DR. SHAPIRO: Any questions for Eric on any of the issues he has raised? Okay, why don’t 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 I’d like to turn it over to Kathi to lead our discussion and then when Tom Murray joins us, he’s 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 it’s beginning to reflect the discussions in Commission. I’m 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 it’s 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 we’re 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 it’s in fact practical—to go back and do that. I think we’ve tried to make a start on addressing what criteria we might use in making a decision about whether it’s 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 you’re 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 that’s okay, and then we can proceed with a more detailed discussion. I’d 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 it’s 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, let’s 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 you’ll 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 that’s something we can work out later. You’ll 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. That’s 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 you’re going to find italicized text in brackets. That’s 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 we’ve discussed before, but I don’t 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. That’s a critical statement because it frames everything else—the 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. That’s on page 178. We’ll 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, I’m sorry.

Professor Capron: In part of the lead-up to that, on page 177, at the end of the first whole paragraph—I don’t understand what’s 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 one’s 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 don’t know what that sentence means. Again, I can understand that the bulk of the sentence is the phrase, "is determined through one’s evaluation of a series of decisions," but it doesn’t tell me anything. At other places where things are unclear but I understand them, I’m 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 that’s okay. I can’t tell if this is really a sentence which ought to say that it’s one thing to talk about the adequacy of the regulations; it’s another thing to talk about the regulations in practice, where the actual decisions that investigators, IRBs, and administrators make becomes crucial. And if that’s 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 don’t mean to either overlook or gloss over it. We’ll 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 NBAC’s 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 it’s 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 researcher—many 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 doesn’t satisfy me. I could say that I have a sample that was on the shelf, put on the shelf unbeknownst to me and now it’s 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 that’s why most considerations then fall into category 2 here instead of 1.

DR. GREIDER: But let’s 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 don’t see why you should say to them "outside the realm of protections" because something is publicly available. It just—

DR. SHAPIRO: Alta.

MS. CHARO: I could be wrong about this, but I think that the intent under the language, even if it’s 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. It’s 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 we’re 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 we’re 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 wouldn’t 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. It’s 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 that’s 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 don’t 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. I’m not sure I agree with Alta’s interpretation of the historical background because we’re in specifically the subsection that says "research involving" and it says "pathological specimens." So clearly they were thinking—we’re in 101-b4—"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 we’re seeing here or what we’re 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 it’s the case that most of those are stored in such a way that they are anonymous or whatever term we’re using for anonymous. So the issue may not arise but it’s certainly logically possible that there could be publicly available in the relevant sense—call up and get it, which also has personal information associated with that. And I think that’s the ambiguity, well not the ambiguity, but what we’re looking at here.

DR. SHAPIRO: Let’s make sure we focus on the substance of this issue because that’s 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, they’re or? So you don’t get the second protection automatically. You can only get it if you make an or rather than an and. And so let’s 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 that’s the case, then we think the current reg is in.

DR. SHAPIRO: That’s 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 Elise’s 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 don’t have any basis for knowing if that’s 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 Carol’s basic point which is the information is being, the developer doesn’t exist. It’s 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 that’s offered, that’s to say, there are no particular restrictions in getting access to it, that it isn’t enough and it ought not to be enough to say that as to information which doesn’t yet exist as information—it is there in a biological sense, but it’s not there in any sense that anyone would have been concerned about previously—that 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, let’s just see what the response is.

Professor Capron: My point is, that I think that it’s 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: I’m interested in what you’ve suggested, but I still feel uneducated enough to make a recommendation at this time. I’d want to know more—in 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 responses—about the number of situations in which we have samples that meet the definition as it’s 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 they’re not doing it commercially to sell it for a profit.

Professor Capron: I wouldn’t 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. That’s just what I said.

Professor Capron: But a commercial outfit that sells the materials, that doesn’t restrict your access.

MS. CHARO: This is an interesting point.

Professor Capron: Unrestricted on demand, to me, the reason that there’s that parenthetical made perfectly good sense. It means that you can’t 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 it’s interesting from some other perspectives, I don’t 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. It’s not clear to me how that would change anybody’s 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 I’m not going to go over, that it really is inappropriate, that just the availability of it would make it—in a sense, publicly available here—is just not adequate protection, if there are identifiers, for example. And, the information request—I would like to know as well. I’m 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 can’t begin to have a clue as to what this whole section is actually referring to. I don’t 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 I’d 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 it’s written, it’s existing data, medical records, foods, questionnaire tapes that are generally available, so I think we have to be very careful that we’re trying to fix a problem that we think is particularly important for DNA testing on stored samples, that we don’t 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 weren’t a researcher, you could get it but if you were a researcher, now you can’t get it is paradoxical. Now my final point is, I think that if we’re going to fix it, it isn’t going to be easy to fix because Alex spelled out that what we’re really saying is, is it legitimate and appropriate that it’s 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 haven’t 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 I’m not sure is the meat of the rest of our report. It’s 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 don’t 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 won’t have to write the change itself. I agree with you that we’ll have to be extremely careful and it’s 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 people’s attention on it and perhaps recommending a consideration of a change in regulation of something of that nature. But I don’t really want to write the regulations. We’re not competent to do it sitting here and, as you say, it’s a complex issue. We just ought to focus our attention. I want to bring us back to the issue just to see what Commissioners’ feelings are, and then we can go about—not 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, let’s 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. That’s 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 available—to get the data. And yet I also would agree with Harold that that wouldn’t necessarily change my view of how I would look at this because we’re not just talking about things that are existing today. We’re talking about things that might occur sometime in the future, and just because there aren’t huge numbers of samples out there right now doesn’t mean that it won’t be different in the future. So that is one point. The other point is, to my understanding, all we’re talking about is whether this even should be considered before an IRB. We’re not talking about shutting down research. We’re just putting it into the IRB mechanisms so that if somebody looks at it—and I don’t see that as a very high bar that we’re 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 people’s 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, it’s 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 there’s no escaping it. It’s right there on the public record. And I think that was part of the thought in the exemption, that we can’t create standards here that are higher, not that there isn’t an interest. I think Carol has done us a great favor by saying we’ve 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 doesn’t 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 I’ve had a chance to think it through. Maybe I would think better with a second cup of coffee, I don’t 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 couldn’t diagnose today. The information is there but not available to interpretation yet, but in ten years, twenty years, thirty years we could—just like today—diagnose things we couldn’t thirty years ago just from observing people. And if somebody were to do that research, they would take the videotapes of the last year’s 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. You’re right, it’s not necessarily a big deal to have to go to the IRB and have them say this is benign, but I just don’t feel comfortable rushing until I’ve 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 it’s not fully adequate as it stands, we have to think about how to do it and so on and I don’t 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 can’t meet the concerns. I take it that that’s 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 isn’t really a problem because most are not publicly available. The point is as to those that would be publicly available, not in most, whether that’s 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 I’m 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 we’re looking at this.

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

MR. HOLTZMAN: The guidance we’ve 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 sponsored—many investigators that get at it but you can’t just say send me some of those samples. There’s a range of instances here and many require clarification.

DR. SHAPIRO: Other comments and questions? Thank you. Just to remind you, we’re 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. They’re 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. That’s 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 doesn’t 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 we’re 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 input—to 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 we’re 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 doesn’t 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 they’re not harmed and maybe I make too much of this as philosophical or legal differentiation, but I think it’s 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 don’t 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 don’t 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 didn’t know when to bring this up, but I think that the first point that Alex made introduced it. In Chapter 4 there’s 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 don’t 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. There’s no distinction here. In the consent discussion in this chapter, it’s 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, let’s 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 didn’t make because I wasn’t 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 weren’t 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 weren’t harmed, they didn’t 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 we’re using but we don’t seem to get back to some touchstones of about maybe what we found out. Maybe people don’t think we found out anything or—

Professor Capron: I thought we agreed that those focus groups were useful for us in teasing out issues but that we weren’t going to recite them as some form of touchstone, that is to say, a public opinion survey.

MR. HOLTZMAN: So I think, I think that’s 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 don’t 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 agree—there’s no real information there. Nevertheless, my belief is that’s 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 let’s 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, that’s 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 it’s truly not "genuinely." I don’t know. It just—

DR. SHAPIRO: If you knew what unidentifiable is, you wouldn’t need genuinely. We’re trying to make the point maybe too hard here.

Professor Capron: You want to drop that?

DR. SHAPIRO: That’s 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 practically—

DR. SHAPIRO: Right. We’ll 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 or—

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, we’ll 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 we’ve 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 we’ve 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 deducible—I don’t know if even that’s the right word and those who are not becomes very blurry, and we’ve been around and around and around and I wasn’t 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 it’s a thousand people and the results are one in a thousand...

MS. CHARO: But it’s being used here...

Professor Capron: It’s being used to bring it into a category of saying it doesn’t 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, we’re going to have many more procedures we have to go through in order to evaluate their risk and the protections that are associated. And you’re asking if I am satisfied by that last paragraph? No, because that parenthetical is about the—

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: I’m 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. It’s fair and more appropriate, so let’s try that, if people can restrain themselves. Larry.

DR. MIIKE: My understanding of what this discussion is about is—not that we’re going to change the regs—that we want to make it clear that people haven’t misinterpreted the regs. Isn’t 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 doesn’t mean that you’re jumping off a cliff essentially. There’s a progression. Then you consider how identifiable. What’s the probability that that person could be identified if you used that in your tabulation of whether it’s 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, I’m 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 I’m looking at that and saying I don’t see this as the way that this is being presented—that we’re going to recommend changing the regs. It’s just that clarification of the interpretation.

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

DR. HOLTZMAN: Kathi, I don’t 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 that’s 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 there’s very textured language in the reg itself, readily ascertainable.... For example, OPRR’s guidance largely seems to be if it’s possible to create the link, it’s identifiable. And we seem to have adopted that. If it is possible—we don’t go with what degree and if what not. If it is possible, and if you take that as your standard, and I personally think it’s a lousy reading of the reg, but I’ll 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. It’s either identifiable or it’s not. Now one of the questions I asked several months ago is reflecting Kathi’s 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 we’ve heard from OPRR that in their view, there has been variability in both IRBs’ and investigators’ interpretations.

DR. SHAPIRO: Carol’s next, then Larry.

DR. MIIKE: I don’t know, Steve. I think you’re over-reading this language. I don’t read this language to say that if it’s possible to be deduced by cell size that it’s identifiable. I think that what it’s 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 it’s 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. We’ve had discussions each way. We’re talking about a situation in which a repository has a list of the x number, let’s say 100 samples, that it’s 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. They’d say we don’t 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 don’t know which is which. So it is that level of information and we know whose samples we have in the lab. In other words, it’s not in our lab anonymous, even though it is to you anonymous. And we’re saying no because they could tell you who the 100 people—Jones, Smith, et cetera, et cetera—who the 100 people were, who were in the group of samples, even though they can’t 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, it’s 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 haven’t 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. That’s where we came out to my recollection. We wanted to change our minds and so on. It’s my own view that that is probably the only way to write—if 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 that’s happening here is that we’re creating various streams down which particular protocols go depending on the harms that are exposed. If there’s a harm that’s possible or a wrong, is it possible or not possible for that to happen. And if it’s possible, somebody ought to at least not rush by this. And therefore, that’s the line I draw. Whether it’s a good interpretation of the regs is another matter altogether, and Steve may be right about that. But it seems to me that’s where we could draw, if it’s possible to go back to the person, it’s 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 it’s minimal risk, it’s a very simple proposition. If it’s not, it ought not to be simple. And that seems to me to be straightforward. I think that’s what, I don’t 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 there’s 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 it’s coming up later, so that you’re not, as I said, you’re not making a final decision here. You’re just pushing the protocol into one direction.

DR. SHAPIRO: We’re not throwing the weight of all the protections that are possible into the hopper just because it’s...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, we’re still talking about that calculus and I don’t recall that we did adopt that. Kathi, I’m sure you studied those transcripts, didn’t you?

DR. SHAPIRO: There are people that want to talk. I don’t think we adopted it in the sense that we had a formal agreement but it’s 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 we’ve thought a lot about and talked a lot about, and we don’t have consensus. All investigators and IRBs need to be aware of these arguments. We didn’t reach agreement. It doesn’t really matter right now because the regs already state you get expedited review or full review, but I think conceptually it’s 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 don’t think it’s expedited versus full. It’s whether or not you have human subjects research. That’s 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 I’ve 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 we’re absolutely correct that it’s 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 it’s 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 I’m covered by the research rules and I’m asking for the requisite review—subject to lots of influences by the department chair, by journal editors in retrospect and et cetera but it’s 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 don’t 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 that’s 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 I’ve become convinced that the current structure is a sensible one, and abruptly here’s how I see it. You’ve got the conceptual distinctions and the ethical considerations, and they look like this. And you’ve got this policy apparatus, which is a totally different sort of being and there’s 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 what’s important, conceptually and morally. Even if it doesn’t capture it at the first level, it may capture it later on when we consider whether it’s minimal risk or not. I hope that if I’ve 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 Larry’s question caused me to divert on that and now Alta’s 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 Tom’s gloss on it that it is a virtue to have something that is implemental. I don’t see the problem with this recommendation being easily implemented. If I’m on an IRB, I know two things. Researchers, I’ve got to rely on researchers asking for permission to do their research. I mean, that’s 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 it’s exempt. If I’m 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 that’s the question I am going to have to answer, I may not know the answer. I may have to call up the repository if I’m 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 they’re 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 can’t 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 it’s a very, I don’t think this is complicated. I think it is a fairly easy bright line. I like your criteria and virtue, as Tom calls it. I don’t think it’s a problem. The comment that I was going to make is right before the recommendation, the sentence beginning on line 7 of 186, and I’m going to turn to my colleagues like Steve and Carol and ask them whether my sense that this doesn’t quite capture what’s involved. This says that the issue of identifiable is further confounded by the researcher’s 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 Meslin’s 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, wasn’t that the point that everybody kept making, which is the irony is that we say that this is unidentifiable but the very process that we’re engaged in looking at is one in which that change–-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 we’re 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 what’s 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 it’s not may be identifiable but may be readily ascertained, so it’s not identifiable in the sense we’re using it. It’s 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 it’s eligible for expedited or full review. I think again it’s 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: It’s 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: Isn’t 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 shouldn’t 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, it’s usually the rule that where words are different they’re 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 it’s made me wonder because ordinarily you’d expect there’s a reason why the language differs and there’s an intent to have different rules apply to different levels, but that’s 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, it’s very confusing because it’s 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 that’s incorrect? Is that what I hear you say?

MS. CHARO: No, I’m not saying it’s incorrect. I’m 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 it’s 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. That’s all.

DR. SHAPIRO: Steve, first.

MR. HOLTZMAN: I just want to throw my support a hundred percent behind Alta. What’s taken place, what’s striking is it’s 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 you’re pointing out, it’s a natural extension to say that if you move down a path in which at every layer you basically say, is it identifiable and it’s natural to then ask the question, other modes of identifiability you haven’t considered before, beyond codes. Okay, now that’s 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 time—it 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, it’s clear what you’re saying. You don’t get caught up in words or how to define or it’s 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 haven’t thought about because we can’t 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 I’ve not seen any evidence yet that that’s really going to be the case. If we’re, to me, I still don’t really care how people get identified, either they get identified or they don’t. And the harm to that person, I understand it’s probabilities, so that if you would have cells—not 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 don’t use "possible." Then you really have a problem because there’s all kind of identifiability. It’s like this minimal risk all over again only you’ve introduced it once more for, I think, very little gain. Bernie?

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

Professor Capron: We’re explaining—our 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 it’s 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 don’t think we have to, if that’s 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. We’re 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 that’s a good point. It’s not only readily available. That’s not the only phrase there. It has an association with them and I don’t know, it depends on how you think about that phrase, but I agree with the point you’re making in this.

Professor Capron: Well, I don’t see the purpose. Larry brought it up before. Are we rewriting the regulations? No, we’re not rewriting them, but we’re urging that they be read to mean the following: Because they could mean we’re 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. Let’s 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, there’s 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 categories—minimal risk, rights and welfare—and 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 of—and again it refers back to Alex’s concern about harms and wrongs—that 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 people’s 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. We’re 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 we’re 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 let’s go to others. Alta.

MS. CHARO: I’d 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 they’ve 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 here’s 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 we’ve 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, we’re 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 somebody’s going to stick a needle in your arm and you say, is this more or less than what happens in daily life. Because we’ve 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, we’ve 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 that’s the current interpretation, whether there’s possibly some value in trying to separate these two categories of risk a little bit because the difficulty in comparison and measurement for them—I know we went around this in Portland, I think I remember doing it with Alex—I 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 it’s no greater than what you’re already experiencing, it’s okay to do this research without further consent, subject to the other criteria. The rights and welfare language doesn’t make a comparison to daily life in any fashion. It simply says, "adversely affects people’s 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 I’m shorter, I’m 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 don’t have to worry about whether or not it’s consistent with what we’re 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 men’s 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, that’s 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. That’s the way that society sets its world up. So I don’t 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, Humphries’ study published under the title "Tearoom Trade," of anonymous sex in men’s 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 didn’t 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 subject’s hands down in some electric shock apparatus. So that was no mere observation study, that was very much a deception and manipulation study. I’m reflecting about Alta’s desire to distinguish the psychosocial from the physical. It can be difficult to weigh the psychosocial, I agree. But I’m loath to introduce another layer of complexity in the analysis of it. I also didn’t 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." That’s 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 it’s less likely, or no more likely, than inadvertent release of one’s medical records. So if that’s the sense in which it is a risk.... That is, it’s not zero but it’s real low. Therefore, it’s something I think we need to explain that rather differently than we explained it here. But I’m not convinced that we should make special provisions for psychosocial risks. I’m open but I’m...

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 that’s being brought up, Alta, and I’m still very stuck with. And initially I thought that we would look at this differently because we’re looking at an inanimate object and a person who’s stealing things. But I’m beginning to consider...I thought perhaps it didn’t obtain in the same way. But as I think about it, particularly thinking about Mulgrom and the Humphries "Tearoom Trade" and so forth, I’m seeing that it really does obtain. And I’m very concerned about that everyday risk, which we might pile on people who have that everyday risk, I’m 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 it’s okay to do this because they’re 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 I’m 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 I’d 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 we’re talking about information that will go into your medical record. That I think if we’re going to use something as an example out there as what is minimal risk, we should avoid the issue of medical records entirely because we’re talking about information that’s going to go in there. And that circularity does not make me comfortable.

Professor Capron: I very much endorse Carol’s 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 one’s 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 they’re 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 risk—I’m making a balance. Whereas here we’re talking about something that is outside the context of consent. And it seems to me that for that additional reason it’s not a good analogy. That said, I’m 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 that’s 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 we’re 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. Let’s not reach a judgment on that until we consider some other things.

DR. SHAPIRO: Larry.

DR. MIIKE: Just a problem I’m having with this whole idea about minimal risk as currently being discussed and as apply in the other areas is that we’re dealing with tissue samples, we’re not dealing the human beings themselves. So talk about the risk of everyday life—What life? So what are we comparing? So it’s 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 we’re sort of having the wrong discussion here. I think we should just look and say, is this an applicable situation? My tissue doesn’t feel pain, my tissue doesn’t 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 you’re not going to hurt the tissue the way you could physically hurt someone. But the nature of the research is it’s generating information.

DR. MIIKE: I agree, but I’m 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. That’s the way I frame the question. The generation of the information, does that create a risk which is more than minimal? And therefore, I’m not sure I agree with people that we’ve got a circularity here because I think it’s 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, there’s a lot of information that’s 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 that’s 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. That’s the way I frame it for myself.

DR. SHAPIRO: I guess it’s 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 it’s really the information that we ought to be focusing on; that is important. And it’s the risk that that information contains, could contain, that we ought to focus our attention on. I’m 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 won’t 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: That’s 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 doesn’t deal with any episodes of illness, simply with having a relationship with a physician, a possibility that that record will fall into someone else’s hands whom I don’t want them to have it, and they might even make use of it to hurt me in some way, that’s a possibility. I hope it’s rare, that it will happen rarely if ever. It’s probably less...it’s 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 says—by the way it includes both the words "ordinarily encountered" and "routine," they’re both in there—says "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 heaven’s sake. By which...I don’t understand exactly what a genogram is, it’s basically kind of a very extended family history of disease as well as those other things. There’s 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 it’s 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 wasn’t 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...he’s 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 somebody’s 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 average—what’s the probability that I’m going to be psychologically disturbed during the course of a day or a year compared to the likelihood of being disturbed by this experiment? I’m struggling, I’m 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 who’s 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 that’s within the control of the institution, that’s in the control of the certification agency.

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

DR. SHAPIRO: Okay, I’ve got four people on the list, including you, Bernie, and then we’re going to take a break. Eric.

DR. CASSELL: Well, step-by-step, Steve, I think you’re right. The harmful thing is information, we’re not talking about direct physical harm, we’re talking about information harm. We’re 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 that’s why it’s in the Hippocratic Oath. And this potential for harm by information that reveals something about me, even that I have cancer if I don’t want anybody else to know that, is enormous. It’s 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 I’m giving this directly and therefore participating in the sharing of information. So I’m...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 isn’t 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 it’s 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 isn’t 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 won’t 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 191—only two pages is not much of a leap, it’s sort of a step—lines 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 there’s 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 don’t mean to predict where you were going. But staff did struggle with where to put these sections—waiver of consent, minimal risk, rights and welfare—and 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 welfare—it’s problematic as to where to put it—is because it is part of the calculus in determining whether you’re going to waive consent. It is not part of the calculus when you’re determining whether you’re going to expedite review. And so you’re 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 that’s a condition that triggers expedited review.

DR. MIIKE: Before we go on, Harold. It’s 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 they’re 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 Alta’s 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 we’re 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 we’re 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 there’s a lot of information going on, as Steve pointed out, or a lot of action going on in terms of medical records privacy. There’s a lot of concern, there’s legislation, et cetera. And for us to tie something that we’re going to say to the medical records are of certain degree of risk, I feel like we’re tying something to a moving target that already is very uncertain. And so that’s an additional reason why I just don’t 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 Eric’s 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 don’t 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 we’re forced to deal with this concept of minimal risk, at least that’s the way the current regs lay it out.

I think we do have to—I mean, again, we’re 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 it’s 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 aren’t. 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 haven’t 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, it’s 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 it’s 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 can’t do that, you’ve got to keep it under lock and key; if you’re going to code it and you’ve 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, that’s subject to the provision that appropriate standard of care for the protection of the confidentiality of information is there. I don’t think that’s really in our report yet, and I think it’s really important because a lot of investigators don’t pay much attention to it.

DR. SHAPIRO: Tom and Steve, and then we’re going to really break. I’m 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 wouldn’t be minimal risk. So this isn’t just an academic discussion in a sense, it really is a very substantive discussion. I’m glad we’re doing it.

Particularly what Carol and Bernie have recently said, I’m persuaded at this point, although I never underestimate the power of my fellow Commissioners to show me I’m wrong, but I’m 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 Bernie’s comment about how sometimes they’re not cared for very well and that’s 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, that’s a problem. And so I’d like to, if anything, heighten the analogy.

DR. SHAPIRO: We can have a break. Let’s try to reassemble in ten minutes.

[Recess.]

DR. SHAPIRO: Colleagues, let’s begin our meeting again. We’re 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. I’m 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 don’t 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 I’m 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 don’t 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 recognize—as Larry reminds us today, the tissue doesn’t feel pain—are 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 don’t 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 don’t 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 don’t 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 don’t seem to be greater. And from that came the concept that when you’re 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 doesn’t say, "By the way, when I’m done with this I might find out you have a deadly cardiac problem." You have the sense this is just a general checkup, it’s routine, it doesn’t involve much physical risk, and I don’t 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. That’s the general sense. And most researchers are in that same category. That’s the origin of this language.

If we’re 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 that’s why they are such a bad example. It isn’t the content, it’s the fact that most people still probably have a sense that you aren’t at risk because it’s 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 you’re going to come up with something that reflects our discussion in the transcripts, I’m not sure that it’s going to get to what seems to me a year ago was already quite clear, which is this language isn’t adequate on its own terms, it doesn’t meet the particular problem that we’re looking at, and we can’t simply say that it’s 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 reg’s definition of minimal risk ought to be changed, that we, NBAC ought to make that as a recommendation, I didn’t hear that in the discussion.

Professor Capron: No. My proposal is not that, because we’ve been told repeatedly that if we say the regulations are going to change we’re 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 shouldn’t be a place where much discussion occurs, it’s a place where we’re 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 doesn’t 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 don’t feel they can gloss it to the extent necessary.

We’re 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 don’t 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 don’t come together.

DR. SHAPIRO: Well, it’s 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 you’ve highlighted here. And if what you’re 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 shouldn’t bother you because it was just like everyday life. One thing since then we’ve learned is that a lot of research was carried on that was very risky and was disguised and hidden. But that wasn’t 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 shouldn’t 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 Alex’s concerns that in our reluctance to overturn the regulations because that wouldn’t be very fruitful, we end up perpetuating uses of language that contradict the plain meaning of the terms.

It seems to me that what we’re facing is similar to what judges must face when they have precedents they don’t 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 what’s wrong with that decision and how what we’re 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 we’re stuck, as I agree we can’t rewrite the regs at this point, but I think we need to be very, very skillful at pointing out we’re 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 shouldn’t try to change regulations. And I’ve 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 that’s 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 shouldn’t miss that adds to the confusion here and it’s 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 anybody’s 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 I’m thinking about the Mary Claire King descriptions, in which she’s 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 we’re 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 it’s with reference to the particular subjects or the general population, because I think that’s going to happen here frequently.

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

MS. CHARO: If we did, then I’ve forgotten it, which happens frequently. I’m sorry, I can’t hear what people are saying. Is there an answer to this question? If I just missed the answer, that would be great. I’d love to know there’s 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 it’s relativized to the people that you’re actually looking at in the sample.

MS. CHARO: All I’m saying is that if we’re going to be doing a serious discussion of the problems with this standard, if there’s an answer, let’s get it, and I’d love to hear what it is. If there’s no answer, let’s 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 we’re 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 we’ll 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 doesn’t mean that they are equal. I don’t get it.

MS. CHARO: I thought that we were agreeing that we’re 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. I’m 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 don’t 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 that’s what you’re 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 finger—

MS. CHARO: I’m not talking about blood pricks. I’m talking about the possibility that you’re going to wind up losing your life insurance. We can’t 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. That’s all I’m 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, we’re 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 it’s the general population. My understanding of what occurred is it’s the general population, whoever that is and however that is. Now Gary can tell us if that’s wrong, but that’s 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: Isn’t that in materials that are available to IRBs?

DR. ELLIS: It would be available on transcript of the NBAC meeting when I addressed it. Alex’s memory is correct. Remember, we had a long discussion and I posed a teaser whether lumbar puncture was greater or less than minimal risk. It’s 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 can’t 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 we’re left with the conclusion that it must be the daily life of the general population, which includes people who are of ill health. I don’t know how better to explain it.

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

Tom has a comment, then we’re 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 that’s 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, doesn’t 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 we’re 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. Here’s how you get it. You go two steps down and it says, if it’s not greater than minimal risk, it’s not practical to conduct the research without the waiver, then it asks, will waiving or altering informed consent adversely affect subject’s 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 can’t 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, I’m not uncomfortable with saying, this is a tolerable way of handling it, even though at the first cut—when you say is it minimal risk or not—it’s 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. That’s my own view of that. We may want to come back to some of that later.

But let’s 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 don’t know how to phrase this, Kathi, but a suggestion or something that you want us to think about or talk about.

So let’s 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 "it’s 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 it’s 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 you’re worried about here cannot be above minimal risk or you’re no longer even worried about practicability. If it’s above minimal risk, you’re 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 we’re 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 couldn’t get it funded, therefore it is impracticable. So that’s 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 simp