DAY 2: AFTERNOON SESSION FURTHER DISCUSSION OF HUMAN BIOLOGICAL MATERIALS REPORT - Dr. Harold Shapiro, Dr. Thomas Murray and Commissioners
DR. SHAPIRO: In a few moments we’re going to start with some cases that Steve was going to present. We’ve sent a scouting party out.
DR. MURRAY: My luncheon colleagues actually asked me to be sure that the chairs of this next session—we don’t have that much time, it will be a bit over an hour—that we be quick with the whip and keep everybody on track. People have even authorized me to throw things at them if I felt that they were getting off the subject. Again, I hope in talking about the cases we can, in each case we can think three ways about it. Number one, does it fit in this conceptual scheme that we have and, if so, where. That’s question number one. Question number two is what are the significant interests, ethical interests implicated, and question three is what are the protections that might be available and useful in that particular kind of case. Carol, did you want to quickly throw up the scheme again, just so we have it? Carol may also want to say a quick word about future impact.
DR. GREIDER: This is the outline that we had gone through this morning and this is dealing with material that is already stored in repositories. There is another issue that we, of course, have before us which is material that will be collected in the future with the future being tomorrow, essentially—not some indefinite date. That is, the future is not a very distant future. So this is exactly the same thing that you saw a minute ago with this whole half as stored material, identified/not identified being the same scheme that we just had. And this just breaks down future material into material that is collected in a clinical setting versus material that is collected in a research setting. And everything that follows is identical to the overhead that we went through this morning. That is, this breakdown—not identified and identified—is analogous to what had been broken here, not identified and identified. And then there are three subcategories in each of these. So if that breakdown is clear, what I’m going to do is to put up the more simple version so that we can talk about more clearly. So if my fellow Commissioners can just keep in mind that when we go through this in the future, we can just substitute instead of stored material, it would be future collected either clinical or future collected research. And then all of these subcategories will be the same.
DR. SHAPIRO: Steve, we would like to turn and consider some of the cases that you have proposed, particularly in light of what Tom said to present the cases as briefly as we can and then consider how it fits into such a schema as this and what the protections might be appropriate in those cases.
MR. HOLTZMAN: Just for the genesis of this, I went out and sent a note to people at the company to come back with examples of kinds of studies that we did or do and how these issues may be at stake. And Eric, these notes are a synopsis, I think, of your discussions with Lena Wu, who works in our technology licensing group. In terms of this schema, for what it’s worth, I asked people to focus on this issue, this box, when you come down to it. The reasoning being that the least ethically problematic kind of case is this box—how do I do this? Because there may be issues of community identification, but certainly in terms of individual identification, they are not at stake. And certainly over here, where you’ve got actual identification of the individual, you’re clearly going to have the most robust issues of consent involved and the highest levels of protection. So it always seemed to me that the cases we’re really going to struggle with are here. Now, with respect to this, again not traceable—I take that to mean that it’s provided to the investigator in such a manner that they don’t know the individual. They have clinical information, not just the sample. It’s clinical information but it’s insufficient to identify the individual, and furthermore, the person in the pathology lab back here with the material can’t tie that sample and clinical record that’s been given to me, the investigator, to it as well. So when I come up with the research result, they can’t tie it back either. So what we struggled with in the Subcommittee—at least in my understanding—was the need for samples provided in such a way with the associated clinical information such that additional longitudinal clinical information could come forward. And so the cases that are written up in front of you, I ask the investigators of the company to ask, "Why is that important?" And I think there are a few things that are illustrative in the examples and I think you all have these. The first point under Case A, this is from the person who actually runs our cardiovascular and neurosciences program, we never need to know that it’s Jane Jones. So we couldn’t imagine a case in which we needed to have personal identifier information, but nevertheless, we needed to have the longitudinal information for the reasons cited in this case. And I think a couple of points that come out from this, and I think Eric summarized them, is the kinds of, what I’m going to call biochemical interrogations we do of these samples are multiple. They are not just mutational analyses. Much will be happening in the future in terms of looking at changes of gene expression, looking at protein changes and whatnot. And that the value of these or what we need is—if you imagine the sample comes in and we interrogate it, what we’re interested in is with outcome. So if I look at these changes in various biochemical parameters, what does that mean in the long run? A good analogy would be something that we’re doing. An example of this would be in the area of cervical cancer. I think people are familiar with Pap smears and whatnot. You get classification of Pap smears by pathological condition: CIN1, CIN2, CIN3. What one is ideally interested in is being able to get molecular markers that correlate with those changes and also are indicative of when those changes go on to a neoplasm or not. Zeke, I’m in your territory here. So that sort of drives to the issue of the longitudinal information requirement. Tom, you want me to address specifically, what now?
DR. MURRAY: Let’s see, do we understand what box? Does everybody agree that goes in the—which box does it go in?
MR. HOLTZMAN: Right. From our perspective, we want it to be in this box, all right? We never need to walk back to the actual—we, from our perspective, the investigator’s—never need to know who the individual is. If there’s a way in which the information can come forward without knowing who the individual is, that’s fine; that’s better. The motivations for going back therefore, are not having to do with the investigation or the research. They are more motivated by issues that people have expressed that are clinical reasons, such as you find out that there’s been a misdiagnosis and from a human clinical concern, you want to be able to go back. But that’s not constitutive of the research enterprise. Alta, you seem to be about to ask a question.
PROFESSOR CHARO: The issue is never going to be what the researcher needs or wants. The issue is going to be whether the possibility exists for the walk-back because the possibility existing means that an ethical dilemma could arise in the future. So I want to understand that what you’re suggesting is that we focus here on a scenario in which we have this magic encryption technique that indeed does allow information to flow to the researcher for longitudinal study purposes. But that through this magic encryption it’s not possible. It’s not only that the researcher doesn’t want to, but that it’s not possible for it to walk back, correct?
MR. HOLTZMAN: And again, I think at the last meeting I raised this issue. When I look at how the Subcommittee thought about this, why we moved to this notion of being what we used to call "used in an anonymous fashion," the question was if that meant this box, then you couldn’t get longitudinal information by definition. If you could get longitudinal information were you, by definition, cast into this box?
PROFESSOR CHARO: What I’m asking is for the purpose of the scenario that we are going to discuss, can you tell us, are we going to premise the discussion on the idea that there has been an encryption scheme developed that does, in fact, allow for a one direction only flow of information from the repository to the investigator.
MR. HOLTZMAN: Okay. What I can say in terms of our studies now being conducted, in terms of an encryption scheme of the type where it’s a computer doing it, the answer is "no." We conduct our studies in such a way that there is the possibility of walk-back as well, given the techniques of encryption that we are using.
PROFESSOR CHARO: So which scenario do you want us to discuss, Tom?
MR. HOLTZMAN: We don’t have access at this point, the way we effectively make it not reasonable/feasible to walk back is that effectively there are firewalls built. But those firewalls can be broken. It’s not an encryption scheme which is unbreakable other than by having to do calculations for longer than our lifetimes.
DR. SHAPIRO: The firewalls are only designed to withstand heat at a certain level for a certain time. So now may not be so bad. It takes some effort to get over, to you can get over there eventually.
DR. MURRAY: So what I’m hearing is that you have—I’m not sure what I’m hearing. Are we in the encrypted feed-forward and that’s it, or the encrypted feed-forward and walk-back? What box?
PROFESSOR CHARO: Steve, if I may? Your current situation is one in which you are at encrypted feed-forward and walk-back. That’s what’s possible, even if that’s not what you intend to do. Just for the sake of clarity, it’s worth noting that current regulations have something to say about the situation. Current regulations say that there is a human subject involved, that this is a protocol that is not exempt from IRB review. And that the IRB, therefore, has to review the protocol for its risks and benefits, etc. That consent from the original tissue donor is ordinarily going to be required unless you meet the four criteria for the waiver of consent that were laid out in chapter 4, when Melissa was writing up the regs. And minimal risk is one of those criteria, but another crucial one is that it be impracticable to reach the tissue donor. So under current regulations, which we could choose to change but we should at least know what they say. If it’s possible to go back to the tissue donor, we have to in this situation. That is the way the current regulatory system works. You may, nonetheless, be able to get expedited review under the IRB if it’s minimal risk, which it may very well be in many situations, but you do have to get consent from the donor if there is a feed-forward and walk-back. It’s just kind of the way it is.
PROFESSOR CAPRON: Could I add one thing there, Alta? Aren’t we talking about here someone who is currently, in every real sense, a participant in a study? This is a person who is going into the hospital and his or her clinical data is being converted into research data and fed forward to a person conducting research. There is, obviously, no difficulty in contacting that person. You know who they are, they are coming into your hospital, and you’re providing that information to a researcher.
PROFESSOR CHARO: I’m not disagreeing with you, Alex.
PROFESSOR CAPRON: Okay. I just want to be clear that it isn’t—I don’t think we get to the point that you were getting where you would say, "Is this a person where you get a waiver of the consent requirement, because this is stored data, although it’s identifiable—are there reasons to waive because of difficulty?" How can there be a difficulty?
PROFESSOR CHARO: I’m not sure. But my purpose was entirely simply to set the stage for what is currently required so that when we discuss what we would like the protections to be, we understand if we’re talking about additional things for IRBs to do or an actual change. Because they can’t violate the current rules of impunity.
PROFESSOR CAPRON: I agree with you. That’s why I thought these discussions were always going to be moving out of the boxes to the decision points that follow below the boxes. Which is where the real action is.
DR. LO: We have two candidate boxes and sort of an example that might be either—and I thought we wanted to push ahead and say in each of these boxes, what are the interests at stake and flowing from that, what are the recommendations?
DR. SHAPIRO: I agree, and let’s just assume for our discussion coming up at the bottom right-hand corner there. So let’s just assume to top that out. Before we do that, Zeke has a—
DR. EMANUEL: I have three or four examples. I don’t know if they would be helpful, I could try to thumbnail them. All of which had been distributed in previous notebooks three or four months ago but they may be worth reminding. The abstracts for almost all of these papers and many other kinds of uses have been distributed in prior notebooks. One is this case of looking at the tumor angiogenesis factor in breast cancer samples. Folkman thought he had an antibody that could identify tumors that caused blood vessels to arise. Went to the Brigham, got 104 slides of women who had been treated 5 to 10 years previous to the date he initiated this study. They were gotten with the names scratched out, but with clinical information. So he knows who relapsed, who died, who has had no problem, what treatments they received. Did his study, I presume without informed consent—I haven’t asked him, but it doesn’t suggest. In that case, I think it certainly could be encrypted feed-forward. There was no attempt that I know of to walk backwards and identify the people with the results.
MR. HOLTZMAN: Let’s not confuse whether there was an attempt to walk back with whether—
DR. EMANUEL: There certainly, if he ripped up the sheet of paper—I don’t know how it was done. But here’s an example, okay? Carol asked, "Why is it coded, not traceable? Okay, so it’s coded, not traceable. Here’s another example. The Nurse’s Health Study, there was a controversy over silicone implants. The Nurse’s Health Study had x thousands of women, they had data, they had never intended, as best as I can tell in their informed consent, to correlate outcomes with the silicone implants. They, however, went back into their database and correlated. These women who had silicone implants have a higher rate of rheumatoid arthritis and other health problems. And that was done in a research setting at a one-time standpoint. Another case of exactly that kind of study was done at the Mayo Clinic with women who had come in for clinical care, not as part of a research study.
DR. COX: Where was that last one, Zeke?
DR. EMANUEL: That’s the Nurses’ Health Study—
DR. COX: Where, in terms of our—
DR. EMANUEL: I think that is traceable because I think it’s encrypted feed-forward.
DR. COX: They were accumulating current information?
DR. EMANUEL: They kept sending out to the women, going into a computer into a database, but no names attached to it. Sorry, thanks, David. And the last example which I bring up because it’s a similar kind of study, but it’s the Mayo Clinic going through its wonderful clinical database of people who have been treated at the site for clinical reasons, for breast implants. Same issue, they went to their clinical records and looked through, got all the women in Olmstead County who had gotten breast implants and then looked in their medical records to see what the outcomes were. And that case, again—it’s not specified in the paper exactly what they did, but they could have done it, I think, encrypted feed-forward or encrypted and not walked back. Or they could have done it "coded, not traceable" by just ripping up the sheets after they had abstracted the information. And that’s in a clinical setting.
PROFESSOR CAPRON: But with all of these, though, as the Chairman reminded us yesterday, the amount of clinical data may be an alternative way of identifying some. I mean, how many black women aged 54 are there in Olmstead County who had breast implants? There may be two and you may have them both in your study. So sometimes—add on the factors, "with six children." Whatever the factors are, you say "well, this is so and so."
DR. EMANUEL: I think the norm with 10,000, 15,000 or even 104 patients out of the last 50,000 that you’ve done—we shouldn’t take that example because I think that’s a pretty extreme case. That’s not the norm, as it were.
DR. SHAPIRO: And then I really want to get back, as Bernie suggested, to deciding we’re in one box here for the purpose of our discussion and just look at the protections or interests and therefore protections we want to provide.
MR. HOLTZMAN: I think it introduces, to this last little point of Alex’s, it introduces conceptual clarity to ask whether the information in the hands of the researcher is sufficient to provide identification of the individual. A name usually is, all right? Sometimes there is a small enough population and sufficient clinical—it will be. So that’s the decision. So I think the question you were raising, Alta, when we initiate these as research studies, full-blown informed consent is involved. I think what the Commission needs to be thinking about is where things are going. More and more of these studies, your paradigm of the family study is irrelevant in genetics. Where we’re going is a situation where we’re going to have very dense biochemical markers, be they the DNA, RNA, protein and all that. Where more and more of what you want to do is be going into broad populations. Which means by definition, what you’re doing is you’re going to the pathology labs. And so the pathology labs know right now that they are going to be accumulating samples which are likely to be used in research. They always knew it, but they know it even more now. So when we find ourselves working with individuals now in labs, more and more we’re sending up tissue banking relationships with pathology centers. And the difficulty you run into is that the kind of robust consents we have traditionally used in a research study don’t really work in the context of the pathology lab that is collecting it in the clinical setting. And yet, we know we are going to be conducting research. I think that’s the issue one is struggling with. It is something you were raising, Alta. If you go to the chart which OPRR has handed out, the first question is are you dealing with human subject research? Well, when we have got a sample from the pathology lab as opposed to in a research context, there is no intervention or interaction that wouldn’t have happened. We don’t receive information that proves sufficient to be able to identify the individual, hence the understanding was that it was not human subjects research. At least that’s how the research institutions interpret that. I don’t know if that’s consistent. Now the next question is if there was no interaction or intervention and there is not information sufficient to provide identification, but there is a continual accrual of additional clinical information going forward, are you still outside of human subjects research or have you somehow come into it?
PROFESSOR CHARO: It probably makes sense to save for a little bit later the kind of detailed step-through on the regs. But I would heartily endorse the notion of simply settling for the moment on the case that Steve presented, which was in fact one in which information can flow forward. And regardless of people’s original intentions, is capable of flowing backward and identifying the interests that people have, both in being protected from harm and in receiving potential benefits.
DR. SHAPIRO: I agree. I think we should carry forward as if we’re in the bottom right-hand corner there and identify the interests and protection we’re interested in. And then we’ll worry about the others as we go along. Let’s see what people have to say about studies that are characterized in that fashion, such as Steve’s example. I think it’s an interesting example.
PROFESSOR CAPRON: One interest that I will put on the table—aren’t we at that point? Okay. What Buchanan talked about is being told that you’re in a research project and being able to say "yes" or "no" to being a subject independent of whether other people looking at this would say that you’re at high risk of physical or financial or social harm from it. Just the notion of being a participant in something that is viewed as giving something; "I’m willing to contribute to research." That is an interest. Alan suggests it in here, but he doesn’t fully, it seems to me, address that. One thing he does is to move very quickly to a notion; "are you saying that your tissue is your property?" And he correctly notes that the Moore case said no, property is not the right way to analyze it and put it in terms of the fiduciary obligation of the investigator, who was also the physician, to inform you that he had an interest in this case, a pecuniary interest that might lead him, as your physician, to do something. I think that’s fine for describing the Moore case. I don’t think it helps us that much when we’re talking about samples that were collected by someone who was in a physician relationship and who was not influenced. And there’s no reason to think that they were influenced because they wanted to contribute to a databank and get your spleen into the databank. They only wanted to treat you. But the pathologist who was taking it and looking at the spleen and then giving back some clinical information, was going to hold onto it. I think the present, this Chart 1 that Steve just reminded us about, addresses that because the question, for me, has that sense of is the clinical decision being influenced? And the answer may be "no," but even when you get to know, then there’s still the further question that can lead you back into a recognition that a human subject’s interests are involved. Will there be identifiable data of the type that would come with a flow-through that would make you a subject? And then you’re back with a "yes" answer to that question, we’re back in the human subjects thing. I want to try and—I can point you to, I think it’s page 49 of Buchanan’s thing—where he comes back because he’s rehearsing three interests which he says might be important. And he dismisses this one by, I think, mistakenly going back and saying, "Well, we wouldn’t think that the subject has any right, property right in the sense of a claim to profit from the research." And I would agree. But that, to me, does not exhaust the issue. I don’t have a property right in terms of profiting because I have some kind of property interest over my ancestors’ graves and no commercial interest. But I have a property interest in keeping you from invading that space. Yes, I have a property right. The reason I can keep you from coming onto that or disturbing that is not because I’m deriving any profit or that I intend to keep it and sell it to someone, and that’s one reason we have property—property is a bundle in interest. And here it’s an interest of not having something used over which you have an interest. The conclusion from all this—I know Eric has pressed informally a couple of times saying, "What’s really bothering people about all this" as though he was going to approach this like Dr. Freud or something. I don’t know what’s really bothering me about this, Eric, but I do—no, no, no, no. I think Buchanan is writing and speaking in terms of interests other than simply the avoidance of harm. But we really are avoiding a harm. We talk about a right that allows you to assert yourself against that. Here we can talk in terms of interest. One of your interests is in not being used because a basic understanding of what it means to be an agent with free will is that you are involved with other people at your choice and not simply at their choice. We seem to have resolved, and the present regulations have resolved that by saying if it’s just your tissue and nothing about you is attached to it, you are not involved and therefore that interest is not implicated. That seems to be the answer. That seems to be the present answer. I think we should ask, "Is that a full and accurate representation, given the kinds of uses that could now arise?" But overall, we think that’s the case. I can recognize, however, that if I had had a tissue sample removed and someone was now going to be developing a genetic engineering technique that I objected to—or if I were against ever having an abortion done, an abortion technique—the fact that they had access to it might still offend me. Now the fact that I don’t know that it’s mine anymore and that it’s anonymous and it could be somebody else’s greatly diminishes that. And it may be such an attenuated interest and it may be so difficult to allow me to protect it, as to those things that are already stored, that we as a society are going to resolve that by saying—and that’s what Buchanan tries to do to some of these interests. It’s too small to erect barriers to its use. But it still does not seem to me incoherent to describe that as an interest, and an interest which may even be offended in a certain sense. So if we could say to the person, "Well, we know that this wonderful breakthrough and something which you abhor was made with your cells which were particularly useful for that," they would say, "Oh, my God!" It’s like a question of a Jehovah’s Witness child who is given a blood transfusion, and because we believe in saving the child’s life, and the child later looks at that and says "I’m now damaged forever in my own belief system." We weighed that person’s life against that interest and we chose their life. But we have to recognize that there was another interest which we didn’t give as much weight to, which we had to override.
DR. MIIKE: If it were feces or urine that was the material?
PROFESSOR CAPRON: If it were material for me—it’s material for me. It’s that participation. And I’m not—please, understand me. I’m not saying that I would resolve it differently than the present Federal rules do. The present Federal rules say that material from a person which is no longer identifiable with them, the answer, again on Chart 1—no, no, 45 CFR 46 does not apply. We’re not talking about something where the interest of the individual is strongly enough identified. I think, in fact, as we work all this through that I’m going to say that we probably don’t have to change that. I’m just saying that we don’t get there because there are no interests. We get there because we’re weighing the difficulty and so forth.
DR. MESLIN: In the interest of disclosure, I just wanted to remind those who are observing the proceedings that we announced at the previous meeting that Professor Alan Buchanan from the University of Wisconsin had been contracted to write a commissioned paper for the Commission on the subject, portions of which you’ve been hearing. He was unable to come to today’s meeting, but the second draft of his commissioned paper has been distributed to the Commissioners. I am sorry that you were not able to get it. It will be available on our web site and will be available to you, as I hope many of our materials will be following yesterday’s presentation. So forgive the conversation about a paper which many of the Commissioners have read, but hasn’t been formally presented to the Commission by its author, Professor Buchanan. So I hope you’ll treat that in the spirit with which it’s intended. We apologize for that.
DR. SHAPIRO: Right now we’re trying to think of interests and what protections are needed, if any. Eric?
DR. CASSELL: I’m trying to stay out of this today, but we’re interested in something that ought to become performative. Whether what we’re about to impose is equal to the kinds of things that Alex described or is equal to the kinds of things that Buchanan talks about when he talks about a descriptive problem with a group. And I must say that I started out this trek through the Sahara more convinced that they were a problem requiring rather strict control than I am now. As you go on, I’ve become less and less convinced that this matters enough to have, to impose big problems for the research community. I understand that there are venal people everywhere. I understand that there are untrustworthy people everywhere and somebody may turn around and screw you at any time. That is not the issue, nor is the issue whether some of the harms cannot be prevented in other ways. If stereotypes are used negatively, we don’t stop that by labeling tissue in some way. We stop that at the point the harm takes place. So I must say that all of you, if that was your intention, have convinced me that we have to be very careful before we erect barriers that are much greater than the interests that are injured.
DR. LO: I want to follow on these last couple of comments, because Alex has put his finger on something that I’ve been troubled with. I think an awful lot depends on the nature of the study being proposed. That’s not captured by this schema we have. And I think in the back of our heads we hear Dave and Steve and others sort of say, "These are the kinds of studies that are sort of cutting-edge molecular genetics that will lead to improved diagnosis and cure." And everybody says, "Yeah, that’s a good thing—let’s go for it." I think there are other types of research that we need to bear in mind. In the other half of our Subcommittee, the Committee on Decisionally-impaired Subjects, we’ve had a lot of examples of research that you really question the premises of the research and they’re the exactly the kind of research that Alex described as—I might well feel that, not just I as an individual, but many thoughtful members of society might feel offended that they somehow participated unknowingly in that research. Whether it’s by having a stored tissue sample used or whatever. And I think we really have to put it in a context of, there’s been research on behavioral genetics which has been very pernicious, which often isn’t peer reviewed. I think that somehow we’ve got to take into account that that’s not just a theoretical possibility; it’s something that’s happened historically. If you look at the IOM report that’s still under review because it’s so controversial and you look at the types of studies being done today, I think a lot of people would say, "Why are we doing this research?" It’s really sort of political statements under the guise of science and I think many people would say that bothers them even more than if they happen to have a personal belief about not wanting to participate in research that have commercialization or fertility implications or whatever. And I think that it also intersects with themes that we talked about this morning that have to do with certain communities that have traditionally been discriminated against. The study that we that we were just given today about how fenfluramine challenges and siblings of kids who have behavioral problems. And there’s a lot of behavioral genetics that’s—there’s a whole chapter of the IOM report that talks about what they call antisocial behavior, which is everything from truancy to setting fires to a criminal record. I would disagree with Alex and I think this may be something more important in the context of certain types of studies that historically have been extremely problematic. Somehow before we say that there’s an existing sort of way of approaching this that says it’s not really that big an issue, it would be awfully hard to erect safeguards that wouldn’t cause a lot of detrimental side effects. I think we need to sort of think through—I guess what I’m saying is the worst case of research that many people would find troubling, not just a few people with certain idiosyncratic beliefs.
DR. MURRAY: If I heard Bernie correctly, you’re talking about a kind of harm to an interest that Buchanan describes as avoiding use of biological samples that the source regards as impermissible per se. Does that sound right to you?
DR. LO: To follow up on Alex, even if I’m not directly identified as being in the study, even if I may not even—
DR. MURRAY: That’s how he intends it.
DR. LO: What page are you on?
DR. MURRAY: My pagination is 9 if you print it single space.
DR. LO: I just want to say that I thought Alan didn’t give it as much weight or consideration as I would want to in the context of certain types of—
DR. MURRAY: That’s the interest. We need to think about what sort of then protection we might afford that particular interest. One conclusion is it’s a cognizable interest, we understand that. But it’s going to be some rare or so insignificant that we’re not going to build a policy around it—that’s one option. One could imagine a range of options. Another option is to say, "Look, this is significant, perhaps relatively rare and maybe what we need to do is not establish like a whole different category for it, but place something in the review process in which this question at least gets raised by, say, an IRB." Is it plausible that some of the people whose samples might be involved in this process would think it impermissible per se? I just want to sketch out that there are a variety of ways that we might respond to some policy—
PROFESSOR CAPRON: And we do that already vis-a-vis consent, but there are certain kinds of studies which involve sensitive matters where the waivers cannot be used in the same way. And so your notion that you get to this and you still have another question you ask and you only get to know, in terms that you don't have to worry about the regulations if you're not in that category. And if you are, then you need some review.
DR. COX: I'm talking about the same interests that Alex talked about and that Bernie is talking about. And these are interests from the perspective of the person or the research subject, let's just call them that. The person from whom the tissue has come. For me—and I'd like to come to Tom's ways of actually, what are the protections in place—I'd like to say that I see this very much a continuum. Not in the way that Bernie was talking about, although I understand what you meant, Bernie, in terms of the actual subject matter of the research. But I want to look at this as a continuum in the amount of information that the researcher has about me. Whether or not it can be used to uniquely identify me. And to me, that's the specific interest because if somebody has some clinical information from me, like a small amount, like basically what my blood type is. But they don't know my name. I've got to tell you—I'm not too worried about it. But now they know my blood type and they know three other pieces of clinical information. Well, it's actually getting a little bit more relevant to me.
DR. MURRAY: But they have no way of knowing whom you are.
DR. COX: Exactly. They don't know who I am, but the information that they have becomes more interesting to me personally. That's the point. And as it gets more and more information, it becomes more and more interesting to me personally, because it's directly related to me personally. So why I'm doing this interest is because for me, it's a spectrum in terms of the protections that I would like to have. So the interest then, is that I feel more and more. The more information that the researcher has about me, whether they know my name or not, the more I feel that I should be able to be part of the process.
DR. MURRAY: David, I think you're a very interesting person, actually, but I have to say that I don't know that you have any more interest in controlling—say again, it goes forward. It's in a box
DR. COX: We're still in the same box, okay. Encrypted, coded, forwards and backwards. That's the box that we're in, I thought.
DR. MURRAY: So they don't know your name now, but they could find out your name.
DR. COX: And the point that I'm making now, no longer talking about the research subject, but talking about a researcher, me being the researcher. The more specific information I have about any sample, the less comfortable I get without making sure that person is a party to my research. And that in that context, one can have protections that are sliding protections. It's not just whether you have some information or no information, it's how much information and it's more than just whether that information provides a unique identifier or not.
DR. EMANUEL: Are we talking about the future and that box?
DR. COX: I'm talking about today.
PROFESSOR CAPRON: A presently stored sample with new incoming information—
DR. COX: I'm talking about today.
PROFESSOR CAPRON: New incoming information where you can go back to the specific person.
DR. COX: That's correct. Because it's possible. And that's that box, that's what I thought we were talking about. Those are the interests. So I'm really trying to stick very specifically to your charge and the protections are ones for me that would be on a sliding scale. So if we have any strict cut-point, I'm not a happy camper because for me it depends on how much information is there.
DR. CASSELL: So we ought to concentrate our attention on the education of the investigator, not on the specialist. Because actually it's how you came to see this that changes it rather than that specimen per se.
PROFESSOR CAPRON: Every investigator in the country should have to sit through three of these meetings.
DR. SHAPIRO: Okay. We have a number of people who want to speak. Alta and Larry, and then Zeke.
PROFESSOR CHARO: I'd like to speak directly to what's unique about that box which is the walk-back possibility. It is not about the researcher's intentions; it's about the fact that things arise in which suddenly there's a surprising...classic division here which said I have a very protectionist tendency. I've always been uncomfortable with the speed with which we have accepted the notion of enrollment for minimal-risk experiments, whether or not they have some potential benefit, and so although it appears in Appendix 2 with the requirements that we’re suggesting in the actual written recommendations, it’s not laid out. And for the purpose of eliciting public comment, I’d appreciate it if we did that, especially because the requirements are the same in both cases, which is no dissent, and there is room here possibly, especially in the area of minimal risk but no potential benefit, which is where it’s particularly difficult to justify, for something slightly different, like the need for assent as opposed to dissent. I’d like to just lay that out.
On the greater-than-minimal-risk categories, no comments on Recommendation 8, which is the one that involves potentially beneficial research. On category 9, which is the one that Laurie was concerned about, that’s greater than minimal risk, not potentially beneficial. Two things: First, I take seriously the assertion that I heard several times that a very large number of people who are in these populations in fact have the capacity to consent and that therefore is not clear to me that something that says, "Only with their consent can they be enrolled in greater-than-minimal-risk research that’s non-therapeutic," will necessarily shut down research in this area. If indeed it’s true that many of them can consent, there will be a pool of people from which to draw for research subjects. Since the research is by definition not beneficial, it’s no wrong to them personally in terms of their interests in getting experimental therapies, and we will, in addition, be able to see benefits for the population as a whole, which is why I’m still comfortable with a protectionist attitude.
On the other hand—and this is related to Larry’s thing where, I’m sorry, I was getting our side of the table out of order before—what I recall from that exchange, and my memory easily could be wrong as well, I recall that we were suggesting that for greater than minimal risk, not potentially beneficial, you would need either informed consent or an advanced directive for research that had been made out at an earlier time when the person was competent to do so, and that this would somewhat expand the pool of potential research subjects for this category of research. I could be remembering it wrong, but that would seem to me to be something worth considering for this category.