DISCUSSION OF TISSUE SAMPLES REPORT (CONTINUED) THOMAS MURRAY, Ph. D. DR. MURRAY: Let us get back to the substance of the report, shall we? Trish? MS. BACKLAR: I am not sure that I made myself clear about one thing in terms of the Tissue Sample Report, and that is I have a concern about cutting out people from getting information about research that-- I am very concerned. Just as though it-- As a private person, if some of my tissue was used for research, I would want to know if something was important to me, so another reason for being very cautious about a firewall. That is all I am saying. I don't think I made that clear before. DR. MURRAY: Let me see if I understand your point. As I-- And let me tie it into-- Because it is one of the things we need to talk about. There are two circumstances under which people may want to reach this-- what we have called a--firewall. We probably need a better metaphor, but that is the image we are stuck with at the moment. One of them is this sort of-- It is David's cadre of researchers who really, really want to find out who those people are. DR. COX: The Spice Girls. They really, really, really want to know. DR. MURRAY: The Spice Girls. (Laughter.) DR. MURRAY: Well, listen I was in England for a week in December and they are already passe so how quickly-- How fleeting is fame? So that is one motivation, right? The second motivation though is one that I heard from the mini-hearing participants in Cleveland--and I gather it wasn't just in Cleveland that this was articulated--that there is a feeling on the part of people who contribute to research, by whatever means, including tissue, that, if it is possible for that research to benefit them, then it ought to benefit them. That they sort of made a kind of contribution. If scientists learn something about them that they ought to know, they would like to have the opportunity to find out. I was surprised at the intensity of that feeling. Now that exists I must say with an equally intense desire to protect privacy. MS. BACKLAR: That is what I am referring to. DR. MURRAY: Yes. I thought it was that latter. MS. BACKLAR: Right. DR. MURRAY: Right. MS. BACKLAR: I just wanted to make sure that I said it. DR. MURRAY: We need to talk about that. I mean, if our recommendation said that this must be a firewall that is as absolutely unbreachable as human ingenuity can make it, then we have eliminated both those breaches, or we try to eliminate all those breaches if possible. Do we want to set up something less than that, at least in certain circumstances? Now, my reading of the summaries of the Primer meetings and the National Action Plan on Breast Cancer meeting is that there was some sentiment there as well; that--you know, particularly of this latter sort, the kind Trish was concerned about--that that ought to be possible when it was really, really important and clinically relevant, or some other intimate personal way relevant to the subjects. So we need to address that. Bernie? DR. LO: Yes. I think it is a really important topic, particularly in the context of anonymized versus anonymous samples; that we have in this grid the possibility of having samples that are anonymous to the researcher but linkable to somebody else. And so it is not a matter that you can't contact the person because you simply don't know. You could if you kind of could work backwards through the system. But we have constructed a system that says, "It is not going to be permissible to do that." And it seems to me there are a lot of reasons why you might want to get back to the patient. One is just the patient is curious, the patient wants to know, the patient thinks that is part of the arrangement of donating tissue. There is another situation in which clinically the researcher, as scientist/clinician, thinks it really is in that patient's best interest in that you have made a discovery which is far more powerful than you had anticipated, so rather than just a slight stratification, you have got a combination of genetic findings that predicts with--whatever--80 or 90 percent likelihood that someone is going to develop a serious form of cancer. And you didn't anticipate quite that at this stage of your study. I think the pressure on the physician/scientist to say this has clinical importance and I would like to at least offer the patient the option of learning it is going to be very powerful. Again, we saw this in the AIDS epidemic where there was a lot of AIDS testing early on that was done on anonymized samples, samples that were taken for other contexts and then stripped of identifiers. And you found, you know, 5 percent of people were HIV positive. And you could have contacted them had you allowed the system to work. They were contactable at one time. But for a whole lot of reasons, many of which I actually argued persuasively at the time, you chose not to do so. I just think it is an issue. It is a dilemma. It is a real dilemma that we need to sort of sort out. And I think a lot of the concerns that were present in the AIDS epidemic, where you really needed to get an accurate picture of the epidemic--you were afraid of biosamples, scaring off people who were at highest risk--really don't apply to the type of DNA-based research we are talking about. So the values that stay are sort of the convenience of doing the research versus either the wish of the patient to be informed or kind of a beneficence-oriented argument that it might be in their best interest to know. And I just think the idea of a firewall sounds neat because it seems to solve some problems at the front-end. It actually makes, creates dilemmas after the research is done and you get--what we all hope for-- smashingly positive results. DR. MURRAY: Steve and David. MR. HOLTZMAN: I just have a quick comment that struck me when you said the kind of DNA research we are talking about. I thought this committee agreed that what we were dealing with was medical research on stored tissue samples, not just genetic research. All right? And I think that is just-- And I think we are going to have to come back to that issue. Just I think that is very important because three times I have heard that in the last half-hour. DR. MURRAY: Let us nail that one down. MS. BACKLAR: Yes. DR. MURRAY: Do we agree with Steve that-- I mean, I think practically I can't find any other way to think about it. If we are going to come up with a set of policies and practices about research of stored tissues; to say they only apply if the research is "genetic" and not otherwise seems like a-- It seems like we are doing no favor to anybody involved in the process. Is that-- Now, if there is any disagreement with that, please let it be known. DR. GREIDER: I agree with Steve. DR. MIIKE: Say that again. MS. BACKLAR: I agree. DR. MIIKE: Are we saying that it is tissue research? But a lot of the concerns that we have been discussing don't apply outside the genetic area. MS. BACKLAR: But they might. MR. HOLTZMAN: A lot of the concerns we have been discussing don't apply within the genetic area. DR. MIIKE: I am sorry. What, Steve? MR. HOLTZMAN: A lot of the concerns we have been discussing don't apply within the genetic area. They apply-- Most of the concerns we have, have to do with a set of findings about biological information that pertain to issues like predisposition, stigmatization, et cetera, et cetera, which cuts across genetic and non-genetic. I mean, if we are going to-- DR. MIIKE: But it is not because I have a piece of bone that people are looking at; it is because of the genetic material within the bone. I mean, you may disagree that stigmatization has nothing to do with genetics, but that is what we have been discussing. MR. HOLTZMAN: Well, it actually-- DR. MIIKE: You know, like-- Well, let us take a ridiculous example. I notice that the definition of tissue includes feces and urine in our draft. DR. GREIDER: It won't. (Laughter.) DR. MIIKE: Okay then. There you go. There you go. Then why are we talking about tissue outside the genetic context? DR. COX: I think there is a compromise position here and the compromise position is--I think this is what you are sort of trying to nail down, Steve--is that we had agreed that genetic information isn't inherently different from other types of medical information. That is-- I recollect that that has definitely been agreed to. Having said that, it doesn't mean that there are not situations where genetic information has some different implications than other medical information, but that we don't-- (Laughter.) DR. COX: We don't want to-- Is that better? Okay. I don't want this-- I am scared of them. DR. MURRAY: Just remember all those Grateful Dead concerts, David. They were right up to the microphone. DR. COX: So I agree with you, Steve, but I don't think we want to carve it out, you know, and just be talking about genetics. But, on the other hand, there can be special situations and we highlight those if we see that they exist. And that was exactly the point, Tom, that I wanted to make in this context of the firewall, too, is that it makes us feel really good if we have a single box we can put everything in and close the lid. But that is not the way life works. So that if we could put most of the things in the box, but then delineate certain exceptions that we think are likely to happen, and we acknowledge that they might happen, and we say-- And if they-- And so these are things we have to think about because the box isn't perfect. Then I think that is reality. And so I am more than willing to go with what you say, Steve, but then if there are specific examples that appear, you know, special for genetics, just highlight those. But it is not to say that genetic information is separate from other medical information. DR. MURRAY: We may be flogging this more than we need to. I mean, I think if our report-- We would say in our report that we just-- We explored this issue of the use of human tissues in research because of the ability to extract large amounts of genetic information potentially from that tissue, and that is part of the opening of the report in fact. We could then simply note that it would make sense to, you know, since tissues can-- DR. MIIKE: Aren't we the Genetics Subcommittee? DR. MURRAY: Pardon? We are the Genetics Subcommittee. I guess all I want to do is not ghettoize genetics and also not make people labor under two, sort of two radically different systems for not good reasons. So we might just say, you know, we think what we are proposing would make sense as a general set of principles and procedures governing research with human tissues, even though we come into this from the genetic angle. I would I think be content to say that much. DR. GREIDER: Why do we need to say that there are special instances in which genetics is different? That is what you just proposed, David. DR. COX: I am saying that, if people want to say that, then we need to define the special instances. And I would give an example myself of what I would consider a special instance in terms of being different. And it is a quantitative rather than a qualitative difference. And it has to do with what the predictive power is. So I would say that if somebody-- If genetics had a 95 percent predictive power, where most other information had a 25 percent predictive power, genetics is different. And it is different because it is more powerful in that specific instance of prediction. Not overall, but in that one instance. There can be specific examples that the-- The specific example--it is a well worn one, but to make the point--is Huntington's disease. Okay? The power of genetic information in Huntington's disease, when you know that change in the DNA, is an unbelievable power. DR. GREIDER: What about the predictive nature of somebody that is infected with HIV virus? There is a very high predictive feature there and you wouldn't say that that is a genetic. So there are predictive powers that aren't necessarily genetic. DR. COX: Oh, no. And I agree with that. All right? So I am not saying this is unique to genetics, but it is unique to the specific case. MR. HOLTZMAN: It is unique to a monogenic highly penetrant disorder. DR. COX: Bingo. Thank you. MR. HOLTZMAN: Okay. Which, when you think about HIV, is monogenic, a single genome, if you will--all right?--and highly penetrant. DR. COX: Exactly. MR. HOLTZMAN: So the point is-- (Simultaneous discussion.) DR. COX: --is an example. MR. HOLTZMAN: --and what we are concerned about-- What I always find very useful heuristically is to forget I even knew the word "genetic" and ask what am I concerned about? All right? And you find that there will be cases where the analyte is DNA, the analyte is RNA, the analyte is protein, instances where it is heritable, instances where it is not heritable but it is communicable, instances where it is DNA but a somatic mutation. All right? DR. COX: Exactly. And you use those examples. MR. HOLTZMAN: And I think that was the whole conversation that we had in the meeting which Larry wasn't at when we talked about, yes, we are a Genetics Subcommittee--all right?--but all of it couldn't be instances of the papers that Zeke brought forward. And I think there was only one out of the six or seven which was a genetic study. And the point he was trying to make heuristically was the kinds of studies that are undertaken and where the ethical engine could get going of concern is not specifically genetic. And I thought we had come to that conclusion. All right? I don't mean to flog a dead horse, but-- DR. MURRAY: That is okay. DR. GREIDER: So, Larry, why do you want to limit it to genetics if not limiting it to genetics is more inclusive, would include more things. DR. MIIKE: No, no. I mean-- DR. GREIDER: What is the reason to-- DR. MIIKE: I am not limiting it to genetics. I am opposed to saying that the issue that we are looking at--tissue sample research--is separate from genetics, and it is not. To me it is essentially the same. I mean, the concerns that are being raised here. Are you telling me that the future of research is diverting away from the genetic basis of the tissue samples? Isn't that where the research is heading? I mean, you know-- MR. HOLTZMAN: I think research is-- DR. MIIKE: --look at me as the lay person. And you are trying-- You scientists are telling me our concern about tissue samples is not primarily genetics or not solely genetics. Convince me about that. MR. HOLTZMAN: Whose concern? That the individuals, the lay people's concern or-- Whose? DR. MIIKE: No, no. What you folks have just raised, which is that this is a tissue sample issue; it is not a genetics issue. I am saying it is a genetics issue within the tissue sample subject. Or have I just been hearing everything wrong just lately? DR. GREIDER: I think that it limits what you will discuss about something to say solely that it is a genetic issue. It is a biology issue, which is greater than just the term "genetics." DR. MIIKE: Well, isn't that what the concern here is? MR. HOLTZMAN: I think you just crystallized it. All right? If what I was proposing to do was to go in and analyze whether or not the tissue had an X and Y chromosome or X and X chromosome, I don't think there would be a heck of a lot of concern being generated and people wouldn't be exercised about the issue. So there is an example of genetic research which is non-concerning. On the other hand, take the HIV example. If you are going into tissue and you are finding out something that is non-genetic, it does generate a concern. Okay? So the only point we are making is that, when one starts to think about it, that the sources of concern all relate to characteristics of the nature of the information you are generating and there are implications for the individual. DR. MIIKE: But, Steve, what I am saying is that, to me, that goes all way over my head. It makes no sense. MR. HOLTZMAN: Well, I am sorry. DR. MIIKE: No. I am-- MR. HOLTZMAN: I mean-- DR. MIIKE: The example you use about what is the relevance of HIV to tissue sample research? MR. HOLTZMAN: What is the relevance of HIV? DR. MIIKE: Yes. MR. HOLTZMAN: I think-- DR. MURRAY: Bernie, I think-- MR. HOLTZMAN: Bernie just went through it and gave an example. DR. MIIKE: Okay. But it is because it has affected the genome, right? MR. HOLTZMAN: No. DR. MIIKE: No? DR. MURRAY: Bernie? DR. LO: Well, maybe one way to try and resolve this is to try and say that there are certain types of research that raise profound ethical concerns. They have to do with telling someone who is relatively asymptomatic that we can very strongly predict what is going to happen to you in the future, and it is going to effect other people as well, and there could be some stigma and discrimination. DR. MIIKE: Right. DR. LO: Those are not exclusive to genetic information. And the HIV example and cancer and other things are examples. But I think what we want to say is that some of the concerns are genetic examples and we expect there will be other genetic examples. And to follow up on Larry's point, to the extent that there will be more and more genetics research being done, we want to kind of anticipate those problems. But the issues we are raising are not specific to genetics; they spread over a whole lot of other-- MR. HOLTZMAN: And that is the point. What you just did is to forget you understood the word genetics. What are the characteristics--almost the social characteristics--that we care about? DR. MIIKE: No, no. I agree with that. I mean, I agree with that. But I am looking at this-- I mean, when we talk about genetic information and the implications of that information, it is like other medical information. I agree. But I am looking at the specific issue of tissue samples. Yes. MR. HOLTZMAN: Right. There are all sorts of analyses that are going to take place on these, Larry, which are not just looking for heritable genetic mutations. You are going to be looking at somatic mutations, you are going to be looking at proteins, you are going to be looking at any number of different things. You could be getting all sorts of kinds of information out of this that are not-- DR. HANNA: Steve, I think-- You keep referring to this. I think you are misinterpreting what I am having a problem with and perhaps what Larry is having a problem with. I don't think either one of us is saying we are only talking about heritable mutation or family studies or, you know, linear transmission of disease. I think we are talking about the fact that DNA is stable in tissues. Other forms of medical information that you can get out of those tissues is not necessarily stable. And I think what-- It is-- Perhaps there is not as much disagreement as everyone thinks there is, but it is-- Maybe we shouldn't say "genetic;" maybe we should say "DNA-based" information. MR. HOLTZMAN: But-- But-- Now you are hanging the issues of the public policy on the stability of the analyte, which I really-- I am confused, Kathi. I mean, why is that important? I mean, if I flesh-- More and more of these samples are going to be frozen. All right? And so in fact you will be able to recover other analytes as well. All right? With respect to urine, which you said doesn't belong in the report, I think maple syrup urine is a genetic condition which one can go and look at urine and, what is more, one can get proteins out of urine and be able to-- So in fact, in a relevant sense, it is tissue. I mean, what we are talking about, or what we care about, and where the engine is going to end up going has to do with issues of informed consent, issues of potential predisposition, issues of stigmatization--all of those things--and the notion of one's relationship to a sample. And all of those issues are not a function of the analyte, are not a function of the nature of the test. DR. HANNA: Well, I think that-- I don't think that the report so far is suggesting that these issues are unique to genetics. I mean, in fact-- MR. HOLTZMAN: I am not-- DR. HANNA: --if you say repeatedly that they are not unique to genetics, then I would think your bases are covered. But I think maybe-- And I have asked for four months for somebody to please write, explain, give me a reference--or whatever--that I can incorporate that will counteract, you know, the tenor and the tone of what is disturbing you. MR. HOLTZMAN: Well-- DR. HANNA: I can't-- I am not convinced, in a way that I can sit down and write it, so-- MR. HOLTZMAN: And that is why-- I am not so much referring to the report. It is just that I picked up a comment, or twice in the last 15 minutes that I was here--and I got here late and I don't know if it was discussed earlier--but I had thought that the committee had discussed the issue and had come to a position. That is all. DR. HANNA: But the position has to be justified in the report, and we don't have that. MR. HOLTZMAN: We-- DR. GREIDER: So, I mean, Zeke pulled out some very nice examples of where tissues were used prospectively, retrospectively, and we had them all in our book, and he had labeled them. And, as I recall, most of those were not using genetic information by any of these definitions that we have given. So if we can go back to those actual research papers that he pulled out for us and look at what are the issues that are discussed there--unfortunately, I don't have them with me--but my recollection is that most of them didn't have anything to do with genetics. That there are issues that go beyond the genetics that are important in tissue. DR. MURRAY: David? DR. COX: This is a very interesting discussion because everybody is right. And it is the relative weight that people are putting on these issues. Of course there are papers that have been published in the past with respect to tissues that don't have anything to do with genetics. All right? And of course it is true that one of the reasons why our government and the public is excited about medical research is because they believe that genetics is going to offer something real special. So it is where the relative balance is. And for this commission to say it is all in genetics is a mistake, but for this commission to say that genetics isn't where the action is, and isn't where the excitement is, I mean, we would get laughed off the stage. DR. MURRAY: I didn't hear anybody who wanted to say that. What I-- I have a very simple-minded view of this, which is--I don't know--I think mainly that I want to keep things as simple as possible. And so if we are going to articulate a set of principles and recommend a set of practices about how to deal with research in human tissue samples, I would like to just do it as that. The door which gets us in there is genetics, and clearly a lot of the action in the future will be in genetics, but probably not all of it. But all that is fine. I just want to keep it simple. I think we do a favor to everybody involved if we don't segregate and sort of say if you are using this sample for genetic research these are the rules, but if you are using it for something else these are the rules. I think that would be a disaster. DR. COX: Okay. But, Tom, then having said that--I am in favor of keeping it simple, too--but this is the point I made before and I will make it again now is that it is unlikely that we are going to have a single set of rules without any exceptions that takes account of everything. DR. MURRAY: Oh, yes. DR. COX: And you will get-- DR. MURRAY: No argument. DR. COX: And if there are some clear exceptions that we can easily identify, then I would rather face them up-front very clearly rather than pretend they don't exist. And I am not implying that people are trying to pretend they don't exist, but I think that in an effort to keep things simple sometimes we don't want to think about the exceptions. DR. MURRAY: Well, there is simple and rigid. DR. COX: Yes. DR. MURRAY: And there is simple that acknowledges the fact that, in an effort to keep things relatively simple, you may do injustices. And so you try to build in some probably procedural means for responding to obvious inequities. DR. COX: Exactly. DR. MURRAY: This is a problem that you find--and one finds--in the law all the time. I have some good articles if anybody wants a reference on it. Steven Tillman(?) has got a wonderful piece on the tyranny of principles about a decade ago and he sent a report on this. I think we are okay on this. Now, there are differences of sentiment here. I am not sure there is a lot of difference at the end in the substance. Kathi needs a reference. I will give you a reference. I have the reference. I will give you the article that I hope will at least articulate one view of this. We have-- It is almost time for public testimony, but what I would like to do is spend a few minutes getting us back to the concern that Trish raised; that is, what happens if there is information generated, through research on tissues which had been used anonymously, that might be clinically relevant for the person who was the source of those tissues? Just to recap where we have been on this. I mean, Zeke-- I think we are here articulating Zeke's position if we say--because I think he said it again today--he would like to see a pretty impenetrable or one-way penetrable wall, not being able to go back, partly on the grounds that if it is-- You know, at least a couple of grounds. Number one, the kinds of "clinically relevant information" generated in research laboratories are not clear level, you know, they are not diagnostic tests as we normally understand them and standardize them, so there is some ambiguity there, number one. And, number two, if it is really important it gets published and it gets disseminated to the health professionals taking care of these patients and so they will get the benefit; they will just get it that route rather than walking, rather than by breaching a firewall. Am I right? Those are two kinds of standard arguments? Now, over against that we have the kinds of concerns that Trish has tried to articulate, I think, Do you-- Why don't you pick up the thread, Trish. MS. BACKLAR: If there is something wrong with me, I want to know about it. If there is something wrong with me and might affect my family, I may want to know about it. I certainly would want to discuss it with them. But the simple thing, if there is something wrong, I will want to know about it. DR. GREIDER: But that isn't necessarily true for everybody. MS. BACKLAR: That is correct. I didn't say it was. I said it was a private-- DR. GREIDER: So that is the issue that you have to deal with, is that some-- MS. BACKLAR: Correct. DR. GREIDER: --people feel that way and some-- MS. BACKLAR: So I want to put that on the table because I don't think that I am the only person who believes that and, in fact, Bette-- Oh, no, it was actually Tom, I think, who substantiated that point of view-- DR. GREIDER: But if you allow walking-- MS. BACKLAR: --from the focus groups. DR. GREIDER: If you allow the walking back, because there are people that do want to know, then what about those people that really don't want to know? So that is the danger of walking back is that there are people who would-- MS. BACKLAR: I thought that-- DR. GREIDER: --want to not know. MS. BACKLAR: I thought that-- DR. GREIDER: So where does the weight come down to-- MS. BACKLAR: Wait, wait, wait. I did think that was why we did all agree that the consent procedures were--the consent refusal procedures were--very important in the tissue issue so that if you refuse it doesn't come back, but I don't-- I would not want to be cut out because of some procedure that was put in place that didn't give me the option. DR. GREIDER: What about the already-collected samples where there was no such-- MS. BACKLAR: Well, I can't live retrospectively. DR. GREIDER: Well, I mean-- MS. BACKLAR: I am not-- DR. GREIDER: --we are dealing with that though. MS. BACKLAR: Right. Well, obviously I can't alter that in which there is no way back. I mean, it is not-- DR. GREIDER: There is a way back. MS. BACKLAR: It is like Orpheus and Eurydice. If you look back it is over with. DR. GREIDER: Well, there is a way back-- MS. BACKLAR: There is a way back? DR. GREIDER: --currently, but those people haven't said whether they would or wouldn't want to be re-contacted. That is the issue. And if you re-contact them, you might be giving them information that they don't want to know and you are already-- MS. BACKLAR: You are giving them the option of saying yes or no, you see. You are giving them the chance to say yes or no. If there is a way that you can go back, you are at least-- DR. GREIDER: Not if you have a piece of information about somebody and you are contacting them because you know this information and you want to get more information from them. Just by contacting them, that is giving them some information. DR. MURRAY: Harold wanted in on this. DR. SHAPIRO: Trish, just ask the question. You are concerned with future samples. Do I understand that correctly or not? MS. BACKLAR: Yes. DR. SHAPIRO: And in all cases, therefore, there is individual consent, according to this. MS. BACKLAR: Right. DR. SHAPIRO: Therefore, does your issue come down--I am asking a question--to what we provide, what the nature of that consent form is in this respect; that is, whether a consent form contains some options in this regard, or not? MS. BACKLAR: Well-- DR. SHAPIRO: I am just asking a question. I am not-- MS. BACKLAR: No, no. I am actually not going to quite answer your question. It seems to me evident that one should have those options there. DR. SHAPIRO: Okay. MS. BACKLAR: I don't-- I have no difficulty with that. I think that Carol has brought up something which is significant in this and that is that, if something was found out in tissue that was already collected that might benefit me and that I had not been able to give my specific consent to and there was some firewall built, I would be very concerned that I didn't have access to that. DR. MURRAY: David, and then Bernie. DR. COX: So, to say it in a slightly different way, but the same point that Trish is making, as a physician if I find out that my-- My oath as a physician is to do no harm. If I find out something about a person--that they are going to die and I have a treatment that can keep them alive--I have a real conflict if I have a firewall that says I can't contact that person. DR. MURRAY: And they don't know. DR. COX: And they don't know. Because most of the patients that come to me as a physician don't know. It is my duty as a physician, if I know, to act on that. All right? So this is an ethical dilemma. Now, it has recently come up in the context of genetics research--we heard it from Bartha Knopper and it was a big symposium at the American Society of Human Genetics meetings--if you have information, genetic information, from your patient, what is your obligation to tell their family members? In this country, it has been very different from what the answer is in Europe. Okay? Now, what was the conclusion at the American Society of Human Genetics meeting about this? The conclusion was that--and it was a compromise position-- that still you would respect your individual patient but there would be designated examples that would be exceptions of which you would be justified of going and telling the family member, examples that would put them at extreme risk. All right? Thank you. So the issue then is again coming up with exceptions, coming up with the examples of when it would be possible to breach the firewall. And it is the same situation of giving people information back. It is not that you have it open all the time. Carol brings up a good point. Some people want to know, some people don't want to know. So you have to deal with that situation. We are not going to have a million of these different examples, but this is one of them. And just to deal with it. Not that we are going to be able to fix it--I don't think we are going to be able to have a single rule that is going to fix it--but we have to open the possibility of going back because otherwise it doesn't, you know, pass the red-face(?) test. There is enough people that want to know and there are enough people that don't want to know that we have to have options for it. DR. MURRAY: The queue is forming. Bernie, Trish, Larry. DR. LO: Yes. I think this is a really important topic for us to think about, and I think we have some tough issues to think through. One, I think we need to do a good job of elucidating what the conflicting ethical responsibilities and principles are because what is most bothersome to me is the reason we built the firewall in the first place was really to further scientific research and make it more feasible by not putting too much burden on researchers to get detailed specific consent. There are a lot of other competing-- DR. MURRAY: I would very much-- My first thought was to protect the privacy of the people whose tissues are being used. That would have been mine. But you don't think so? DR. LO: Well, I may be more cynical. I hang around with researchers too much. I mean certainly if you hear some of the professional societies, their biggest concern is they won't be able to do research that they think really benefits humanity and science in the long term. But, I mean, privacy of the individual is on that side, but then the right of some individuals to know, and the duty to protect, you know, give them information that may make it a benefit clinically. That needs to be laid out because I think scientists and the public are very confused about those issues and don't realize that there are really pretty fundamental conflicts. Secondly, if we look to other situations--this goes back to Steve's point--this is not unprecedented. You know, HIV again gives you a lot of examples. The procedures for how you go back, under what circumstances, how do you bring in the private physician as opposed to the researcher cold-calling the patient directly, are things that we should all think about. There are better and worse ways of doing this kind of re-contacting. And then there are sort of different kinds of re-contacting. Trish, I think, was talking about clinically relevant information that an individual subject may or may not want to know, but should we at least offer them the option of finding out? Carol brought up another example, which is sort of a twist; that if I take David Cox's model of how I am going to do 21st Century genetic research, I start with a huge prospective cohort study and, out of that, I find the 1 percent of patients of interest, and I want to go back and study them. Now, either I can do it up-front, full consent, contact them a second time and say I would like to sit down and tell you about a study I am proposing, get your feedback, and get your consent. Or I can do it in an anonymized way where I say I am going to not get involved like that. I am going to have the steering committee of my prospective trial add-on to the next battery of questionnaires that comes out in six months some specific questions for that 1 percent that deal more with family history and other phenotypic information. Technically, under our boxes, you know, I have met the letter of the law. Carol brings up an interesting point which is, you know, if the 1 percent, if I am one of those 1 percent and my neighbor isn't, and we sit down and compare our questionnaires, I say, "Hey, how come they are asking me all these cancer questions and not asking you? Why? What did they find out about me?" That is, you know, it seems to me an ethically, you know, shaky situation. And the reason we got there is that there were incentives for some researchers to opt out of a sort of true dialogue with the subjects by sort of taking the anonymized route rather than the full consent route. And I think that, you know, we are building in some very, some incentives that are pushing us away from the ideal of research as a partnership between the scientists and the participant. And I think we just need to be aware that that incentive is going to push some of my-- It is a lot easier for some of my colleagues to say, "I don't have to talk to the patients." Somebody else is hired to get the information, anonymize it, feed it back to me. It is a lot easier for me. MS. BACKLAR: I think also--I said this as though I was a private citizen from a personal point of view, but I actually think there is another issue here which has been sort of touched on in terms of HIV and so forth--there are also public health issues. I just want to put that back on the table. Public health issues. DR. MURRAY: You mean where third parties are affected by the results? MS. BACKLAR: Where it may be necessary to give information to a group. DR. MIIKE: My turn? I don't think you can have a practical policy with all those exceptions and all those individual decisions. The way I would deal with your situation, Trish, is to say here is your informed consent form, in the beginning. And you say, "Can you assure me that if some research is done on my tissue and it is beneficial I will get it back; I will get that information?" My answer is no. Then your choice is to either sign that or not sign it. MS. BACKLAR: But we are talking about tissue that may have been taken without consent. That was the whole point Carol brought up. DR. MIIKE: Well, but if we are talking-- Our proposed scheme is that, for prospective, you can't use it. MS. BACKLAR: For prospective-- DR. MIIKE: You have to give a general or specific consent so, in that case, they would not be able to use it in our scheme. The way I understand our scheme being proposed. MS. BACKLAR: I am sorry. It is very hard to hear in here. Can you-- DR. MIIKE: Well, what I am saying is that in the scheme that we are proposing-- MS. BACKLAR: Yes. DR. MIIKE: --not already collected samples, but samples to be collected clinically or in research, you must give a consent. MS. BACKLAR: Prospectively? DR. MIIKE: If you don't give a consent-- DR. MURRAY: Yes. MS. BACKLAR: Yes. I understand that. DR. MIIKE: So what I am saying is though is that if you then say but if in the future something happens and it is beneficial to me, or if it is something significant and I want to be assured that I know about it, and can I give that assurance, then your choice is to say, "Okay, I won't sign," or you accept the consequences of that and sign the form anyway, given that knowledge. But I don't think we can have forms and consents that vary all over the place. One last comment is my disagreement on the tissue sample. I just suddenly realized that I was focusing on the community aspects of it and we are dealing with individual with no community, so in those instances then, then genetics is not the only issue. So I would agree with you when we are talking about individual harms and benefits without the community aspect. DR. MURRAY: We are going to run out of time. Arturo and Carol had indicated a desire to speak. Let me just say how I would propose to play it from here on in. To hear Arturo and Carol, and if there is anything urgent that must be said in response to them: we will have that. To ask-- I believe we just have Mark Sobel speaking as public testimony. And then to use the remainder of our time to make our plans for tomorrow. Arturo? DR. BRITO: I just want to briefly respond to what Trish is saying. When I originally heard Trish make a comment, it made a lot of sense about of course if you take a tissue sample of mine and later on you find out there may be some information about me, of course I would want to know that. But going along with what Larry says it seems endless; that there are so many scenarios--just looking at the table here--so many scenarios. When we talk about anonymous, we are talking about anonymous really to the individual but not necessarily-- Well, we are also talking about the researcher, but it is a very paternalistic way of looking at it in terms of-- If you take a tissue sample of mine, unless there is a way of me having accessibility to that tissue sample in the future--me as the patient or as the person that the research has been done on--unless I have accessibility to that, then what you are doing is leaving it up to the physician/researcher to determine what is good for me and what is not good for me. So going back to what Larry says, it is just endless what you can do here. And I think that you really have to make the decision at the beginning whether or not you are going to agree to the research knowing that you are not going to have accessibility to that, or that no one is going to tell you of any problems with that. I see Trish shaking her head, but unless-- I am not sure there is a simplified manner of doing this. It just gets so complex. DR. MURRAY: Carol? DR. GREIDER: I think part of the misunderstanding here is that, in some cases, we are talking about tissue samples that are already collected and, in other cases, we are talking about prospective collection of samples, which is part of the reason that Zeke laid out this nice grid, which now has two rows and multiple columns. And so what I would find very helpful--we have had a lot of discussion about this--it would be very nice to have, you know, written down, so that we could look at them, what all of our recommendations are for each one of those different instances. And then we could discuss them piece by piece, rather than having misunderstandings about whether it is prospective or retrospective and jumping back between the two. DR. MURRAY: I think we are there actually on most points. I don't think we are there on this issue of do we ever permit breaches of the firewall. DR. GREIDER: Absolutely. But to go back and forth and have these misunderstandings is a little bit frustrating. DR. MURRAY: Yes. Especially-- DR. GREIDER: It would be nice to go through and discuss that issue, but on the right side of the prospective versus retrospective. And we have to discuss both of them. And I agree that I think we have talked about all of the boxes, but I don't think that, you know, we have ever really articulated exactly what is going to happen in each of them. DR. MURRAY: Well, maybe not, but I think we pretty much know, for each of them, what we are doing. DR. GREIDER: But this issue between Larry and Trish-- DR. MURRAY: Not for every question. DR. GREIDER: --I see as one being a prospective issue and the other being a retrospective issue. DR. MIIKE: No, no. No. DR. MURRAY: No. I think it is-- DR. MIIKE: No. It is a question about how much she wants to be able to know in the future, when you can't tell at the time that you are giving consent what is going to happen. And I am saying that you cannot devise a policy that will satisfy the Trish's of the world in every instance that she wants. And so you must make a choice at the beginning about either to say, "Well, then I won't participate; I don't want to participate," or "I will participate given those limitations on what is accessible to me." I mean, I think that is the only kind of practical choice that you can make. You cannot make these very specific consent-type agreements and promises down the road that cannot be fulfilled. DR. BRITO: Can I just-- I know you want to get on to the next thing, but when we are talking about these boxes, we are talking about the-- What I am seeing here is the anonymous tissue and then the identifiable tissue. That is identifiable to the researcher. Unless there is a way to make it identifiable to the individual involved in the research, then I would agree then there is a way. But I am not sure if that is logistical. Maybe David or somebody who does a lot of research can answer that. But would it, you know, maybe at the beginning, you could make some access code or something so people can identify their tissue in the future. I don't know. But I think unless you can do something like that, I agree with Larry. DR. MURRAY: Steve? MR. HOLTZMAN: The sense in which we have been talking about anonymized is research conducted in an anonymous fashion by which the paradigm would be that there is a sample, it is associated with an individual, it is held by someone who is distinct from the researcher, the researcher knows it by a number--all right?--but the researcher doesn't have the ability to go and identify the individual. So the issue boils down to here, in your consent process--we will come back to the retrospective ones in a moment; let us deal with the prospective--whether or not you are going to include in that consent either a statement that says there will be findings made, some of them might be relevant to your future health status, but you will not know about these. You will not be informed. Or rather you will create a process, such as for example Yale has a process which Levine describes in the notes from the national breast cancer stuff, the Arena Primer stuff or, as you see in what Primer struggled with, should we have something where it can be a very generic statement. If a finding is made in the study which is potentially beneficial to you, or could be actionable by your physician, your physician will be informed. Whatever. A mechanism would be set up. You don't have to be specific. All right? Just say it is basically that you leave the avenue open to go back if there is benefit. The downside on it? The downside is if the major concern is privacy--the major concern is discrimination based on privacy--have you put the, have you opened up, by opening up the possibility of going back, have you created more problem than you have solved? What we clearly heard I think from the fora, the public fora, is people think, "Hey, I can learn something that, if it benefits me, I should know about it." It just seems like the human thing to do. All right? DR. MIIKE: That is not the situation I am talking about. I am talking about the research down the road after that one. MS. BACKLAR: Oh. MR. HOLTZMAN: But if you think about-- In the case of the sample collected in the clinical context where there is no specific contemplated research, all of the research is down the road. The national breast cancer example is specifically oriented to stuff collected in the clinic. DR. MIIKE: Oh, no. That is my point. When you know what you are going to be doing in that research, of course you can make promises like that. But it is the subsequent uses that I am talking about. MR. HOLTZMAN: Well, that is what I am talking-- DR. MIIKE: And those are the kinds of things that she wants to-- MR. HOLTZMAN: Which is what I am talking about, too, Larry. DR. MURRAY: Yes. MR. HOLTZMAN: I am talking about that. DR. MURRAY: And I think that is what showed up in the Primer Conference and what actually showed up in at least the mini-hearing that I attended. MR. HOLTZMAN: Right. Because it is also the case it is in that future research and/or things that come up in the research that you find out which may not be the object of your study even to begin with. Okay? DR. MURRAY: Trish has something to say on this-- MS. BACKLAR: It is just a-- DR. MURRAY: --and this may well be something we are going to have to talk about again tomorrow. MS. BACKLAR: It is just a request. I would like to have in front of us--maybe tomorrow if it is not too difficult--Bartha Knopper's remarks that David alluded to because I remember them but rather vaguely. DR. COX: Just very quickly, Tom? DR. MURRAY: Yes. DR. COX: I think you articulated beautifully. You responded to Carol's challenge and articulated beautifully where, with respect to the boxes, this point was. We were in prospective. And also the options. We either have a process for going back or we don't. And a final point that you made that I would like to really emphasize is a motivation for doing this is different public interest groups and different IRB groups really think that this is something that is worthy of consideration, even though it is difficult, Arturo, as you point out. It is very difficult. You know, it is hard to imagine how you can do it comprehensively, but is it worthwhile thinking of mechanisms? Okay? Is there any mechanism that is possible? Well, these other groups are thinking of such mechanisms. In some ways, we should at least consider potential mechanisms. DR. MURRAY: An historical note. I was on the committee of the ASHG(?) that wrote, with Bartha, this paper that she spoke from. And basically the paper, as I recall, simply adopts the sort of points to consider of the previous President's Commission article about when, if ever, do you breach confidentiality under certain circumstances. And I don't remember the exact list, but there are three or four things--some of you here may have them memorized--that might fit quite well in a kind of recommendation that we would make in these circumstances, so they would be the rare occasion when the firewall might be breached for the patients, for the tissue contributor's benefit. But we don't have any more time to talk about that today, I am sorry to say. I think we owe-- I apologize to Mark Sobel for putting his testimony off but, Mark, may I ask you please to take the microphone? And if you don't mind one more time indulging us with the ritual of identifying yourself and your institution.