN: Can you check to see if the microphones are working? We are not having any feedback here. Thank you.

DR. HANNA: I think probably the best way to proceed would first be for me to tell you where I think in Chapter 5 we need to focus discussions and help us to fill out the report. But, then, I would propose that we just have some general discussion at first to get a sense of the Commission on where the conclusions and recommendations are going and then move into a more detailed discussion of Chapter 5, recommendation by recommendation. You can see that there are probably some new ideas that have been introduced into Chapter 5, so obviously weíre interested in what you think about that, but in particular, I hope that we can refine more today the discussion about what constitutes "minimal risk" on research using human biological materials. Staff, I think, spent a great deal of time trying to work through this and trying to distinguish how research using human biological materials differs from other kinds of research, and how the research context in the usual consideration minimal risk, which often has to do with physical harms, has to be rethought in the context of use of stored materials where there is no immediate risk of physical harm. We also, in some of the e-mail exchanges back and forth between staff and Commissioners, have tried to figure out how to develop this concept of "special scrutiny" categories and what that means in terms of the IRB and how we might define protocols that deserve special scrutiny and by what criteria. The other thing is practicability, one of the conditions for consideration of waiver of informed consent has to do whether itís in fact practicalóto go back and do that. I think weíve tried to make a start on addressing what criteria we might use in making a decision about whether itís practical to go back and get consent. And along those lines, I think the Commission also has to think about what criteria it might use to guide IRBs when reconsidering the re-contact and under what conditions human subjects should and can be re-contacted for various reasons. Whether to get their consent, to inform them of the nature of the research that is going on or whether youíre giving them the option to opt out of research. So these are very broad issues that I think are at the crux of getting these conclusions finished and I hope that today we can get a little bit further along in there. I would like to just get some general comments first, if thatís okay, and then we can proceed with a more detailed discussion. Iíd like to go through the chapter sequentially if people can abide by those rules only because it was a challenge for staff to lay this chapter out in the way that itís been laid out and trying to lay out the logic in a way that you can actually start and go to the end and understand the reasoning behind the recommendations. As you can imagine, the argumentation can get very circular here and so it would be helpful if we would just start at page 1 of Chapter 5 and progress through to the end.

DR. SHAPIRO: Page 1 is 176 for those who are flipping, page 1 of Chapter 5, page 176. All right, letís check to see if there are any comments of this initial parts of Chapter 5. Do you want to go recommendation by recommendation? Is that your idea, Kathi?

DR. HANNA: Well, some of them, we could go page by page and youíll see that in some cases it reads more like a conclusion than a recommendation. One thing that Eric and I have talked about is eventually we will have to have some kind of consistent style across NBAC reports about how recommendations will be phrased and written, but thatís something we can work out later. Youíll see that the way that we phrased the recommendations and presented them in this report are stylistically different than they are in the capacity report. Thatís something that we can resolve, but right now any place that you see bolded, italicized text is where we are presenting what we think is a conclusion or a recommendation of the Commission. There are some other places where youíre going to find italicized text in brackets. Thatís really just to signal to you that this is where we think we need further discussion.

DR. SHAPIRO: Thank you. The first of the items in bold print or italicized is a subject weíve discussed before, but I donít want to just rush past it. It occurs on page 178, which talks of the adequacy of the Common Rule for research using human biological materials. Thatís a critical statement because it frames everything elseóthe context in which we would deal with other issues here, clarifying issues and other issues that need attention. So we should pause here and see if there are any questions/concerns on this issue. Thatís on page 178. Weíll take silence to be on this issue that we have discussed it before, of course we have at other meetings, to be the way the Commission wants to proceed. Okay. Thank you. Alex, Iím sorry.

Professor Capron: In part of the lead-up to that, on page 177, at the end of the first whole paragraphóI donít understand whatís intended there. Let me just read it. It says, "The Commission recognizes that the extent to which the Common Rule is adequate is determined through oneís evaluation of the seriousness of the decisions that currently must be made by the investigator, the IRB, administrator, or full IRB and in some cases, a human biological materials repository." I donít know what that sentence means. Again, I can understand that the bulk of the sentence is the phrase, "is determined through oneís evaluation of a series of decisions," but it doesnít tell me anything. At other places where things are unclear but I understand them, Iím simply tempted to get used to some new language. But it would be a lot clearer if there were a reference to at least an example or something. Can you respond, Kathi?

DR. HANNA: Yes, I think you made a good point, Alex. I think if we would add some context there that there are a series of decisions, questions that have to be answered as one progresses through the language of the regulation, and we probably should introduce what those questions are right there.

Professor Capron: Since the whole point of this...two things. The whole exercise here is mostly an exercise in refinement and this first conclusion, which comes on the next page said, basically things are adequate. One is that NBAC seems to be, well, mostly thatís okay. I canít tell if this is really a sentence which ought to say that itís one thing to talk about the adequacy of the regulations; itís another thing to talk about the regulations in practice, where the actual decisions that investigators, IRBs, and administrators make becomes crucial. And if thatís the point, you ought to just flat-out say that.

DR. SHAPIRO: Thank you. Other comments, questions around this recommendation or the material leading up to it? Okay. Thank you very much. The next item, and in some of these cases there is a lot of material between these items. I donít mean to either overlook or gloss over it. Weíll just go with the next item and then feel free to raise issues that occur in the interim. Carol.

DR. GREIDER: I had two comments. One regarding the language on page 179 under the title "Activities that Constitute Research." The sentence, line 11, that begins, "The current regulations and NBACís recommendations do not apply to purely clinical interventions even if they are experimental in nature." I had to read this a number of times to really understand what it referred to and I thought that it might be construed to mean samples collected in the clinical context as opposed to clinical use of the samples. And that is something that we discussed many times and if we just clarify, I think that, I do understand part of the intent there. If you could just clarify that language so that others could as well. And then the other comment is on page 180, line 14, regarding the issue of criteria for exemption. And in criterion number 1, samples are existing and publicly available. Now I understand that there is a footnote that describes what "publicly available" is but I still feel somewhat uncomfortable that itís not really clear, if we really recommend this as being an exemption, that we be very clear what "publicly available" means. What publicly available means to me as a researcherómany things are publicly available that I would not feel comfortable with them being completely exempt because it was easy for me to obtain them.

DR. DUMAS: I had the same problem. And I noticed on the next page, line 4, there is an attempt to clarify the meaning of publicly available but it still does not, it doesnít satisfy me. I could say that I have a sample that was on the shelf, put on the shelf unbeknownst to me and now itís going to be used with research unbeknownst to me, without my permission. Is that what we mean to imply by that?

DR. HANNA: We sent a specific question to OPRR to ask them to provide us with some clarification on that and to tell us whether they had issued any guidance in the past to define what "publicly available" meant. And you see that in footnote number 3 there. I agree that it remains confusing, and the Commission can take the tack that it wants to on its own terms clarify what that should mean. I think that perhaps that OPRR might welcome that kind of interpretation. And we are also trying, Elisa Eiseman is also trying to get a sense from the material that appears in Chapter 2 about how many of those repositories would consider themselves to be publicly available. Our sense is that there are not too many that would meet that criteria of being publicly available and therefore thatís why most considerations then fall into category 2 here instead of 1.

DR. GREIDER: But letís say some of them do consider themselves publicly available. I would think that all of the issues that we discussed regarding the protections for those samples should equally apply. I donít see why you should say to them "outside the realm of protections" because something is publicly available. It justó

DR. SHAPIRO: Alta.

MS. CHARO: I could be wrong about this, but I think that the intent under the language, even if itís not being conveyed clearly, has been "facilitate research that uses things that are already in the public domain, and it probably was not written with human biological materials in mind. Itís probably written with a great deal of other inanimate objects or information sources, such as publicly available lists of names and phone numbers, as found in the phone book, and that one might do a survey of, you know, the ethnic distribution of names and the names with vowels on the end of them. So the question I would have is if you were to think of it in that context, which it was probably developed for, what would you want in this definition and then the next question would be, is that a good working policy as far as weíre concerned about human biological materials?

DR. GREIDER: One of the main points is that it says on line 14 there, "the samples are publicly available." And what weíre all concerned about is the information that has already been extracted. If you have something and the information that you are going to take out of it is already publicly available, I understand why then there wouldnít be the same level of protections for it. But because, from the samples, additional information can be obtained when you have a sample in hand and that information is not necessarily publicly available. Itís the information content that is important here and the word, it says the samples are publicly available. Joe Smith might have his name in the phone book and thatís publicly available but all the information about the sample might not be publicly available.

DR. SHAPIRO: Rhetaugh.

DR. DUMAS: I wonder under whether or not there are conditions that are defined to determine when a repository is justified in labeling a sample publicly available. How does the repository get to that point? Does anybody know? And is that a concern for this group?

DR. HANNA: I think that it is a concern of this group. Whether anybody knows is a good question. I donít know. Elise, do you know? We can try and find out for the repositories that consider themselves to have collections that are publicly available. We will find out what conditions have to be met for it to be labeled that way.

DR. SHAPIRO: Steve.

MR. HOLTZMAN: A couple of points. Iím not sure I agree with Altaís interpretation of the historical background because weíre in specifically the subsection that says "research involving" and it says "pathological specimens." So clearly they were thinkingóweíre in 101-b4ó"research involving the collection or study of existing data, documents, records, pathological specimens, or diagnostic specimens," so I think there was in mind biological materials. Second off, there are clear examples of repositories which are publicly available in the relevant sense. Take Coryell, for example, where you phone up, you specify a sample, and you get it. ATCC would be the other one. I think what weíre seeing here or what weíre reflecting on is an oddity, if you will, in the existing reg. If all of the emphasis about human subjects is protection, why is public availability the criterion when it seems, as you can imagine publicly available stuff where there is and is not personal information associated with it. So if I call up ATCC to get someone thus and such, or Coryll to get a sample, I believe itís the case that most of those are stored in such a way that they are anonymous or whatever term weíre using for anonymous. So the issue may not arise but itís certainly logically possible that there could be publicly available in the relevant senseócall up and get it, which also has personal information associated with that. And I think thatís the ambiguity, well not the ambiguity, but what weíre looking at here.

DR. SHAPIRO: Letís make sure we focus on the substance of this issue because thatís a really very important issue. There are repositories which have publicly available under some reasonable definition of publicly available, as in footnote 3 on the page close to that. And the way the regulations are written, it seems to my understanding that these two criteria are not and, theyíre or? So you donít get the second protection automatically. You can only get it if you make an or rather than an and. And so letís try to focus on the substance of this and what the Commission feels that what is required in this case, one way to phrase it but not the only way, is an and here rather than an or.

MR. HOLTMAN: If thatís the case, then we think the current reg is in.

DR. SHAPIRO: Thatís right. Alex.

Professor Capron: Well, I think that although they disagree, that Steve and Alta are on the right track when asking us to say what is the interest that is implicated. And if Eliseís examination showed Steve that all those repositories that were publicly available met one of two criteria, either the data stored was anonymous or the data was stored with identifiers and explicit informed consent from the individuals involved that they knew that the study, that their identifiers would be there and it would be used for research involving anything about themselves, the kinds of concerns that we have would largely be met. I donít have any basis for knowing if thatís the case, and it seems to me that although Alta may be wrong in that the regulations are exclusively talking here about samples and specimens and so forth, my suspicion is that the kinds of concerns that motivated people in having the regulation make this exemption, was not to burden research where people are dealing with material which a reporter could call up and get or anybody else who is in the position to publicize information. This is not information which people would regard as confidential. And that takes us back to Carolís basic point which is the information is being, the developer doesnít exist. Itís not as though you would, if you were a reporter, could call up and say I want to know if they are at risk for this disease or not. And so it seems to me that the present regulation is inadequate in addressing the issue and if there is any reason to think there are repositories which meet the criteria of, you have access on demand, I guess that is the only criterion thatís offered, thatís to say, there are no particular restrictions in getting access to it, that it isnít enough and it ought not to be enough to say that as to information which doesnít yet exist as informationóit is there in a biological sense, but itís not there in any sense that anyone would have been concerned about previouslyóthat it ought not to be enough to have or. And I would put forward there for the recommendation that we would urge a modification as to biological samples and specimens, human biological materials, to insist that they are publicly available and will not be used in such a way that they could be linked to an identifier.

DR. SHAPIRO: Well, letís just see what the response is.

Professor Capron: My point is, that I think that itís consistent with what I would take to be the intention behind this, whether or not Alta or Steve is right about the exact history.

MR. SHAPIRO: Alta?

MS. CHARO: Iím interested in what youíve suggested, but I still feel uneducated enough to make a recommendation at this time. Iíd want to know moreóin some ways exactly what Rhetaugh was asking and maybe, Steve, you could help by talking more about Coryll, maybe OPRR can help now or through written responsesóabout the number of situations in which we have samples that meet the definition as itís currently interpreted and how they came to be that way. Was it a case of where samples were collected, for example, surgical waste, and that for one reason or another a repository chose to then make them available without payment and without restriction to members of the public. I mean, how often can that actually be happening and why should it be happening to understand whether or not there is...the interpretation says, "unrestricted availability subject to limited quantities and/or related costs." What I mean is noncommercial. I understand that related costs means you can be asked to reimburse for the actual costs of handling the material by the repository but theyíre not doing it commercially to sell it for a profit.

Professor Capron: I wouldnít agree with that. I would simply say that unrestricted does not mean that anyone can just get it because they asked for it. There can be processing fees, there can be charges for the materials. But there are no restrictions on a member of the public getting it.

MS. CHARO: Right. Thatís just what I said.

Professor Capron: But a commercial outfit that sells the materials, that doesnít restrict your access.

MS. CHARO: This is an interesting point.

Professor Capron: Unrestricted on demand, to me, the reason that thereís that parenthetical made perfectly good sense. It means that you canít just say send me a hundred samples, thank you very much, by return post. They may say, well fine, send me a thousand dollars.

DR. SHAPIRO: I think two things. One, although itís interesting from some other perspectives, I donít think it would help us clarify this by wondering whether the cost is for a for profit or nonprofit organization and so on. But secondly, although I think the information that you are requesting is interesting, we should try to find out about it. Itís not clear to me how that would change anybodyís mind about it in respect to this proposal. That is, if we feel or if members of the Commission feel, that for reasons Carol explained that Iím not going to go over, that it really is inappropriate, that just the availability of it would make itóin a sense, publicly available hereóis just not adequate protection, if there are identifiers, for example. And, the information requestóI would like to know as well. Iím not quite sure how it would bear on the question. Could you help me with that, maybe? Maybe I just misunderstood.

MS. CHARO: I feel very insecure about making any recommendation at this point only because if it is this hard to understand the meaning of related costs or the meaning of unrestricted or the meaning of public, I canít begin to have a clue as to what this whole section is actually referring to. I donít want to shut down a research venue that might actually be benign until I know what it means.

DR. SHAPIRO: Bernie.

DR. LO: I think we have a problem that has heretofore been unnoticed, but I think Iíd be very careful. First of all, if we start to recommend rewriting this part of the regs, it actually affects a lot more than research with biological samples. I mean, as itís written, itís existing data, medical records, foods, questionnaire tapes that are generally available, so I think we have to be very careful that weíre trying to fix a problem that we think is particularly important for DNA testing on stored samples, that we donít also undercut practices in quite different kinds of research. And second, I would just like to say for number one, the fact that it is publicly available means that anybody can get it. If you werenít a researcher, you could get it but if you were a researcher, now you canít get it is paradoxical. Now my final point is, I think that if weíre going to fix it, it isnít going to be easy to fix because Alex spelled out that what weíre really saying is, is it legitimate and appropriate that itís publicly available. I mean, outline some criteria having to do with consent...so that we should decide whether we want to just call attention to a potentially serious problem that we really havenít done much more than just say, look, there might be a problem. Or do we really want to go the distance of just try to rewrite this one little part, which Iím not sure is the meat of the rest of our report. Itís not going to be easy. We could get really hung up trying to fix these two.

DR. SHAPIRO: Could I say a word about that? I donít think we should think of ourselves as in a position of writing regulations. Regulations will have to be written with great care no matter what we recommend, but if we still could recommend something here, a principle, by which we think the reg should be changed. We wonít have to write the change itself. I agree with you that weíll have to be extremely careful and itís a very tough job itself to write the regulations. But it seems to me that if there is an issue here which the Commissioners feel is important, that we should find some way, without knowing exactly what the right way is at this moment, of focusing peopleís attention on it and perhaps recommending a consideration of a change in regulation of something of that nature. But I donít really want to write the regulations. Weíre not competent to do it sitting here and, as you say, itís a complex issue. We just ought to focus our attention. I want to bring us back to the issue just to see what Commissionersí feelings are, and then we can go aboutónot right this second but sort of producing language and so on. On the issue which, as I understand, it is that public availability, reasonably interpreted, letís say for example, as footnote 3 outlines it, is something that provides inadequate protection to people who have provided biological samples either with consent or without consent. Thatís really the problem Carol raised.

DR. GREIDER: I just want to address two points. One was that I agree with Alta that it would be nice to know are there examples of the repositories where these are publicly availableóto get the data. And yet I also would agree with Harold that that wouldnít necessarily change my view of how I would look at this because weíre not just talking about things that are existing today. Weíre talking about things that might occur sometime in the future, and just because there arenít huge numbers of samples out there right now doesnít mean that it wonít be different in the future. So that is one point. The other point is, to my understanding, all weíre talking about is whether this even should be considered before an IRB. Weíre not talking about shutting down research. Weíre just putting it into the IRB mechanisms so that if somebody looks at itóand I donít see that as a very high bar that weíre even talking about establishing.

DR. SHAPIRO: Alex and Alta.

Professor Capron: I want to agree and make two points. We are talking about where the river splits, and the important thing is even under the existing regulations, the reason why there is an exemption, as I understand it, is not because peopleís interests are not involved and not even because people cannot be harmed by what happens to the information, but rather, in a way, in reflecting what Bernie said, itís that that harm is not something that grows uniquely out of research. It is a harm that is already there. If your criminal records are publicly available, someone could go and print them in the newspaper. The information is there and may be embarrassing to you, may be harmful to your life but thereís no escaping it. Itís right there on the public record. And I think that was part of the thought in the exemption, that we canít create standards here that are higher, not that there isnít an interest. I think Carol has done us a great favor by saying weíve got to look at that split in the river and say is the right stuff getting down the way where there will be no further examination of it. Not that it has to stop. And I think that we can, consistent with what we say in the rest of the report about the interests that are involved and the needs of consent urge that this be narrow without writing the regulatory language and the same consideration operate here. Narrow the exemption as the information which in a real sense doesnít exist until the research occurs.

MS. CHARO: Again, just to emphasize why it is that are, I will probably abstain from any motion at this point until Iíve had a chance to think it through. Maybe I would think better with a second cup of coffee, I donít know. But I find myself thinking about other situations that might or might not be similar. For example, this morning on the Today show they have people lined up showing signs, there was even someone from Waukesha, my home state, right? Hi, mom, in Waukesha. Now once on TV, that particular footage, where they scan the crowd, I would assume meets the definition as publicly available, and over the years I suspect that more and more often we will have to look at all of those hundreds of people that they scanned and diagnose more and more disorders just by close observation that we couldnít diagnose today. The information is there but not available to interpretation yet, but in ten years, twenty years, thirty years we couldójust like todayódiagnose things we couldnít thirty years ago just from observing people. And if somebody were to do that research, they would take the videotapes of the last yearís worth of Today shows and begin counting the number of people who meet certain diagnostic criteria and there are some degrees of identifiabily because we know this person has a mom in Waukesha, right? I want to spend a little time contemplating whether I really want to say that this needs to go to an IRB for review prior to the researcher being able to do his or her magic on it. Youíre right, itís not necessarily a big deal to have to go to the IRB and have them say this is benign, but I just donít feel comfortable rushing until Iíve figured out all the situations this is intended to encompass.

DR. SHAPIRO: Okay. Other comments. Again, we cannot rewrite the regulations now, but how do the Commissioners feel regarding the basic point being made by Carol, namely that there is something here that needs some attention. And itís not fully adequate as it stands, we have to think about how to do it and so on and I donít want to propose any motions about fixing it today but that has to be thought through more carefully. But that we focus some attention on that and try to see if we canít meet the concerns. I take it that thatís something we should therefore try to do.

DR. HANNA: Yes, we will try to find out some more information in the next week.

Professor Capron: In that process, may I recommend that the present sentence, which has footnote 3 attached to it, be dropped and it would be helpful in the text itself to explain the OPRR understanding. The present sentence suggests two things. First, it makes factual statement for which the footnote does not provide any support. And secondly, and I agree entirely with Carol, it says that this isnít really a problem because most are not publicly available. The point is as to those that would be publicly available, not in most, whether thatís 90 percent or 55 percent or something are not such.

DR. SHAPIRO: Arturo?

DR. BRITO: I agree with Alta. We need some time to think about this, but one of the things that Iím thinking about, having thought through fully, is what about the process that makes something publicly available? What are the potential processes that could make something publicly available and I think that would be key when weíre looking at this.

DR. SHAPIRO: Other comments and questions? Yes, Steve.

MR. HOLTZMAN: The guidance weíve got from OPRR here is the minimal guidance. It would be useful to go to them and go through cases and say what is and is not publicly available. ATCC, Coryll, those are paradigms of publicly available: pay your money, get your sample. And what about the NIMH collection? A federally sponsoredómany investigators that get at it but you canít just say send me some of those samples. Thereís a range of instances here and many require clarification.

DR. SHAPIRO: Other comments and questions? Thank you. Just to remind you, weíre heading toward the next italicized position, which occurs at the bottom of page 184. We can go directly to that unless there are some issues on any other pages that people would like to raise at this moment. Alta?

MS. CHARO: On page 184 in the discussion about group interests. I would urge that we more explicitly acknowledge the root interest issue and the kinds of solutions that were discussed and rejected, such as obtaining community consent, community notification processes, and such. Theyíre kind of buried in here and since this is the place we are in fact coming down in favor of individualized harm and consent only, I think we should be more open about it.

DR. SHAPIRO: Thank you, Carol.

DR. GREIDER: I just want to agree with that. Thatís one of the things I had starred, as well. That we had so many discussions of group versus individual interests and that sort of the driving issue and it really doesnít occur in this first section at all. In the second section on prospective, it does occur and I really urge more information, or more explicit discussion in that at the very bottom of page 184 before the italics.

DR. SHAPIRO: Bernie.

DR. LO: I would like to make sure that what weíre suggesting is a regulatory requirement and what might be good practice, and I would urge us to say that under certain sensitive studies it would be prudent and praiseworthy and good practice as many scientists have already done, to obtain some sort of community inputóto not make either/or, but to explicitly invite scientists to get some community input on the sensitive studies.

Professor Capron: An additional issue that we might try to bring out here and it might even lead to a recommendation, although it may be that this would come later on when weíre talking about the future collection, is the notion of being more explicit with people as their samples are collected about the range of uses. We recognize that it doesnít make sense to say that I am consenting to something if you cannot begin to imagine all the particular kinds of things that we talk about the need for re-contact. But, particularly the wrong that occurs to a person if they indirectly participate in research in which they find abhorrent and, obviously research around abortion is an example of an issue that people feel very strongly about. We could at least put language in that talks about identifying the fact that they really have no control and that a wide variety of research could take place and just be sensitive to that. At the bottom of 183, it seems to me that at earlier times we talked about the notion of people being wronged even if theyíre not harmed and maybe I make too much of this as philosophical or legal differentiation, but I think itís worth, Kathi, thinking there in that last full sentence on 183 of saying that there are ways in which people can be wronged even if they are not harmed. That is, even if they donít suffer the kinds of things that we enumerate under our reason on pages 9-13 of 184 where we talk about insurance or employment discrimination. Those are harms, but there is a notion of being used even if you are not harmed, that may be upsetting to people. And we donít end up saying this is enough to stop research but when we are reaccounting it we should at least make a reader who wants to be sensitized to these issues aware there is an issue there.

DR. SHAPIRO: Larry?

DR. MIIKE: I didnít know when to bring this up, but I think that the first point that Alex made introduced it. In Chapter 4 thereís a discussion about layered consent. But also in Chapter 4 it just sort of lumps together samples taken for clinical purposes and samples taken for research purposes, and I donít see any of that stuff reflected in this chapter. If you recall sometime back, I thought we needed to change the consent process for clinical samples. At least take the piece out that says I consent to research in some way. Thereís no distinction here. In the consent discussion in this chapter, itís not reflective whether the discussion was in Chapter 4 in terms of possibilities of giving various kinds of information for various purposes, and I really think we need to make a distinction in the informed consent process of clinical sample collection versus research sample collection.

DR. SHAPIRO: Okay, letís make sure we come back to that.

DR. MIIKE: Yes, there was just no place to discuss this. I was just trying to help.

DR. SHAPIRO: We do commit ourselves to come back and discuss that more fully because it is an important issue. Okay, other comments and questions in this particular area? Steve. Raise your hand, bang the table, or something.

MR. HOLTZMAN: Make up for the comments I didnít make because I wasnít important, right? I think Alex makes a good point about the "harm" point here or the "wrong" point. But what we might also do here since we seem to be talking heavily in theory about what one might envisage as a potential harm, is it worth noting that when we went out into focus groups, what we found was the overwhelming majority people we dealt with found that that was not really an issue. All right? That they werenít concerned. They had a certain vision of how it would likely be used and that it would be good for medicine, et cetera, et cetera. As long as they werenít harmed, they didnít have a sense of potentially being wronged. So I think we have a philosophical discussion going on here in these few paragraphs. Look at the nature of the language weíre using but we donít seem to get back to some touchstones of about maybe what we found out. Maybe people donít think we found out anything oró

Professor Capron: I thought we agreed that those focus groups were useful for us in teasing out issues but that we werenít going to recite them as some form of touchstone, that is to say, a public opinion survey.

MR. HOLTZMAN: So I think, I think thatís fair enough. So the question I would then ask is how stridently are we going to push the theoretical concerns here, and for those people in this room who have had a lot of experience actually dealing with people in these contexts, what have they actually found? Does that matter?

Professor Capron: I certainly hope we are not strident on this issue.

DR. SHAPIRO: I look at this, this particular issue, which will come up in different ways and different contexts here, I feel it would be quite important to provide a framework for readers to think about these things although they donít have equal importance in my own mind. That is, I think in this particular case despite the inadequacies of those groups in terms of information, I quite agreeóthereís no real information there. Nevertheless, my belief is thatís probably right, but for other reasons, not because that focus group took place, but for other reasons. And therefore, we do need to provide some framework to go through this, so letís tick this off in their mind and then go on. Other comments. Again, there is an italicized observation on the bottom of page 184. Any comments, questions, concernings about it? Okay, this has to do with unidentifiable samples and the claim here is the potential harm that these individuals effectively disappear.

DR. DUMAS: Okay, thatís assuming that we know what we mean by unidentifiable.

DR. SHAPIRO: Yes, we will have plenty of opportunity to look at that. Yes.

DR. BRITO: The only problem I have is that the word genuinely, for some reason, bothers me. I think that sort of creates a sort of feeling that it, it almost implies that maybe itís truly not "genuinely." I donít know. It justó

DR. SHAPIRO: If you knew what unidentifiable is, you wouldnít need genuinely. Weíre trying to make the point maybe too hard here.

Professor Capron: You want to drop that?

DR. SHAPIRO: Thatís right. We can try to go to some effort to define that carefully, so it ought to be enough.

DR. BRITO: And then we drop it then it would read right. It would practicallyó

DR. SHAPIRO: Right. Weíll come back or have a chance to look at these definitions.

Professor Capron: The definition is on the page before. Are we coming back to it oró

DR. SHAPIRO: As it comes up in the previous chapters also.

Professor Capron: I mean this is a summary statement.

DR. SHAPIRO: Okay, as we go back through some of these other chapters, weíll pick up some of these things again. The next italicized comment or bold print comment, however the right way to describe that is, occurs on page 186, and has to do with linked materials and has a section on identifiable sentences. Questions and comments?

MS. CHARO: Yes, beginning with the explanatory material on the previous page 185 in the middle of the paragraph, line 12? We state in other cases the repository might retain enough about it.... And, I would just like to suggest that the way I am reading this, this reflects many discussions weíve had. It is absolutely an expansion of the notion of identifiability beyond that which is currently in use commonly around the country and beyond that, which as I understand it, OPRR has insisted upon. And, I want to make sure people really want to expand the definition of identifiability that way because weíve gone around this and around this. To do this means that we get into the problem of the kind of blurry categories. The easy, bright-line categories where things that had some kind of code or other obvious linkage, and this one is based upon essentially cell size. Being able to deduce from indirect evidence something about the identity of the source of the sample rather than using a code or link that was designed to make that possible. And once we are going to define identifiability through the ability to deduce identity, the classification of those people whose identity sufficiently deducibleóI donít know if even thatís the right word and those who are not becomes very blurry, and weíve been around and around and around and I wasnít sure I remembered if there had been a clear consensus to go this way. If there is, I think we need to be very explicit in the recommendation which follows on the next page, that this goes beyond the current Federal, common Federal practice and interpretation. But I also want to double-check on the consensus about this.

Professor Capron: Is your concern met by the parenthetical at the end of the paragraph?

MS. CHARO: The parenthetical in the paragraph?

Professor Capron: At the end of the paragraph where in effect it says if the cell size, the group size is 10 and the results are 9 out of the 10 have the marker for rapid heart rhythms that will cause instantaneous death, if you are known to be in that group, you might as well be identified. Whereas if itís a thousand people and the results are one in a thousand...

MS. CHARO: But itís being used here...

Professor Capron: Itís being used to bring it into a category of saying it doesnít automatically go over in the group about which we have no concerns, see our last bolded statement.

MS. CHARO: Right. I know. I understand that. It is, it is absolutely a big divide because once things are considered to be identifiable, weíre going to have many more procedures we have to go through in order to evaluate their risk and the protections that are associated. And youíre asking if I am satisfied by that last paragraph? No, because that parenthetical is about theó

DR. MIIKE: Can I jump in without putting up my hand, too, then if this the way this discussion is going to go?

MS. CHARO: Yes, you may.

DR. MIIKE: Iím asking for procedure. Do I have to put up my hand to talk or can I just talk?

DR. SHAPIRO: Well, it would be helpful if people waited to be recognized. Itís fair and more appropriate, so letís try that, if people can restrain themselves. Larry.

DR. MIIKE: My understanding of what this discussion is about isónot that weíre going to change the regsóthat we want to make it clear that people havenít misinterpreted the regs. Isnít that the point of what this section is about?

DR. HANNA: Well, I think that certainly in the past year of discussing this, it has been apparent that there are various interpretations of what constitutes an identifiable sample. My understanding of where the petition came out was that coded equals identifiable. That was pretty clear from the Portland transcripts. The reason we added the parenthetical phrase was because it doesnít mean that youíre jumping off a cliff essentially. Thereís a progression. Then you consider how identifiable. Whatís the probability that that person could be identified if you used that in your tabulation of whether itís minimal risk and then you move through the next steps. Does that mean then it can go to expedited review? Does it mean it you can waive consent? So, we tried to build a continuum of decisions.

DR. MIIKE: Well, Iím just looking at that sentence on page 186 about line 4, 5, 6 where you state that apparent from our discussions, that some investigators...so Iím looking at that and saying I donít see this as the way that this is being presentedóthat weíre going to recommend changing the regs. Itís just that clarification of the interpretation.

DR. SHAPIRO: I agree with that. Steve and then Carol.

DR. HOLTZMAN: Kathi, I donít think that next sets of issues you just raised about harm and whatnot really should infect this discussion. I think there has to be clarity as to what identifiable means. I think thatís a bright-line test. Has to be, has to be set up. And I think how we get to this point in the discussion, is even though thereís very textured language in the reg itself, readily ascertainable.... For example, OPRRís guidance largely seems to be if itís possible to create the link, itís identifiable. And we seem to have adopted that. If it is possibleówe donít go with what degree and if what not. If it is possible, and if you take that as your standard, and I personally think itís a lousy reading of the reg, but Iíll go with the Commission as long as we have clarity, okay? Then, how you come about the identifiability such as cell size is kind of irrelevant. Itís either identifiable or itís not. Now one of the questions I asked several months ago is reflecting Kathiís point: we think there are lots of different interpretations out there. But maybe we ought to go find out how people are actually interpreting this. Did we ever do that? Are we finding out that if we codify in our own recommendations an interpretation that says identifiable essentially means logically possible? Would that change a lot of current practices, which is your concern with the cell issue? Correct? Do we have an answer to that question?

DR. HANNA: We have several answers to that question. We heard from many people that there was confusion out there. I think we heard from Mary Claire King in Portland that she had interpreted the regulations in a way that perhaps was very conservative, and if you really tried to parse out her understanding, she probably misinterpreted it and maybe intentionally on some things. So, and I think weíve heard from OPRR that in their view, there has been variability in both IRBsí and investigatorsí interpretations.

DR. SHAPIRO: Carolís next, then Larry.

DR. MIIKE: I donít know, Steve. I think youíre over-reading this language. I donít read this language to say that if itís possible to be deduced by cell size that itís identifiable. I think that what itís trying to clarify is that if there is a code there that can link it regardless of whether that is in a repository or research or et cetera, there is a linkage possible. So itís not as wide open as I hear you interpreting it.

Professor Capron: I think we need some clarity. I think Alta was right in highlighting this. Weíve had discussions each way. Weíre talking about a situation in which a repository has a list of the x number, letís say 100 samples, that itís sent over. When it "coded" them, it just numbered them 1 to 100 and it could not tell you if you provided the code and said I want more material on sample number 47 because it got lost or damaged in the lab. Theyíd say we donít know which one number 47 was. We can sell you all 100 samples again, however, if you want to start over in your research because we know which 100 we drew from but we donít know which is which. So it is that level of information and we know whose samples we have in the lab. In other words, itís not in our lab anonymous, even though it is to you anonymous. And weíre saying no because they could tell you who the 100 peopleóJones, Smith, et cetera, et ceteraówho the 100 people were, who were in the group of samples, even though they canít link them, that still falls within some level of identifiable. I thought that sentence was quite clear in saying it, and I agree with the conclusion, but I think that Alta was right in saying this is something we have gone back and forth on. So, itís not coded in the way we usually mean, which is the name Capron is replaced with the code 721.

DR. MIIKE: I think that we need to clarify that situation.

DR. SHAPIRO: I agree we need to clarify. I think we spent, my recollection, although I havenít read the transcript at all. My own recollection that "really possible" was the best way to define what position we came to whether we all liked it or not. Thatís where we came out to my recollection. We wanted to change our minds and so on. Itís my own view that that is probably the only way to writeóif you want something clear, it is almost the only way to do it and provide the protections. And I want to repeat, once again, that this is what people have already said a number of times this morning, all thatís happening here is that weíre creating various streams down which particular protocols go depending on the harms that are exposed. If thereís a harm thatís possible or a wrong, is it possible or not possible for that to happen. And if itís possible, somebody ought to at least not rush by this. And therefore, thatís the line I draw. Whether itís a good interpretation of the regs is another matter altogether, and Steve may be right about that. But it seems to me thatís where we could draw, if itís possible to go back to the person, itís possible then that these harms and/or wrongs and with whatever else we are concerned with will happen and therefore, someone ought to think about this. If itís minimal risk, itís a very simple proposition. If itís not, it ought not to be simple. And that seems to me to be straightforward. I think thatís what, I donít know, Kathi, now you tell me, was that what you were trying....

DR. HANNA: I think we were trying to reflect in that parenthetic phrase that thereís a continuum of identifiability, that within the category of identifiability there is a continuum based on probability of identifiability. And that that probability calculation enters in when you get to the minimal risk section. So we introduced the notion there just kind of to forecast that itís coming up later, so that youíre not, as I said, youíre not making a final decision here. Youíre just pushing the protocol into one direction.

DR. SHAPIRO: Weíre not throwing the weight of all the protections that are possible into the hopper just because itís...Bette?

MS. KRAMER: I also have not gone back and reviewed all of the transcripts but my recollection is a little bit different. I did not think that we as a Commission had come to consensus on the example you just cited, when the repository knew what 100 samples they had sent, but they did not know, they themselves could not match up any particular sample with an individual. Now I know that the gentleman from Mayo said they regard that as identifiable, but I did not think the Commission itself had adopted that definition of identifiable. I thought that we, weíre still talking about that calculus and I donít recall that we did adopt that. Kathi, Iím sure you studied those transcripts, didnít you?

DR. SHAPIRO: There are people that want to talk. I donít think we adopted it in the sense that we had a formal agreement but itís before us now and we can decide right now where we want to come out. Bernie and then Alta and Tom.

DR. LO: It seems to be that this an issue which weíve thought a lot about and talked a lot about, and we donít have consensus. All investigators and IRBs need to be aware of these arguments. We didnít reach agreement. It doesnít really matter right now because the regs already state you get expedited review or full review, but I think conceptually itís important because to the extent that anybody changes policies later using identifiability as the branch point for a very different set of issues, then what gets put into which stream becomes more important.

MR. HOLTZMAN: I donít think itís expedited versus full. Itís whether or not you have human subjects research. Thatís why I think we need a bright-line test, because there is a lot at stake.

MS. CHARO: I think that part of the reason why Iíve been having so much difficulty coming to a conclusion myself about how I would like to see this problem handled is that there are two distinctly different spheres of consideration. One is a matter of principle and pure logic. As principle and pure logic weíre absolutely correct that itís a continuum of identifiability in which this kind of example of cell size falls on one end of identifiability through deduction, and where obvious explicit codes, it falls at a different end. As a matter of practicality, however, I think that we are talking about very different beasts and itís for precisely the reason Steve just mentioned. If we recall that the research review process begins with a self-referral by an investigator to his or her IRB, presenting him- or herself to this committee and saying I believe Iím covered by the research rules and Iím asking for the requisite reviewósubject to lots of influences by the department chair, by journal editors in retrospect and et cetera but itís fundamentally a self-referral process. It argues for a system of rules that are easy enough for investigators who are not spending all their time thinking about regulations to know when they are or are not subject to the rules and when they do or do not have to go to the IRB. This is why at the level of practicality one might want to have bright-line distinctions that donít follow the continuum of logic and principle simply because of the level of workability. We might achieve higher levels of compliance when compliance is simpler. Now, as a body that is supposed to be doing ethics in a governmental context, I struggle with whether our duty is to identify the kind of ethically purest way to go and leave it to the regulatory people who will interpret this to then ratchet it back to something thatís more workable or whether we should incorporate that concern from the very beginning. But at a minimum, if we continue to take this definition and use it in a way that emphasizes as a principle the notion of identifiability based on any possible identification by any methodology, codes, or deduction, we should at least openly acknowledge that this may not be workable in practice and that some balance between an idealized system of protection an a workable system of protection may have to be made at the level of changes in the wording of the regs or the actual OPRR guidance that goes out to the IRBs following our report.

DR. MURRAY: I thought I knew where we were until I just heard Alta. But let me just give you my crude version of my understanding of it. I think I was one of the people from the beginning who insisted that this continuum actually, that the ends of the continuum were very different in terms of what they engaged in both conceptually and how easily identifiable somebody was. But Iíve become convinced that the current structure is a sensible one, and abruptly hereís how I see it. Youíve got the conceptual distinctions and the ethical considerations, and they look like this. And youíve got this policy apparatus, which is a totally different sort of being and thereís no way to make them fit in a precise manner. So what you want to do is ascribe a certain virtue. You want to make it easy to follow, simply you want to catch all the relevant cases and so the rules you are going to set up are intended to solve this set of practical problems on the policy side. I think if I understood what Carol said a few minutes ago, I agree with it that this approach does seem to be a reasonable response and allows us to capture most of whatís important, conceptually and morally. Even if it doesnít capture it at the first level, it may capture it later on when we consider whether itís minimal risk or not. I hope that if Iíve got that wrong people will straighten me out.

Professor Capron: When I had my hand up and was called on before, I was going to make another comment, and Larryís question caused me to divert on that and now Altaís comment makes me divert. I agree. I have two comments. The one I wanted to make in response to Alta, I agree, Alta, and I agree with Tomís gloss on it that it is a virtue to have something that is implemental. I donít see the problem with this recommendation being easily implemented. If Iím on an IRB, I know two things. Researchers, Iíve got to rely on researchers asking for permission to do their research. I mean, thatís the whole superstructure of this important system. Yes, there are going to be penalties on people like Martin Klein who go off and do it without any consent. That can happen and does happen. But what is likely to happen here, is the person comes forward with a protocol and says I believe itís exempt. If Iím on the IRB, I have developed a very simple form for such studies, and it asks several questions. Will the samples be coded where the code is linked to an identifier that is for a particular person. Or, will the repository draw from a sample that is identifiable and be able to identify the members of the sample? And once that becomes known that thatís the question I am going to have to answer, I may not know the answer. I may have to call up the repository if Iím not a researcher and say are you going to keep a record of the samples you send me? They say yes, we always do and you can tell who, particularly the names of the people who are in that or are your samples anonymous to start off with? They say theyíre anonymous to start off with, I can check "no" in that box. No, there would be no linkage to identifiable people and if they say yes, then I have to say yes. And at that point the committee is going to say we canít exempt it. We now have a process of other things we look at to see whether it could be expedited or whether consent is necessary, et cetera. But itís a very, I donít think this is complicated. I think it is a fairly easy bright line. I like your criteria and virtue, as Tom calls it. I donít think itís a problem. The comment that I was going to make is right before the recommendation, the sentence beginning on line 7 of 186, and Iím going to turn to my colleagues like Steve and Carol and ask them whether my sense that this doesnít quite capture whatís involved. This says that the issue of identifiable is further confounded by the researcherís growing ability to identify the sample even when unidentifiable. And then it goes on to say because of the uniqueness of clinical information, I thought what was growing was their ability through finding genetic markers and so forth to be able to say the sample we have here turns out to be Eric Meslinís sample because we know with his genotype over here and we know the sample. It may be that there is also, but not growingly so, clinical information. I would add therefore, the uniqueness of the biological sample itself or of the clinical information that comes from that material. And do my scientific colleagues, wasnít that the point that everybody kept making, which is the irony is that we say that this is unidentifiable but the very process that weíre engaged in looking at is one in which that changeĖ-is that right?

DR. LO: Like Alex, I have a two-pronged comment. To just follow up on the last comment by Alex, I think that in addition, another way in which apparently unidentifiable samples get identified is through fancy computer techniques that allow you to use census data, phone book data, and so forth just from very apparently scant demographic information, go back to who the actual individual was. So I think there are a lot of ways that weíre talking about and we might want to highlight them all. The comment that I wanted to make and I really want to get back to is my confusion over whatís at stake here because, when I look at chart X and chart Y, I think of two different ways in which identifiability enters in here. Chart X, identifiability comes in as to whether it is even considered human subjects research, but my reading here is that itís not may be identifiable but may be readily ascertained, so itís not identifiable in the sense weíre using it. Itís associable in regulatory language and seems to me is different according to the footnote. Is that not a correct reading of the reg or does it say identifiable? I need to defer to Alta or Alex. Because where the term identifiable link comes up apparently has to do with whether itís eligible for expedited or full review. I think again itís an issue of logically what do we mean but also what are the consequences of the protocol.

DR. SHAPIRO: I think that question comes up in chart X, just one second. I apologize. Your question, Bernie, on the issue of how it comes up in the definition of human subject.

DR. LO: Itís not just is it identifiable but is it sort of readily identifiable. Why is identifiable possible versus likely? It seems to be the same term is being used with different probability weights depending on what the branch point is.

Professor Capron: Isnít there an error in the chart X, by the way? Before we discuss it further, on the right-hand column coming down from the phrase "are those data or specimens publicly available." No, it shouldnít be. You need two different boxes. You have a "no" box coming down from "will the information be recorded in such a way that it can be linked. "No" leads down.... Does everyone see where we are?

DR. MESLIN: We have it on transparency, if that would help.

Professor Capron: Well, maybe you should put it up.

MS. CHARO: Bernie, itís usually the rule that where words are different theyíre intended to mean different things. But the interpretations at these various places in the regs, the interpretations given to all of these phrases on the subject of identifiability have been the same, and itís made me wonder because ordinarily youíd expect thereís a reason why the language differs and thereís an intent to have different rules apply to different levels, but thatís simply not been the case in practice. So that our discussion about what constitutes identifiable, the possibility of identification, is one that is key to whether or not an investigator is obligated to present himself or herself for review by an IRB as well as coming up in other contexts. And so, right, itís very confusing because itís surprising to see no use made of the different language, but I have no knowledge of the history of the drafting of those regs and whether this uniform interpretation at every level is consistent with that history or not.

DR. LO: The star at the bottom of the page says that identity of the subject used in...

DR. SHAPIRO: This is chart X?

DR. LO: Excuse me. Chart X. Now the big star with the two footnotes at the bottom. That is the second one thatís incorrect? Is that what I hear you say?

MS. CHARO: No, Iím not saying itís incorrect. Iím simply saying that again, to my knowledge, and I happily stand corrected by people in the audience who know this better than I do. That the interpretation of identifiable up until now in practice has been samples that have codes, links, et cetera. That deduction from cell size have not been used as a form of identifiable, has not been interpreted to mean identifiable in practice up until now. And that this notion of identifiability has been used consistently throughout the process no matter where you are, whether itís at the level is there a human subject or the level of is this research exempt. Therefore, our discussions need to take that practical matter into consideration. Thatís all.

DR. SHAPIRO: Steve, first.

MR. HOLTZMAN: I just want to throw my support a hundred percent behind Alta. Whatís taken place, whatís striking is itís very textured language, different in different cases, and yet it seems consistently the answer is effectively a standard of "possible." Basically, I think except for the cell point youíre pointing out, itís a natural extension to say that if you move down a path in which at every layer you basically say, is it identifiable and itís natural to then ask the question, other modes of identifiability you havenít considered before, beyond codes. Okay, now thatís what puts us on that logic train where Harold ends, where I think the Commission largely has come to. And I think these charts are actually very clear. I mean you could spend a lot of timeóit works. These charts work.

DR. SHAPIRO: It seems to me that if we use the criterion "possible," I think it has tremendous advantages in the point of view the way we deal with the material. That is, itís clear what youíre saying. You donít get caught up in words or how to define or itís readily available, not readily available, what it means, what cost means, so on and so forth. It just says if it is possible or not? And as Bernie has pointed out, there are all kinds of ways things are going to be possible that we havenít thought about because we canít think them all out right now. But it seems to me to lead us into a pretty clear framework. Now we could decide at the end of the day, once we accumulate all this, that using "possible" is unworkable or is so costly to some other valued activity we want to pursue that we want to make some compromises. Now Iíve not seen any evidence yet that thatís really going to be the case. If weíre, to me, I still donít really care how people get identified, either they get identified or they donít. And the harm to that person, I understand itís probabilities, so that if you would have cellsónot 1 cell and not 10,000 but 378, versus 78 which changes the probability of being identified. And we talk about risk, you have the harm of the standard calculus that we all go through. But that can all be dealt with, within the system, within this framework, with people making sensible decisions as they go along. But if we have to, it seems to me, the hardest decision we can give an IRB is to decide what identifiable is if you donít use "possible." Then you really have a problem because thereís all kind of identifiability. Itís like this minimal risk all over again only youíve introduced it once more for, I think, very little gain. Bernie?

DR. LO: I actually agree with that completely. Iím just concerned that when I read the section of the reg, apparently what weíre advocating something different from what the regs say. Then weíre back in our problem. First thing we say is that we like the regs and now weíre finding little places....

Professor Capron: Weíre explainingóour understanding of what you just said is when it says the identity of the subject is or may readily be ascertained by the investigator or associated with the information. We are saying that means itís possible to do so. One such example of possibility is...

DR. SHAPIRO: To me that seems to be, of all the things we talked about, the clearest and also satisfying in some sense, unless we find out in the end we produce an unworkable...

Professor Capron: OPRR or the Interagency Committee ought to make clear that this language means it is possible. For example, when a repository keeps a list of the samples that it sent over. And I donít think we have to, if thatís the case, do statistical studies to say well how many people are like the Mayo Clinic who already read the regulation that way, and how many are like Mary Claire King who reads it her way, and how many and somebody else reads it a different way. Weíre just saying this is the reading that we think is the most congruent with the interests which motivates the whole set of regulations. I endorse that view and I hope that we can finally resolve this and move on.

DR. MIIKE: I think that we are going to need a little bit more explaining because the plain meaning or "readily ascertained" is not "possible." So I think we need to talk a little bit more in our discussion about how circumstances have changed in the ability to identify people compared to when that language was drafted.

DR. SHAPIRO: I think thatís a good point. Itís not only readily available. Thatís not the only phrase there. It has an association with them and I donít know, it depends on how you think about that phrase, but I agree with the point youíre making in this.

Professor Capron: Well, I donít see the purpose. Larry brought it up before. Are we rewriting the regulations? No, weíre not rewriting them, but weíre urging that they be read to mean the following: Because they could mean weíre giving our sense of the meaning not as an exegesis of the text itself, but as going back to the policy that lies behind all of this, in light of the changed circumstances, the greater ability to make much more use of what was just a lump of tissue in a paraffin block or something.

DR. SHAPIRO: Okay, we will take a run at this in that framework and see how it comes up. Letís move on. The next section of this deals with criteria for expedited review, and in fact, there is an insert which is, as Kathi referred to as an italicized line on page 189, lines 11 through 13, which has to deal with "special scrutiny" studies and the material leading up to that. And if you turn the page over to 190, thereís another one of those phrases which has possible recommendations. Kathi or Eric, do you want to say anything about this particular section and the possible recommendations?

DR. HANNA: Well, to lead in to that, I want to explain about what staff was thinking was here, and I want to thank Andy Segal who is sitting in the audience for helping us work through some of this. When we were trying to talk about minimal risk, and then also, I am going to throw in here the rights and welfare criterion, which is also one of the considerations. We were trying to separate out those two categoriesóminimal risk, rights and welfareóand understand what they mean in terms of interpreting the regulations. We went back and forth a great deal on this. One of the things that fell out of this, and I think Bernie helped in some e-mail that he sent, was this issue ofóand again it refers back to Alexís concern about harms and wrongsóthat there might be some categories of research that an IRB would struggle saying it is actually above minimal risk, but perhaps might fall into the area of concern about peopleís rights or their welfare and Bernie, I think, used the phrase "special scrutiny." That there might be some classes of research that fall into a special category where risks might be minimal, but other concerns might not be. Weíre trying to grapple with that, and Bernie supplied some examples that show up on page 189, in paragraph lines 7 through 13, as some examples of research in those categories, and I think we just need to think about that more and staff certainly needs your help in trying to figure out how to actually define that. If weíre going to talk about special scrutiny categories, we need to be very clear about what would fall into those categories.

DR. SHAPIRO: All right, I have some questions but letís go to others. Alta.

MS. CHARO: Iíd like to discuss this section which grapples with minimal risk. I feel like I can only do it if I talk about the rights and welfare language. Just as an organizational point, it might be that we should consider flipping the discussion so we start with the waiver of consent when minimal risk and right and welfare are both implicated, and then move on later to expedited review because it will allow us to have integrated discussion of minimal risk and rights and welfare. At this point now because theyíve been separated. I just want to share with you an e-mail exchange I had with Kathi because I would like to put it on the table as possibly something for us to consider. We were going back and forth on what rights and welfare might possibly mean. And I said, well hereís a speculation that minimal risk really is more concerned with invasive research and focuses more on physical risks. And that rights and welfare is about the psychosocial problems that weíve all identified, the problems of stigmatization, insurance discrimination, employment discrimination, etc., and that one might find that this actually creates a sensible division in this language. And that, therefore, when you talk about the risks of daily life, weíre talking about the risks of getting a broken arm or the risks of being run over by a car and that you then measure what happens when you go into this research study and somebodyís going to stick a needle in your arm and you say, is this more or less than what happens in daily life. Because weíve all acknowledged that psychosocial risks are particularly difficult to measure as against daily life. And then Kathi e-mailed me back subsequently to say well, actually, weíve got the following interpretation from OPRR, had nothing to do with this possible separation between physical risks and psychosocial risks. And yet I still find myself circling around and wondering if, regardless of whether then thatís the current interpretation, whether thereís possibly some value in trying to separate these two categories of risk a little bit because the difficulty in comparison and measurement for themóI know we went around this in Portland, I think I remember doing it with AlexóI still feel like the measurement problems are qualitatively different. It also admits of the following possibility: The minimal risk category, as was gone over in perhaps incredibly enthusiastic detail here, is one that looks at physical risk relative to what you are already experiencing, and then says if itís no greater than what youíre already experiencing, itís okay to do this research without further consent, subject to the other criteria. The rights and welfare language doesnít make a comparison to daily life in any fashion. It simply says, "adversely affects peopleís rights and welfare." This struck me as being important in the psychosocial area because of a point that had been, I forget where now, about whether even if something is within the realm of what people experience in a daily life, it is justifiable for us to thrust more of it upon them. So even if I face the possibility of discrimination every day of my life because Iím shorter, Iím curly-haired, or whatever, is it really right to thrust yet another possibility of discrimination upon me? Another quantum of it? And then by using language that simply says "adversely affects rights and welfare," we donít have to worry about whether or not itís consistent with what weíre already going through, we get to simply discuss de novo at the IRB, whether it is something that we think of as being harmful in some fashion. And so I find myself wondering if there might be a new way to use minimal risk versus rights and welfare that might help untie this knot. As a final comment, as it now exists when I read the rights and welfare discussion that comes later in this chapter, I found it extremely difficult to distinguish it from the discussion of minimal risk that had preceded it, which was simply kind of performance art of the problem.

DR. SHAPIRO: Thank you. Eric.

DR. CASSELL: This has a quality of "sticks and stones will break my bones but words will never hurt me." And I call to mind two studies in the social sciences which bear on this. One was the famous menís room study in which people were exposed...there was no physical harm involved at all, but people were horrified at what that study did. And the other was one that was done in which people thinking that the subject was in pain kept causing more pain because the investigator pushed him. Leaving aside the validity of the findings, thatís a different issue entirely. Both of those things exposed people to a kind of risk which was greater than everyday life. In fact, everyday life is set up to avoid those risks. Thatís the way that society sets its world up. So I donít find the distinction here, as in a lot of other places, between physical and other than physical risks to be a useful....

DR. MURRAY: Eric has referred to two studies, Humphriesí study published under the title "Tearoom Trade," of anonymous sex in menís rooms in...I forget where it was, in parks and things. What people thought particularly horrifying about that was that Humphries took down the license plate numbers of people, and he then disguised himself and went to their homes, tracked down their addresses, and went to their homes to get information about them. So part of it was that the anonymity didnít exist, he breached it coldly. He did not publish the names of his subjects, but he knew who they were, and without their consent. He got information at home but also observed them and linked information. The Mulgrom stuff is definitely human subjects interaction. In some of those conditions, the experimenter required this "subject" who thought he was the experimenter, or she was the experimenter, to actually hold the subjectís hands down in some electric shock apparatus. So that was no mere observation study, that was very much a deception and manipulation study. Iím reflecting about Altaís desire to distinguish the psychosocial from the physical. It can be difficult to weigh the psychosocial, I agree. But Iím loath to introduce another layer of complexity in the analysis of it. I also didnít agree with your comment that the discussion of minimal risks, if I understood you correctly, seemed to be a distinguishable from the discussion of rights and welfare. It includes expressly, lines 11 and 12 on page 192, "The subject may be improperly denied the opportunity to choose whether to assume the risks." Thatís quite different from the definition in my understanding of minimal risk. I have one difficulty with the passage of minimal risk, primarily the stuff that begins on page 188, from line 12, and goes through that paragraph. It seems to me to be needlessly confusing and negative and almost apologetic. I would put it much more positively. I would say something like, "yes, insurance discrimination and the loss of access to insurance would be a harm of considerable magnitude." How likely is that in a study that uses human biologic materials? In most cases itís less likely, or no more likely, than inadvertent release of oneís medical records. So if thatís the sense in which it is a risk.... That is, itís not zero but itís real low. Therefore, itís something I think we need to explain that rather differently than we explained it here. But Iím not convinced that we should make special provisions for psychosocial risks. Iím open but Iím...

MS. BACKLAR: I think that some of the same problems that are obtained here, with all the struggle we went through about minimal risk in the capacity report and that is the issue thatís being brought up, Alta, and Iím still very stuck with. And initially I thought that we would look at this differently because weíre looking at an inanimate object and a person whoís stealing things. But Iím beginning to consider...I thought perhaps it didnít obtain in the same way. But as I think about it, particularly thinking about Mulgrom and the Humphries "Tearoom Trade" and so forth, Iím seeing that it really does obtain. And Iím very concerned about that everyday risk, which we might pile on people who have that everyday risk, Iím thinking about groups of people who might have a certain ethnic attribution or a certain diseased population. Just because they have that, we consider that itís okay to do this because theyíre exposed to this anyway, and we are then putting that much more risk on a group of people, a certain group of people, where we might not put it on other people. So Iím still...I think the same problems obtain here in how we identify minimal risk.

DR. GREIDER: I like the rewording of some of the language on page 188, lines 12 on. And Iíd like to add one other thing that disturbs me about the language that is there, and that is it seems to me a very circular argument to use an example of medical records as everyday life when weíre talking about information that will go into your medical record. That I think if weíre going to use something as an example out there as what is minimal risk, we should avoid the issue of medical records entirely because weíre talking about information thatís going to go in there. And that circularity does not make me comfortable.

Professor Capron: I very much endorse Carolís comment. Let me put it...a different spin on it, as it were. I think if the concept of ordinarily encountered in life makes any sense, the notion is, without oneís consent, just like deciding to get up in the morning, go out in the world, you encounter certain kinds of risks. Now, where you go beyond that and you are seeking medical care with your consent, there are risks that go with that. We have now put on the table that in that kind of situation, those are things which you would be told about the risks are, decide if theyíre worth taking under the circumstances, and so forth. The whole point of the minimal risk discussion is potentially to exempt the process from that consent. And so for an additional reason, not only does the very category of information you may put the information into the medical record, but the content of the medical record is having faced a potential illness, I make the choice that it is worth running the risk that my record will now say I have a disease which will make me uninsurable because getting treatment for that disease is today more important to me than that riskóIím making a balance. Whereas here weíre talking about something that is outside the context of consent. And it seems to me that for that additional reason itís not a good analogy. That said, Iím not sure that we have another analogy that leads to the statement on line 4 of page 189 that most research on biological samples must be deemed minimal risk. And if thatís the case, that the reason this example is in here, although it ought not to be, is that it is the argument which makes the case that, hey, all this is minimal, then more important than removing the example is rethinking the conclusion. We go on to talk about, "however," the next paragraph in effect begins, "having said that." So you know, if what weíre saying is on the face of it as an initial matter, compared to having a physical procedure done on you where your life could be at risk or something, these kinds of things strike us, initially, as not being in that high-risk category. Letís not reach a judgment on that until we consider some other things.

DR. SHAPIRO: Larry.

DR. MIIKE: Just a problem Iím having with this whole idea about minimal risk as currently being discussed and as apply in the other areas is that weíre dealing with tissue samples, weíre not dealing the human beings themselves. So talk about the risk of everyday lifeóWhat life? So what are we comparing? So itís more of a rights and welfare of the individual that is at risk in any other concepts that traditionally associate with direct human research subjects. So I think weíre sort of having the wrong discussion here. I think we should just look and say, is this an applicable situation? My tissue doesnít feel pain, my tissue doesnít feel embarrassment. So I just think the discussion is sort of off in talking in traditional contexts and what this minimal risk issue has been applied to in the past. I think we should just sort of say it right off.

DR. SHAPIRO: Okay, Steve.

MR. HOLTZMAN: I guess the way I think about that, Larry, is you are working on tissue so youíre not going to hurt the tissue the way you could physically hurt someone. But the nature of the research is itís generating information.

DR. MIIKE: I agree, but Iím saying the whole concept of minimal risk and the issue about the risk of everyday life is inapplicable.

MR. HOLTZMAN: Well, except that the way I think it through is that what is the risk and is it more than minimal in terms of the generation of the information. Thatís the way I frame the question. The generation of the information, does that create a risk which is more than minimal? And therefore, Iím not sure I agree with people that weíve got a circularity here because I think itís proper to say is the information generated in a research study qualitatively different than, more risky than, that which is generated in a routine medical exam and gets recorded in a medical record? So I think that is important, all right. Larry, you look puzzled. Remember, research results are not recorded supposedly in your medical records, okay. So a proper comparison is to ask the question, am I generating information that is more risky than that which is generated in a routine medical examination? So I think that is a proper question to ask. And then the second thing is I think in terms of yes, going out into the world of everyday life, but then you have to fill in that context. When you get out into the world, thereís a lot of information thatís part of your being in the world a certain kind of society. And I sent an e-mail out over the summer on this subject; it was an example of that. And so if I were writing that I would want to contextualize the question of is there minimal risk in generating this information from a study of the tissue thatís qualitatively more risky than the kinds of information that generate in everyday life and the kinds of harms that come from it? And secondly, that which is generated from a medical exam. Thatís the way I frame it for myself.

DR. SHAPIRO: I guess itís the word "routine" that caught my attention.

MR. HOLTZMAN: A diagnostic exam.

DR. SHAPIRO: Well, okay, but routine means to me, at least I interpret it that...

MR. HOLTZMAN: A PSA test that most men get, which is predictive of prostrate cancer.

DR. SHAPIRO: I agree with the premise you made that itís really the information that we ought to be focusing on; that is important. And itís the risk that that information contains, could contain, that we ought to focus our attention on. Iím just trying...but I also appreciated the point that Alex made that certain types of information in a medical record have some implied consent. You decide if you want that in your record, okay, because otherwise you tell your doctor not to give you this exam, or you wonít take the exam. And there is some consent implied in it. There might be certain types of medical information which is really not so formalized, where the analogy might hold a little better, but I want to think that through some more. But in any case, let me go back to my list.

DR. MURRAY: Thatís a very creative use of the notion of risk encountered in ordinary life. And where the medical record fits. And if I stand back and say, well, what are the risks in everyday life associated with me having a medical record at all, even a medical record that doesnít deal with any episodes of illness, simply with having a relationship with a physician, a possibility that that record will fall into someone elseís hands whom I donít want them to have it, and they might even make use of it to hurt me in some way, thatís a possibility. I hope itís rare, that it will happen rarely if ever. Itís probably less...itís probably more of a danger than most people realize, as Alex pointed out. But it seems to me to fall within the definition. And remember, as I read the reg, lines 3 through 6, it saysóby the way it includes both the words "ordinarily encountered" and "routine," theyíre both in thereósays "probably and magnitude of discomfort, anticipated in research, are not greater in and of themselves than those ordinarily encountered in everyday life, or during the performance of routine physical or psychological examinations or tests." I think I would be comfortable with offering as our interpretation of these regulations that information which would be routinely gathered in the course of medical care and entered into the medical record, that the information gathered in the course of the research is no greater risk and is not more likely to be exposed than any risk that would be encountered in everyday life. Maybe we disagree about that. I need to be shown why that is wrong. I mean when our family physicians at our university do their initial visit with you, they do a genogram, for heavenís sake. By which...I donít understand exactly what a genogram is, itís basically kind of a very extended family history of disease as well as those other things. Thereís a lot of genetic information in that record per se.

MS. CHARO: First, just as an aside, having heard about this tearoom, is that what itís called, the "Tearoom Study"? It made me think back about the discussion about publicly available data and wonder how that would be played out onto that portion of the regulations.

Professor Capron: It wasnít existing data, Alta. He collected it.

MS. CHARO: I was simply thinking about the observation in an apparently public space. But putting that aside, first, I find that Larry has articulated the distinction that I was struggling for...heís gone now...and perhaps overstated when I was focusing on psychosocial or invasive. I think when I think about the problems of health insurance and life insurance and employment discrimination, I think about the language of rights. And that rather than thinking about that in the context of minimal risk or non-minimal risk, I think about it in the context of rights and welfare. That something might be minimal risk in all of its other attributes and nonetheless have a significant potential for adversely affecting somebodyís right to get reasonable treatment from these third-party actors, like insurance companies or employers. And I think maybe Larry put his finger on a better way of trying to split this, and it certainly certain can be used to supplement the notion of minimal risk, or you can yank those out and separate them, whichever. I would like to understand better, though, within the concept of minimal risk, how people are understanding the part of the phrase that deals with probability of harm anticipated in the research, not greater in and of themselves. Because outside this whole thing about employment discrimination and such, are we doing kind of a gross mathematical averageówhatís the probability that Iím going to be psychologically disturbed during the course of a day or a year compared to the likelihood of being disturbed by this experiment? Iím struggling, Iím truly struggling to figure out how to handle this. And last, just as an informational note that goes in the medical records stuff. You alluded, I think, to the fact that the research results are not recorded in the medical record. My understanding is that at least at some hospitals, as a condition of certification, every lab test done in the hospital on somebody whoís got a record there has to have the results recorded in that record, even if a lab test is done as part of a research protocol. And as a result, a number of protocols that we review we required this kind of notice to people that the results will be in their medical records, not in some special vault. And that thatís within the control of the institution, thatís in the control of the certification agency.

MR. HOLTZMAN: Just on that point, I think itís an area thatís in tremendous dispute right now. Thereís legislation thatís in various places saying it ought not be.

DR. SHAPIRO: Okay, Iíve got four people on the list, including you, Bernie, and then weíre going to take a break. Eric.

DR. CASSELL: Well, step-by-step, Steve, I think youíre right. The harmful thing is information, weíre not talking about direct physical harm, weíre talking about information harm. Weíre so blunted about the invasion of privacy in the current world that we forget that it has been considered a risk of harm, medically considered a risk of harm for at least 2500 years, and thatís why itís in the Hippocratic Oath. And this potential for harm by information that reveals something about me, even that I have cancer if I donít want anybody else to know that, is enormous. Itís a risk that I take when I go to a physician. There is a second part of it, of course, and that is that I give consent in the sense that Iím giving this directly and therefore participating in the sharing of information. So Iím...three points at least, I find no distinction. I think the concept of minimal risk does apply and can be overridden here in information terms. And it isnít merely physical and we ought to be very, very careful about it.

DR. MESLIN: Just very quickly. As staff was going through this discussion, we want to have Commissioners pay attention to at least two things, and I think they have paid attention to them and itís now a question of what you want to do. The first is in the definition of minimal risk, which Tom Murray has read out to you. There isnít more with respect to how one makes that assessment. The everyday life part or the routine care part. There is no requirement that IRBs adopt one or the other. This is just the definition of minimal risk under 46.102i. Having said that, which means you wonít have to make the determination as to whether the risk that one is exposed to in this study is comparable to the risks of everyday life were you an IRB member, you may choose as a matter of your discretion and judgment to adopt the other referent, which is routine care. Having said that, and this is probably where Alta was going when she talked about where the sections of this chapter might best be illustrated, were you to leap forward to page 191óonly two pages is not much of a leap, itís sort of a stepólines 15 to 20 and then on to the following pages, describe what IRBs with respect to the Federal regulations may do, should they, must do rather, should they wish to waive consent requirements. And those are listed as 46.116d, etc. And these are cumulative. These are not ors, they are ands. All four criteria must be met. If they are not, meaning if any one of those criteria are not met, and you, for purposes of argument here, select one, the research involves no more than minimal risk to subjects, then it immediately kicks back the trigger to IRBs that they must think about consent. And if consent is required, then it becomes an issue of how one discloses the risk to subjects, what the consent form looks like, whether individuals may choose as a result of that disclosure to participate in research, knowing that thereís a probability of a certain type of risk which they, the subject, can judge to be acceptable or not. This may have been where Alta was going, I donít mean to predict where you were going. But staff did struggle with where to put these sectionsówaiver of consent, minimal risk, rights and welfareóand I hope that in the course of the conversation that continues, you can both advise us what would be the most logical order of that presentation and not confuse the illogic of the order, so to speak, with the content.

MS. HANNA: I just want to add one thing. The reason rights and welfareóitís problematic as to where to put itóis because it is part of the calculus in determining whether youíre going to waive consent. It is not part of the calculus when youíre determining whether youíre going to expedite review. And so youíre right, if we flip them, then we would introduce the concept of rights and welfare first. Because rights and welfare can and should be considered even in expedited review, although it does not say that thatís a condition that triggers expedited review.

DR. MIIKE: Before we go on, Harold. Itís just that on page 190 I get totally confused between minimal risk...the separation between minimal risk and rights and welfare. It looks as though theyíre put together.

DR. GREIDER: I just wanted to agree with the discussion we had that what we were discussing here as minimal risk is the information content. And I appreciate Altaís way of thinking about some of these issues, but just have to keep coming back to the fact that the term "minimal risk" does appear in chart Y and these other areas. And even if weíre going to think about it in terms of rights and welfare, we need to somehow incorporate that language, because minimal risk is a yes/no box on this chart. So we have to somehow fit what weíre going to say into that category to some degree. And then the other issue I wanted to do is to get back to the medical record discussion that we were having. I think that what Alex said relative to my first comment about the circularity of it was probably more clear as to what was bothering me about using medical records as an example. Tom disagrees with that view. He thinks that medical records are a reasonable example of the risks that you encounter in everyday life. But I think we all have to keep in mind that this is a moving target. That right now thereís a lot of information going on, as Steve pointed out, or a lot of action going on in terms of medical records privacy. Thereís a lot of concern, thereís legislation, et cetera. And for us to tie something that weíre going to say to the medical records are of certain degree of risk, I feel like weíre tying something to a moving target that already is very uncertain. And so thatís an additional reason why I just donít feel that using the risk associated with your medical record being disclosed is an appropriate one as a criterion for minimal risk.

DR. SHAPIRO: Bernie?

DR. LO: I want to follow up and support Ericís comments calling our attention to what the policy implications of our analytic discussion of minimal risks. And the real question stated here for researchers and subjects is the informed consent issue. That if we donít think that research on human subjects involving DNA testing is minimal risk, then it automatically kicks in to the "get consent from subjects" category, which has a lot of implications for doing this kind of work. So weíre forced to deal with this concept of minimal risk, at least thatís the way the current regs lay it out.

I think we do have toóI mean, again, weíre dealing both with sort of a philosophical clarification of policy implications, but somehow whatever we decide what minimal risk means, we then have to deal with the issue of do we think itís appropriate or inappropriate for research on stored tissue samples to be done without consent of subjects, subjects of the other three criteria?

I was particularly attracted to the notion of special consideration or special scrutiny, because I think one could plausibly argue that even if you think that a lot of research involving stored tissue samples and DNA testing is minimal risk, there are certain examples that we can all think of that probably arenít. And we need to make some distinction between the special cases and the more usual cases.

So I think that the more we can highlight the differences, the gradations that intuitively are there and concern people, I think the richer our discussion.

I want to make another point about minimal risk. We havenít talked very much about the protections that are built into the protocols. It seems to me that risk is not just a function of the probability and magnitude of harm occurring, itís the steps you take to mitigate or minimize those harms. And it seems to me one big difference between research and clinical medicine is that in clinical medicine there are a lot of protections that get built in in terms of risks that have to do with confidentiality. And I agree with Carol that a lot of itís up for grabs now.

I think the way research data is handled is very different than the way medical records data is handled, and only because you have a medical records department that really has as its sole job the collection, dissemination, and storage of medical data. But with researchers, I keep all them. Students who work with me, they keep their stuff piled on their desk and someone could just walk in and look at it. And I have to say no, no, you canít do that, youíve got to keep it under lock and key; if youíre going to code it and youíve got to keep the code somewhere else.

It seems to me we need to somewhere say that even if we do decide that a lot of research on stored tissue samples has minimal risk, thatís subject to the provision that appropriate standard of care for the protection of the confidentiality of information is there. I donít think thatís really in our report yet, and I think itís really important because a lot of investigators donít pay much attention to it.

DR. SHAPIRO: Tom and Steve, and then weíre going to really break. Iím writing more names down.

MR. HOLTZMAN: When Alex began the discussion about whether medical records were inappropriate, sort of an analogy of the standard of care, Alex has made an argument which is quite correct. The conclusion of the argument was that therefore by these records we deem minimal risk, and in fact the risk of revealing information from medical records is more than a risk of everyday life, or that this risk of having records revealed from this biological research would be greater than that of somehow having it revealed from medical records, then that wouldnít be minimal risk. So this isnít just an academic discussion in a sense, it really is a very substantive discussion. Iím glad weíre doing it.

Particularly what Carol and Bernie have recently said, Iím persuaded at this point, although I never underestimate the power of my fellow Commissioners to show me Iím wrong, but Iím persuaded at this point that, if anything, it heightens the need to stress the relative similarity between the medical records and the records generated in this kind of research. Yes, protections, we hope, will change and in fact become more stringent to medical records. To me, that is a good thing about stressing the similarity because then IRBs ought to be mindful of the protections afforded to medical records and they ought to insist that if you want to call this minimal risk research, then you better make sure that your records are protected at least as well as the medical records are protected, heightened by Bernieís comment about how sometimes theyíre not cared for very well and thatís a problem. If, in fact, information gathered from the biological materials are left strewn around the lab and anybody can walk in and look at them and figure out who they belong to, thatís a problem. And so Iíd like to, if anything, heighten the analogy.

DR. SHAPIRO: We can have a break. Letís try to reassemble in ten minutes.

[Recess.]

DR. SHAPIRO: Colleagues, letís begin our meeting again. Weíre going to have to move on through this document although we have not resolved a series of issues here. Let me turn to Eric for a proposal as to how we take our next steps and then try to move on to some other aspects of this chapter.

DR. MESLIN: Very briefly, I think the break was helpful for some of the Commissioners who have been trying to put some ideas forward to come up with a proposal. Iím going to suggest or request that the Commission ask the staff to spend some time on pages 189, lines 7 to 13, describing two things. The first, the actual problem that the rights and welfare issue raises for IRBs who must make an assessment of minimal risk. And secondly, to relate that discussion to the earlier discussion in this text about how minimal risk itself is a problematic concept, not so much in the regs alone but as applied to our report.

I think it is fair to propose that based on that kind of writing, the Commission can still retain its belief that the regulations with respect to minimal risk are adequate, which was our initial statement, adequate, but that further substantive direction would be useful for IRBs in this area. Staff, I think, is very able and willing to provide that material, with input from Bernie and Alex and others who have been offering comments on that.

I think that if we spend more time on this, we will spin our wheels. There has been enough conversation and we can go back to the transcripts. I donít want to offer this now, but it is possible, since there are laptops around the room, that before the end of the meeting tomorrow some initial suggestion can be provided to Commissioners so that they can at least offer their assent to that direction rather than having to wait for a new draft months hence. If that would be acceptable, then Iím sure we can oblige. We will try to write something and we will try and get it back to you before the end of this meeting which meets some of these concerns?

Professor Capron: I donít believe material in Chapter 4 or here adequately addresses what we already have in the transcripts. Early on there was a very good statement from Alta I thought that, as I recall it, had two parts. One was the problematic nature of the present definition for what it covers. The other is the particular difficulty of applying that definition to psychosocial harms which we recognizeóas Larry reminds us today, the tissue doesnít feel painóare the only kinds of harms that are really at issue here.

And for all the wandering around on the issue, and some examples about screening and so forth, I would like to see us take a much more direct approach here and say that the regulations as presently written donít do a very good job here. The concept which the present draft points out, that if there are risks in ordinary life that are much greater, that are "substantial" is the language used, that those still would qualify as minimal risks is, of course, incoherent.

The whole idea of this goes back as far as I know to a study done more than twenty years ago by people from the Research Office, I donít think it was even called OPRR at the time, and Bill Dommel I think was the lead author when it was published. That study looked at the then-existent findings about research studies and said, they donít seem to cause a lot of harm; indeed, researchers seem to be more careful than ordinary physicians. So all this stuff about being so concerned. And then they looked at some of the data on what are the risks of ordinary life to people physically and they said, gee, these donít seem to be greater. And from that came the concept that when youíre below that level, when your research is just some ordinary kind of research, it is like going to the doctor and having an ordinary test.

The thing about routine physical or psychological exams is that they are done without real consent. You go in and you see the doctor and they take the urine and the blood, and they take your weight, they listen to your heart, and so forth. The doctor doesnít say, "By the way, when Iím done with this I might find out you have a deadly cardiac problem." You have the sense this is just a general checkup, itís routine, it doesnít involve much physical risk, and I donít really get much informed consent for it. It is only once the findings are going to be there do you really get a chance to say anything about it. Thatís the general sense. And most researchers are in that same category. Thatís the origin of this language.

If weíre saying in fact in ordinary life now, because medical records are totally insecure, if you have a medical test, you are potentially wiped out in terms of getting health or life insurance. We would not consider that a minimal risk in any ordinary sense. And thatís why they are such a bad example. It isnít the content, itís the fact that most people still probably have a sense that you arenít at risk because itís confidential; the doctor will keep your records confidential. You have to sign something every time they supposedly release it.

I just find the discussion just does not match our prior discussions. So when you tell me that youíre going to come up with something that reflects our discussion in the transcripts, Iím not sure that itís going to get to what seems to me a year ago was already quite clear, which is this language isnít adequate on its own terms, it doesnít meet the particular problem that weíre looking at, and we canít simply say that itís all fine and hunky-dory.

Now would you like to hear something I feel strongly about?

DR. MESLIN: Let me just give a quick response. If your proposal is that you think the regís definition of minimal risk ought to be changed, that we, NBAC ought to make that as a recommendation, I didnít hear that in the discussion.

Professor Capron: No. My proposal is not that, because weíve been told repeatedly that if we say the regulations are going to change weíre just whistling in wind or something, whatever the phrase is, or a futile activity.

What my proposal would be is that Chapter 4, Chapter 5 shouldnít be a place where much discussion occurs, itís a place where weíre supposed to come to conclusions. I would like Chapter 4 to say what kinds of problems you face with using that definition just as an IRB facing anything, and then why there are particular problems here. It does some of that, and it gives some examples, but it doesnít really come fully to grips with the notion that the language about "ordinarily encountered in daily life" or "ordinarily encountered during the performance of routine physical exams," what does that mean as it would be relevant to thinking about examining tissues and cultures and so forth, and to show just how inadequate it is in addressing that.

We could then do the following in this conclusion. We could say what we think should be the view, and then go on and say, if that is not consistent with the present regulations, then we believe the regulations need an interpretive gloss from OPRR and the Human Subjects Interagency Committee, or revision if they donít feel they can gloss it to the extent necessary.

Weíre dealing with regulations that were not written to address this subject. I do not in any case think we should spend a lot of time on the exegesis of the regulation themselves. We should come to the conclusions. There are more-than-minimal risks in studies that should not be called minimal, although very substantial, and thereby evade the whole notion, which we keep coming back to, which is those are situations in which we donít want expedited review and in which potentially you do want someone to be faced with the notion that this could be a study to which they should consent.

All those ideas swim around here but they donít come together.

DR. SHAPIRO: Well, itís my own view that the minimal risk as defined in the regs is not any kind of normal meaning of that term "minimal risk," which leads to all kinds of issues which youíve highlighted here. And if what youíre saying, Alex, is we need to really go at that directly. I agree with that because, as you pointed out, minimal risks can be very substantial given the way they are defined in the regulations. We do have to deal with that. And we circle back all the time because the word "minimal" keeps on fooling us.

Professor Capron: Let me emphasize, I think the origin of all of this, to the extent that it is connected to the Dommel study, was trying to make the point that people thought of research as very risky and that it really was the kind of thing that shouldnít bother you because it was just like everyday life. One thing since then weíve learned is that a lot of research was carried on that was very risky and was disguised and hidden. But that wasnít on the table when Dommel looked at it.

Secondly, I think we recognize that the risk of ordinary life vis-a-vis things like private information being disclosed are much greater than he was looking at. Ergo, the term that is going to remain there ought not to override common sense. That when you get substantial risks they shouldnít be saying, "Well, it could happen in ordinary life." Ergo, waiver, exempt, expedite, or whatever.

DR. SHAPIRO: I agree with that.

A number of people. Bernie, then Diane, Steve.

DR. LO: I share Alexís concerns that in our reluctance to overturn the regulations because that wouldnít be very fruitful, we end up perpetuating uses of language that contradict the plain meaning of the terms.

It seems to me that what weíre facing is similar to what judges must face when they have precedents they donít want to overturn because it would just be too messy but that they really in some sense disagree with. So I think what a lot of clever judges do is they say we uphold the previous decision, we agree with it, and then 99 percent of the decision is saying whatís wrong with that decision and how what weíre doing is really different. We may need to do some of the same chicanery. I just, however, want to make a plea. I just taught a big class yesterday to bright-eyed, eager, first-year research fellows on the ethics of research. They are going to be totally confused when they see the term "minimal risk" and then our discussion. I think the price we pay for upholding the precedent is that we perpetuate some fairly peculiar uses of the language that lead to a lot of confusion among young people. I think weíre stuck, as I agree we canít rewrite the regs at this point, but I think we need to be very, very skillful at pointing out weíre keeping the term and basically redefining it.

DR. SHAPIRO: Diane.

DR. SCOTT-JONES: I think it would be useful to get the study Alex mentioned, the Dommel study that led to minimal risk. I think it would be very useful for all of us to read that.

I would like to say that I very much agree with Alex and I think we do need to make some sort of statement about minimal risk. I agree that we shouldnít try to change regulations. And Iíve probably said this before more than once, but in our research with children there is a fairly widespread recognition that the standard "minimal risk" is one thatís confusing and not that useful, and some researchers, Ross Thompson is one of them, have recommended that we substitute a standard of "decent treatment" for children for the notion of minimal risk.

DR. SHAPIRO: Steve.

MR. HOLTZMAN: I think Kathi mentioned earlier that I think it was OPRR 4-6 years ago issued an interpretive gloss in the context of genetic studies about minimal risk and that it should include psychosocial harms. Have we distributed to ourselves a copy of that?

DR. MESLIN: That was part of the OPRR Guidebook that we previously distributed to the Commissioners.

MR. HOLTZMAN: Right. So we have in hand what a gloss of minimal risk from OPRR looks like in the context of psychosocial. So it might be worthwhile for us to look at that again.

DR. SHAPIRO: Alta.

MS. CHARO: A few quick items. First, something we shouldnít miss that adds to the confusion here and itís very pertinent for this kind of research is the enduring confusion, at least in my own IRB about whether the assessment of minimal risk, whatever that term means, is made with reference to the particular subjects you are going to be studying or with reference to the general population.

Sometimes the particular subjects you are going to be recruiting are people who live in unusually dangerous circumstances or they are people who are already very sick and are seeing doctors regularly for big-time, big-risk medicine. The question arises, does this research protocol which has a risk level of this, which would be more than minimal risk by anybodyís understanding of it for the general population, nonetheless remain minimal for this particular subject population because they are already going through so much more? And it comes up, for example, in cancer studies where people are undergoing chemo, et cetera, et cetera.

This is pertinent here because Iím thinking about the Mary Claire King descriptions, in which sheís looking at people who have already been extensively involved in the medical system, extensively tested for one genetic marker or another, and who are now being faced with the question of being tested for yet a different one, for whom the risk of things like psychological upset due to confusing, potentially alarming results about which you can do little, or the potential for discrimination or stigmatization has already existed by virtue of previous interactions.

If weíre going to make a serious run at the problems with minimal risk, I think we probably want to make a serious run at this problem of knowing of whether itís with reference to the particular subjects or the general population, because I think thatís going to happen here frequently.

Professor Capron: We have a presentation adopted by Gary Ellis about that.

MS. CHARO: If we did, then Iíve forgotten it, which happens frequently. Iím sorry, I canít hear what people are saying. Is there an answer to this question? If I just missed the answer, that would be great. Iíd love to know thereís an answer.

DR. SHAPIRO: I guess the issue to me, Alta, that is relevant but yet another example of the problems with the uses of the words "minimal risk."

MS. CHARO: I agree.

DR. SHAPIRO: There could be quite substantial risks, and I think the question you pose is an interesting one, whether we always refer to the population as a whole or whether itís relativized to the people that youíre actually looking at in the sample.

MS. CHARO: All Iím saying is that if weíre going to be doing a serious discussion of the problems with this standard, if thereís an answer, letís get it, and Iíd love to hear what it is. If thereís no answer, letís identify the problem and we might even want to take a run at an answer.

Finally, on the question of how to handle this section which has been the discussion up until now, it may be that weíre going to wind up having to say that most of these psychosocial risks either exceed our best understanding of minimal in magnitude, or that they adversely affect rights and welfare. One or the other, or both.

But that with regard to the minimal-risk portion of it, the safest thing that researchers can do is work not on the magnitude, work on the likelihood it is going to come about. There is a little bit of language in there now about focusing on efforts to ensure confidentiality and protect information backflow. That may be in the end the only real solution is to work on the likelihood of the harm coming about because weíll never be able to adequately characterize the harm as minimal or non-minimal intrinsically.

Professor Capron: Why not? Being hit by a tricycle and being hit by a truck are two different things. Despite the fact that I have equal probability of them doesnít mean that they are equal. I donít get it.

MS. CHARO: I thought that we were agreeing that weíre having difficulty in identifying what constitutes a risk that is or is not similar qualitatively to the risks of daily life.

Professor Capron: The probability and magnitude. They used the term "risk" very sensibly.

MS. CHARO: I understand. Iím saying that the focus on probability may be more fruitful because the focus on the quality of the risk may get into these endless moving discussions that donít have good answers. If you minimize the possibility of the truck accidents sufficiently, you are allowed to not characterize the overall risk as greater than minimal. And this may be a more fruitful way to design your protocol is to focus on minimizing the probability of harm.

Professor Capron: Well, as to any one protocol, the magnitude may be a given, if thatís what youíre saying, and you want to minimize the probability that it will happen. But as between protocols, one could be minimal although it involves a substantial likelihood of something happening. I mean, the fact that I will get pricked by a needle to draw a sample is 100 percent in certain situations. But a prick to get a drop of blood from my fingeró

MS. CHARO: Iím not talking about blood pricks. Iím talking about the possibility that youíre going to wind up losing your life insurance. We canít say if losing life insurance is greater or lesser than daily life because you can lose your life insurance in daily life. But if we minimize the probability sufficiently, we can still meet the minimal risk standard. Thatís all Iím saying is that it may be more fruitful to focus on probability.

DR. SHAPIRO: I understand Alta simply to be saying that research designs, whatever the harms are, should be designed to minimize risks given whatever the harm is.

Professor Capron: No. I understood Alta to say that probability is what the IRB and the investigator should focus on.

DR. SHAPIRO: In any case, weíre going to have to move on here. First, Alta, in response to your question, I had really meant to respond directly to it. You were wondering whether itís the general population. My understanding of what occurred is itís the general population, whoever that is and however that is. Now Gary can tell us if thatís wrong, but thatís what I recall. So whatever that means and however you feel about that.

All right, Gary, tell us. Was I right or wrong, Gary?

DR. ELLIS: You were correct, Mr. Chairman.

Professor Capron: Isnít that in materials that are available to IRBs?

DR. ELLIS: It would be available on transcript of the NBAC meeting when I addressed it. Alexís memory is correct. Remember, we had a long discussion and I posed a teaser whether lumbar puncture was greater or less than minimal risk. Itís possible that Alta was not at that meeting.

But Chairman Shapiro is correct. Just to be brief, we know it is not the daily life of a healthy person because the department specifically turned away from that language in 1981. We know it really canít be the life of a person who is very vulnerable because then we would be inflicting more harm or discomfort on the most vulnerable person and we go down a slippery slope. So weíre left with the conclusion that it must be the daily life of the general population, which includes people who are of ill health. I donít know how better to explain it.

DR. SHAPIRO: Okay. Thank you very much, Gary. I appreciate that.

Tom has a comment, then weíre going to move on to the issue of practicality.

DR. MURRAY: I hope this comment can serve as part of the segue. The discussion has been helpful in clarifying some things. Alex had called for sort of a beefing up of the discussion of the problems with minimal risk in Chapter 4, is that correct? Do we all agree with that? I think thatís right. I think we should say that, be very blunt about it. Then we still have to make a decision in Chapter 5 about how to cope with it.

I hope I read this correctly, but as I understand it, with all the problems, if we were to follow the interpretation, the definition of minimal risk, what happens is suppose you say, well it appears to be not greater than minimal risk, that kicks us into Chart Z, doesnít it? Is that right? Where the first entries were the research in its entirety involve greater than minimal risk. If the answer is no to that question, and sometimes weíre going to think it sort of defies common sense to answer no to that question because we think the absolute risk is high, you get a second bite of the apple. Hereís how you get it. You go two steps down and it says, if itís not greater than minimal risk, itís not practical to conduct the research without the waiver, then it asks, will waiving or altering informed consent adversely affect subjectís rights or welfare? And you can say right, it does. It puts them at risk of losing their insurance. There you get to look at the absolute level of risk and say yes, it would adversely affect and therefore you canít waive consent.

So I mean, in a set way, common sense gets a second hearing. And so if I understand the way it would proceed, Iím not uncomfortable with saying, this is a tolerable way of handling it, even though at the first cutówhen you say is it minimal risk or notóitís not the common meaning of the term. You do get to revisit it later on, if I understand it correctly. And so as a practical matter, you do get to introduce his concerns about the absolute level of risk.

DR. SHAPIRO: Okay. Thank you very much.

There are, between where we had begun looking and the practicality section, which begins on page 194 with a call for recommendations two pages later, there are, of course, some comments on consent and on the rights and welfare issue. I think Alta had a very helpful, I thought, editorial comment before. Thatís my own view of that. We may want to come back to some of that later.

But letís go directly to the so-called practicality section. It begins on 194, then it has a bold-type conclusion, I guess, at the bottom of page 196, and then, I donít know how to phrase this, Kathi, but a suggestion or something that you want us to think about or talk about.

So letís see what comments and reactions there are to that bold-faced conclusion, and the material that Kathi has been involved with about that.

Alta?

MS. CHARO: Page 196, lines 6 and 7. A clarification. Where it says "itís important to remember that reasonableness has to be reviewed in light of the level of risk of a study that is above or below minimal risk," I think itís important to keep in mind that this issue or practicability is only coming up in the context of the waiver of consent, which is only permitted when you have research that is minimal risk. So that the level of risk that youíre worried about here cannot be above minimal risk or youíre no longer even worried about practicability. If itís above minimal risk, youíre not allowed to waive the consent anyway. So just as a clarification, I find it increasingly difficult to keep all these rules in my head at the same time.

I would like to just ask for the purpose of trying to flesh out the discussion here, which is struggling because weíre struggling, whether we would like to start from one threshold question, whether people should be required to at least try to obtain funding sufficient to permit contact, and only when that funding is not going to be available be able to make the argument that it is uneconomical and therefore impracticable to get consent.

It has an effect on the way in which people write their grant applications. It kicks some of this question back up to the funding agencies about their priorities in terms of funding numbers of protocols versus funding fewer protocols and greater protection. And it begins to get a handle on the economic question.

DR. HANNA: I actually talked about that possibility with some people who are grants officers at the NIH. They expressed a concern that it might initiate a trend by study sections to deny funds for that use and therefore give the ammunition to the investigator to go back to the IRB and say I tried and I couldnít get it funded, therefore it is impracticable. So thatís just their side of it.

DR. SHAPIRO: Carol?

DR. GREIDER: Another response to that, that was a very creative answer about the grant funding, but just in terms of practical issues, the turnaround time for applying for and getting a grant is a year, year-and-a-half. So that would definitely change the ability to at least initiate something. People should be aware of that, that it is not a simple thing of just applying and being denied. That would be a delay of a year-and-a-half.

DR. SHAPIRO: Other comments or questions with the issue of practicability and what we might want to say about this?

Steve?

MR. HOLTZMAN: Itís a question and I think Alta pointed at it in those specific lines. Do we read practicability as a standalone condition, or is the reasonableness modified by something else? I think what Altaís just pointed out that the way it was written, you sentence reads, "the reasonableness of the contact effort has to be viewed in the light of the levels of risk." Alta rightly says thatís not in play anymore.

My reading of it is practicable sort of stands alone. Practicability is not a function of whether or not it is worth doing for other reasons. You seem to want to modify it. What is our reading of this? What is the interpretation thatís out there right now?

MS. CHARO: This is a very imprecise answer, right. Weíre completely within the realm of things that are minimal risk, whatever that means. The kind of gut reading of this thing is, of course, youíre supposed to still go out and get permission from people unless you can show that itís really not going to make any sense to try, and here are the reasons why itís not going to make any sense. And thatís what weíre trying to fill in.

Now I agree with you that the not making sense could be that the cost exceeds the cost of the entire protocol or some substantial portion thereof. But I do feel like somewhere buried in there is also the degree to which people would care that they were never contacted. I do think that there is still some role for this, not so much level of risk as much as perhaps expectations of privacy, personal autonomy and dignity on the part of the people who are suddenly not going to be asked somehow is a factor and looking at the amount of money that one ought to spend to recontact. I think there is still a mix there, although it may not be risk.

DR. SHAPIRO: Alex?

Professor Capron: I agree with Alta. The notion of reasonableness can mean reasonable under the circumstances. And sort of the interest you have in not having something found out about you or a group of which youíre a member or whatever comes in there as well as in the additional requirement of the other conditions; namely, Tom reminded us that you still have to have a rights and welfare barrier before you waive consent. And if whatís being found out is not anything thatís likely to be very upsetting to most people, et cetera, et cetera, it comes in there.

Reasonableness, we can comment what reasonableness takes into account what youíre saying. If youíre finding out whether or not a person carries a very deadly illness, the effort you would make to get hold of them first and ask if they are willing to have a study done, you can grade them to be reasonable then if itís a trivial matter.

DR. SHAPIRO: Steve?

MR. HOLTZMAN: When I read the regulation I donít see the word "reasonable" anywhere in there with respect to this. And I think whatís psychologically taking place is because weíve read "identifiable" as "possibly identifiable," because weíre reading "minimal risk" as "any risk." Weíre looking for escape valves but I donít think "practicable" is the place you should be finding the escape valve.

DR. SHAPIRO: Eric.

DR. MESLIN: Just a couple of quick comments. We have heard case examples of studies for which the re-contact effort or the consenting effort would be difficult either because of feasibility issues (it would involve a great number of people, a great amount of money, or might take longer to do that than the study was designed for in the first place). Those are study design issues which are what staff has described on page 197 in the italicized box, which is the "Cliff Notes" version of things we would like you to think through, lines 1 to 7 on page 197.

The other portion of that practicability is the cost issue. At our previous meeting in Portland, we tried to spend a bit of time talking about whether cost alone should be seen to be a ground for declaring consenting to be impracticable. I just hope that as you go through you consider the following options: (a) do nothing because the regs, as weíve seen from our personal communication with OPRR, do not provide us with a criterion for defining practicability, which kicks it into the discretion of the IRB to determine on a case-by-case basis; (b) the option is to focus only on research design issues where practicability is the equivalent of feasibility; or (c) practicability being simply seen to be a financial barrier which either for budget reasons in a grant or other reasons, just the volume of dollars that it would take would be seen as a bar.

So I think what weíre saying in the draft is there are a number of options you have. Option A is to do nothing and suggests that IRBs think about this very carefully and provide some explanatory language for what makes it difficult; or B, to make this distinction between financial practicability and design feasibility. Thatís, I think, the direct that we were trying to suggest you deliberate.

DR. SHAPIRO: Alex?

Professor Capron: I guess I want to first disagree with Steve. The word "practicable" here is not the word "impossible." It seems to me that our use of the word "reasonable" is more in line with whatís involved in interpreting whatís practicable than you suggest. You said it is a bad place to put our interpretation to allow a study that has made a reasonable effort to go forward because it doesnít say "reasonable" it says "practicable." I would look at it the other way and say it doesnít say "impossible."

MR. HOLTZMAN: Can I just quickly respond to that. I think the kinds of considerations that Eric was pointing to in terms of practicability, in terms of itís in the nature of the study that you canít recontact those who were in the study, all of that correctly builds in. My argument about practicable was not trying to build into that concepts of it is reasonable given that it is minimal risk or given that it is the cost versus the potential harm. I think those kinds of considerations play themselves out elsewhere in the regulation. Whereas, if you look at our language here in this part of the section, what counts is that for reasonable effort to be made clear, self-compliance, you know, specifically when weíre looking at things like the potential adverse impact of the rights and the welfare of the subject. And I donít think that does play into practicable. Thatís my point.

Professor Capron: I guess I disagree. If I could continue the comment. I do agree that there is a design issue where you can say itís not practical because you will end up with results that donít mean anything if we design this way or that. I disagree, however, about the inclusion of the material from lines 3 to 5. And maybe you could explain that to me and I would be convinced. On page 197, the argument that the research is so valuable that it ought to be conducted even though an effort could be made and so forth, I find is a totally different kind of argument. It is a collective interest which individual research and IRB ought not to be able to exercise. And if anything, it would seem to me that the argument would be if youíre really getting something of such extraordinary benefit, you ought to be willing to pay the extra design. Because on the other side, as suggested in that exchange, although I think Carol is right and it is kind of burdensome to say go and submit your research, put in the extra $100,000 to hire a private detective to trace all these people down, to be told that thatís a ridiculous part of the budget, we wonít fund it, and then come back to the IRB. But itís more a matter of common sense that a person says look what Iím doing, clearly Iím not imposing a huge risk on people, these are 10-year-old records, the chance if I try to find these people is very small given what information I have that Iíll reach most of them, Iíll ruin the research design because Iíll have this random factor thatís introduced and I donít know the meaning of it, it would cost $100,000 to track them all down, itís a $50,000 project, it isnít practical to do this." A person could say all those things and not be misusing the English language, and an IRB hearing all those things could say, yes, I agree, that criterion of impractical is being met here by those considerations.

DR. SHAPIRO: Tom?

DR. MURRAY: Partly Iím going to try to restate. People will tell me whether you think Iíve got it right. As I read the language, which is research could not be practically carried out without waiver or alteration, it seems to me that some sort of proportionality judgment is being called for. It is not some absolute standard of practicality, is just some fiscal impossibility, or is more money than the world has. That canít be the standard. Some kind of proportionality.

If I understood you correctly, Alex, certain factors can figure into that judgment, like how big, what can figure and what canít. One thing that I think cannot be figured in is, well the study is really important. Thatís not a practicability consideration. I donít think Steve and Alex disagree on that. Okay. So it is proportionality. We understand it to be a kind of proportionality judgment from which certain things are excluded from consideration.

Professor Capron: Proportionality of the risks to the individuals involved and cost of allowing them to consent? Not just dollars, but cost to the value of the research and all the other burdens.

DR. MURRAY: Because in fact one of the things that in my view affects practicability, among the costs of that you factor in, is maybe the subjects wouldnít want to be bothered about it, wouldnít want to be reminded. But it could be intrusive. I think we need to count that. Youíre right, we need to guard against it becoming kind of an excuse in terms of being an excuse to not talk to people you donít want to. But we need to consider their interests and all the interests are not necessarily in favor of being contacted.

DR. SHAPIRO: Alta?

MS. CHARO: Looking on my own experience on IRBs and on this conversation, I have a feeling that whatís actually happening in the world is that these four factors, these four criteria, which each in theory in the regulations have to be independently met, are actually being considered in kind of a gemisch. And that it might be that our best contribution here would be to emphasize the following points in terms of implementation of this language. That first, there is a presumption that consent has to be obtained for all research, minimal-risk or otherwise, and that it is up to the investigator to prove to the IRBís satisfaction that there are sufficient bases for either waiving or altering the nature of that consent. And second, that the investigator needs to prove each one of these separately and explain for each one separately why that criterion has been met. That might focus the IRBís attention a little bit, too, so the discussions donít get mixed up, in which practicality and risk begin to get mixed together and one loses the separateness of the issues. Third, that we take advantage of the fact that the IRBs are constructed to have a committee that is made up of peers as well as public members reviewing this. Because when it comes to this last element of practicability, I think it is probably fair to make a list of things and the peers are in a good position to make some judgment calls.

One, is the cost of contact for the purpose of getting consent going to be high enough to prevent the study from occurring? Peers are in a position to understand the issues surrounding grantors, et cetera. Now the answer to that might be, yes, weíll never get the money for a full recontact. Does that mean that necessarily consent can be waived or altered? No, because weíve already independently had to determine that the rights and welfare are not being adversely affected. So if the study is really not a good study to do without consent, it doesnít matter that the granting agency wonít give the money. Thatís not going to be an excuse to go ahead do it without consent because weíve already given grounds to require the consent.

Second, the design issues. Third, and here I think maybe we probably need to go a little farther, is the response rate going to be so low if you require consent that it will undermine the statistical validity of the study? Diane had quite a strenuous critique of Mary Claire Kingís point in Portland about that and it may be that in some studies there really will be a sample bias caused by nonresponse and in others there wonít. Again, itís up to the PI to prove that there will be a sample bias caused by nonresponse that would undermine the value of the study.

I think it is also, finally, something that we should maybe emphasize, which is that the section talks not only about waiving consent, but also altering the consent requirements. This is perhaps a place where we might want to take advantage of the discussion about opt-out versus opt-in consent that takes place later.

It may be that you could make the case that opt-in consent is going to create a sample bias from nonresponse or that it is going to be extremely expensive because it requires multiple contacts to generate the final consent. But thatís not sufficient necessarily to waive consent entirely. A simple one-time mail-out with an opt-out option as kind of a notice of opt-out. Thatís an alteration of the requirements for consent. Remember, it is still minimal risk, it is not adversely affecting welfare. This may be enough to bring the money down.

But this may be our best contribution: the emphasis on the presumption of consent, the need to prove each element separately, and just a list of these factors that the IRB can take into consideration as peers review these special pleadings.

DR. SHAPIRO: Carol?

DR. GREIDER: Just one comment that I agree with your dividing this up into four very carefully. And I think that this chart does that. I think about it very differently looking at that chart than I did reading it here. It looked like four things in a gemischó

MS. CHARO: You like that word, huh?

DR. GREIDER: Itís actually a German word so I know how to spell it. But this chart, I think, helps. It goes a long way toward doing exactly what you want, which is to divide these up and have people think about them separately.

DR. SHAPIRO: Alex?

Professor Capron: In passing, Alta gave an example vis-a-vis the design issue. Iím not sure I heard her correctly. What I would find an acceptable issue to highlight under the design is the bias that comes if you can only reach certain subjects. If you insist upon going to them. You were sort of saying you go to people and some of them agree to do the study and some of them donít, that bias. That argument, if it were an argument made on research design, would eliminate consent entirely.

MS. CHARO: I disagree that it would eliminate consent entirely because you would still have to determine itís minimal risk, you would still have to determine that it does not adversely affect rights and welfare. So it would not eliminate consent completely.

Professor Capron: But the basic argument that the fact some people agree to these studies and some people donít is a reason on a research design basis for saying that we should get rid of consent, whatever category of research for that matter. It is an argument that could be generalized, but, clearly, is contradicted by the whole presumption, which you correctly stated, the regulations start off with, which is that ordinarily people ought to be asked to consent, even if this introduces a bias to the research, that some people were unwilling to consent may be more group A or group B in your outcome and you bias things. Sometimes we have to live with it is what Iím saying.

The issue here is a re-contact study, if it ended up biasing because you could only reach a subgroup and you didnít know that were different, that bias is different it seems to me. And as you say, the researchers would have to argue why the difficulty and the chance variation would be enough to make them say people arenít going to believe my result if you insist upon this criterion.

DR. SHAPIRO: Eric, then Diane.

DR. MESLIN: Just very quickly, and this is a function of us going through Chapter 5 first rather than Chapters 1 to 4. We do give an example of the NHANES-3 study earlier on page 80 and have heard testimony from Dr. Speers at previous meetings on this. So while you read through that section, you may wish to revisit pages 79 to 80. Weíre aware and have had communication from the CDC that as they design NHANES-4 they are going to be thinking about just precisely these issues. So I encourage you to remember that case study because it was one that was considered very carefully by the CDC for recontacting the twenty-odd thousand individuals who participated in that.

DR. SHAPIRO: Diane?

DR. SCOTT-JONES: I just wanted to say again what Alex said, and that is that the research design issue may exist for all studies that you are going to allow that research should be voluntary. We always have the problem that not every person is going to be in the study. You therefore would have to show some systematic bias created by your contacting people by telephone and some people donít have phones. You would have to show some category of bias and not just that a personís right to consent means that you then have a voluntary sample and itís not the whole population.

DR. SHAPIRO: Weíre going to break in a few moments. But I tried to listen carefully to this discussion and I think the statement at the bottom of page 196, lines 17 to 19, without worrying right this minute about its particular wording, it reflects something I think the Commission supports; namely, other conditions are satisfied. That it is still possible to go ahead if an IRB is convinced that appropriate efforts have been made. And then itís a question of filling that out in some way by giving some examples and giving some flavor of our thinking of the kinds of things that might be considered as opposed to making another recommendation. As I understand, thatís where this conversation has led, and I think thatís the way we ought to proceed.

Professor Capron: In a way, Carol, I think it is somewhat separate because maybe, Iíve tried to rewrite this sentence, or maybe I misunderstood it, but this seems to be describing a situation in which initially the researcher said, I will try to get consent and then came back to the IRB and said Iíve tried, it hasnít succeeded, I think I meet the other criteria, please allow the study to go forward without consent. Is that correct? Now it is actually a separate issue to say what about the researcher who wants to say I want a waiver of consent, I donít want to go through this effort, I donít have the money or whatever to go through this effort, and here are the reasons I should be allowed not to go through it. And most, it seems to me, of our discussion here. So, in a way they are related but they are conceptually somewhat different.

DR. HANNA: So youíre proposing that there should be two?

Professor Capron: Iím proposing that there should be two statements, and that in effect what weíve done is gloss the word "practical." Weíve explained the kinds of factors that an IRB could.... And then, as Alta said, weíve reminded the IRB that that is only one of the four questions they need to ask to reach a conclusion that they may alter or waive consent. Is that correct what weíve done?

DR. SHAPIRO: Okay. Anything else on this issue? If not, then I suggest that we break and reassemble approximately 1:00. We have two hours left on our agenda, if I remember correctly, to go through other aspects of this. I hope we can get most of the way through this chapter so we can give the staff appropriate ideas about what our next steps should be.

So letís break for about an hour.

[Recess.]

DR. SHAPIRO: Iím going to turn the microphone over to Eric in a moment, but I just want us to get under way. Iím going to try to run this session, if necessary, as late as 3:15 if we need that time. Beyond that I donít think we can goówe have another subject we have to pick up this afternoon. We have a guest coming who will make a presentation and it would be inappropriate to go much later than that.

I also want to remind Commissioners, as we do often, that itís very difficult for people in the audience to hear if we donít lean pretty close to our microphones. So, while itís often inconvenient and awkward, depending where our microphones are and so on, please do your best to remember that for the benefit of those who are in the audience.

We have two sections in front of us now following all that we dealt with this morningóone dealing with the so-called opt-out provision, and then a series of important issues to be summarized into recommendations regarding the use of existing samples which are, I think, really quite important to look at carefully. So, let me turn the microphone, now, over to Eric to take us through those two sections.

DR. MESLIN: Actually, Iím going to pass it right over to Kathi. Itís easiest to get right into this and let her describe what some of the italicized text on 199 and what follows. Kathi....

DR. HANNA: Right. The discussion about "opt-out"óitís been kind of bandied about at previous meetings, and in Portland it was discussed a little bit more specifically. But in trying to figure out where it fit within the regulatory structure, in staff discussions and in some discussions I had with Bernie via e-mail, I was trying to get a sense of where we would put "opt-out," because it doesnít really go into the consent category, and how it might be considered. So, the way itís presented hereóweíre presenting this, suggesting that it be considered as an extra measure of protection that an IRB might suggest or an investigator might undertake in cases where opt-in is either not required or necessary; where, in fact, consent can be waived; but where the investigator feels thatóor the IRB feels that there might be sufficient reasonómaybe itís because of special scrutiny casesóto contact research subjects, let them know that their samples might be used in this way and give them the opportunity to opt out. Itís not a surrogate for consent in any way; itís just an extra measure of protection. So, that is how we presented it there and weíre interested in hearing what you have to say about that. So, why donít we just stop on the opt-out for now.

DR. SHAPIRO: Thank you, Kathi. Itís an extra measure of protection. I think the way itís written itís an extra but optional measure, so itís another tool to give IRBs a way to help. Alta?

MS. CHARO: Okay. First, on the issue of the organization and where it fits in whole analysis, I want to remind us that the previous discussion in which we looked at the four criteriaóminimal risk, etc.óthatís with regard to waiving or altering the consent requirements. So, the discussions at opt-out actually fit very nicely in there because itís a form of altering the consent requirement. A PI that has persuaded the IRB that he or she has met the four criteriaóminimal risk, practicable, no effect, no adverse effectócan be given by the IRB either no leewayóyouíve got to go for full consent anywayóor can be told, "Yes, weíre going to let you do Ďopt-out,í" or can be told that itíll be waived entirely. So, this fits in under the concept of alteration.

It also fits in, however, in a second senseóand this is, I think, what youíre talking about with the additional protections in whichónot that consent could be waived or altered, but in situations where there is no need for any kind of IRB review if youíre talking about trying to create a category of things in which people apparently are not obligated to present to the IRB, are presenting themselves for IRB consultation nonetheless. And this is your special scrutiny kind of categories, and weíll have to talk later about how to operationalize that. Then this might be one of the many things the IRB could recommend to such a PI, along with study design alteration, consultation of community leaders, etc. But I think that we need to be very careful about separating out the two ways in which opt-out arises, and clearly the second one is in context where the person is not ordinarily going before the IRB at all at this point. Itís not that consent could have been waived, itís that they didnít need to be in front of the IRB.

DR. SHAPIRO: Thank you. Bernie....

DR. LO: When you presented orally, you made an addition to the text that I thought was very important. You said the investigator or the IRB may have the option. I would suggest we include that language wherever possible so it doesnít sound like the IRB is running after nasty investigators saying do this/do this, but that in many cases a thoughtful investigator would welcome the chance to have a wider range of options for herself.

DR. CASSELL: Put this in the simplest terms. This means that there is a group of people from whom we do not have to get consent but they can say no, and that means that you donít have to go through the clumsy business of going and finding each one of them, but I canít say no if you havenít somehow gotten in touch with them. So, you have to find out who they are, and you have to send them some kind ofóbut you donít have to go and meet them and have them sign. Is that the intent of it?

DR. HANNA: Right. We were trying to separate out the various reasons why we might recontact an individual. One would be to have them opt in. One would be just to inform them that the research was being done, not asking for them to respond in any way. One would be to allow them to say that they did not want their sample used for that particular protocol and to opt out for that study or any future studies. And, then, the fourth would be to communicate research results to them that might be clinically significant and meaningful. So, youíre right. In all of these cases you have to know who the people are and be able to find them.

DR. CASSELL: Itís like "Take me off your mailing list."

DR. HANNA: Right. Right.

DR. SHAPIRO: Rhetaugh....

DR. DUMAS: Thereís a thin line between opting in and opting out. If the person does not opt in, have they automatically opted out? If they opt out theyíre not in.

Professor Capron: Right.

DR. DUMAS: But if they decide they donít want to opt inó.

Professor Capron: If you have an opt-in, the usual consent requirement is an opt-in requirement.

DR. DUMAS: Yes. And if they donít consentó.

Professor Capron: Then theyíre not in. If you had an opt-out requirement and they donít say anything, then theyíre in.

DR. DUMAS: Okay.

DR. SHAPIRO: Diane, Bernie....

DR. SCOTT-JONES: When this process is used with research on children, itís called passive consent, and what happens is that a letter is sent home to the parents of the child and it says "Return this letter if you donít want your child to participate," and itís often used in a somewhat deceptive way because that language is usually at the bottom and fairly smallóso a parent not reading the letter carefully, who throws it away, has in effect consented to the child being in a study. And I think that unless you write this very carefully, it seems just like thatóthe so-called passive consent, where you send out a notice and the person has to contact you to say that you donít want to be in the study; otherwise you consider them in the study. And itís not very much of a protection at all.

DR. HANNA: I think that maybe itís not worded clearly. But I think that the way the text is written right now, "opt out" is only an option where consent has already been waived. Or could have been waived.

DR. SHAPIRO: Bernieís next.

DR. LO: Maybe it might be helpful for us to recall Mary Claire Kingís comments in Portland on this issue, where she said that there are studies where you have a whole population that youíd like to study and youíd like to give people the option to say "I donít want to be in your study." And what happens, not uncommonly, is you mail out well-written, meaningful descriptions of the study and say, "You know, we will use your sample unless we hear back from you saying you donít want to, in which case weíll respect your refusal." And she said what typically happens is a lot of people get the letter and say, "Oh, I donít care. Let them go ahead and use it." But you have the opt-in alternative, where they had to get back to you and say "Yes, itís okay to use me," a lot of people who in fact donít object to a studyówhich, you know, has had to meet all kinds of requirements for a level of risk and stuff to get the waiver for consentóa lot of people wouldnít mail it back, but it wouldnít be because they didnít want to be in the study; itís just that they didnít want to take the trouble. So I think it is important we make it very clear the difference between the situation Diane was talking about, where it really is a surrogate for consent. Weíre saying that the protocol is such that the IRB approved it with a waiver consent but the investigator of the IRB is saying, "We want you to go beyond that and give people a real chance to opt out by contacting them and giving them an option to say ĎNo, thank you.í"

DR. SHAPIRO: Alta?

MS. CHARO: I would understand this to be usable in the following situations: (1) where consent isónot where itís been waived, where it could be waived, because the four criteria for the waiver has been met, but instead of choosing to actually waive the consent, weíre choosing instead to do something a little less easy on the PI and simply alter the consent requirement and use an opt-out. Thatís one. And, the second would be where consent was previously obtained, where the change in the nature of the research does not rise to the level where new consent must be obtained but where thereís some feeling of discomfort at doing this without giving people some chance to pull their stuff out. That kinds of grays out where itís just below the threshold of meeting genuinely new consent. Am I correct when Iím saying those are the two circumstances weíre talking about here?

Professor Capron: Howís the second one different?

MS. CHARO: Because in the first, there may never have been any consent of any sort obtained for this research, and weíre determining that it meets the criteria of minimal risk, no effectóno adverse effect on rights and welfare, etc., and that therefore this research can go forward without any consent. For example, I have tissue removed at a biopsy in which the only thing I was asked was, "Are you willing to have a biopsy?" And then that tissue was stored. There was never any consent that had anything to do with future uses of this tissue, right? And the IRB now gets a request for a protocol thatís going to study this and they determine that while it meets all the criteria for waiving consent completely, but rather than do that weíre going to ask for an opt-out. So itís more stringent than what they could already be doing. Thatís the situation, the second one is where they recontact because there is an underlying consent; it meets adequately the standards of adequacy for further work with that tissue. But for whatever reason, the IRB would like to go...

DR. SHAPIRO: Itís an additional step.

MS. CHARO: Right. And thatótherefore, Diane, I think that the concern you have is maybe notóit needs to be placed in a context. Theyíre getting a letter that they donítóthat they donít have any "right" to get at all.

DR. SHAPIRO: Okay, Tom, then Alex.

DR. MURRAY: I really like Bernieís example. Anyone who wishes further proof that the principleóempirical principle that youíve articulated, all you have to do is cite the Book-of-the-Month Club and any of those other places that rely on sending you stuff that you have to mail back. And, how many of us have gotten books we didnít really want because we somehow or other failed to mail them back?

DR. MIIKE: Well, you can keep it.

DR. MURRAY: You keep the book, and pay for it. Thatís the problem. Nonetheless, I think this notion of an opt-out letter is a good one. Clearly, people could do one somewhat deceptively and abusively, as Diane described, but presumably IRBs ought to be on top of that. We want to see the letter youíre going to send out. And I thinkóletís add that additional level of protection so that if someone felt strongly enough about it, objected strongly enough, they would at least at this point be given an opportunity to say "I donít want to be a part of it. I donít want my tissue to be a part of the studies." I want to commend the staff. I think itís a good innovation and sensible.

DR. SHAPIRO: Diane....

DR. SCOTT-JONES: Tomís example of the Book-of-the-Month Club is an interesting one because in a court case, that phrase was used where the so-called opt-out or passive consent. It was referred to as a "book-of-the-month-club procedure," because if you donít send it back, you are in the study. So the burden is inappropriately placed. But I suppose in the context that Alta has explained, itís not exactly that youíve waived consent; youíre somewhere in between the waiver of consent and actual consent. So, it just seems sort of like double talk to say that you waived the consent when, in fact, you havenít. Youíre using this sort of variation in actually getting consent.

Professor Capron: I was going to agree with you, Diane, until your last comment. It seems to me that Kathiís original description of the situation is important. This is a situation in which the first step that the IRBs should reach is that there is no requirement of consent. For precisely the reason that you describe, the opt-out procedure is not the equivalent of consent. It is, rather, because of the concerns about special sensitivity, a sense that, well, we donít have to get consent but there might be a few people who, when they get this notice, will tell us, for whatever reasons they may have a special sensitivity about this, that they donít want to be included. And it would be better that we give them this opportunity even though we donít have to because weíve met all the criteria, and not treat this at allóas you were saying in your last commentóas a form of consent. It isnít a form of consent. It is an opportunity to object, but it is not consent. How, for example, would this be used with the "addressee-unknown" response? In other words, if you were asking for consent and you got "addressee unknown, return to sender," youíre back with saying, "We got to find some way of finding this person." I assume that here you sayówell, that person isnít actually ever going to know about their opportunity to object because we donít know where to reach them, and weíre not under any requirement even of finding some other practical way of doing that. Is that right?

DR. HANNA: Right. I think in the first case where consentóthe waiver of consent was not granted, where the IRB said you have to get consent, and you canít find the personówell, then you canít use that. But in the second case, where the IRBís already said, you donít have to get consent, then either the IRB or the investigator decides that they just feel better if they gave the option to opt out and they didnít get a response. They could still use the sample, because the requirement for consent was already waived.

Professor Capron: You might want to say something like that explicitly.

DR. SHAPIRO: I have Steve, Eric, Larry, DianeóI hope then we can move on to the next part of this.

MR. HOLTZMAN: I think what weíre all agreeing is the IRB has concluded that it has met the criteria necessary to be eligible for a waiver of consent. The key issue is then say.... Altaís formulation that this be an alteration of the form of consent, and Iím taking Alex to say in order to make clear that this is not consent in any meaningful sense of consent, we ought not say that. I think thatís the argument, right? And that, we should say consent has been waived, right? Now, for myselfóbecause I donít know if anyone else finds this usefulóI have struggled for a long time with the notion of harms vs. wrongs. And I have really understood that the welfare and rights is much more real to me in terms of harms than wrongs. And the one of the ways I understand the opt-out is when it is in the nature of the study that there is no harm, but thereís a potential for wrong because there is this sense that even if I donít view my cuticle as myself in hearing in it I may not want it to be part of certain kinds of studies. Oh, I see this as where that can potentially get addressed. Is that just me? I donít know if anyone else wants to go down that path.

DR. CASSELL: You are either contacting the subjects or youíre not. The fact that the addressee is unknown and you can say, "Ho-ho, weíre relieved now; we donít have to worry about it," then donít call it ethics; call it etiquette. Itís polite to ask if they would like to opt out, but, you know, politeness only goes so far, whereas ethics is supposed to go a little further, so politeness rules should be followed....

Professor Capron: This is not virtue ethics.

DR. CASSELL: Itís virtue ethics.

DR. MURRAY: Superarrogationóremember that word, Eric.

DR. CASSELL: Superarrogation. Well, okay. I just want to know in what category it fits. Now I know itís not etiquette; itís virtue ethics. I want to ask Ed Pallegrino about that.

DR. MIIKE: I think the concept is attractive but then Iím having difficulty about the actual implementation because if you meet the four requirements that weíve been talking about, and practicability is one of the issues in which you would waive, that raises one question in mind. If there was a practicable question about getting informed consent, how is that going to affect the practicability of contacting these people to get an opt-out? And then I think more importantly, from my standpoint, is that if youíve met all the other conditions and then you add these other things that people should consider, and thereís minimal risk, thereís a practicality argument, thereís a rights and welfare thing, then what experiments are we going to apply this opt-out thing to and what directions are we going to be giving the IRB to say that even after youíve done all of this, you still should have an opt-out provision? And I suppose one you argue that, if thatís what you say, then after youíve gone all through that you should have an opt-out provision for everything that has passed that screen. So, Iím just sort ofóI would get confused by this direction about how I would pick and choose which projects I would require it of.

DR. SCOTT-JONES: I suppose Iím still bothered by the language requiring that the investigator contact subjects to allow them to opt out because you never really know that youíve contacted them. The nonresponse means that theyíre okay with being in there, but you never know that you actually contacted them, and I suppose I would fear that what would happen in practice would be that studies that really did need consent somehow got put into this category of the opt-out instead of getting consent in the usual way, and I suppose if the study didnít really require consent maybe it would be better to let it go without having this step, because you never canóyou never have any documentation that you actually contacted the participants. You never know that theyíve gotten a letter or that you were able to contact them. But if you want to go to the trouble of contacting them, why not get consent? It just seems to me to be too possibly open to studies being moved down into this category that really should have consent.

DR. LO: I would agree that itís important to make sure that this isnít the back door to getting out of consent, but maybe what we should do is go back to the transcript from Portland and actually use Mary Claire Kingís example. As I remember, it was a big genetics of breast cancer study, where people had previously given informed consent to a study and now they wanted to extend the study, and Iím blanking on the exact extensionówhether it was a longer follow-up or a....

DR. HANNA: Itís going from a marker to a gene.

DR. LO: Marker to a gene. And she was concerned enough that she went and talked to representatives of the community who were Ashkenazi Jewish saying, you know, is this going to be a problem? They said, "No, no, we want you to do the study." She felt concerned enough that she said, "Iím not happy just doing that," and I think in that sort of situation you should say itís a good thing to take the effort to try and contact people. To get back to the practicality issue, she would not doóshe said she would not have done the study if sheíd gotten less than a 90 percent of the samples to be studied because the power of the study and the numbers would have been compromised. So, had she used an opt-in procedure, knowing that sheíd never get that degree of people returning back the opt-in papers, she wouldíve said, well, weíre just not going to do the study. So, I think that the practicality is not that you canít contact them, but youíre not going to the response rate that the study design requires to make a scientifically meaningful and valid result, and therefore there wouldnít be any point in doing the study if then you couldnít possibly get any information.

DR. MIIKE: Can I just make a comment on that?

DR. LO: You can give the example, because that might help people because when youóas I recall, when we heard the example, the response was, "Yes, itís good that you did that." Itís not that, you know, you were wrong or morally obtuse. But itís not coming through in the abstract discussion aboutó.

DR. MIIKE: But thatís not a good example, because what youíre describing is a situation where she really would have liked consent, but found that it might affect her experiments or it would not be a worthwhile experiment. Weíre talking here about an additional requirement when there is no requirement for consent, and it seems like that thing is muddled aboutómisgivings about wanting consent.

DR. LO: No, no. I think itís important that that proposal clearly met the requirements for not needing consent. That sheíd gotten prior consent for a study that was well within a reasonable interpretation to say that they gave full informed consent for this. But the original studyówhat weíre now proposing to do is a little add-on, butóso technically thereís noófrom the IRB perspective, there was no sense that she was jumping out of a tough ethical dilemma. The IRB reviewers were happy to say to her, "You donít need consent for this, what are you worried about?" She went to representative subjects and they said, "What are you worried about? We want you do the study, donít waste your time worrying about this kind of stuff."

DR. MIIKE: Then, why was she worried?

DR. LO: Well, because she took seriously some of the things that have been kicked around hereópeople saying that, well, if youíre clearly a member identifiable ethnic group and youíre going to do more and more studies pointing to genetic risk, there may be some group sense that, you know, the group is being singled out in a way that may cause problems with either stigma or discrimination or whatever, or self-perception. I mean, I think we have to go back to the transcript, butó.

DR. HANNA: I had discussions with Mary Claire King about this. ItísóI think a lot of it was just based on her respect for the population that she was studying. She had been working with that population for 20 years. It was important to her that she offer them that measure of respect and that they see her as somebody that was concerned about their interests. I think itís as simple as that.

DR. MIIKE: Thatís fine, but an individual investigator can always do that on their own initiative. Do we need to get involved to sort of institutionalize that at this level?

DR. SHAPIRO: I have two other people on the list weíre going to have to get off this subject. Alta, then Bette.

MS. CHARO: When Diane she that she was concerned that this might turn out to be a way for IRBs to loosen up the requirements for actual consentóthat when consent is required they might be tempted to say, "Oh, we can use opt-out" and slide over the criteriaóactually that made me perk up because I can easily imagine exactly that discussion taking place. Iím not sure that that means we want to abandon this as not a mandatory thing or meddling, Larry, but simply as a highlighted option for IRBs to recommend to their investigators, but I do think it probably argues for some language that says that to do this properly you want IRBs to really go through the discussions and confirm first and independently that consent may be waived, and only then proceed to whether or not they then want to add back in the opt-out protection so that thereís no chance of letting them slide. But they first have to firmly identify that they really could waive the consent.

Second, Larry, you asked about the triggers and what would trigger this, and the list has already begun to develop and I think itís probably present here someplaceóI forget, but, it goesóthe list actually is generated, I think, by actually using not virtue ethics but the much more accessible language, although perhaps less preciseóof etiquette. I really like that because good manners is mostly about putting yourself in somebody elseís position and imagining what they would want. Thatís the essence of good manners. And, that means putting yourself in their position and ask, would they actually be kind of put out? And, on political hot topics you can pretty much guess that somebody might. And on a practical level, Larry, the difference between getting consent and doing this is this only requires one mailing, one effort. Some donít get delivered, but you made an effort. You tried. Thatís what itís about. Itís that you tried. And thatís the good manners. That you tried to just let people know. You didnít have to, but it was good manners to do it even though you didnít have to.

MS. KRAMER: Iíd want to go back and look at that transcript again, but my recollection is that Mary Claire King said that even though the community told her it wasnít necessary, that she had done this because she was very concerned as to what kind of guidelines we might come up with, and she wanted to make sure that she didnítóthat she was notówould not end up in violation of them. In other words, she took a very ultra-conservative approach and I think she also said to us, "But be careful. I had plenty of money; I could do it." And I think that there was implicit in what she said if not explicit that this might not be something that we would want to even think about incorporating in guidelines because it could be impractical. So, I donít know if her presentation was very powerful but Iím not sure that from that one case we ought to be making some type of policy guideline.

DR. SHAPIRO: Okay. Letís just see what our sense of this is. This is not central to what weíre doing here and I donít want to take any more time on it. There is a point of view that this is just another tool that the IRB could use to be extra-conservative for whatever reason it has for wanting to behave in this way, and the concern, I guess in some Commissionersí minds is that somehow, some way, one way or another you let a thing like this out and itíll come back and haunt you in other ways and undermine the consent form. Obviously, both these things are possible. Let me just have a show of hands to see how many people think we should leave this in as a possible additional tool for IRBs or investigators to use. How many people think thatís a positive thing to do? Iíd say a clear majority of those that are here, so weíll keep it in the draft that goes forward. We can benefit from a lot of the suggestions made here, and so itíll be probably coming in somewhat phrasing but weíll keep it that way.

I want to now go on to a number of suggestions here that have to do with the use of the existing samples. That material is on page 199 through roughly 202. Eric or Kathi, however you want to proceed.

DR. HANNA: We tried to separate these consent issues out between those concerning existing samples and those concerning future collections. So, the first recommendation that wraps around 199 to page 200 starts to developóit begins the discussion about the criteria that an IRB might use to determine whether an existing consent is applicable and still relevant, which will then figure into their calculations as to whether consent can be waived or reconsent is required, whether it be opt-in or we follow the opt-out measure. And we just provided some examples in here. These examples will not stay in this chapter. We just provided them for discussion purposes at this point about some of the language thatís been adopted by the LC working group and the Heart, Lung, Blood Institute in giving their IRBs guidance concerning review of existing consent documents.

DR. MURRAY: This is very good. Iíd want to add oneóprobably a sentence to the highlighted material on page 200, a recommendation simply to remind researchers that we go on the record as saying that any cases in which subjects have explicitly refused to consent to use of their tissue in research, that that must be honored.

DR. SHAPIRO: Carol....

DR. GREIDER: One thing that struck me when I was reading through this section, really starting on 199 through 200, is that we seem to have lost the issue in the text about samples that were collected in the researcherís clinical context, and I believe this is what Larry brought up and this is where that issue came to me. If that issue does come up again in the future, samples collected in the future, but here we donít directly explicitly bring that up. The only thing is the very first sentence, which says that "Samples may have been collected under a variety of conditions." I think we should explicitly say that a lot of the times in the clinical context, the consent may have been relatively weak or bring some language to that to bring out that distinction, which has been one of the issues we spent a lot of time addressing.

DR. SHAPIRO: Other comments or questions?

Professor Capron: Do you want them on the charts? Could you put A back up, please? One of those bottom boxes there.

The result of a situation in which you donít have prior consent or the prior consent isnít applicable is stated to be "obtain consent or consider appropriateness of retaining identifiers." Itís that latter phrase that I wanted to have us explore for a secondóIím not clear that what that means is "consider the appropriateness of removing identifiers" in fact, but beyond that whether it means that thatís one alternative besides obtaining consent. Is that an alternative? Is it really obtain consent or remove identifiers? Or is it obtain consent, consider the appropriateness, and if you wonít do one of those thereís yet another option. Is that what you meant? The latter?

DR. HANNA: Yes. And then thereís a section that follows this that talks about rendering identifiable samples as unidentifiable, and one reason might be because of the consent requirement.

Professor Capron: Well, I understand that, but then when you say "consider appropriateness of," you getóin the end itís either going to be you will have decided that you can get consent and youíll get it, or you will have removed the identifier. I mean, you could just as well say "consider appropriateness of obtaining consent or appropriateness of removing identifiers."

DR. MESLIN: I was just going to add in that although this colorful overhead contains larger text than the chart which appears in the draft in front of you, the chart which appears in the draft in front of you has a series of boldfaced questions which are designed to elicit the answers that Professor Capron was asking for. The short answer is, "Yes, Alex, do one or the other," but in order to get to that answer such questions as how and when should subjects be recontacted to get consent; how should consent forms be designed to provide adequate protections for human subjects; and under what conditions is it appropriate to remove identifiers from existing samplesóthe answers to those questions should be in the text, which would render this more colorful chart easier to decipher.

MALE VOICE: It would be easier to decipher, but why canít it just say what we.... Are the things which are in boldface on this chart that we have in our book things which you think we have to address because they arenít in the chart now?

DR. MESLIN: Yes. Or for which we would like to have clarity from you.

MS. KRAMER: Will they be retained with the charts as lead questions for the IRB, or is this just for our purposes?

DR. MESLIN: We havenít decided. If you think itís helpful for the chart to contain the questions, thatís fine, but thatís an aesthetics issue. The questions will not go away. They may be contained elsewhere in the text for convenience. If theyíre all in the same chart, thatís fine. Thatís a graphic design issue more than a conceptual issue.

MS. KRAMER: Okay. I wondered if it might be helpful to the IRB in thinking through or in addressing their own questions.

DR. MESLIN: Youíll see again in the table version there are numbers associated with the boxes, and those numbers are helpful guides for the questions that follow below. Those are not on the overhead, not here.

MR. HOLTZMAN: For those of us who can only handle one question at once, are we specificallyóarenít you asking for guidance here specifically to the question in 3B? They want consent; consent is necessary; there are consents in play. How should the IRBs interpret whether or not they constitute sufficient consent? Letís try to answer that question first. And then if they do or they donít, what then happens? So, this idea of anonymizing them or rendering them unidentifiable....

DR. MESLIN: The next chart.

Professor Capron: In going back to page 200 you want us to spell out the criteria.

DR. MESLIN: Or to not spell out the criteria and allow IRBs to make their own judgments as to the answers to that question.

DR. LO: Thereís an issue here I think we really have to address. Thatís the situation where a sample is obtained in clinical context, the patient signed a blanket, all-purpose consent for the clinical procedure that, buried in the middle says, "And, by the way, you could use any removed tissue for education, research..." and whatever else the standard language is, so youíve got a signature and technically thereís some language in there that pertains to future research and itís pretty clear the patient probably has no idea what that meant if they ever read it. I think the question we need to address and that investigators have to struggle withódoes that count under any circumstances for consent to use that sample for DNA testing? I mean, isnít that the issue that weówe can do whatever we want to do as general criteria but I think we can use some guidance on that one, and Iím not sure weíve come to any agreement on that, so Iíd like to see if there isó.

DR. SHAPIRO: Larry, are you following up Bernieís question?

DR. MIIKE: Yes. My view on that question, Bernie, is that we look at what we just discussed this morning and up to now, but whether itís actually going to be subject to the IRB review. If itís subject to the IRB review, my view of the clinical consent form is itís inadequate. So I would have to treat thatóconsidering that itís more than minimal risk, etc.,- I would have to go on to the next phase, which is then whatís inadequate consent. I donít believe the clinical form where youíve got that consent buried in what is essentially a treatment agreement is adequate in any was as an informed consent document.

DR. SHAPIRO: Why donít we stay on this issue, because it is an important one, and letís make sure we understand where we all are on that. Rhetaugh....

DR. DUMAS: Iím back on what Alex was bringing up earlier, and I want to make sure I understand what heís saying, that in cases where you canít get informed consent you render the sample unidentifiable and then youóyouíre able to use it?

Professor Capron: I think youíre over at a different chart.

DR. DUMAS: Well, what are the ethical implications of that? If I donít give consent for use of my sample, then you can just take my name off of it but you can use it anyway?

Professor Capron: Thatís right. Itís not "research of human subjects" if itís totally unidentifiable.

DR. DUMAS: But it wasnít totally unidentifiable, initially.

Professor Capron: Well, it was before I got it. The researcher cannot see the name Jones, take the name offóas I understand itóand say "Iíve got unidentifiable." Itís a matter ofóin the research design you would go to the repository and say, "Send me samples which you donít keep identifiers on and I donít have identifiers on." Thatís unidentifiable by our description. Thereís no possibility, to use the Chairmanís term.

DR. DUMAS: Yes, I was referring to a statement you made about "obtain consent or...."

Professor Capron: Well, this is part of the research design. Itís notóitís not when youíre in the middle of a study that you ask this question; itís before you begin the study in terms of the design.

DR. DUMAS: Okay.

Professor Capron: Could I respond to the interchange?

DR. SHAPIRO: We can come back to that issue as we get down this chart, but I do want to respond to the question Bernie raised and Larryís response. Carol and Alex.

DR. GREIDER: This is just quick. Getting back to the same issue that I just said, that I think we need to add the language of research versus clinical for exactly that reason, and under this highlighted section on 200, where it asks for us to make a list of criteria, the first thing I wrote down was, "Did the subjects consent in a research protocol or clinical setting?" as one of the criteria in that highlightedóbecause I think this issue is important.

DR. SHAPIRO: How do you feel about the issue? Someone is given kind of a consent that Larry talked about. Do you think that amounts to anything?

DR. GREIDER: I think itís worthóthe IRB would have to look at the actual consent. I think a lot of the ones weíve heard aboutófrom the things that weíve heard in testimony, I would agree with what Larry said, that are probably not real true informed consent. But there may some hospital intake forms where it is. And so I think that if thatís part of what is usually submitted to the IRB, look at what was the actual consent form that was signed.

Professor Capron: I have a general sympathy with whatówith Larryís position, but I found some of the discussion from the LC Working Group pointed me in a somewhat different direction, which was towards the context as opposed to worrying about the particular language in which the consent was given before. And, Carol, earlier meetings of this group convinced me that my initial instinct on thisówhich was there was a difference between "consenting to future research in a clinical setting and consenting to future research in what was initially a research setting"ówas wrong. I originally thought, look, if youíve agreed to be in research, then it makes more sense to say someone doing some further kind of research or study is dealing with someone who at least has said Iíll be in research. And you all convinced me previously that that was really wrong, that the fact that you agree to be in one kind of research and that it was a "research setting" was irrelevant. Now, that was mostlyóyou know, we were talking about stored tissuesóthat you would be no more likely to be willing to have your sample used for this new kind of research than a person within a clinical setting. And the LC statement makes the point that if you came in in a clinical setting, where you were being treated for a disease which you understandóit had occurred in your family and collateral relativesóand youíre all in for biopsies of tissue from your colon because there seems to be some kind of genetic colon disease in your family. And thereís a statement in there saying weíd like to use the sample for research and the researcher is looking at colon cancer disease, it seems to me more likely that the person from that "clinical setting" would have a "wish" for the sample to be used to determine why his or her family had a particular inherited disorder. So, theyíre going from looking at the tissue to see is there disease in the tissue already to looking at it to say is there a gene that need to be associated with the disease, that the person would beóhad thought, "Yes. When I agreed to research thatís exactly what I thought I was agreeing to."

DR. MIIKE: The discussion is about existing samples; itís not about futureó.

MR. CAPION: No, Iím talking about existing samples...Youíve got a sample from a person who went in for a clinical biopsy of tissue from their colon, and they were one of a number of people in their family was going through that because it turned out Aunt Sylvia had come down with some hereditaryó.

DR. MIIKE: Iím saying in general the clinical samples collected in a clinical setting wonít meet that criterion.

Professor Capron: No, butóexcuse meóI think that the value of being concrete about this is what the LC did here, that to say in the absence of specific language about DNA testing, it may be appropriate to infer consent from the sources, which for the sample to be used determine why his or her family had this particular inherited disease. No one told them they were going to be looking for DNA markers because it was ten years ago and they didnít know that they would find them. But they did know that they were coming in for something having to do with a familial disease they were concerned about, and they said, "Yes, you may use this for research." So, although I start off with your assumption that that kind of blanket language is usually as useful as any other blanket language that you sign when you go into the hospital; i.e., it means nothing....

DR. MIIKE: Alex, are you using the exception to generalize through the whole clinical situationó?

Professor Capron: Iím not using the exception to generalize. Iím taking instruction from the LC Task Force, who spent a lot of time thinking about this, and saying they may have a point, which is: What ifówhat kinds of risks would the person have in mind when they agreed to that research. Does the IRB or the investigator looking at those consent forms think it is reasonable to infer that a person would do that; in other words, rather than saying "You may never do it," the clinical consent that contains blanket language is worthless. Donít bother to bring it to me. I mean, if I were a hospital attorney and someone came in and said, "The person signed a life consent form on the way in saying ĎYou may do whatever is clinical necessary for me,í and the surgeon now wants to do a biopsy without additional consent," Iíd say, "Get that document out of my office; you know itís worthless. Donít even argue with me about it." But if an IRB is faced with a stack of consent forms from people who came in for diagnostic studies on familial colon disease and you now have an investigator sayingó.

DR. MIIKE: I donít know what weíre arguing about. I mean, youíre describing such a particularized situation. Iím talking about the general clinical consent form.

DR. SHAPIRO: Okay, letís see what some others have to say about this. Alta, then Carol, Bette, Steve.

MS. CHARO: It seems to me that a way to synthesize these points of view might be to do the following: To instruct IRBs to understand that previously obtained consents, whether in clinical or research context that were not particular to this protocol, will be presumed to be inadequate for this one unless the investigator can show why it is. And, that opens the door for the exceptional circumstances, whether in a research or clinical context, in which people can be, after some discussion, judged to have genuinely intended that this particular kind of research now under review be covered by the consent they gave at that time. It allows for a highly individualized context-specific evaluation, but it starts with the general presumption that consent that wasnít given for this protocol is not consent to this protocol, and so you show me why it isóand lets everything else then be very case-specific.

Professor Capron: I agree.

DR. GREIDER: I agree with Alta.

DR. SHAPIRO: Bette....

MS. KRAMER: I agree with Alta, unless we want to say and particularly for samples captured in the clinical setting. But Ió.

MS. CHARO: I think in the IRB discussions that will be one of the factors thatíll go into their assessment of what people genuinely intended at the time and whether it overcomes the presumption that this was not on their minds.

DR. MIIKE: Harold, can I just comment on that? I donít think we need to be that specific. Any IRB thatís worth its salt will take a look at the clinical consent form and say, "This doesnít have any relationship to this particular project." So, I donít think we need to even set that as a guide if you just sort of saying that youíve got to look at the pastóall Iím saying is if you look at past consent documents and match it up against whatís proposed, I am willing to bet that a whole or a great majority of the clinical consent forms wonít pass muster. Thatís all Iím saying.

DR. SHAPIRO: Steve....

MR. HOLTZMAN: The urgent issue which prompted the formation of a subcommittee 18 months ago was this question, and itís kind of striking that here we are sitting and saying, "Well, what are we going to do about it?" And so I think Altaís put forward a recommendation. I donít think you can judge whether thatísówe should accept that until you follow through with the consequences, because what we all recognize is most of the stuff on the shelf came though the clinical contexts where, as Larry points out, the consent was thin at best. So, most of the studies that would concern us are ones where consent is necessary, that thin consent does not suffice. So, now you either say you have to go back and reconsentówhich would be often if you take that paradigm cases will not be possible because most of those people are dead, or alive but difficult; the second case is you donít do it; or, the third is you render them unidentifiable. We have a very, very stringent sense of unidentifiable which we have put in play. So, before I can agree with your way of handling it, you have to play through the implications of what weíve adopted on the other end.

 

DR. SHAPIRO: Alta....

MS. CHARO: I think thatís entirely fair, okay? If weíre going to take seriously the idea that research with identifiable samples on living individuals that poses more than a minimal risk or adversely affects their rights and welfare should not proceed without consent, I donít think we can escape the conclusion that an enormous amount of material now stored in repositories will not be usable until consent has been obtained foróin some fashion, or rendered it unidentifiable, with all the concomitant loss of potential scientific value that that entails. Right? Either you canít do the studies at all, or you can only do them imperfectly. This is the nub of the problem; it has been from the beginning. Itísóin my mind, itís the nub of the problem in the capacity report, and weíll talk about it tomorrow; and about no research more than minimal risk without consent. Itís the nub of the problem in human subjects protection to begin with because from the very beginning when people thought that human subjects should be used only when they volunteered with adequate information, the response was that you were going to shut down important research if you insist on having any degree of information or consent on the part of the subject. And, I feel like weíve lived with this decision to go by the self-proclaimed moral high ground before and I would like to argue explicitly on the record that we should do it again.

DR. SHAPIRO: Eric....

DR. CASSELL: I think itís thatóitís not necessary that scientific research go ahead at all times; itís just not necessary. Itís one value among others, and in this instance another value takes precedence. I think thatís the issue. There goes my phone.

DR. SHAPIRO: See if someone agrees with you. If you were a true Luddite you wouldnít be carrying that, Eric. Excuse meóTrish.

TRISH: Iím sorry, I tend to agree with Eric.

Professor Capron: I agree with Eric. Thereís one additional issue thatís raised by the material on 200 and 201 that we havenít discussed, and that is the suggestion that the subjects, although theyíre not required to consent because their prior consent was found to be adequate for this new study, would be informed about the test results, and that then leads into the Heart, Lung, and Blood Instituteís statement of criteria, which struck me as good criteria but relevant only really in the context of that follow-up step; in other words, that one wouldnít expect. You were putting these forward as things that we might want to consider, and I would consider them in that context and be happy, indeed, quote from them as good criteria, not for the question the adequacy of theóthe necessity of the extent but looking to the future of whatís going to happen when we reveal these results.

DR. SHAPIRO: Alta....

MS. CHARO: I want to follow up, also, with one other thing in response to Steveís comment, because it could leave the impression that the only choices are to obtain new consent or to render unidentifiable virtually all the samples out there in order to facilitate any research. That ignores the large category of minimal-risk research that could be carried out without consent. And that in turn is a reminder to emphasize again that minimal risk incorporates in it not only the notion of the level of the harm, kinds of harms, but also the likelihood it will occur so that stringent efforts to prevent any harm from coming to somebody by virtue of the use of their tissue can make it possible to meet that minimal-risk criterion and open the door towards being able to use tissues without consent, so that our insistence here on consentóon a standard of review of prior consentsódoesnít necessarily make these samples virtually useless that are at the repositories today.

MR. HOLTZMAN: Let me get back and just comment. I agree with you Alta; itís justówhat I was asking us to do and you pointed to another thread in the webóis you have to stand back in the end and say, "How have you constructed the web?" Because if you said "minimal risk," you set the bar very low. Most anything is minimal risk, and you set the bar very high or low or whatís right for practicability and for identifiability, etc. You can have the consequence that I fear making. Everyone fears, okay? So, then you have to look at checks and balances. Thatís theóthatís what Iím saying.

DR. LO: Let me try and jump into this with a contrary view to what people have been saying. First, I would want to stop and question whether we state as an abstract principle the notion that research is optional and erring on the side of protecting human subjects at the cost of not doing research is the preferable high moral ground. I have no concerns about that as a general principle, and Iíll have the same concerns tomorrow when we talk about basic research on people who lack decision-making capacity. I think thereís an alternative version of research issues that thereís a moral obligation to do it in situations where thereís a good possibility itíll lead to real therapeutic advances. I think we at least need to debate it. Secondly, I would say letís really talk very specifically. Weíve heard from a number of people the types of studies that people are proposing to do or may in fact already be doing under mistaken notions once weíre in under current regulation.

So, I would like us to think of specific examples of DNA testing on stored tissue samples where youíre really not going to be able to do the project if you go back and get consent, and weíve heard examples from Steve about taking very large tissue samples looking for markers for polygenetic diseases like coronary disease or whatever, and so weíre not talking about autosomal dominant conditions. And, the concern I remember from several times ago was not so much doing the study in the first place, but wanting to back and recontact the patients to get further information to do more refined tests or get more clinical information. But, I think we really need to ask ourselves if weóas you run through this and see how it plays out to then go back and check with the specific protocols and ask ourselves, "Are we really willing to say that research, which is not yet done when someone goes out and gets a new sample with tiered consentóthe way some investigators are now trying to do. We may set back research and we may say thatís perfectly fine because it is optional, or we may make it really hard to do even the preliminary studies. I think thereís a lot at stake here and I want to make sure we look at what weíre giving up if we follow through the recommendations that weíre making.

DR. SHAPIRO: Eric, then Larry.

DR. CASSELL: Well, Bernie, this tension between the acquisition of scientific knowledge and other human values is a marker throughout this century, certainly in the last 25 or 30 years, but the impression thatóyou know, when weíre giving up something itís like thereís this piece of knowledge that sits right under the ground there and itís not us. Itís there. Itís apart from us. And yet, in point of fact, the direction in which we moveówhat we consider to be valuable and not valuableóall those things are also value-laden issues and not truly objective in some higher form. So, this argumentówhich is a real oneóI mean, if the real tension is here, but in terms of the way the century has gone and the way things have gone generally in the scientific community is as though in fact there is no higher value than the acquisition of scientific knowledge. I think that there is, and I think that when we discuss this we have to keep that in mind. Now, you and I can argue, you know, whichówhich advanceówould have been terrible if we hadnít made it, but we could also argue about which advance was terrible because we made it. So, I donít thinkóIím not trying to dismiss it in this quick interchange. I think it always sits there or we wouldnít be here, and thatís why weíre here, and just that reason, because of the tension between higher human values and the value of knowledge, although as Aristotle said, "All men by nature desire to know." But there are those things, too.

DR. MIIKE: As these discussions go on I keep reminding myself that theyíre not all sitting there independently. Theyíre all interrelated. Weíve got a whole web of checks and balances before we even get to that particular position. Youíve got to get past the minimal riskóand, weíre never going to be in a position to say precisely what each of those parameters are. So, thereís going to be a lot of room for interpretation.

Lastly, if we are indeed using any research where itís not a one-shot deal with a particular tissue but you want to continually go back, that argues more strongly on the part that I want to know. If thatís my tissue and youíre continually coming back for information, thatís a strong argument that we need people to go and say, "Yes, you can continue to do that." So, Iím not that worried aboutóI donít think itís a dichotomy between individual rights and research progressing. I just think that the web, again as I say, that thereís enough flexibility and enough points in there that we really donít have toóI think weíre overblowing the case here.

DR. SHAPIRO: Alex....

Professor Capron: I would add to this that, in agreeing with Eric. We are a particular institution within a web of other institutions, to use Steveís phrase, and the eventual shape of the process is one on which we only can put certain weight in, and it seems to me that it is likely that the voices of those who would cry that research is essential to the most important human good, which is the advancement of knowledge and the conquest of disease, those voices will be heard loud and clear. And they are powerful voices. And they have much persuasive ability within those who form public policy, as well as those who administer those policies through our private research institutions and so forth.

In effect, someone trying to reach a balanced view on all this might at some point say, "Well, what do the ethicists say about this?" And, if the main thing the ethicists say, as I think the present framework of our report atóin its opening pagesóis that research in this area is terribly exciting and enormously valuable and gives benefits to millions of people, which is howóif you pick up this report you would think the first few pages were coming from NIH and the National Academy of Sciences to Congress asking for more funding in this field or, within this area, more liberality in the rules so that private enterprises as well can blaze forward. I think we ought to see ourselves as focusing on those values which history has taught us, as Eric says, in this century are often neglected and try to speak up for those values knowing that we donít want to seem unbalanced, that we give due recognition to the reasons people want to do this research, which are good and valuable reasons. But, if we had to err one way or the other, I think it should be towards putting the importance of taking the interests and welfare and all the other concerns about social harms and wrongs, that those get very carefully attended to and then we put the balance there. The present regulations say you need consent if youíre dealing with research that is more than minimal risk with subjects, and what weíre trying, in this point 3 here, to say is, "Is prior consent enough?" And I agree that the view should be, "Usually you need consent for this research; if you think otherwise, explain why." And if that seems too much on the side of protection, there will be others who will talk about why what we have said is too burdensome and make their arguments. We donít have to take all the possible counterarguments and weigh them ourselves. We ought to speak up for this set of values in that debate.

MR. HOLTZMAN: First off, I think itís important to be clear that the example people have been using of going backóin terms of the issue of reconsent or whatever, people saying, "Iím going back to the individual"óthat need not be at all what weíre talking about here because of our definition of "identifiable." It may have nothing to do with going back to the individual. So I use an example and I use a non-genetic example since it comes up in nongenetics and do an initial study to look at sexual transmission of diseaseóchlamydiaóand I get the consent for it. Okay? Fifteen years later, ten years later, people start pointing out that chlamydia infection might be very important in the formation of heart disease. Itíd be very interesting to go backónot talk to the people but ask the question, "Those folks from whom I got that initial sample, did they develop heart disease?" I donít care who they are. Iíd never know that it was John Jones and Mary Jane and everyone else. But, the way weíve rendered it, unless it was severed I canít get that. Okay? So, itís not a question of going back to the person the way weíve set up the issue.

DR. CASSELL: Well, what are you going back to?

MR. HOLTZMAN: I just thought Iíd want to go back to the record, right? But I canít go back to the record because weíve defined that as identifiable because there was a code.

MS. CHARO: Right, so you have to go back to the individual.

MR. HOLTZMAN: Thatís what Iím saying. So, thatówhat weíre saying is when this breakthrough comes through, itís suggestive, because Iíd like to look at the record. Iím not saying itís right or wrong.

Professor Capron: How would you get to that record without their consent? Itís not attached to their chlamydia file, as it were. You have to getó

MR. HOLTZMAN: Youíre not listening.

Professor Capron: I am listening.

DR. CASSELL: I hear the same question.

MR. HOLTZMAN: I do an initial study in which I get the samples, with consent, for example. I do that study, right? Ten years later, the potential link to heart disease comes out. It would be interesting to tie together the subsequent outcome data if you will give these people...

DR. SHAPIRO: You want to go back to the medical record.

MR. HOLTZMAN: You want to go back to the recordóyou wantóyou donít evenó

Professor Capron: Why do you want to go back there?

MR. HOLTZMAN: What you want to know is the samples that tested positiveódid they then correlateó

DR. CASSELL: Where are you going to find out about heart disease!? Donít shake your head! Where are you going to find out about heart disease?

MR. HOLTZMAN: From the medical records.

DR. CASSELL: Ahh! I donít have any say in whether you go back to my records?

Professor Capron: I thought you were asking a practical question. I went into a Sexually Transmitted Disease Clinic and they found I had chlamydia. They have that record there. Where is my medical record on my heart disease? Thatís not with that clinic. Iím not even living in the same town. Youíre going to have to go back to me, find out where Iím getting my health care, and look at my records.

DR. SHAPIRO: Alta....

MS. CHARO: Iíd like to continue to try to answer Bernieís challenge, because regardless of the details, the hypothetical that you raised, Steve, itís really about Bernieís challenge. And I recognize the interest that we bring to this table. I mean, you work in a company that Iím going to presume has a very big financial stake in how this kind of stuff happens because research that can or cannot go forward without consent will in turn determine the scale of the research thatís possible and the kind of investment oneís going to get from the private sector. Many people here are investigators whose livelihood depends on getting grants to just this kind of research. Some of us are kibbutzers whose very salaries depend on having something to complain about in print. And all of us are potential human subjects whose records are going to be used. So we bring a lot of interests to the table when we debate this kind of balance between scientific research thatís relatively unimpeded and these kinds of standards of personal control that weíve elevated the level ofóhighest principle of autonomy. I donít know that we could ever actually weigh these two together and determine that one is more important than the other intrinsically. But in a more pragmatic way I would suggest that over the very long run, because I think it echoes things that Eric and Alex and others have been saying, we depend completely on the trust of the public in the research enterprise. And while this year, in this decade, genetic research and tissue sample research seem to be the key to everything, twenty years from now itíll be something else that seems to be the key area of research, and the long-run question isnít going to be did we benefit sufficiently from this era of research and tissue samples, but the question is going to be in the long run, do we have the publicís cooperation and willingness to go along with a large-scale research enterprise? And when we seriously contemplate allowing a slide-by with a legal technicality because somebody signed a consent formóweíre going to call that genuine consent and allow ourselves to slide through this difficult discussion by suggesting that prior consents might be usable, as one option. I find myself very uncomfortable because if anythingís been demonstrated this last week in Washington itís that, you know, technical, legal interpretation of documents and words are not going to engender a great deal of public trust and we donít want to make that kind of mistake. The last people we want to be in control of this question are the lawyers. And we really want to go for the heart of it, which is that whatever it takes to have the public go along willingly is important to maintain. The fragility of that trust as witnessed through the radiation experiment furors and the Cleveland Plain Dealer furor has been evidenced and I donít think we can afford to make that trust any more fragile than it is.

DR. SHAPIRO: Trish....

MS. BACKLAR: I think thereís another way, also, of looking at this. I think itís very difficult to compare and contrast the general; and the particular and the partial. And Iím thinking even in clinical care, the patient in front of you is going to be the person youíre going to have to be thinking about. You may be looking at that patient in a general context. You may be in a closed system like a single-payer health system, but youíre still going to have to think about the effects of that care on that particular person in front of you, and I think itís the same thing in research. There may be some generalizable knowledge, which is going to benefit this person in front of you; on the other hand, those particular subjects who are going to donate themselves for that generalizable knowledge, you need particular and partial care.

DR. SHAPIRO: Bette and Carol.

MS. KRAMER: Iím trying to diagram this for myself, and I hope somebody will tell me where Iím wrong if Iím wrong on this. If we deem the prior consent invalid and say you need to go back and get consent, if the person is still alive, either theyíre going to give it or theyíre not going to give it, so youíre going to get it or not get it. If the person is not available so that you can even try to get the consent, then thatís when you would end up stripping the identifiability, right?

DR. MESLIN: No. You canít use the sample.

MS. KRAMER: Whatóyou canít use it? You canít use it; you canít strip it? I thought that you could. I thought thatís what you were saying. You could then strip the identifiability and use it as unidentified.

DR. MESLIN: If you try to get their consent but you canít, then you canít use their sample unless you then have your plan for stripping, which we havenít come to yet. But based on your diagramming, if you require informed consent and you try to recontact the person and they say, "No," then you canít use their sample.

MS. KRAMER: But if theyíre not available.

DR. MESLIN: Then you canít use their sample, because they havenít given you consent.

MS. KRAMER: Even if itís stripped?

DR. MESLIN: Well, if weíre doing it in phases, the answer so far is no. Then weíll decide whether thereís a plan foró

MS. KRAMER: Nonetheless, could not a repository supply to the researchers those samples along with the informationópertinent information from the medical records in a stripped fashion for use in unidentifiable research?

DR. MESLIN: So far, yes.

MS. KRAMER: But it could be provided. Is that correct?

DR. MESLIN: Yes.

DR. GREIDER: Itís not within one protocol, right? Itís not like some of them consent, but some of them donít and theyíre stripped. Thereís a differentóyouíd then go back and you strip all of them and the entire research with stripped samples. Youíre not going to have a mix of some stripped and some not stripped. Right? It puts you in a different box than that last....

MS. KRAMER: Iím trying toóyou know, I guess Iím trying to get a handle on this in terms of youíve got all this tissue thatís archived. Some of it goes back a hundred years, eighty years, fifty years, forty years. You can make the presumption that a lot of those people are no longer alive and that therefore under no circumstances would you be able to get consent from them anyway. You can use it, but itís stripped?

DR. GREIDER: No, no, no! You can use it with an old identifier. Once theyíre dead, theyíre not considered human subjects.

DR. SHAPIRO: Carol and then Bernie.

DR. GREIDER: I want to get back to this issue that we were discussing. We had a little bit of a discussion here, which started with Steveís statement that if what Alta had proposed, which is setting the moral standard high, were to be adopted, that a large amount of research on stored samples that are sitting in repositories wonít go forward, and I just want to think through whether we really think that is a true statement or not, and maybe Steve could help meóto give me an example of why you felt that was the case because, first of all, thereís all the previous discussion that we had this morning that a lot of research is going to be done because itís being considered minimal risk. And so a lot of the kinds of studies could go forward, anyway, because it will fit in that category, and so are we really discussing a major issue here or not?

MR. HOLTZMAN: I think that is the right question. All I was saying is so you have to go back and ask, "What now will fall in the category of minimal risk?" You ask to see how broad the bucket is. And if thereís been a tendency to say we should construe risk in a protective sense, because probably in Ericís type of argument that we will want to err on the side of safety, youíre going to have more things that fall in the category of greater than minimal risk.

Now, what Alta suggested as a sort of a counterbalance to that, or when you multiply the level of risk by the probability of risk if you can the lower the probability via confidentiality schemes, encoding schemes, well, then you may still be able to then bring things more back within, but we had a long discussion about how should we construe minimal risk, where we tended to say that in some ordinary language sense, we want to view it in terms of the nature of the risk and separate that conceptually from probability of it occurring. So, Iím just saying you have to bring those matters all together. I canít answer your question, Carol, until I see how we as a Commission came out on every one of these things.

DR. GREIDER: I just wanted to clarify that. Just because we seem to have split into a conversation about this sort of more high-level, philosophical issue, if you will, of individual protection versus research going forward, and I didnít really feel like weíd gotten to that point yet. I wasnít with everyone, really having to make that decision yet at this point with this issue that weíre discussing.

DR. SHAPIRO: Well, let me try to see if I can try to characterize where we are. We are going to have to move forward even as we struggle with this issue. There is the point that Steve made that whatever we decide on this, and whatever we decided on some of the previous ones, at the end of the day we have to look at the system, and it may tell us something which none of the individual components have told us. So, thatís, I think, quite correct; itís absolutely something weíll have to be conscious of. When we have our drafts that weíre ready to send up on the Web, weíll be able to assessóothers will be able to assessówe donít have to resolve that issue. It has to be resolved, but we donít have to resolve it today, and weíll have lots of input on the assessment of that kind of general equilibrium problem, if I could use those particular words. But itís a very important problem.

There is a second issue, which has taken up most of our discussion here, which started out with the issue of whether these general blank checks, as we call them, really amount to anything, and the general consensus of the Committee was, they donít amount to very much, and therefore we need to find some way toóand some appropriate wayóto let IRBs know that they have to think of some additional consent of some kind here thatís going to be required if you want to go ahead. And we have to think that through. Alta made a particular suggestion about how that might be phrased in a general way; that might be very helpful. So, I think what we have to do here is go back and try to rephrase it. I do take it as a sense of the Committee although not a unanimous view of the Committee. The oneóthe blank checkóis not sufficient. And that the presumption ought to be that some form of consent is required hereósome form of additional consent is required here in order to proceed if the other barriers have not been exceeded, if itís more than minimal risk, etc., etc., I donít want to review that long list.

Now, itís my own sense that we will have to be extremely carefulóand this way I think I feel somewhat the way Alex feels. We have to be more careful about giving away an ethical argument for the purpose of not getting in the way of research, than the reverse. Now, hopefully itíll be somewhat balanced. But if weíre going to err anywhere, we have to err on the side of bringing to the fore what we believe to be the important ethical issues. Weíll have all kinds of people telling us what weíre doing wrong. We donít have to worry that no oneís going to notice or that we wonít before we get to our final report have some kind of view as to whether weíve somehow blocked all the benefits that people are going to get from the scientific research, which most of us are committed to one way or another. But I do think that the balance we have to reach here, the perspective we have to have on this, is to bring these other issues to the fore, look at how it impacts our overall scheme, as Steve has pointed out to us, then letísóas the expression goesóput it out there on the Web and see from others who perhaps know more about some of these things than we know. So I think that weíll have to restructure this in some way, but I doówe do have to get pastóthis is a critically important issue. We canít put it away for all time today. So, Iím glad we spent timeómore time than I expected on it. Thatís where I sense weíre going. Bernie....

DR. LO: Iíd like to make a few procedural suggestions. I actually think this is an important discussion, and itís a very important issue that we need to think through, and I completely agree with people who say that we have to look at how our little decisions on each issue add up to sort of a web or system. I guess I would urge us to, as we think about this, to go out of our way to invite people actually working in the field to give us specific examples of studies on existing samples that may be problematic and to help us think through how our suggestions would affect their ability to do the study. They may say, "Youíre absolutely right. We shouldnít be doing this. Itís a bad idea. Thank you for letting us know." But we also need to understand what kinds of studies are going to be much harder to do. I think we need to understand issues like minimal risk. Many of us have pointed out, you know, you can compensate for a tougher definition prior to consent by loosening up your definition of minimal risk and vice versa.

Iíd like to have people give us examples of prior consent forms that they think justify the exception to Altaís presumption. Iíd like scientists to tell us what sorts of sacrifices in particularóscientific sacrifices you would need to make in order toóif youíre going to strip identifiers in order to do the study under the right-hand column. I mean, I think youíre right. We need to put it out there on the Web and see what happens, but we have to ask very specific questions, like weíre really interested in feedback on these particular issues.

DR. SHAPIRO: Thatís certainly a good idea. Larry....

DR. MIIKE: I donít really thinkóIím just recollecting that Dave Cox, Carol, Anne, and Steve said that the real research in this area is longitudinal studies, where youíve just got to go back and back and back and get more information. If that is so, then the great majority of important research in this area, which is beyond minimal risk, has an independent need for getting informed consent, which is that youíre going back and back and back and getting additional information. So, I donít think itís going to be that big a problem if what they tell me about where the important areas of research are going.

DR. SHAPIRO: Thank you. We will try toóhowever our recommendations get articulated, we will try our best to get people who we think might be impacted by them to take a close look at them and let us know if there are issues we havenít seen. Okay. LetísóEric, do you want to take a look at the recommendation that comes to the bottom of page 201, 202?

DR. MESLIN: In effect, the recommendation regarding disclosure, etc., is part and parcel what weíve already been mentioning. This is where Carol and Bette, I think, were going previously. I think the only thing that probably needs saying there is we have laid out a number of options, principally on page 202, and these are a summary of collected options that have emerged from those presentations which the Commission has had from various organizations and individuals. So, we are providing a set of suggestions there for what various consent options might be. And, this is for your consideration, with the exception of "D," by the way, which Haroldís already said something aboutóthe blanket of consentóbut weíll leave it all open on the table.

DR. HANNA: I think itís pretty self-explanatory. These are just, obviously, just as a reminder, this is for research where the waiver of consent has not been granted and where itís deemed that the existing consent form is either nonexistent or is inadequate. So, here are the various options.

MR. HOLTZMAN: A quick question. A lot of these options are phrase in terms of going back to the subject. Theóas opposed to the repository just simply saying, Iíll anonymize it. And therefore itíll no longer be human subject research.

DR. HANNA: Going back to the subject would be explicit intent to either get consent or get dissent, not to go back and get additional information or whatever.

MR. HOLTZMAN: No, I understand that. So, do we have hereóyouíre laying out the options, right? And I donít see an optionómaybe Iím just missing itóin which the investigator of the repository or whatever says, "Iím not going to go back to the subject at all. Iím simply going to anonymize the sample, rendering it unidentifiable." Are we saying thatís not an option?

DR. HANNA: It is an option; it just happens to come later in theóit comes on page 206.

DR. GREIDER: I just have one point of clarificationóI donít want to go into the wording now, but as I read the three lines on 201, 18, 19, and 20, I have a very hard time understanding what they mean. I understand now that you just said what you said, but I donít think it said that in the language used to clarify that. I was very confused by what this is even about.

DR. SHAPIRO: Bernie....

DR. LO: It seems to me that thisóthe discussion on page 202 boldfaced should be very similar toóidentical to the discussion for prospective future collections. And, one thing I would like to see in this section 202 is the option of tiered consent or layered consent. I think just to say, you know, "blanket consent" without some sense that you may consent to some things but not others so faróthatís where a lot of the activityís directed now on the part of researchers and advocacy groups I think, to the extent that that may offer the best solution to a meaningful consent, we ought to play it up here.

DR. SHAPIRO: I agree with that.

DR. MURRAY: Iím just reading this over. A and D, for example, are not mutually exclusive, at least, as I remember it. Itís not either/or. I actually like Bernieís idea of trying to have this parallel, in which case I think it would be most appropriate here to, if we want to instruct the staff to try toóyou know, justóI think youíre very much going in the right direction. Just redraft this a bit and limit our comments at this moment, given the shortage of time, if we have something very central and substantive about this point that we want them to bear in mind as they redraft.

Professor Capron: You would see these as a spectrum in certain ways. The order is really D, A, C, Bóbasically saying, "You donít have to come back to me at all, even with aógive me assurance and Iíll hear if there are results of clinical importance," consenting to the specific protocol, consenting if itís unidentifiable, and saying, "never use it." I agree with Tomówe could say "and/or" at the end between C and B.

MR. HOLTZMAN: I just want to second Bernie, effectively by defining the premises here. Youíre dealing with what is tantamount to a new studyóas if you donít have an existing sample, and maybe thatís the simplest way to say this, as opposed to trying to make sure they mirror each other.

DR. SHAPIRO: Okay. Thereís a hint at the bottom of the next page. I donít know what to call some of these questions that are in our text, which says we may wish to develop more fully discussion on the "special scrutiny" category of research. Letís see how people feel about that. Kathi or Eric, you may want to say something.

DR. HANNA: Well, I think the special scrutiny category kind of resurfaces periodically throughout the chapter. And, again, it might be determined that the existing consent form is applicable; however, for other reasons you think this protocol deserves special scrutiny and therefore you might want toóI mean, again, we getóI donít think weíve defined yet what those other reasons might be beyond concerns about minimal risk or adversely affecting rights and welfare. Itís this kind of vague other category that does it concern potential harms to others, does it implicate groups? There might be a lot of things that fall into that special scrutiny category. So, itís justóspecial scrutiny issues seem to come up every once in a while, so we just highlighted wherever it surfaces again.

DR. SHAPIRO: Alta and Diane.

MS. CHARO: I want to just put on the table one possible way of going about this, but Iím not real sure that itís necessarily the best. Frequently you find guidance to bodies that says, "You got to figure it out yourself because we want you to do whatever was asked that you do," so we have determined that. Whenever you have this kind of groupóand then they give a list that says, "including but limited to," so that you give them freeóyou give them free rein but you also give them concrete samples. And the concrete samples that immediately came to mindóif we were to use a list to get started, to give people concrete ideasóincluded protocols relying on groups made up of specific ethnic, racial, or religious groups; protocols examining the diseases associated with sexual activity; protocols involving reproductive organs and tissue, gametes, embryos, and fetuses; and protocols that are looking at any kind of addictive behavior. And then I put in huge question marks a fifth possible category for the "included but not limited to" list of protocols that are examining mental illness. Keeping in mind the many comments we got about not wanting to overly stigmatize but at the same time recognizing the existence of stigma. Andóthis is a kind of compromiseówe can try to come up with a good definition and try to come up with an exhaustive list.

DR. SHAPIRO: Eric. Excuse meóDiane. I apologize. Youíre next, then Larry, and then Bernie.

DR. SCOTT-JONES: The category of special scrutiny bothers me a bit, although I understand why itís needed. The suggestions that Alta just made were good. It seems to me that one doesnít avoid research because the subject is controversial, and I think that that notion just wonít sit well with most people, that you should avoid research because itís controversial. So I was wondering if maybe in addition to the kinds of things that Alta mentioned, we could say something about past harms from the way research has been done. Iím not sure, but just the notion of special scrutiny because something might be controversial is not the best hook or the best way to get to the goal of this.

DR. SHAPIRO: Okay. Larry.

DR. MIIKE: I understand special scrutiny category to talk about a stronger, more select consent process. Iím afraid what this raises is a specter of our opt-out provision, and the discussion that Dianaís worried about and what our current draft says that opt-out is not related to consent. Well, if weíre going to have an opt-out provision, I think we also have to deal with what do we mean when we opt out, and weíre going to do a special scrutiny of those areas in which weíd want to opt out. So, if we talk about special scrutiny, we unavoidably get into what kinds of things are we going to say need an opt-out provision and what kinds of things are we going to need a more selective consent provision. So, now the two are bound and so I donít know what the dilemma isóI mean, I donít know how to get out of that dilemma. But if weíre going to have an opt-out provision and then a special consent provision, weíre stuck with that dilemma as far as Iím concerned.

DR. SHAPIRO: Okay. Letís go down my list. Bernie...?

DR. LO: I support Altaís approach of giving a "for example," a "but not inclusive" listóand I would also include under there not so much mental illness but behavioral genetics, where there has been past abuses and good evidence from a forthcoming IOM report that the level of research done is pretty sloppy in some instances. And I would follow Dianeís comment about controversial. Itís not just so much that itís controversial, but these are the types of research that we can expect some individuals to have particularly strong objections to participating in. So, itís not just that it may be misused or itís a hot-button political topic, but certain people say, I just donít want my tissueóif I had a choice I would choose not to have my tissue used for that type of research, although I may well allow it to be used for all kinds of other research. So, itís a way of recognizing that autonomous choices, to the extent we can make them meaningful, are even more important in certain types of research involving DNA genetic testing as well as other types of research. And, again, Larryís point that there are lots of different ways to get out of that and the opt-out is only used in a situation where there is sound justification for not doing anything at all. And weíre saying, well we want you to do a little more than that for just the reasons Altaóas Alta was saying beforeówe want to err on the side of protecting people in the sense that they could feel wronged if not outright harmed if their samples were used in certain types of research.

DR. SHAPIRO: I have to confess, I myself have very ambivalent views about this particular special scrutiny category weíre trying to construct here. Itís very convincing in cases that I hear you talk about here. But then I start reminding myself that this isóif I understand our web well enoughóthat this is research which has already satisfied all the rights, welfare, etc., etc. Itís all satisfied. And yet thereís stillóon top of that, somebody somewhere sitting says, "There is in addition something else that doesnít come under rights and welfare, donít come under minimal risk, donít come under one of those things. And we have determined that somehow additional.... I do have an unsettled mind about this. Iím not yet convinced on either side and I find myself in an unfortunate position of agreeing with the last person that talked. Thatís a dangerous sign. So I apologize for interrupting, and Tomó

DR. MURRAY: You threw me with that comment, now. Can I wait to be the last person? I guess on the whole I favor the special scrutiny category, the reasonóthe primary reason being that all the other stuff effectively deals with the individual, harms to the individual, whereas the special scrutiny springs into operation when you talk not about individuals in isolation but rather something about them as members of a group. A group of people is a small group of identifiable people. They areóa number of them have agreed, they donít have any in-principle objection to research of tissues. However, they have a very important origin story they tell about themselves. Theyíve given blanket consentóeach individual hasóand the researcher proposing to do it could in fact threaten that origin. I would like IRBs to say, is that something weíd really want to do without going back to people and saying can we get your consentóthatís a case one can imagine. I think Altaís notion of giving a list is an excellent one. We should preface the list with a statement like Bernieís. It isnít that the research is controversial; itís that research to which people might have objections because of something about the nature of the research or the expected outcome. And then give some examples, delimitedóincluding but not limited to. I think that makes sense. Then we still have to decide if youóif youíve referred it to the IRB for special scrutiny, what do you do with itóshould the IRB do with that? Here we turn the page and Iím not sure we have the only answer on page 204.

DR. SHAPIRO: Okay. Steve, I still have you on my list.

MR. HOLTZMAN: I want to make sure I understand the staffís recommendation. So, we go back two italics before, and we deal with a paradigm case of the sample in the repository where it was gotten under a general consent, right? And I think weíve concluded that that general consentósince we use "gemische," we can use another Yiddish term, the general consent is worth bobkes, right? So we start there okay? So, if the general consent is worth bobkes and youíre in an area where youíve got a reconsent, clearly weíre not recommending in here in this italic, "opt out." So now we go on back to the individual under your next set of italics and weíve gotten from them a general consent? And now the recommendation is to layer on top of that second general consent, as it were, the opt-out as well for special scrutiny. It seems that if you were back getting the general consent the second time, one might have said, "There are various categories of research which you may or may not find objectionable." Did I get it right? Is that what you were saying?

DR. HANNA: Yes. There are two kinds of opt-outs, and we probably shouldnít use the same term for both situations.

DR. SHAPIRO: Okay. Thank you. Alta.

MS. CHARO: On page 204 weíre talking about opt-out in these various senses. I think thereís an entirely distinct situation which the special scrutiny category could be used, and here I want to just reference my lunch-time conversation with Karen Rothenberg from the University of Maryland. We talked about it a lot. Where researchóand thisówe talked about it beforeówhere research is being done in such a way that the source of the sampleóthe individuals out there in the world are totally unidentifiable, but nonetheless the research is being done in a way that might characterize the entire group of people. We have struggled over the question of community and communal effects, and it seems to me that in those situations, opting out is not a realistic possibility as a response because we donít know the individuals are whose samples are there because they are unidentifiable. But there are, nonetheless, other things that can be done, and we did discuss this at the Portland meeting and before. One proposal had been that investigators, although under the current multiple assurances that have been executed generally are not required to go their IRB administrator and ask for a finding that there is no human subject involved. Itís kind of a self-referral thing. And on most multiple assurances, if thereís no human subject involved there is no need to see an IRB. We could recommend that they be encouragedóor some institutions might even want to requireóthat anybody who is dealing with human biological materials or with medical records that describe human beings at least have a conversation with the IRB administrator about whether or not one of these categories is present and that there be conversations about ways that the study design might be changed to minimize the prospect of these kinds of group effects or that the scientific basis for the research be doubly checked. And the whole thing could be done with a very light touch as a way to have some entrée into the question of community consideration, without ever touching on the question of community consent, dissent, mandatory consultation, etc. I mean, thereís a world of this discussion, thatís in our transcripts now, where the special scrutiny of categories would be implicated. But it all begins by saying people who currently have no obligation to be interactive with an IRB system would suddenly be encouraged or required to have at least some minimal contact with the IRB.

DR. SHAPIRO: Okay. I have Bernie, Diane, and Bette. Bernie....

DR. LO: Harold, I want to go back to your comment a couple of rounds ago about your ambivalence about this whole notion of special scrutiny. I wanted to ask a couple of questions, really directed to all of us, as what the grounds of that ambivalence and uncertainty are. First, is there a sense that weíre maybe not going far enough, that when we say "special scrutiny" weíre obviously concerned and have we pegged the level of concern too lowóthat we really should be saying, "This is in the category of full informed consent, not this sort of opt-out middle ground." I thinkóDiane articulated that a little while ago in another context. I think we need to think that through. I mean, weíre proposing this as a middle position, and part of the discomfort is that maybe it really should be bumped up to a higher category.

Secondly, is the source of our ambivalence and dissatisfaction that we canít really articulate clearly yet what it is about all these things that makes us group it together and separate it out from an awful lot of other studies? And is it our concern that somehow weíre missing something we should be able to articulate more clearly; we just havenít gotten it yet?

And third, I guess, is to suggest a way of looking at this that any time weíre designing recommendations for a very complicated subject with a lot of interweaving parts of the web, we should be humble and say that weíre going to miss some things or some things are going to fall through the cracks. And this goes beyond the "any time you have rules and guidelines there are going to be exceptions," that there are certain situations where we have this instinctive sense we may be even more likely to need an exception in that situation than just...and weíre just trying to highlight things for IRBs.

Iím very concerned throughout both these reports that we are giving IRBs a lot of new heavy responsibility. I think someoneís got to do it and theyíre probably the best people to do it. Butóitís the background. A lot of concern that IRBs now are stretched too thin, donít have the resources, are overwhelmed; are undertrained; donít understand; etc., etc. And so I thinkóI mean, thatís a whole issue in and of itself. I think anything we can do to really help IRBs in specific terms to look for caution areas or for danger spotsóI think would be useful. So, thatís what I see this as being, saying that these are particular areas where you want to try to be a little bit more careful all the time, because though youíre trying your best to be careful all the time, because this is where the next trouble spot might come up. I think itís important to try and understand why weíre uncomfortable with this.

DR. SHAPIRO: Well, first of all I wouldnít want to say that we are uncomfortable. I tried to say I was uncomfortable. Iím not sure that anybody else besides me is uncomfortable on this, but Iíd be glad to respond to the very helpful framework youíve laid out.

It was not my concern that we hadnít set the bar high enough and so on, nor was it my concern thatónor is my concernóthat we might miss something, which we certainly will no matter how long we work. Life goes on and there are things that weíll miss.

What concerned me at times concerns me since I am ambivalent about thisóis that who it is that decides whatís special, and what set of forces does that respond to? And when you lift this issue of consideration up to some relatively central organization, like an IRB on a university campus, it responds to all kinds of forces up there. And itís trying to think that through in my mind as to how that would play out over time on issuesóall the examples youíve given are controversial to somebody. There may be other examples, but I think thatís why thereís some concern. Thatís what was in the back of my mind that I was trying to struggle with. That was really where my ambivalence came from.

Alexóexactly on this issue? Iíll have to go back to Diane in a minute.

Professor Capron: It seems to me actually that one of the arguments thatís long been made for IRBs is some notion of localized reflection of a community senseóthe notion of special scrutiny with some examples given or some categories to think about, but basically loading this onto the IRB. Otherwise, our recommendations about the IRBsóstuff like the old line about the man who ran a discount store and said, "Well, I lose money on everything but I make it up in volume," and weíre justówe already know the problems in IRBs. It doesnít make sense. But here, if there is some reflection of what this community in some sense might think of and then another IRB wouldnít regard that as a category of special scrutiny. That doesnít bother me too much. What I wonder about is what are the things that we are thinking about that donít amount to an adverse effect on a personís rights or welfare but which do fall into a category where something beyond the waiver of consent, or if youíve gotten consent something beyond just that consent and going back to them makes sense. And it does seem to me that beyond the group effects, the notion that some people object to categories of research or types of research results, even if their own direct rights or welfare are not implicated does make some sense. I think we sort of capture a little bit of that withinó. And as I said, Iím not bothered here by the fact that IRBs are going to react differently. This isnít being done out of OPRR; itís being done at the local level.

DR. SHAPIRO: Okay, Eric. And Diane and Bette are waiting patiently.

DR. MESLIN: Very quicklyóone of the issues staff had considered in putting this together but did not make its way into the draft comes up in the regulations at 46-111, section 2, and Iíll just read it quickly. "The IRB should not consider possible long-range effects that will apply knowledge gained in the research, for example, the possible effects of research on public policy as among those research risks that fall within the purview of its responsibility." Itís a rarely discussed provision of the regulations and we have not had a conversation with OPRR about this and we obviously could. But in light of much of the knowledge that we have been hearing that results from the use of genetic information, this was an opportunity for us to think about types of research where the knowledge generated would not be of particular concern to that individual but might have a long-range effect on the insurance policy or employment policy, or the like, and if itís true that IRBs are prohibited from considering underójust to remind you again 46-111.a.2 on page 8 if youíre looking in the back of your regulations in our guidebook, you will see that language. So, we might wantóyou might ask us to consider that in more detail.

DR. HANNA: Just one point of clarification is that in discussions with OPRR, they said that an IRB cannot disapprove a study on that basis. However, they can consider those issues in their deliberations.

Professor Capron: This is notóthis is the part of the regulation that does not relate to what weíre looking at. This is the weighing of benefits and risks of the research. Weíre dealing with the rights and welfare of the subject. And itís possible to say that the IRB says that a subject hasómay have reasons means to object that do not rise to the level where their consent will be required, but where enough extra scrutiny is deserving that they ought to be notified that research is going on and give them opportunity to opt out.

DR. SHAPIRO: Okay, I think we want to go Diane and Bette now without interruption from anyone else, including myself.

DR. SCOTT-JONES: I tried to think of language that would be better for this section, and I believe that certainly "controversial" should not be used because scientific controversies are what research is about. And so to use that term is inappropriate, and I think that this section might be made more explicit regarding the concerns that actually underlie it because I think the language does say that, you know, thereís behavioral genetics protocols or research where the subject matter is particularly controversial. I think that if we want to keep this section, it needs to be more straightforward in what is meant, and some of the things that I thought of that might possibly be met would be studiesóand this is not consistent with what Eric just read to you from the regulationsóthat is that studies that not only address scientific concerns but might be seen as bearing on social and political choices in society. I think we should spell it out if thatís what the issue is there. Also I think we should use language of the kind that Bernie mentionedófor example, referring to an individualóreferring to the issue of choice, respecting the choice of people in society, and I think also if some of this has to do with race in our society, that we should spell that out. And I just recently saw a series of articles in the American Journal of Public Health that says that perhaps we shouldnít use race at all in medical or biomedical research. But at any rate I think that the special scrutiny category has importanceóbut we need to do a better job of it than is here and work on specific language that could be used.

DR. SHAPIRO: Bette.

MS. KRAMER: My concern was that what seems to be the problem is the whole additional category, and Iím wondering if in examining the kinds of things that we feel are raised to that category of special scrutiny might have particular relevanceóif those concerns might be captured in consideration of the rights and welfare when that comes up.

DR. SHAPIRO: I thinkóas Iíve understood it (and Iíve asked the Commissioners here to correct me)óthat what those are people are concerned about are primarily issues that go beyond the individual. They may have trivial effects on a single individual but may be some in other way important to a group.

Professor Capron: Another category would be particular belief of the individual. For example, in behavioral genetics or abortion research or somethingóI mean, there are categories.

MS. CHARO: I think Diane is absolutely right that it is not about political controversy and that that gets us down a very dangerous road. I do think what it might be about is some degree of courtesy. Some degree of courtesy for people who would like not to be complicit with a particular research agenda, whether because they feel like it tars some group that they care about or because it implicates a political belief that they feel strongly or for any other reason and that all weíre doing is struggling to give our best guess of those situations in which there might people who would say, "Itís not about me and the harm to me; itís about my willingness to be complicit." And thatís always, I think, also a little bit to Rhetaughís concerns about stripping of identifiers, thatís also part of that discussion. And maybe with that as a kind of the dominant thought weíll be able to come up with language thatís not off-kilter the way weíve been struggling with it.

DR. SHAPIRO: Iím going to appoint a special privilege only to Jim since he hasnít said a word yet today, and then we have a guest here. We really must take a short break and then give our attention to our guest.

DR. CHILDRESS: It strikes me, hearing the discussion, that part of the difficulty may be calling this a special scrutiny category because itís not carefully scrutinizing the research in terms of evaluating risk and benefits, but rather offering certain kinds of opportunities for individuals to make some choices which might be symbolically significant. It might deal with their views about the long-term consequences, but we called it something else. And I donít have a proposal. We might get away from some of the issues that arise in trying to think about it.

Professor Capron: Page 189 says it might be a reason for saying that something is greater than minimal risk, so it goes beyond individual consent.

DR. SHAPIRO: We will have to wind up this discussionófurther discussion by this particular report. By returning to it weíll have to squeeze some time tomorrow into itóinto our schedule to return to this for half an hour or 45 minutes. I donít want to take any further time this afternoon. The approvalóif thereís no objection weíll take, hopefully, a very short breakóhopefully itís about five minutesóand then turn to our guest C.K. Gunsalus, who is here today. Sheís the Associate Provost of the University of Illinois; thereís a paper we have here. Weíve seen a draft before. And Iím very grateful that she has taken time to be here. So, later weíll turn the agenda around. Weíll take the human subjects and project research plan and do that last this afternoon and weíll deal with the issue of standard models for human subjects oversight immediately at the end of our break. So please, five minutes, because weíll need the extra time.

DR. SHAPIRO: As Iíve told you before, weíre going to make a number of changes in our agenda. First of all, Iíve taken the unilateral action of deciding that we will try to start as close to 8 oíclock tomorrow as we can to see if we can squeeze in a little extra time. I guess this afternoon, as I said before, weíre going to move directly to the item "Standard Models for Human Subjects Oversight," for which we are very fortunate to have a paper from C.K. Gunsalusóthis is the paper here. Everyoneís had that at their place today. And, fortunately for us, Ms. Gunsalus, who is Associate Provost at the University of Illinois, was willing to come here to make a presentation and answer our questions. We are very grateful to you for the work itself and for your willingness to be here this afternoon. Thank you very much, and let me turn the floor over to you.

STANDARD MODELS FOR HUMAN SUBJECTS OVERSIGHT

MS. GUNSALUS: Well, thank you for having me. Itís a pleasure to be here. I think the last time I spoke with you I introduced myself by telling you that I come from the "train wreck" school of professional ethics. I mostly deal with the lapses and aftermath of problems, which leads to my personal interest in effective and credible self-regulation, which is at the root of most of what Iíve done and most of what Iíve talked about with you here. Iím a very applied person; Iím not a very theoreticalóI donít have a very theoretical approach, so a lot of what Iíve done in the paper and a lot of what I talk about today are very pragmatic sort of considerations.

The dilemma that I think youíre dealing with in human subject protection models is common to many forms of self-regulation, which is that it tends to become routine and to drift a little in the absence of scandal. And then you have scandal and people immediately stand up and thereís a lot of hoo-ha and then the scandal fades and it tends to start drifting again. Meantimes, while all this drift is going on, times and technology and states of research change and standards of accountability change, and thatís what leads to the dilemma. So I used as a starting place, actually, the resolution that you passed in May of 1997 that "no person in the United States should be enrolled in research without the twin protections of informed consent by an authorized person and independent review of the risks and benefits of the research." There is an interesting restatement of that, if we could go to the next one. The next day President Clinton in a commencement address made a statement that "we must never allow our citizens to unwitting guinea pigs in scientific experiments that put them at risk without their consent and full knowledge." Itís kind of an interesting restatement because it focuses on "without their consent" and it talks about risk but it doesnít talk about independent review, which I think is a pretty interesting sort of twist on how these things happen.

As I thought about these two statements, but particularly your resolution, the thing that kept coming back to me as I thought about the issues of expanding Federal oversight, which is really where my charge startedówith expanding Federal oversight, I couldnít ever get to the expanding part when it was go glaringly clear to me that, even in our present system, the twin protections that your resolution talks about are just not always available to human subjects. And it just was a huge stumbling block for me. Every time I got to thinking about the expansion part, I kept getting to the fact that I donít see how itís actually responsible to say, "Well, weíre not doing so hot with what weíre already doing, but letís expand and do more." I couldnít get there. So where I kept coming back to is looking at the shortcomings in our actual application before you get to the areas that we donít cover at all. I think we have...oh yes, the present regulationsóthis isnít on the listóbut the present regulations, just as a reminder for people who perhaps are not as immersed as you are, is that we actually cover right now three areas of human subject research, in marked contrast to non-human animals. There are only three kinds of research that we coveróthat thatís funded or conducted by an agency subscribing to the Common Rule, things that are regulated by the FDA, and research thatís covered by a voluntary assurance negotiated with OPRR. We know that there are a lot of problems with this system, and I just excerpted a few of them here. The OTA congressional testimony by Dr. Nishimi in 1994 talks about the current system, while though changing incrementally, has fallen short of implementing or did not implement at all recommendations made between 1973 and 1982 by an ad hoc congressional committee of the Department of Health, Education, and Welfare, a congressional report, and two congressionally mandated commissions. I actually think this latter point is one that has serious implications for your work, because, if you are going to put in all this time and energy and effort at writing reports and making recommendations, I think it behooves you to think carefully about what are the strategies that will maximize actual implementation rather than falling into this category of recommendations that never get implemented. And I would be fairly concerned about that in your shoes. And at the end of my paper I made a specific suggestion in that I think the more specific you are in your recommendations in terms of statutory implementation, in terms of it should be this way, it should be in red ink, it should be Thursday afternoons, the better off I think youíre going to be rather than saying "Think good thoughts and honor your mothers."

I pulled out one other finding from 1995 from the Advisory Committee on Human Radiation Experiment Findings, which talks about the shortcomings in current Federal agencies. In most Federal agencies current mechanisms of oversight of research involving human subjects are limited to audits for cause and reviews of paperwork requirements. These strategies do not provide a sufficient basis for assuring that the present oversight system is working satisfactorily.

So my effort resulted in the following recommendations, which Iíve just summarized here for you. There are really three recommendations. Thereís four bullets, but thereís three recommendations. One is to start by focusing on correcting the identified deficiencies. I donít see credibly how you can expand the scope of regulation if we canít do our present job adequately. And furthermore, since we have so much documentation about how weíre not doing it as well as weíd like to be doing. The present system has many, many strengths. The present system does many things well. But we have a plethora of documentation talking about the places it falls short. I think thatís an important starting place.

Unify Federal oversight in one office or agency. I spend a fair amount of time in the paper talking about that, and Iíll talk a little bit about that today. Use existing offices as a model. This comes from the pragmatism of my life, which is that I just donít think that weíre likely to get enough sustained attention to invent an entire new model, so Iím saying letís take a model that exists and adapt it. And there are some interesting ones out there, I think.

And then expand regulation incrementally rather than globally. Iíve suggested essentially a "known risks" or "known dangers" approach. Take places that we know there are problems and use a cost-benefit model and expand and use those to expand regulations to places that we know humans face more than minimal risk and deal with those.

I told you that I really kept getting hung up on the identified deficiencies. And you know, in addition to these three that Iíve summarized, just looking from 1995 forward, you have the Advisory Committee on Human Radiation Experiments; you have the General Accounting Office review; you have the HHS Inspector General reports. None of these are trivial pieces of work, and I thinkóyou have the reports from Drs. Fletcher and McCarthy talking about some fairly significant problems in the current system. You have the interagency working group that preceded the AdvisoryóI mean it follows the Advisory CommitteeóI mean it goes back. You have the 1983 Presidential Commission, many of whose recommendations were, as best I can tell, never implemented in this area. So I think the one thing that youíre going to find at root of all this is a question of resources, and that comes back again to this issue of how do issues of self-regulation arise and present themselves. And the way that they present themselves is that theyíre scandal-driven. And so then in the absence of an immediate and burning scandal, the resources and the energy and the attention tend to drift away, and so I think youíd better think about that structurally when you go to resolving these problems because, unless the structure is built properly, it is inevitable that, once the scandal isnít absorbing peopleís attention or some different scandal is absorbing peopleís attention, the system is going to drift again. So I think thatís an important issue.

I summarized for you some of the identified deficiencies in the systemóthe effectiveness and IRB oversight; the Inspector General reports; the GAO reports. All of them talk about aspects of the current system, and they really focus issues on the mismatch of effort for result in a lot of cases. The message that you can take away from a lot of these studies is less paperwork, less procedure for less-than-minimal risk. Put the energy where the risks really are. But the effectiveness of IRB oversight, there have been changes in the environment that have dramatically affected itóthe increase in clinical trials, multiple-site clinical trials, etc.

Inconsistency across the government. It strikes me that this is a place you can really make a difference. There is enough impetus out there that with your added weight it strikes me that this is a place that you could actually just get the problem taken care of. Weíre not that far off. You have the Presidential Executive Order to build on. You have your own staff work that I think is probably, when that survey is complete, will be pretty compelling proof. You have...you know, we have data from 1983, from 1991, from 1994, and your own staff work. There will be a pretty compelling case that thereís really no excuse that we have 17 Federal agencies that subscribe to the Common Rule, more or less, and implement it more or less, and at least 23 or 24 Federal agencies that conduct themselves research as well as sponsor it. Hello!

The regulatory burden is again this issue that is a recurring theme in terms of trying to do a better job of matching the effort with the paperwork and the procedural burden that we put on people. There is a significant regulatory burden, I can tell you, from the institutional perspective. Itís worth it in almost every case. But there are some cases where the degree of the burden is simply disproportionate to the gain and it doesnít help breed respect and credibility for the system when we ask people to put in empty work. The ACHRE report estimates that 40 to 50 percent of human subjects research that it surveyed involved less than minimal risk to the subjects. Now I donít know if that number extrapolates, but itís sure a pretty interesting starting point for discussion in thinking about where should the regulatory burden and focus and where should our energies and really precious resources of time go, because itís the time of the investigators, of the subjects, of the review boards, of the people who have to review the review boards. Where should those resources be devoted?

Weaknesses in the present Federal structure. I think that those topics are really fairly definitively covered from the OIG report, the Fletcher, the McCarthy papers, and the GAO, all of whom talked about this structural deficiency of the location of OPRR and NIH. I understand that thatís getting some attention right now. Again, itís an issue that maybe we could just solve once and for all, particularly if you weigh in on it.

Resource and commitment issues. I really think these are the major issues. I really think that this is where your weight needs to go because the glaring problem in a lot of these casesóaside from some misdevotion of resources in terms of the procedural heaviness on places that perhaps donít have a cost-benefitóbut the real issue is how serious are we about protecting human subjects who are at risk? And if weíre really serious about it, then weíd better think more seriously about the resources we devote to it, because giving it lip service and not providing the support, either in the Federal apparatus or in the educational support for the IRBs and for investigatorsóthis is never going to go anywhere. And so unless this resource issue is grappled with fairly directly, I think that youíre doomed for another report that sits on the shelf. And so I donít think that your work deserves that. I hope you donít feel that way. And so I hope that this resource issue will sort of front and center when you get to thinking about these issues, get very serious attention.

And then, finally, we get to the unregulated activities, which was again where I was supposed to start. Iím sorry; I just couldnít get there with all these other issues in my way. So Iím recommending that you correct the identified deficiencies, which is...and Iíve again sort of laid out some of the issues that recur over and over and over. Streamline the assurance system. Focus resources on areas of greatest risk. Require full adherence to the Common Rule. Unify government oversight. Assure independence of the government monitoring function. Provide adequate resourcesóthis is a theme. And then finally, expand the regulatory scope. So the themes for the change that Iíve talked about in the work that Iíve done for you look...are really threefold I think. One is achieving consistency. We can do better. We ought to do better. I hope weíre better than how weíre doing right now. Unify Federal oversight. And then expand regulation incrementally.

For achieving consistency I think there are really four issues. Iíve zoomed past the next one and Iím on the slide that has "Achieve Consistency" at the very top. Adherence to the Common Rule, absolute minimum. Unify government oversight. Independence of the monitoring function. Adequacy of resources. These are all issues that Iíve talked about. I just tried to group them under the heading of achieve consistency.

Under the heading of "Unify Federal Oversight"óthis issue of reducing the burden on regulated entities to focus resources more effectively I think is a very serious one, and I think itís one where some thoughtful consideration could yield real gain without any particular cost. There are real costs in some of the things that I think youíre going to need to do. But by a better balancing and better focus and better devotion of energy that already exists I think you could find significant gain. Streamlining procedures is part of that. Thereís been a lot of talk about streamlining procedures. OIG reports talk about reengineering the process. The GAO report talks about it. Some of the Presidential Commission issues talked about it in 1983. Improving accountability. This is again back to the issue not only of IRB effectiveness, but of how we use our own existing Federal resources. I think there probably need to be more Federal resources, but we can improve accountability if we use what we are already devoting better and thereby I think build a better case for more.

Strengthen educational efforts. I really think in a system of professional self-regulation or self-regulation of any form, the educational efforts are the absolute cornerstone. And in a system that is as full of transients as the research system isóyou have graduate students, you have investigatorsóit calls for serious ongoing educational effortsófor the investigators, which the OIG, the ACHRE talked about, and for the IRBs themselves. Thereís two different categories of educational efforts required, and theyíre both very important. And I donít think you can substitute one for the other. I think you have to have both, because for self-regulation to work, for the whole system to work, you have to be able to tell people what are the principles upon which it rests, why is it important, and how does it apply to them, because people are always so involved with their own very important work, which is how we get useful things done in this world, is because people have a form of monomania about this really interesting, neat thing that they personally are doing, you have to be able to penetrate that enough to say, "Yoo-hoo. Thereís a bigger picture and itís worth your energy to pay attention to it because here are the ethical principles around which we have consensus and to which we all subscribe. Hereís why it matters to you." I personally thinkóand again this is a pragmatic conclusion that I came toóis that maintaining separate FDA and OPRR jurisdiction seems to me the most sensible way to go. Youíve got two entire separate statutory operating instructions. You have two entire constituencies. You have different goals, really. So I think pragmatically, rather than trying to go at redoing the whole thing and change the statutory authority and all those things, my recommendation would be to consider maintaining their separate jurisdiction but really putting on a lot of pressure to improve their already good working relationships and coordination. I recommend a Memorandum of Understanding that lays out more explicitly. And for example, if you look at some of the recommendations of the General Accounting Office and the HHS Inspector General, it strikes me again that thereís real gain to be had in a Memorandum of Understanding between the two that looks at, for example, who has responsibility for the effectiveness of the IRBís operation. Who has responsibility for the human subjects, as opposed to who has responsibility for the validity and efficacy of the results of the trial. So I think thereís gains to be had there.

There may be other settings that youíre going to need to explore where specialized provisions may be helpful. I donít know enough about it, but it strikes me that there may be similar specialized issues with, for example, things that the Centers for Disease Control does; some of the things that the Department of Energy does. I donít know enough about them, but it strikes me that those are areas that somebody needs to look at with a little bit more care.

Finally, Iíve said about unified Federal oversight that there are some interesting existing models, and I proposed three. And the reason that I selected these three, aside from the fact that they were the best ones I found, is that they each have an element that I think commends itself to your attention. The Office of Government Ethics distributed model is very intriguing, where they have designated Agency Ethics Officers in each Federal agency with joint reporting lines, so they achieve work with the people inside the agencies and they also achieve a consistency of policy interpretation through the educational mechanism, through the reporting mechanism, and through the connection in the networks that they build of the government ethics community. Itís a very interesting model, and I think you could extend it beyond the government to include the regulated entities. It wouldnít just be an intra-government kind of function. So I think thereís a lot to commend it there, and Iím very grateful to Stuart Gilman of the Office of Government Ethics, who spent a good deal of time talking with me about how they function and how they work. Thereís a lot here, I think, that you might look at with some care.

The Office of the Special Counsel is interesting, I think, particularly for how it works inside the government. And then the Nuclear Regulatory Commissionóalthough the scale is sort of, the dimension that weíre talking about it off the scale in terms of all these other things weíre talking about. The model part of it there that I think is particularly useful for you is how it works with a commission and then the whole agency itself. There have been many observations about the fact that the United States is one of the few places that doesnít have a standing bioethics commission. Even you have a limited term. Yet another commission with a limited term. So there is no standing body. Thereís been a lot of conversation about that in terms of how do we deal with those issues. The Nuclear Regulatory Commission, I think, raises some issues that bear consideration for you in that arena.

I think youíre going to need to commission some additional research. And again this goes back to the issue of all the reports that are sitting on the shelf out there. I think the more specific you can be, the more likely you are to make headway and not have wasted some of this effort. And so I think that you might consider commissioning some additional research. I simply donít have the expertise about the government model and inside, working in the government in the political environment and bureaucratic environment is beyond me. But I think, to be really effective, youíre going to need some really top-quality advice there.

Okay. Finally, on my last slide Iím going to tell you about the task I was actually given. It really did take me this long to get to it, and Iíve listed some examples on pages 23 and 24 of the paper that you have, where Iíve suggested some places to start for known risks, places that we know there is unregulated research or at least research over which there is no authority to investigate or assist the subjects when they complain. What we say to subjects in these cases is, "Gosh. I guess youíd better go see a lawyer." We ought to be better than this, folks. I mean, this is just not a sensible or morally appropriate environment, I donít think. And so I listed a set of examples for you. I think that there areóyou know, the unapproved invasive procedures is a fairly obvious area of a clear known risk to human subjects that I think would provide a basis for saying, "Thereís a risk and weíre going to take jurisdiction." Genetic tests. Youíve spent a lot of time on issues related to that. Problem reports. It strikes me that there could be developed an appropriate regulatory or statutory basis for when you can document that there are a sufficient critical mass of people at risk that the government would take jurisdiction. But I think that a cost-benefit analysis, where you document that there are problems and people who are at more than minimal risk, is the way to expand regulation, not by sort of globally doing it and then trying to back off of it.

I spend some time in the paper talking about the issues, the pragmatic issues involved. If you say, "Weíre going to treat humans in a corollary way to non-human animals," as the Animal Welfare Act does, immediately you run into the issue about the definition of research, which was by design from the original National Commission in the 1970s quite broad. I think I do have a slide there at the very end that has what the definition of research is; itís the last slide. Itís also not on the handout. I thought maybe it might be useful at the last minute. Itís a very broad definition, and it is intentionally broad. And I think that its durability over these decades speaks to the wisdom of the breadth of this definition. Then there are the exemption categories that were developed with much pain, and again, taking practically 10 years to develop. So one approach would be to take global jurisdiction over humans in a way corollary to animals. It is ironic that we provide more protection to some animals than to humans in this country, but there are also some reasons when you get down to it. So you could take global jurisdiction and then try to back out by building new exemption categories and things like that. I wonder if the time and effort that that entails is not ultimately more costly than taking the known cost-benefits, so documented risks and then you go forward. Because what worries me a great deal is it is just not difficult at all to envision the creation of an extensive, possibly profit-driven, rubber-stamping review system that dilutes attention to the really serious ethical issues. You could have a lot of people spending a lot of time, moving a lot of paper around. And you could have really good documentation and not much substantive ethical consideration of the really hard issues. And so I personally thinkóand my recommendation to you and where I ended up after all of this sort of extended musing on your behalfówas to focus on the places that we can document that there are people at risk and focus the energies on that in several quite concentrated ways: streamline our system so that weíre doing a better job of devoting the resources we have. Devote the additional resources that it takes to do the appropriate education. And then make it very plain that what weíre going to protect and why are human subjects at risk. So thatís a summary of what Iíve done for you.

DR. SHAPIRO: Thank you very, very much. I think this has been very helpful. Some of you...colleagues, questions they may have.

Professor Capron: Two questions. The first is that you recommend as an avenue for asserting jurisdiction for this broader review of research that is not now covered by the Federal regulations, an interpretation of the 1974 Research Act. And I think you are correct in suggesting that we return to legal counsel for the various departments, particularly for HHS, and ask them about that. But have you given consideration as to whether or not, as so interpreted, that statute would run into problems comparable to the problems the Federal government faced in the Grove City case, involving whether or not an institution could be forced to adjust the way it did businessóI think an educational institution in that case, City Collegeóbecause it took certain categories of Federal funds not related to the activity that the government was trying to have it change?

MS. GUNSALUS: I acknowledge that those problems exist. And Iím not sure that itís particularly useful to you to adhere to my own philosophical basis of "There is no free lunch." But there are some serious legal problems there. I think that HHS has some very competent folks, and I think you could get some useful advice. My instinct is, both from the perspective of the regulated andóIím sorry, Alta, a lawyerómy instinct is that thereís some room to be gained here. And, again, if thereís some principled focus and itís accompanied by some streamlining of the regulatory burden, I think you could strike a reasonable middle ground.

Professor Capron: Well, that gets to the second question. When we discussed this topicóand we agreed that we were going to have papers sort of pro and con from people with a government perspective and we ended up with the Fletcher and McCarthy papersóthe suggestion was made by David Cox that we commission yet a third paper, which was the one that youíre doing, because David was speculating that, in fact, many people in the nongovernmentally funded research sphere would be happy to have this kind of oversight because it would give the sponsors greater assurance that the research was something that they wouldnít be embarrassed by and because many of the researchers would be happy to do it because theyíre also people who do governmental-sponsored research anyway. There were just any number of reasons. That I donít think comes out in the report, and I wonder whether, among the avenues that you looked at but maybe havenít fully reported on here, was any touching base with relevant industry groups, I guess when the project was originally described, which is not to criticize the project that you didóand I actually agree with the two-thirds of the paper that you say is basically crepatory to the topic. I think youíre right. We can hardly recommend imposing a system on the private sector if we canít say itís well implemented for the public sector. But do you have any avenues for giving us that information? The Pharmaceutical Manufacturers Associationódid you find out what they think...?

MS. GUNSALUS: I talked to a fair number of people along the way, and the general response was in theory this sounds pretty interesting. Show me something specific and weíll react. Well, I wasnít there. I am going to throw this back to you and say I think youíre going to have to refine a little more which direction youíre going to go or else the response is going to be equally amorphous.

Professor Capron: Well, the way that youíre talking about here, the major decision point is whether to identify particular categories of research and say they ought to be included, or the other, which is to say all research, but of course we donít really care too much about this trivial stuff. The trivial stuff supposedly already off the table because it either doesnít involve any risk to human subjects or some other reason.

MS. GUNSALUS: Well, talk to somebody in an IRB thatís had to deal with the FDA. Iím not sure they all feel that way.

Professor Capron: But the FDA is already dealing with a large part of the private research entities. I guess....

MS. GUNSALUS: Iím just telling you that the regulatory burden and getting the trivial stuff of the table, Iím not sure you will find uniform acceptance out in the field that weíve achieved that in any meaningful degree.

Professor Capron: It just seems to me that youíre evaluating examples of things happening in a wide variety of settingsóin vitro clinics, dentistís office, doctorís office, psychotherapistís office, which donít have any particular unifying aspect. I mean, they donít all involve general anesthetics, or they donít all involve surgery.

MS. GUNSALUS: No. Thatís why I went back to try to build some categories that I thought represented starting places for consideration. I think this issue of expanding the scope of regulation isóthe more I got into it, the bigger a topic it appeared to me, which is why I came back to this issue of places you can construct a really compelling governmental interest.

Professor Capron: But your example on page 25 says, "Other research activities that could present risk to human subjects include health services research and internal evaluation research."

MS. GUNSALUS: That was there just to illustrate the breadth of this. If you go back to all research involving humans, there are arguably some forms of journalism that would be encompassed, and new exemptions would be required, I am convinced. And the process of developing exemptions is not a pretty process, not is it an expeditious process.

Professor Capron: But you are saying, just so that I understand your oral presentation, you are saying here that these are examples of things that a well-factored rule might encompass, might well encompass, because they involve known risks.

MS. GUNSALUS: Well, I personally think that what should happen...I mean, if I get to be king and say itís this way, I would define a fairly small number to begin withóthe invasive procedures, the genetic tests. I mean, I would start there. And I would accompany that with the other reforms and show that we can do a credible and effective job and do it well and build incrementally. I wouldnít start out by encompassing very large areas that Iím not convinced we can handle credibly and effectively.

DR. LO: I want to thank you for your talk and I appreciate your urging us to think hard about the implementation of our recommendations and not to have a report that sits on the shelf and to focus on the serious problems and cost-effective revenues and intervention. I want to ask your thoughts about something thatís troubled me as Iíve read, what, two draft reports. But I think we have tried to look at big problem areas involvingósubjects who may lack decisionmaking capacity and DNA testing are two examples. One of the themes that one gets out of our recommendations is that we are calling on IRBs to take on the responsibility of exercising their discretion to add in additional safeguards, which are not strictly required by the current regulations but are consistent with them and would promote greater protection of subjects. This, in a context of numerous reports that youíve documented, our concerns are these arenít doing well what theyíre now supposed to be doing. In fact, theyíre getting eaten up by too many protocols, limited resources, inadequate education, etc., etc., etc. Can you give us a candid appraisal of whether you think the approach weíre taking of "letís try and ask the IRB as thoughtful local representatives who are currently charged with providing on-site oversight to do even more." Is that a sensible approach and a cost-effective approach to...?

MS. GUNSALUS: Well, I think it is a sensible approach because my experience is that there are a tremendous number of thoughtful, sincere, deeply caring people who really want to do the right thing. But in order for them to do those tasks, I think youíre going to have to try to clear some of the underbrush of the places that we really do put regulatory burden and try really better to balance the resources, because there really is a finite amount of time and energy and human capital. And I think that our system of local control is inspired in many ways, and I think it has lots to recommend it. But if weóand I think that thatís exactly the sort of issue that you want people to grapple with. But if theyíre busy looking at subsection 9/4.e, subparagraph 4, and not thinking about...you know, what do you really want them to do? Do you want them to give the thoughtful ethical consideration? I think so. Is there a better way to balance getting some of the other stuff done and is there some of the stuff that weíre doing that doesnít need to be done?

DR. SHAPIRO: Thank you, Jim, Larry, and Eric.

DR. CHILDRESS: Thanks very much for that clear and helpful presentation, although I want to press you a bit on exactly why you feel we should not try to extend the system that you do concede has many positive features and virtues. Itís broad...

MS. GUNSALUS: Iím not here to knock the system in general.

DR. CHILDRESS: So why shouldnít we extend that as broadly and comprehensively as possible? And I heard at least three different sorts of things, and let me just press you and see where you stand all over. What really is the critical thing for you? You say, and you said particularly at the beginning, that the system is too flawed as it stands to extend as broadly as we might be thinking about. But it seems to me, if thatís the case, that would also be an argument for not extending it incrementally. That itís an argument for not extending it at all at this point; to fix it. Then you might have a second argumentóand it seemed to me this was presentóthat we shouldnít even have tried to extend it globally because we couldnít do it, it wouldnít be the political will and opportunity to do so. And then a third one would be that, even if we could do it, it simply wouldnít be worth the investment of resources required to have it as globally as we might want it to be.

MS. GUNSALUS: Could I choose "D"?

DR. CHILDRESS: Iím just sort of interested in where you finally stand...?

MS. GUNSALUS: The fundamental reason is I donít think you should extend it globally because I donít think it will work. I mean, thatís the bottom line. And then if I can go back and choose "A," which isóI think what I said in the paper, and I may not have been as clear today as I tried to be in the paperóis that yes, I believe that some expansion is warranted. But I donít think you get to that step until you correct the identified deficiencies first. I think itís a prerequisite. Now, I think we need to get to the expansion, but I donít think that thereís a good, strong ground to stand on for getting there until, in a very clear-sighted way, some of these issues are acknowledged and addressed.

DR. CHILDRESS: I guess thatís where I have the problem is. I think thereís many positive features, as youíve emphasized.

MS. GUNSALUS: I think there are.

DR. CHILDRESS: Then Iím not sure why we shouldnít go ahead and extend those. That is, Iím not sure we have to correct all the flaws in the system. If there are some really positive features that might well...

MS. GUNSALUS:...because I think that more will break it. I think itís the straw that breaks the camelís back. I mean, I think that there is...you know, I have seen IRBs do really magnificent things. I mean, they are neat. The discussions that happen when you get to what you really want the IRB to do are really very impressive and inspiring. How often do IRBs get to have those discussions? And then youíre going to add more? I just donít think itíll work. Now, I offer it for your use and of whatever use it is to you. You may, in your collective wisdom and your work, come to a completely different conclusion. Thatís okay with me.

DR. MIIKE: Let me get it straight first. You want a more focused system than currently is, but then you want to expand it broadly?

MS. GUNSALUS: I want to expand it in targeted, focused ways. Yes.

DR. MIIKE: No, what I mean is to the areas where itís not being used now. Isnít it more a question, though, of the mechanism that we use, because when you set up a formalized process, you must have rules. And I think I could argue that, conceptually, the way that all the things that weíve discussed now is supposed to provide IRBs where itís going to be implemented in the system. A method of filtering out the unimportant from the important. And I think that what youíre saying is that theyíre not doing a very good job of that, that theyíre erring on the side of caution, so they want to review everything.

MS. GUNSALUS: I donít think weíve let them do a very good job of that because of some of the regulatory burden.

DR. MIIKE: Okay. But what Iím saying is that if I look in what is in the administrative rulesóand the legalese asideóitís not a question of saying youíd better review everything. Itís saying, "Here are some ways in which to filter out the things that you donít really have to pay attention to, and here are the areas that you really should. So is itówhat is wrong with the system? If the way that youíre saying is to just focus on some immediate issues. Donít we also then face the problem with, itís your idea of what is an immediate issue, itís your idea whatís a great harm, itís your idea of arbitrarily picking out all of the kinds of experiments that go on. And so how do we get to the point at the beginning?

MS. GUNSALUS: I would refer you toóI think you could spend a pretty instructive couple of hours reading the Presidential Commissionís Report from 1983; the Advisory Committee on Human Radiation Report, particularly chapters 17 and 18, that focus on the flaws with IRBs as they function; the OIG Executive Summary Report, the one thatís called "Institutional Review Boards, a Time for Reform: The Executive Summary." I think that that would give you a really pretty focused picture. I mean, it talks about streamlining the assurance system, which is a very low-cost, very immediate, I think, very high-gain reform you could make tomorrow afternoon. Okay. Government time. Six months from now. But there are, in those reports, there are enough quite explicit, well-based, well documented examples of places that weíve just put the emphasis on the wrong syllable. I donít know if the transcript will pick that up.

DR. CASSELL: I also want to thank you for your presentation, but one aspect of it I think is important to remember, and thatís the pragmatic business of what will in fact make what we want to happen happen? I agree that the IRBs are burdened with regulatory stuff that they donít have to amongst the less-than-minimal-risk proposals that they go back over and over again, send back out to the investigators so that they can come back to them and so forth, in part because thatís what the regulations call for, and in part because you canít underestimate humansí desire to evade responsibility, big stuff. And I would think that one of the things that we could do that would have a big impact, because it would make a grateful nation of IRB members, would be to recommend the cutting way, way back of that kind of burden. I mean, in concrete terms, at the same time as we offered the educational opportunities which you stressed and which weíve talked about here at some length, and that the doing of that would gain us some fans in the IRB system at the same time as you suggest a change in the overarching regulation. I think that those three things alone might be doable. And then we have the issue of extending because weíve got peopleís attention and weíre the "nice guys." And that always helps.

MS. GUNSALUS: And effective. Itís nice to be effective while youíre nice, too. I mean, I really like nice people but I prefer my nice people to be competent and effective at the same time.

DR. CASSELL: If I do something nice, most people think itís effective, and so...

MS. GUNSALUS: Iíll take you up on that some time.

DR. CASSELL: So I think that stress on those in your comments is proper and would be very helpful.

MS. GUNSALUS: Did I leave out the GAO report, by the way, the General Accounting Office Report? Okay. Good. I didnít mean to.

MS. CHARO: Iíd like to turn to a very pragmatic issue...

MS. GUNSALUS: Oh, my favorite.

MS. CHARO:...from your paper which, by the way, was wonderful. It went far beyond the presentation in terms of detail and scope. Your very strong call there and here for NBAC to take up this issue with a high attention to detail and specificity. Youíve mentioned it several times. Now, since at first blush, some of the crucial considerations are going to be things that have to deal with peculiarly governmental concernsóscope of authority of various agencies, the realistic mix of respective certain agencies to take on additional duties or to receive congressional support over the years, and such. I find myself wondering if the reason youíre making this recommendation to us is because we think that this group of people constituted with these purposes in our charter has some peculiar expertise that we can bring to bear on the question of how to implement the ethical commandments that I think youíre leaning us toward. Or whether itís simply out of desperate frustration at years of there being no action on previous reports, you simply turn to this body and say, "Take a shot at it."

MS. GUNSALUS: Could I answer your question "Yes"?

MS. GUNSALUS: I think that you have a lot to offer. Not only do you have your collective expertise and wisdom, you have the moment and you have the resources. I say, "Capitalize on it."

MS. CHARO: You answered my question.

MS. LEVINSON: This morning I was concerned with some of the discussion about being reluctant to attempt to rewrite the regulation, to change the rules in a dramatic way. And I think that that was a laudable attempt to be pragmatic, to think about the concerns that will be attached to a major change in regulations. Having said that, I would like to encourage you to take this recommendation that Tinaís made to think about, to think outside the envelope, to think about where the deficiencies are that was your charge in the Executive Order to consider and advise and make recommendations on the accuracy of the current system. If the system isnít adequate, point to that and be specific. I donít think that you necessarily need to think about as pragmatic concerns as the statutory authorities. Thatís the sort of thing that the regulatory agencies are going to have to consider and you donít. But if you identify the principles and the inadequacies in the current system in addressing those, I think Bernie made a point earlier in considering the capacity report about his discomfort in recommending additional roles for the IRBs when itís already evident that theyíre overstressed and overburdened. If you focus on that and say that they canít possibly take on more, which you would like to recommend, unless the streamlining or other deficiencies are addressed first, I think that that can be heard and implemented.

DR. SHAPIRO: I have a comment. I think itís relevant, I hope itís relevant, to the discussion weíre having here. I have some other questions as well. But probably the single phrase youíve heard most often here now over the last two years is overstressed IRBs. Somehow that comes up in every venue and every problem and so on, and I really have to say that at some important level I donít understand that. I understand that some people think theyíre working too hard. I understand that issue. But itís either because IRBs are doing work they donít need to doójust one of the things you suggestedóthat is, thereís some low-risk material or some totally unnecessary paperwork, and so that we have imposed burdens on them which have no dividends to anybody. And that I understand is a possibility, that maybe we have aspects of the system just completely unproductive of anything that we care about. And if thatís true, of course, we ought to streamline them. I guess thatís what you meant by streamlining.

MS. GUNSALUS: Itís one of the aspects.

DR. SHAPIRO: One of the aspects of streamlining. But thenóand of course I think we can all agreeóto the extent that those dividends are available, we ought to grab them and bank them for some better purpose. I donít think this really gets to be a real benefit. But then thereís the other tension, which has always bothered me, that is overstressed IRBs versus protections we really want. And I donít want us to get...thatís a dangerous territory to be skating on. And soóI mean, Iíd rather the solution to that, if you have attention there, to appoint another IRB. Instead of having one, youíd have two; if youíre going to have two, you can have three. And you worry about their education and so on. But I want usómy own view is I want to be very careful. We do want to eliminate the unproductive work we have.

MS. GUNSALUS: I think thereís three things in what youíve said that it really might be a help to pull them out separately. One is making sure that the IRBs have the tools to do what we really care that they do, and thatís partially an educational function; itís partially a guidance function; itís partially what we assign them to do. One is the point that you bring up, which is how many IRBs do you have? I participated in a site visit with OPRR once at an IRB that, when the entire group was assembled because they were all there for this official function because OPRR was site-visiting them, there must have been 23 or 25 people around the room. And you looked at their agendas and you looked at what they had done, and GAO and that OIG report both point out that if you divide the number of protocols by the amount of time allotted to the meeting, how much time did they give each one? Well, 94.6 seconds. Twenty-three people in the roomóit might easily been a much more productive approach to have two 11- or 12-person IRBs than one 23-person IRB, where they all sat and looked at it. And there are many institutions that are doing very neat things with having specializedóyou know, a dental IRB, where you actually focus in so that you focus the expertise and do some interesting things. You know. So the tools.... But thereís also the issue of collective wisdom. Thereís a level to which every IRB, I think, has to grapple and build a group sort of personality and go through some of the fundamental ethical issues for itself. I mean, some of this you only do by hands-on grappling with it. But thereís alsoóand I believe that itís in the outline that youíre not discussing now because Iím talkingóis this issue of maintaining some kind of repository or central place. We are very shortóI mean, one of the things that has struck me since Iíve been in this "train wreck" business is how poorly we as institutions share our expertise and hard-earned wisdom with each other. I mean, we really do a crummy job of learning from each otherís mistakes. And Iíve become fairly cynical about our ability actually, really to learn from each otherís mistakes, but we could sure make some efforts at sharing information and sharing decisions or at least hereís a list of things that we found it really effective to talk about when we have a case of this nature. So that the IRB doesnít have to come up with that list as well as work through them. So thereís some economy of scale that we could achieve if we just configured ourselves a little bit differently in several dimensions.

DR. SHAPIRO: I just want to be...I mean, those are very helpful remarks. I just want to be careful that we donít define a zero-sum gain for ourselves that puts us in a box we canít tolerate, because there are all kinds of tradeoffs in the margin between these activities and these other activities, all the kinds of things that go on in these various organizations. Iím not going to focus all the costs on just protections we think are important or some of the costs, not all of them.

MS. GUNSALUS: I think weíre talking about more at several levels. And my only plea is letís really make it an effective use of more. I think that there are compelling arguments for more, and I believe that we ought to have more. But I sure wouldnít want to see it wasted because I think that undermines the argument.

DR. SHAPIRO: Although the institution of accreditation has both good names and bad namesóbeloved and hatedótheyíre all kinds of controversy in that area which I donít want to discuss. I was just wondering whether that model or some transformation of it, where there would be in some sense peer review of systems is something you gave any thought to at all as you went through this. Itís something that might work. Itís a way of sharing information; thatís all. Itís one of the thingsóis that something youíve thought about or...?

MS. GUNSALUS: I didnít think about it much more than to reflect as I read the General Accounting Office report and the Office of Inspector General report, where they talked about looking at IRBsí effectiveness and auditing the functioning rather than the output. I think there were some pretty interesting ideas there, and the report about interesting approachesóI mean, hereís this OIG report that went out and collected innovative, useful, helpful, neat things that IRBs are doing to improve their functioning. What can we do to propagate that? So beyond the concept of reading their reports and thinking, "Boy, this is pretty interesting and somebody ought to think about this more," no.

Let me ask one final question. There areóI canít think of any close analogiesóbut there are other situations in society at large where there are risks, where people are exposed to different kinds of risk. Letís say for a corporation, itís financial risks; and they have auditing procedures, which distinguish precisely this. They try to focus on the risky areas and just let the other stuff go by in some sense and at least have a much smaller level of scrutiny. And there must be many other entities like that which Iím not really familiar with.

MS. GUNSALUS: Well, handling conflict of interest inside academic institutions is, if you look at the way that we do it, itís functionally a risk-management model. You know, we try to identify what we think the risks to our missions are; the risks to teaching; the risks to research; the risks to service; the risks to public credibility. We try to identify what they are. We try to assess what are the circumstances that the risks to the missions arise. And then we try to focus our energies on those rather than...and define out things. You know, our rules say weíre not really very interested in activities that you would report on in a promotion and tenure dossier. If there are things that we are going to assess you on, scholarly activities that weíre going to assess you on, within parameters, those donít concern us. Hereís the universe that concerns us. So there are a lot of risk-management models out there that are already in use.

DR. SHAPIRO: And my question was whether you had identified any that you think might be especially appropriate here or just asking us, which is perfectly fine, to try to look at that model and see what we can discover.

MS. GUNSALUS: Thatís why I tried to focus on what are the principles and what do we really care about here? And thatís actually how I got to known identified, documented risks to real human beings that we can look in the files and say, "Hereís a human being who was hurt because..., hereís a human being who was...." And this was a human being who had no recourse. And surely weíre better than that.

DR. SHAPIRO: Okay. Well, thank you very much. Well, thank you very much for being here and sharing your paper. Iím sure weíll have more conversations about this as we go ahead with this particular project.

MS. GUNSALUS: May I just add my thanks to the incredible value that Eric Meslin added to this paper through his iterations with me, and Iím very grateful.

COMMENT: Thank you for mentioning that; Eric, thank you for your assistance. Letís now go back to what is now the last item on our agenda today, and that is to hear briefly from Alta and Kathi on some plans they have for a project thatís upcoming this year. Alta?

HUMAN SUBJECTS PROJECT RESEARCH PLAN

MS. CHARO: Let me just reiterate the thanks because I think that set us up really nicely as well as having youíve done an awful lot of the work thatíll be necessary to fill out this outline. What was handed out to you today was a proposed...itís a memorandum from Kathi and me dated the 16th with an outline that looks like this, entitled "Human Subjects Protection Comprehensive Project," which can be found at your seats. If not, there are extra copies back by the staff. I want to emphasize that this is absolutely a proposed outline, and the purpose of discussing it here is to begin to discuss the scope of this particular task as well as the details on the outline. So let me just take a couple of moments to share with you some of the discussions that have been going around within the staff on this.

If you look at the reports weíve issued or are issuing so far, you begin to see some thematic concerns. The difficulty of suggesting regulatory change, knowing how slow the process is in part because of the diffusion of authority, which comes up in the context of the human biological materials reportóbut concern about the capacity of IRBs to implement a complex set of special protections that is raised in the course of discussing the capacity report. The dilemma posed by the knowledge that most activities will take place in the private sector, probably beyond the scope of current regulatory authorityóthat came up in the context of cloning. And the lack of consistency across the Federal government and Federal agency report. Itís probably time to take these observations and put them together into something more comprehensive. What has been discussed so far has been something that would be a little different from the kinds of papers weíve been working on, which tend to be enormous tomes that are encyclopedic in their recitations of history and empirical data, as well as being very specific, to the point of being new regulatory language, in their recommendations. Whatís been discussed so far is something much more on the order of a white paperósomething very short, very pithy, not aimed to be at the regulatory level, something thatís more at the level of a challenge to both lawmakers and regulators to find a way through statutory change and regulatory change, to implement suggestions that grow out of a fundamentally ethical set of concerns and resolutions having to do with the quality of protection that human subjects ought to enjoy, and the universe of people who ought to enjoy their protection. And Iíll simply reiterate very quickly that the resources we have in hand to do this, by the way of background, are substantial. Both the Presidential and National Commission reports, the excellent Gunsalus paper, the Fletcher, McCarthy, the McKay study, and a GAO 1996 study. I hear rumors there might be more interest by GAO now again in the topic. The NIH activities currently with regard to the placement of OPRR, which may wind up as early as December of 1998. And so this outline reflects that discussion of something thatís in that white paper context. Its scope, as discussed so far, is something closer to what Rachel was describing than what Ms. Gunsalus was describing, because it would be quite specific about the problems that need to be addressed. It would outline the possible solutions and some of their big advantages and disadvantages but, as currently discussed, would not purport to decide that the new system should be something that is like the Office of Government Ethics or that is like the NRC or that is located in Justice or HHS, but would simply point out the strengths and weaknesses. And we would be able to use our power to ask for an appropriate response from the appropriate agency every 6 months to see whether or not what is coming back at us meets the concerns that have been identified. So I would be very interested in hearing your reaction both to the kind of conceptualization of the project as well as to the outline.

One last thing...the timeline for this. The idea was to have some kind of draft late this spring, and so that is intimately related to the scope of the endeavor. The larger the scope, the longer the timeline.

DR. SHAPIRO: Letís see what few little questions there are. Larry?

DR. MIIKE: To summarize here, instead of a prescriptive approach, we want to have a suggestive approach, and the main reason is that we work real slow.

MS. CHARO: And people call me blunt, Larry. No. Actually not. As the discussion developed, it was about whether we as a body are really the best people to make decisions about fundamentally political matters, like where in the government something is going to be located or whether our expertise is stronger in simply saying, "This is the level of protection that people are entitled to. These are the people that are entitled to it. These are the identified obstacles to achieving that that weíve come to understand from long, hard experience with the current system. Hereís our assessment at first blush of which of the major options out thereóaccreditation, certification, testing PIs, changing the officeís location. Hereís our best assessment of which of those would actually answer these problems in a way that we find that to be satisfying. Please come back to us with a plan of action on how youíre going to actually do it."

DR. MIIKE: Just a thought off the top of my head. At this very moment, I think I would lean toward the prescriptive report; at least from our side talk about the pros and cons of the complements of that prescriptive report. Then we would have something concrete out there for people to react to. Iím worried about what Ms. Gunsalus had mentioned. We may just have another in a series of reports that really just, the latest report and you donít really have much of anything.

DR. CHILDRESS: I like this outline, but thereís something that may be missing and perhaps there are thoughts to put it somewhere else, perhaps a separate document, and thatís the Federal agency survey, because at one point we had talked aboutóand Iím not sure. Maybe Iím missing it here. It seems to me this is...if this is item 7, this little section here, the national Federal survey, then the reports would be a lot more than a little white paper, right? Because even the material circulated in a Federal agency survey, while itís relatively brief, would still constitute a pretty huge Section 7 in your report. So I guess what sorts of thoughts you had about that?

MS. CHARO: I think thatís a full Commission decision about how to handle this. My understanding had been that the Federal agencyís report is moving along separately and that we would simply draw lessons from it for this particular item in the outline. But how that agency report is handled and whether itís incorporated completely or issued separately is a full Commission decision, or full staff decision.

Professor Capron: A couple of responses on the linkage of this to other projects. One has already been raised, which is the agency report. Another one is how this relates to any reexamination of the principles, the "Belmont Revisited" aspect of the Commissionís work. Point I.A. says "the origins of the justification for protection." I wasnít sure if that was a typo and it meant the origins and the justification for, or if we were interested in the origins of the justifications, meaning the history of use. It wasnít clear to me. But certainly part of the way of looking at a document of principle, like Belmont, is that it provides the justification for human subjects research by explaining principles that ought to guide such research. And if so, then, as to the Federal agency thing, does this relate to anything dealing with Belmont?

The second comment is that one of the criticisms that has been raised about the IRB system, which is still where the rubber meets the road in all of these, is the question of resources for the IRBs. And Iím not sure whether the McKay report, the Inspector General, the General Accounting Office, or any of the others really talk about how much money is spent now on this activity. How does the amount that is spent compare with the amount that is spent on the underlying activity of research? Again, whether you take the prescriptive Miike approach or the commentary, "get back to us on how youíre going to handle this," Charo approach, it would be helpful, it seems to me, to give some sense of what weíre talking about so that people would have a way of saying, well, it turns out that we spent so many hundreds of billions of dollars on the research and a trillion dollars on health care or whatever and we spend $2.5 million running the Federal side of the oversight and institutions themselves spend in kind another $15 million, or $50 million, or whatever the number is. And if our view is that doesnít do the job, what would be involved with doing the job? How much greater educational effort? How much greater staffing so that the idea of monitoring consent, getting reports on an annual basis and actually having someone read them as to whatís the experience of the researcher, all the things that are in the regulations that these reports say arenít being met. Give the readers some handle on that because it seems to me one recommendation for your III.B, "Changing the Federal System for Protections," would be better funding. Some kind of a percentage of the research budget ought to be taxed to go to support the oversight function. I mean, that wouldnít be unusual, whether itís a private researcher or an NIH sponsor. So I hope that, even in a slim report, we can give the reader some sense of the magnitude.

DR. SHAPIRO: Hold on a second. I think the resource issue is really quite important, even if itís too difficult to get a comprehensive numberówhat do we spend nationallyóthe scenario, I think sampling really works and we could learn a lot from the Belmont moment and...

Professor Capron: I suspect that a lot of this is not well monetized by the institutions involved, but you could talk about levels of effort.

DR. SHAPIRO: Levels of effort, hours spent, and so on. In any case, Eric?

Professor Capron: Did I get an answer on the first question, which is whatís the conceptual linkage between this and Belmont?

MS. CHARO: It incorporates the stuff going on with Belmont in that first item. That was the intent.

Professor Capron: Well, again, I guess Iím a little bit with Jim in that, although our thoughts about Belmont was not perhaps it would be as thick as the Federal agency report, which will have to have lots of data and reports in it, we did think it might take a good deal of effort and time on the part of the Commission to come up with a refined statement of the principles circa 1999.

MS. CHARO: As far as I know, the only thing thatís been scheduled so far for Belmont is the conference that will take place in April in Charlottesville, and I certainly hope that some take-home lessons or insights from that meeting could be incorporated into this. I had not had discussions with anybody that envisioned this as a substitute or anything else that people might want to do with the work done at that meeting.

DR. SHAPIRO: Let me say a word about that. Obviously we all hope that the conference that will take place at the University of Virginia will be very helpful on a lot of these issues. It is not a Commission activity. It is not being financed by the Commission; itís not Commission staff thatís going to take care of it and so on. But I obviously hope it will be relevant for what we do because I interpreted the discussion we had last time as this is not being a high enough priority for us to take our staff and resources and devote to that. So, yes, I hope it will have an impact. Weíll wait and see. But itís not a Commission activity.

DR. CASSELL: After listening to all these comments and Dr. Gunsalusís, by the time this comes out weíll have been in operation almost 3 years, and it seems a reasonable thing at that point, like the French meal, a "coup de cognac" to help you digest whatís gone on before, to come out with a shortóalthough as you all talk itís getting longer and longeróa short prescriptive statement about what we have learned and what we think is necessary to move ahead, including changes in the IRB system, in the regulatory structure and so forth, and also what subjects, deriving from the past and going on, what subjects need to be addressed in the larger sense as we go forward. But short, because otherwise it wonít do its job. It ought to come out there and say, "Hereís an experienced body thatís telling you what, on the basis of their experience, we ought to do now," as they then move forward with their larger task.

DR. LO: Alta and Kathi, I want to thank you for a very thoughtful outline. I wanted to pick up on some of the themes our guest speaker encouraged us to think about, the implementation of the report. Iíd like us to think strategically or tactically about it. What is it about this report thatís going to make people sit up, listen, and act as compared to all the other reports that are lining my bookshelf at home? And I think if we can think about that as weíre planning, it would be very important. Because it would be nice to have an impact, and yet itís not clear to me what weíre doing other than just being very thoughtful and well organized, and persuasive, which probably is going to be enough.

DR. GREIDER: I liked Altaís earlier characterization of a lot of the way that the system is currently based, as being investigator self-referral, that the whole system kind of keys into that. And the one thing that I donít see listed, at least not explicitly under weaknesses, is the fact that the system is investigator self-referral and most investigators really donít know much about this.

DR. HANNA: I just wanted to mention two things. First is I think thereís a compromise between Altaís approach and Larryís approach and whether the report will be prescriptive or not. And I think we will probably know after a period of time certain areas where I would imagine the Commission can feel it can be quite prescriptive. And I think probably it would be a good idea to be prescriptive in those areas where thereís great confidence. There might very well be some areas where itís not clear or the statutory language or the enabling legislation is so complex and it really needs to be worked out by regulators and rulemakers, that in those cases the Commission might defer the details to somebody else and not be as prescriptive.

MALE VOICE: Kathi just says, with the OTL alumni among us, I think the model that we could use is a fairly comprehensive report but focused case studies that say in these areas we can offer specific decisions and recommendations, which we should do.

DR. HANNA: The other point I wanted to makeóIím glad the issue came up about whether we were getting input, either through Timís routine as paper or in other ways, from the private sector or whatever. And I think weíre beginning to talk on staff about possibly convening a one-day panel meeting that would not be a full Commission meeting, where youíre also dealing with a lot of other issues. But more of a hearing format where we might have panels to talk to staff, and whatever Commissioners are able to attend. Maybe a panel of people who represent a point of view from the private sector, perhaps from professional, medical, scientific societies. We need to hear from those groups about what problems they have with the system, and I donít think weíve really given them the opportunity to present their case from the investigatorís side. So I think there are a lotóeveryoneís correct. There are a lot of data out there and there are a lot of reports already, and I think it would be a good idea for the Commission to hear from some primary sources some perspectives that help us put all of that data in perspective. Because some of these reports are in direct conflict with each other.

DR. SHAPIRO: Thank you. Other comments, questions. I think that this reportówe donít know what its form is quite yet, so I think these comments have been fairly helpful. Weíll have to think this through again, but I think, coming out at the end of the tunnel with a report that Eric characterized and Alta characterized partly also, which reflects our best judgment about the significant things that need to be attended to, is really quite important at this stage. And whether thatís an executive summary of some bigger report or accompanying the large report in some other aspect is an open issue.

Professor Capron: Two questions. I realize this is a proposed draft outline, as Carol pointed out. It sounds very tentative. Iím not urging you to change something thatís great and in stone, but under the possibilities of major change, in light of what Tina was saying, just a good sense, it seems to me one might want to switch A and B because the reform of the Federal system would be the first step. And then under what is now A to differentiate, if what that standing scope protection means to research that is not now encompassed under federally funded or federally regulatedóthatís what it means. It ought to be clear because one could just....

DR. MESLIN: Just very quickly. It wasnít already obvious from the authors of the memo, we have determined that Kathi Hanna will be the project director for this. Weíre grateful that sheís able to be on staff now on virtually a full-time basis, and this is going to be something that will be her primary responsibility. And with Altaís helpful Commissioner leadership, we hope to bring this very quickly to a close. Having said that, I donít want to leave Commissioners with the misunderstanding regarding what we had talked about as early as our January meeting in Los Angeles, which was that the several commissioned papers that we have made available to us, the survey of Federal agencies, and, if you will, the residue of the several IRB reports that have been made available, would not be included in this. They are intended to be included in some way, shape, or form, that the proposal that is before you is a systematic one that hopes to get an answer that could be presented to the National Science and Technology Council as NBACís considered judgment. So we are not talking about a proposal that replaces the combination of those three things, but how to use them most effectively. They need not be included within the covers. They are part of a volume of commissioned papers and additional materials. The proposal and a shorter than the 160- or 230-page documents that we have here before us is still consistent with Altaís proposal.

Professor Capron: But even those documents themselves have appendices probably published in separate volumes.

DR. SHAPIRO: Any other comments or questions this afternoon? Okay. Itís time to move to adjournment since itís just about 5 oíclock, exactly 5 oíclock. Let me remind Commissioners that weíll try to start as early as 8 oíclock tomorrow morning. We will turn first to the Chapter 5 of the biologic materials report and try to at least go through that. Hopefully we can do that in a half-hour or forty-five minutes. Weíll have to see. We should also bring the Commissioners up to date and make sure you understand where we are in a variety of projects that donít happen to be on our agenda today. We want to do that, and then weíll turn to the capacity report, which will take up most of our day tomorrow. Again, I want to apologize in advance to the Commissioners that I will have to leave early tomorrow afternoon, but Jim will be here for that part of the session. Thank you very much.