February 6, 1998
Los Angeles, CA
Tissue Samples Report2:45 pm
Thomas Murray, Ph.D., Kathi Hanna, Ph.D., and Commissioners
Discussion on Tissue Samples Report Continuation5:15 pm
Next Steps5:30 pm
Harold T. Shapiro, Ph.D.
DR. SHAPIRO: When I mentioned two oíclock I rather thought that was hopelessly optimistic but weíre only a few minutes after that. But I appreciate people returning so expeditiously. We have really the entire afternoon, whatever that turns out to mean in our minds, to deal with the tissue samples report, and you received a lot of material of various kinds in the book, which Iím sure will be referred to as we go through this. We in fact looked at some of that material yesterday afternoon. The comparisons that the staff put out between current regulations and our quasi-tentative position, vis-a-vis the positions of other professional societies that have an interest in this matter. And thatís generated some discussion, which I think probably foretold, at least in some small way, some of the discussion thatís going to take place here this afternoon. So, with that, let me turn it over to Tom, and ask Tom to lead us through the discussion of this issue. Weíll try to break maybe around 2:30 or something of that nature and then just continue as.... Excuse meó3:30. I apologize. Tom?
DR. MURRAY: Thank you. Thank you very much, Harold. The scheme insofar as we have one for this afternoon is that Iím going to present for a few minutes some of the considerations that Iíd like you to think about. Carol has very graciously offered to present the most recent version of the matrix. Have to try to articulate what it would mean and how it would function for us. She also will help me, I think, on some of the earlier presentationóI invite others to join in.
Let me set a framework. The goal as Iíve assumed of our work on this subject is to come up with a workable, defensible policy. So Iíve just scribbled four virtues of a policy that I hope we can embody in this. One is it should be simple; that is, it should be no complicated than necessary than absolutely necessary. If we reach a point where keeping or collapsing a distinction is about a 50/50 call, to me that says we vote in favor of collapsing it. We keep the policy as simple as we can without doing an injustice. Second, it should be transparent. That is, it should be obvious to a reader, both as to what is required under the policy and as to the policyís rationale. Third, it should show respect for donors. And weíll talk more about what it would mean to be respectful for the donors of tissue. And fourth, it should facilitate research; that is, it should not impose unnecessary or unjustifiable barriers to valuable scientific research.
And I just want toóI put them up there because I want to keep them in mind. There will be a tendency to multiply difficulties. And focus on subtleties. I just donít want us to lose sight of what weíre in the end after. Please disagree with me if you think those are the wrong virtues. Iím sure thereísóothers could improve on that.
Second, I want to indicate where I think we agree on points that are significant. When I say "we," I certainly meanóI believe I mean the Subcommittee. I donít know if I speak for the full Commission on all of these or not. But let me try to mention five points where I think we agree.
Number 1: We agree that there is an important distinction to be made between samples that have been collected prior to whenever the report is effective and samples to be collected in the future, and that our policy should reflect that distinction. If anybody obviously disagrees with that, I think itís probably good if you indicate so right now.
Second: For previously collected samples, I believe we agreed to collapse the distinction between samples collected in the course of patient care and samples collected in the course of research. We haveówe give reasons why thatówe think that distinction probably can be collapsed. We have not agreed to collapse the distinction for samples to be collected in the future. That remains an open item for discussion.
Third: I believe we agree that research is important and that human biological materials, including those collected in the pastóin some cases with minimal or even no concernóare a very valuable resource for science.
Fourth: I believe that respectful treatment of donors is essential, and that will mean several things. It will mean in one instance no use in research when the donor has objected. And the objection can be a general objection; that is like the donor says, "I donít want my tissues used in research, period." Or it might be a specific objection. A second meaning of respectful treatment will be that we should protect donors of tissue against discrimination, against intrusions on privacy or other harms to that individual. We can do that in a number of ways, two of them being by assuring within reason that the sample tissues, which they donated, are not identifiable; or, alternatively, we could obtain meaningful consent.
MS. CHARO: By collapsing the distinction between samples collected in the course of clinical treatment vs. research?
DR. MURRAY: Weíre talking about samples historically collected.
MS. CHARO: I think we lose the opportunity to use the notion that the samples were ever donated, because those collected in a clinical context often are not donated in any sense; they are surgical waste. People did not necessarily donate anything. Even though, even in a research context we say, well, tissue was being collected and donated, although it may be for several different purposes, none of which are currently on the table. You could use the word "donate," by collapsing the earlier distinction, I find myself particularly nervous now when you talk about people having donated things in the context of your respectful treatment of their donation wishes. In many cases, there are no donations and therefore wish.
DR. MURRAY: Carol.
DR. GREIDER: We talked about the issue of clinical care versus research and how they were obtained, and I feel that the consensus that we came to is because there were such a variety of circumstances in both cases and there was no way to really ascertain in many cases what kind of consent was given, that we should assume the thinnest possible or no consent for both cases and give the highest standard of protection that we would give whatever we decide that is. So, because we were going to have the sameówe donít really see them necessarily as the same issue, but the way that we would treat them are going to end up being the same because we donít have any control over them.
MS. CHARO: Right. I have no problem with the collapsing of the distinction if the focus will then shift to what information, if any, exists about their choices concerning the use of the tissue. Itís simply that I think at this point we can no longer use the phrase "donation" with all the connotation it brings to mind...of people having anticipated use and agreeing to it in any capacity.
DR. GREIDER: And we didnít have that in mind. We had in mind that we could not....
NEW SPEAKER: Thatís my term. Itís probably a better term, Alta, because much of it, probably the great bulk of it was donated in some form, even if it was done minimallyóI mean, for decades at least that Iím aware of, people have been given the option of agreeing or not agreeing to have their tissue used for research or education. And, I think itís appropriate to call those folks donors. Itís, I think, beyond question that some tissue is collected probably more recently than weíd like to thinkócertainly in the distant pastówithout even that sort of minimal request. And itís not precisely correct to call such people donors.
MR. CAPRON: I thought your focus group showed that most people were not aware that this had happened to them.
DR. MURRAY: Thatís correct.
MR. CAPRON: So, again, Iím with Alta. Why donít we just describe the fact that the tissue is possessed by the pathologist and not used tissue that they donated. I mean, just totally avoid that phrase where we have good reason to think....
DR. MURRAY: Itís the thinnestóitís the thinnest sense of having to donate.... I think something is to be gained byóby referring to the sources of tissue as donors rather than merely in some sort of neutral fashion or sources but thatís not the central point. I donít want to fight over it. Jim.
DR. CHILDRESS: When you ascribe to the person who did not give consent at any point for the use. As a donor, then you are actually gaining our respectability for the obtaining of that tissue that does not hold, so there are gains and losses, and as long as itís a matter to be sorted out and if the Committee agrees, I think that weíre on the right track.
MR. HOLTZMAN: Maybe the way to express your thought, Tom, is that we believe that sources of tissue going forward ought to be though of as donors and be treated respectfully? With respect to the XTAN collections, we canít make the assumptions that they were donors and that therefore we may treatówe wonít make the assumption they were donors with full-blooded intentions and then weíll have to come up with the framework but on a go-forward basis.
DR. MURRAY: I donít have a problem with that. Iím sorry, actually, that I used the word "donors" in that context if it created a problem. Because it isnít at the heart of what I wanted to say. I think we do agree about the collapsing of the distinction for previously collected samples.
Okay, the fifth point of major agreement, I believe, is that even when individuals are notóeven when the tissues, biological HBMsóhuman biologicaló materialsóare used in a nonidentifiable matter, I think weíve acknowledged that at times the interest of communities are implicated and ought to be considered. Those are....
DR. SHAPIRO: In this case, nonidentifiable refers to individuals as opposed to groups of individuals.
DR. MURRAY: Thatís correct. Thatís correct. So information that goes forward, samples that go forward with all individual identifiers per se taken off, which could be race, ethnicity, sex, whatever. Okay, we have some big issues yet to be decided. I do want to try to offer some distinctions here. Again, if I cause you grief, speakóIím sure you will speak up, actually. Iím completely confident. And I have to accept some of the responsibility for this. There were two different families of distinctions that were being used and not alwaysóthe families were not always carefully themselves distinguished from one another.
The first is tissue that would be used in an unidentifiable manneróin researchóversus the tissue as it exists in its (forgive the metaphor) virginal state in some tissue collection somewhere, which may well have identifiers attached to it. So, the thesisóthe difference here is between tissue collection, which is held in a pathology laboratory or in an institute or the National Institutes of Health where there is identifier attached. An investigator requests samples of those tissues and certain clinical or demographic information about them. Thatís all. No specific identifying information. So, we want to focus onóin a sense what the researcher has. Thatís the first distinction.
The second--and that one I believe that the Subcommittee, at least, felt that that was a significant distinction and a useful one.
The second family of distinctionsóhereís where I think we tripped up last timeóis betweenóthese are among tissues that are used in what weíve called an unidentifiable or nonidentifiable manner, adopting Altaís terminology. There are several different possibilities here. First of all, it might be that this tissue nowhere exists in an identifiable form, that the original tissue bank is nothingóall you have is the tissue and little bits of info, not enough to figure out who theyíre from. The second possibility is what the researcher gets in the researcherís hands has been sufficiently stripped of potentially uniquely identifying information to satisfy a standard of reasonableness, that isóand that there is no retained coding scheme linking back to the samples. So, there are two conditions here, right? Number 1.... What goes to the researcher is, number 1, bits of tissue and perhaps some information. Again, ethnicity, whatever. Not sufficient information to be, given the contextóthis is very contextualógiven the context from where these came from. Very important. And IRBs will have to be sensitive to that. Cannot go back and sayóI can figure out who this came from because I know what bank itís from.
MR. HOLTZMAN: Twenty-two-year-old black womanís the only one that....
DR. MURRAY: Right. Right. You know, a Denver Broncos fan in Cleveland. [GROUP LAUGHTER] Immediate give-away. Thereís probably not even one of those....
MR. CAPRON: That is a differential diagnosis.
DR. MURRAY: Right. And the second condition isóin this group I want to talk about right thereís no coding schemeónumeric, alphanumeric, whateveróthat would link the tissues the researchers received with whatís held in the bank.
MR. CAPRON: No code at all. It doesnít exist.
DR. MURRAY: Canít get back.
MR. CAPRON: So thatís nonidentifiable.
DR. MURRAY: Theyíre identifiable. Itís unidentify....
MR. CAPRON: Those are two categories of unidentifiable.
DR. MURRAY: Right. Andóand the third one is the same as B; that is, it went forward withónotówith some information but not enough to identify. But, somewhere somebodyís got a coding list.
MR. CAPRON: Well, that is to say the sample has a code number on it, and the lab has a code.
DR. MURRAY: Perhaps itís been mailed to a third country. So thatóso that recovery of identification, reestablishing identity is at least a possibility. And I thinkóI didnít sufficiently make clear how I was thinking about the two families of distinction. Now, thereís like a possibility of D and E. Well, thatís okayótheyíre not important. I think we should makeóthe question we have to face is A and Bóremember, A is nowhere is there identity; B is with what the researcher has thereís no way to get identity back. Itís only in C where identity might be recoverable, okay? Do we want to distinguish between A and B on the one hand and C, or we do we think A, B, and C ought to be treated as the same? And I think what Iím hearing from some of us is that A and B are the same, technically; but C is different.
MR. CAPRON: A is where the sample comes from a repository; it doesnít have personal identification with the samples, just epidemiologyóthey just have a whole lot of tissue.
MS. CHARO: Iím calling it unidentifiable because there is no code link....
MR. CAPRON: No, no. Anonymous samples.
DR. MURRAY: Nobodyís got it, not even back....
MR. CAPRON: B... BóThat information is there, but when it is sent to the researcher, it is not coded.
MS. CHARO: Itís coded at the tissue bank but the code is stripped before itís sent to the researcher?
MR. CAPRON: In the repository it says "John Jones" next to the sample. "Eighteen-year-old white male, blah-blah-blah," and they say send me all your 18-year-old white males who have leukemia and they send a whole lot of samples, and they donít send any bitóand they say, "You can put any numbers you want on the samples for your study; weíre not putting any numbers on them--theyíre justóhereóhereís a bunch of sample." So, if you turn around to us and say we want to get back to John Jones and tell you something we found or we want you to have John Jones to tell you something about himself beyond what you know now, it canít be done.
MS. CHARO: Okay. C is the one that has....
MR. CAPRON: A coding, so you could have...either way across the code barrier information could pass....
DR. MURRAY: Potentially.
MR. CAPRON: For scientific reasons.
DR. MURRAY: Alta, this is a very crucial point. It was well worth having it explained more than once. Zeke?
DR. EMANUEL: I just wanted toóthereís a second possibility. Sorry. I want to go to the middle possibility. Because as Alex explained it, thereís no clinical information that goes, but there are ways of dividing such coding schemes where clinical information could travel but you couldnít walk backwards. If youíll remember the woman from the Heart, Lung, and Blood Instituteówhose name I have forgottenóexplained that they do it by having three coding arrangements and destroying the middle one so that you have a name to a number, a number to a number, and than a number to another number and you take ut the first number to a number and you canít walk backward. You simply canít. That still permits you to have a sample with clinical information but no way to identify back to the person. That I would take or I have always understood was in the second category. And I think itís important that we come to that agreement because my suggestion is thatís the best in the majority of the cases.
MR. CAPRON: Itís a refinement, another description for how to get to the point, where the repository and its identifying codes or names is not linked with anything the researcher has.
DR. MURRAY: And yet if I understand you correctly, Zeke, if future information came in under that scheme, it could actually be passed on forwardóis that right?
DR. EMANUEL: On this schemeóthe scheme she identifiedóit couldnít be passed on. On other schemes where you actually donít destroy it but have certain locks and keys that only go one way, certain encryption technologies, you could have a continuous update. I think these are important things to be clear about. Itís not C, because...the researcher canít go back even if you can feed in one direction.
DR. COX: Iíd like to make a point here. To me, anybody can go back. Itís possible to go back, right? And Iíd like to leave us a very important point. Weíre talking about these different classes. Either no one can go back or someone can go back.
DR. MURRAY: No disagreement, David. Do I hear a disagreement from anyone?
DR. COX: Then the distinction is if someone can go back, the question is whether....
DR. MURRAY: Itís reestablishable. Identity is reestablishable. And I think I prefer using a term like that because itís a little fresher. I think itís a little bit more precise. Alta?
MS. CHARO: ... In this middle group in which the researcher could not send information back to the tissue bank in a form that allows the tissue bank then to immediately send the information further back down the line. The researcher has no code by which to alert the tissue bank to which sample has which thing, right?
DR. MURRAY: Yes, I believe thatís correct. The researcher cannot... There is still the following kind of scenario. I donít know if itís realistic so I donít know whether or not we should be worried about it in terms of its characterization. The tissue bank does have the names and addresses. Theyíre asked to send all the samples for women in their 30s, 40s, and 50s who had any breast cancer. There are frequencies of things that we expect to discover, some of which are of dubious but possible clinical significance for people in terms of prophylactic treatment. They could communicate that to the tissue bank and say you now have an opportunity to go and send letters to every person whose tissue was in that sample, because you know who they are, and ask them if they would like to have their tissue specially tested for individualization of this kind of information.
So, to that extent, it offers up opportunities for going back to people that canít exist when the tissue in the tissue bank itself is not at all linked to an identifiable human being, where these options about walk-back simply are not present. What I donít know is how likely it is that this kind of two-step process could become of concern to people. And that, to me, is part of how I would want to consider this middle group.
DR. MIIKE: This is Larry. Can I say something?
DR. SHAPIRO: Yes. Go ahead, Larry.
DR. MIIKE: I think what she is describing as the second one would take it out of the class of anonymized and you would have to go back and get informed consent if weíre going to be dealing with a new research study where you want to get more specific information or identifiables of the people who have donated the tissues. I think weíre mixing the two categories already in that example.
MR. CAPRON: I thought what Alta was trying to achieve was to point out the difference between A and B. In B, at that point youíre no longer saying research, youíre saying you may wish to go to a clinical lab, not a research lab, because your tissues were among X hundred that were sampled and found to have some subgroup of that. Weíre not saying you were one of the people, we donít know who had it, but there is enough of an indication, this is a preventable disease that your cells indicate you may be exposed to. Thatís a whole separate ó
DR. MIIKE: Itís again Larry. Iím looking at that example as more like, to put it unkindly, first, thereís a fishing expedition where you donít really care about identifiables, and then you find something thatís a good hypothesis where you really need to know more precisely who the donors of the tissues samples were, but then that takes you into another realm. Itís a different experiment altogether.
MR. CAPRON: Yes. Yes.
DR. SHAPIRO: David?
DR. COX: And so, Larry, I agree. So letís just go into that other realm for a second, weíre going there, so that weíve done the fishing expedition. Now weíre the researchers who have material that receives no codes whatsoever, and we go back to the bank and we say out of these thousand people that we looked at, weíd really like to study these hundred. And the bank says we canít help you because we donít know who those hundred are because we didnít give you any codes. And so itís not possible for the researcher, either for research purposes to go back to those hundred people, or, if they happen to find something in one of those hundred people that says that person was going to die and they could basically prevent it, they couldnít go back and say who that person was.
MR. CAPRON: Thatís right. They would have to go to the IRB and say are you willing to allow us to send notices to all thousand of these women if theyíre still alive ó and tell them where the ball is in play here, that thereís a 1 in 10 risk of being ó
DR. COX: And the reason for that is because there was no codes. On the other hand, if there were codes, it would be possible to go back and identify individuals.
MS. CHARO: But please notice that the thing that happens here is that if there is at any level a link between an identifiable human being and the tissue at the repository, it opens up these kinds of possibilities like going back to all thousand women and saying weíd like to test you to find out which were the hundred that tested positive on our test. If the tissue bank repository has no links to identifiable human beings, the tissue exists only with demographic information and medical records as they existed at the time the tissue arrived, then this never comes up.
And thatís one of the reasons why Iíve wanted very much to keep these things separate. It may turn out in the end that the rules you adopt are nearly identical for the two situations. But there may still be a few special circumstances that youíd want to be able to isolate and focus on.
MR. HOLTZMAN: So then what youíre imagining, for example, is Beth Israel Hospital has a thousand samples, it just has those samples with phenotypic information but no idea anywhere who they are, so suppose now we do this study with those thousand samples and we conclude whatever it is we concluded, which we would have had we been able to say you really ought to contact all thousand. We canít do that.
MS. CHARO: Yes.
MR. HOLTZMAN: What is the difference between that and then of a newspaper article that says this study was conducted on samples from a thousand people who came from Beth Israel Hospital over the last X years? Is it a lot different? I mean, in one sense, youíre positing ó
MS. CHARO: Wait. Wait. Back up because I didnít follow the details of your facts.
MR. CAPRON: Rather than getting a letter from Beth Israel, you pick up the New York Times and it says ó
MS. CHARO: Well, in fact, this has been one of the reasons why thereís been some critique about science coverage in the newspapers, that itís serving as an information conduit. People do get alarmed, they do start going in for retests of various sorts. It is not necessarily something weíd want to mimic even if that is something we canít control.
MR. CAPRON: But what response does one have to that? One response, which I sort of thought was the direction that David was going a moment ago, is when the researcher comes in with that study design, you say to him donít use that design because youíre not going to be ó the construct that youíre looking for here is going to be the kind of information that you would have an interest in conveying to patients so you can find out more about them. So you ought to use a design which allows that walk-back of the information. Once you have it, deliver it to the actual individuals for whom you found on your research level ó and letís always be clear, these are research lab research results, theyíre not clinical results yet. And the IRB would say yours is a bad design, go out and redesign it. Then there was someone else on the IRB who says, "Wait a second, thatís going to require our allowing without consent research to go forward on identifiable tissues, coded identifiable tissues." And that has another set of problems. Thatís the dilemma as to which design is better. But both of them are theoretically possible.
DR. SHAPIRO: Zeke?
DR. EMANUEL: I would just urge people to think about, instead of parsing distinction upon distinction for the sake of understanding distinctions, letís remember, and I donít want to speak any more as a Commissioner, but the goal is the ethical rules for the use of the tissue. And the distinction in your parsimony way is valuable only if it means weíre going to treat them differently. So I think when we make a distinction, letís suggest how they might be treated differently or lead to different rules for safeguards. Because if theyíre not going to lead to different rules for safeguards, then the distinction, while it may be conceptual, isnít material from the ethical standpoint.
DR. SHAPIRO: Alta?
MS. CHARO: Well, I think actually the difference in the rules already exists, although I know Steve does not believe this. I think that the most obvious, reasonable, and commonplace interpretation of the existing regulations at 45 CFR state that any research that involves tissue for whose use consent could be obtained, and where the use does not represent minimal risk, you have to get the consent. And in light of all of the concerns about the privacy of this information and its possible implications for things like your insurability, notions of minimal risk become difficult to comprehend. But it is very much an arguable nonminimal risk.
DR. MURRAY: I got confused. If somebody ó
MS. CHARO: Let me just finish the sentence and Iíll give you a very concrete example, okay? You get information about mutations that may possibly predispose people to some kind of disorder in the future. They work as contractors for the NBAC staff and, therefore, have to pay for their own health insurance on an individually purchased plan rather than buying in through the Federal group. Therefore, theyíre screened, right?
DR. MURRAY: Right.
MS. CHARO: You want to go back to people and say do you want more information. Itís not even we necessarily have information to give you, itís do yo even want to have more information. And at that point, you begin to get people in this kind of loop where they have trouble answering questions in the future about knowledge of their own conditions, which can affect their insurability. So whether or not youíre still under the threshold of minimal risk becomes complex. And if youíre not and itís at all possible to get back to people, you need to get the consent.
DR. MURRAY: If I understand you correctly, that could conceivably arise but only in the case, in the sort of third group, where some possibility of reestablishing identity exists. Is that correct?
MR. CAPRON: No. Alta is saying if the repository that has the information has names and you could go through this step of saying you gave us a hundred samples, we found that ten of them have this late onset lethal disease thatís preventable, we think itís important that they know, and the person gets a letter in the mail saying your tissues were looked at along with others, the researchers donít know which ones they found but ten of you out of the hundred have this condition, do you want to come in and be further tested by these people who have just developed this new test as part of their ongoing research study. P.S.óOnce you have that information, youíll never be able to answer the question on the insurance ó
MS. CHARO: Worse. P.S. You now know that you have a 1 in 10 chance of having this. My point simply is that the rules that exist may well have trumped some of these questions of whether or not the distinctions do run with different treatment of the situation and the tissue sources.
DR. SHAPIRO: Excuse me, we have several people in line. I agree with Tom that we ought to at least be establishing some discipline in the speaking list. Do you want me to keep it, or do you want to?
DR. MURRAY: Go ahead, you keep it.
DR. SHAPIRO: Okay. Steve, then Carol.
MR. HOLTZMAN: Since you think weíre disagreeing, weíre not disagreeing on what is minimal risk. Itís very clear that the psychosocial harms, risk of insurability, et cetera, et cetera are clearly established as something which rises above the potential for minimal risk in certain kinds of studies. The issue is the sense of identifiability thatís required of the current rule, okay? And coming to Tomís distinction, youíre reading, that is the point youíre pushing here is that in other terminology unless the sample is anonymousófull-stop, anonymousó"ainít nobody knows" that this hunk of tissue belongs to this person, that in itself means it requires consent. And thatís how you read the reg from what I can tell. And thatís how Melissa interprets the reg under A.
Melissaís interpretation of B is what Tom has been calling C; namely, the notion that itís ó no, letís hang with this, it is important ó that is thereís a code. In between is what has been called somewhat ambiguously by others "anonymized," where that sometimes means people that came in and that came in with John Jonesí name attached but it was irrevocably stripped away, and sometimes, and this is how Susan Old meant it in NHLBI or whatever it is, is that no, somewhere it still exists as John Jones is the sample but it was anonymized with respect to when it was handed to Alexís study so that thereís no way of knowing.
Now, with respect to how things are being practiced today, in the overwhelming number of cases of samples out there they do not exist as anonymous samples. They exist in pathology labs where there is a place in which this is John Jones.í So thatís the state of most of the samples. The state of most of the research studies that are taking place under what is believed to be the exemption is with respect to these studies and where there is no code, there is no walk-back. They are, in other peopleís terms, anonymized when theyíre handed off.
So I donít know if we agree or disagree, because it seems to me implausible to say that the correct interpretation of the reg is one in which people have been violating it day after day, year after year with the overwhelming majority of studies. Well, itís a practice. And so if one is saying this is the plain language interpretation of it, one would have to say how is it this practice has arisen in the face of it. I think thatís a reasonable question.
DR. SHAPIRO: Okay. We have quite a number of people who want to speak. Carol, first.
DR. GREIDER: I just wanted to back up a little bit from going through the details of the language of 45, whichever number it is, the common rule, because I think that weíre trying to do here is to lay out a framework for how to think about things. We donít necessarily have to interpret what is already out there to at least get our ideas down on paper and say this is how it should be, and then how do we enact that. Once we get that on paper, then we can figure out, okay, how does that fit with what is currently there, does it jive, does not jive. And so I donít want to get too mired into analysis of what is already out there.
DR. SHAPIRO: David?
DR. COX: I would like to follow up in what Steve just said because I think it accurately describes the state, and also what Carol just said, which is with that accurate description of the state, then what kind of a framework do we have. I donít know what the answer to your question is, Steve. Whether people have been violating the law, whether people have been turning their eyes, averting their eyes for this, but for whatever reason thatís whatís been going on and itís causing lots of confusion right now. Thatís a fact. So, given that, that one group of people, and itís some scientists, in particular epidemiologists, and some patient groups say this is not the way to do business. That the price for protectionówhich is basically not being able to go back to people, not being able to link to other information, and, in fact, the reason why these things are being anonymized is for protection, thereís no other reason, thereís no other scientific reason, thatís for sure. So itís a protection. Some people on both sides, the research side and on the patient group side, say that price of protection is too great because in order to protect, what weíre giving up are some of these other things that we were talking about. And so the possibility of going back either to inform for whatever reason or for research...
So the question then becomes, are there other vehicles by which one can protect and not have to pay that kind of a price? And that would be not anonymizing, maintaining these links so that there are codes. So I would just like to make that distinction because whatís been going on is exactly what Steve said. And what a lot of people are uncomfortable with, they say the way the future is going to be is that thatís too high a price. I would personally agree with that because I believe that itís going to become more and more important to get more and more information.
On the other hand, that there are groups of people, and I would think that this is particularly the way itís been in the past, and this is a view that I interpret being championed by the pathology community, that nothing has really changed, nothing is really going to change, and so itís not such a high price to pay to not be able to go back. But I think we should be really clear that thatís what weíre talking about. And thatís a first decision. If NBAC believes that itís not such a high price to pay and that we should just do this; that is, to take these things off, then itís simple.
DR. SHAPIRO: Zeke?
DR. EMANUEL: Two things. First, at least at the last hearings when the woman from the National Breast Cancer Coalition came up she did not have your opinion, David. She had the opinion that weíd prefer the research to go ahead, it to be anonymous, and to find out in press reports and research updates. That was quite clearly her view. So the idea that people say itís too high a price to have anonymous research, at least in that group it is not the prevailing view.
DR. COX: Zeke, I did not say whether the research was anonymous or not. I said whether the links were broken so that you couldnít go back.
DR. EMANUEL: She urged to break the links and she said that was the cost they were willing to pay. That was my hearing of the testimony.
The second thing I would suggest is I donít think itís an either/or status here; I really donít think this is either/or. What we need are rules for all the possible contingencies. In some cases, you will want to do the research in a way that doesnít allow you to go back. In some cases, you will want to do the research and you might want to retain the ability to go back and identify the individual person. You donít have to make the choice now that the possibilities of research are too varied. We need to have rules for both of those contingencies at least.
DR. COX: I completely agree with that.
DR. SHAPIRO: Alta?
MR. CHARO: I would like to reiterate yesterdayís plea for a set of vocabulary choices that will consist of mutually exclusive categories, each one capturing a single situation. The word anonymous has come around a few times on the table and I have a sneaking suspicion itís being used slightly differently each time. I think thereís a lot of potential for people to appear to be at odds with one another when theyíre actually not, in part because weíre not able to hear each otherís meanings. Thatís one.
And I struggle with what those choices might be. I would suggest that unidentifiable means that there is no link of any sort any place. I take your point about coded being more complex than merely coded and need work on that category of coded with the links intact, and coded with the links broken, and then, finally, truly named and addressed. Third, Iím not sure yet whether in the case of materials that have codes that still link them to individuals that are used by researchers in ways that do not permit the researcher to go back to the tissue repository and individually report on the results of one particular sample to the repository in a way that could then in a second stage, or third, or fourth be linked back to a person. I donít know yet if that needs any kind of separate treatment. I was genuinely asking before when I said epidemiologically, you might find a situation where there are ten out of a hundred samples. But the fact that it offers this possibility, and itís a possibility Iíve already encountered on my own IRB and led to months of agony about what to do about going back to people ó
DR. MURRAY: Excuse me, Alta, which possibility did you encounter? Where you had links?
MS. CHARO: The possibility that researchers that had no codes attached to anything who were working with blood spots from a State lab found a particular mutation. Those blood spots were collected in the course of newborn screenings at a time when there was no genetic test for this disorder. They now wanted to have the State lab go back to the people who were the parents of the infants from whom the blood had been drawn and tell these people that a genetic test now exists for this disorder, would you like your child to be tested? It was CF, for which there was no clear benefit medically to knowing you had the disease before symptoms appear because there had never been a prophylactic treatment. But, of course, we could never research a prophylactic treatment because we never knew who was bound to get the disease. So there was an interest in getting back to the parents in some waysónot even for clinical benefit, but to think about them enrolling in research for very valuable purposes, which was presymptomatic CF prophylactic strategies. We agonized about the fact that if they did go back to the State lab, the State lab went back to the parents, sent parents into a flurry of worry about their kids, especially because of the uncertainties about the course of the illnessóyou all know the CF story.
Thatís why it occurred to me that we might want to just slow down long enough to say letís isolate this and wonder about whether or not youíd want the rules to be different. But this might have been a completely unique situation. Maybe it will never arise again, we never have to worry about that again.
DR. SHAPIRO: Tom, do you have anything else?
DR. MURRAY: I think Altaís done us a service by pointing out that the first ó I sketched three groups and I was just trying to get these conceptually distinctive. I was not at that point making recommendations about how they ought to be treated. The first group, just to quickly remind, nowhere does there exist identifiable information, even in the original collection. The second group is the researcher doing this project has no way of going back and identifying the individuals. And third, the researcher doesnít have the information but somewhere there is a possibility of reestablishing identity. You might call the firstóI donít know what you want to call the first oneó"unidentifiable." The second, "unidentifiable, identity unreestablishable." The third one is "unidentified, identity potentially reestablishable." And the fourth, of course, is where it goes with identifiers.
Now I had thought one and two likely to be functionally the same for our policies. They may still be. But Alta I think has usefully pointed out that there might be some occasions, they might be so rare that you donít want to write the policy around them, but there might be some occasions where one and two are different. And I think thatís correct.
DR. SHAPIRO: Okay. Alex, then Bernie.
MR. CAPRON: I agree with Alta that A and B are different. I agree with Steve, however, that B is covered by the present rule, which says you donít need consent in that circumstance. I think we need to address the circumstance that Alta raises. Frankly, my sense of the research that she described would lead me to say you contact the newspapers and say any child born. Thereís nothing unique about that sample.
But another example that might be different would be if there is some extraordinarily rare disease where youíre not thinking that itís showing up in 2 percent or 5 percent of the population anyway and you can now discover that you can do it on these samples, which is what I take to be the CF thing you described, where you really think somewhere buried in these 100 people is someone with a time bomb ticking that we just happened to have found, itís really 1 in 100,000, weíve got it down to 1 in 100. I think at that point it would be guidance to the IRB to say you have a new question to ask. If the question is going to come up rarely enough, then I donít think we ought to burden all of category B with the assumption that itís going to be a routine question. But we ought to make clear that itís not an automatic walk-back and then you have to balance the risks and benefits of this new step of recontacting this particular group of a hundred people and scaring them all out of their wits to save one life. Thatís sort of what youíre talking about there. If I could just comment on Carolís point. You werenít here yesterday and we did talk a little bit about this when we were looking at the first presentation here. I believe we do have to make some reference to the existing rules even as weíre thinking through. Obviously, we can as a thought process say where do we think we want to come out. But we have to frame that or temper it by saying that what weíre talking about potentially are modifications in that rule. There may be extremely good reasons to modify that rule. But we ought to realize that if the reason is simply that weíre standing in the way of valuable research, the rule was written with that in mind. People who drafted the rule knew that and there is something which, to me, would cause me pause if the first major act of this Commission was to say, well, for tissue research we ought to loosen up the rules a lot because this is the burgeoning age of molecular genetics and itís time to start reaping the benefits and so forth and so on. This is the framework. We are charged, on the one hand, with protecting human subjects; on the other, looking into genetics. And we have to keep the one context in mind when weíre going about the other.
MR. GREIDER: Just to clarify. My only point was I donít think itís necessarily a useful thing at the outset to always be referring back to this is covered, this is not covered. What I would like to do is get a consensus about what we think the protections should be and then, once weíve reached that consensus, then of course we have to go back and see is this already covered, is it not covered. But thatís a relatively simple thing to do once weíve decided what do we really believe the overarching principle should be that we should lay down here without worrying about the details of the current regulations. I think it just makes it more cumbersome to always be worrying about those details.
MR. CAPRON: But on the other side, it seems to me just as well to say this is the way things are now, is there a good reason to modify it.
DR. SHAPIRO: Okay. Bernie, youíve waited very patiently. Thank you.
DR. LO: I think this whole exchange has been really fruitful and I think itís helped clarify things for me. I wanted to make a distinction between the various reasons we might want to sort of walk backwards in C. Some of these scenarios being talked about are really clinical scenarios, where weíre going back because we have some information that some people in the study may benefit from knowing for clinical reasons. Now Alta complicated it by saying but there are also risks to going back because people might get scared, they might lose insurability and so forth.
It seems to me that is a question that is very difficult but there are a lot of precedents for that; all these HIV look-back studies when your surgeon turns out to be HIV-positive. Thereís a lot of experience on kind of what kind of potential information, what kind of risks, how you do it and so forth. And you usually do a combination of newspapers and direct mailings when you can.
Some of the harder questions, and I think of the more novel questions, have to do with going back to the sources of the tissue for research reasons. It seems to me there are two different ways you may want to go back and get more information. One is just going back to the tissue repository and saying, you know, when you sent us those tissues you sent just the following fields of information. We know that you have more information on these people. You donít have to go contact the person again, but, in addition to what you sent us last time, please give us whatever other phenotypic information we think is of interest. That, it seems to me, is one situation.
Thereís another situation that no, we really need to go back to the individual people because they have to give us more information. It is not in their record and we really have to take a more detailed family history or age of onset of the illness or something. It seems to me once you go back and contact people, youíre really inviting them to participate in another research study and then you really are now talking about individual, full, informed consent for a new study.
As I understood what Alta was saying, she was saying just the fact that Iím calling these people up and saying weíd like to invite you to be in a new study may be more than minimal risk because it may tip that person off that there is something wrong and it may be hard for them to say no, and they may be sort of sucked into a study where all of a sudden theyíre uninsurable. These are all very difficult dilemmas but theyíre different kinds of dilemmas. I think we need to kind of keep straight why we might want to go back. A lot of times we sort of mix it all up; it may help the patient, it could help the research. But the considerations arenít the same in those cases.
DR. SHAPIRO: Steve?
MR. HOLTZMAN: The first motivation for considering the notion of a code, and that being essentially focusing on it not being identifiable to the researcher, focusing on that, yet there could be a code, was the notion that not that you would want to go back to the individual, but you would want to, for example, get further information about what happened to sample 27's progression in the disease, further epidemiological clinical information. And the issue that we never satisfied to my mind was whether it was possible to have a code which you could continue to get information that hooked up this medical record to this sample and kept coming across but couldnít be equally broken back to go back. I think we need an answer to that question. That could be very important.
What then got clouded into it was the issue of wanting to go back because you found out a result either of your study or found out something about that individual, for example, a misdiagnosis where there seemed a moral imperative, right or wrong, to go back and help. Two very, very different motivations. If, in fact, there can be a one-way code which allows new information to come across the barrier but essentially is impossible to go back to find out where it was coming from, you can satisfy I think whatís the gist of your concern, Alta. Youíll fail to address the people who are worried about not being able to go back to help someone, but you will simultaneously satisfy the impetus to be able to get additional epidemiological information that could enhance the study.
DR. SHAPIRO: Just to ask a point of information. If the situation is such that you want a continual supply of new information, somebody has to know the connection between the people supplying the information and the identities in those samples.
MR. HOLTZMAN: Except the follow ó well, letís work this through, right. The pathologist knows that he or she is sending information about the following thousand named people to you. And each day is sending further information about the progression of their disease, right. And somehow that information is coming through to you and what youíre getting is the hook of this additional piece of information goes with sample 1, this additional piece of information goes with sample 2. Iím not sure whether itís possible for an encryption scheme where it can keep hooking up to the right record but which sitting here with the record you canít go back.
DR. EMANUEL: Thereís a clinical and a research situation. In the research situation, this happens all the time. It happens all the time because, like the Physicianís Health Study, every two years they send out more and they get more. But for the guy who is actually analyzing it, he doesnít know where these data comes from. And, again, I do think we need an encryption expert here. I have again spoken to a friend of mine who works for an encryption company and he says this is possible. This is exactly what the NSA is afraid of, is that it doesnít have the key. You can send information one-way, but the person who actually gets that information canít go backwards. There is not a collateral key.
So the pathologist would say John Jones, 1, feed that information in. The person at the other end would get 467 with that information and wouldnít know that corresponds to 1 and John Jones.
DR. SHAPIRO: I really understand that, and that seems like a straightforward, even simple scheme to accomplish where the researcher has no knowledge of who this is and canít establish any knowledge him or herself. Thatís very different, if I understand it. The situation is still the same that somebody could do this. And if not, why not? I donít understand.
DR. EMANUEL: Iíll tell you what the difference is. Because it is the researcher who has the result and canít connect that to John Jones. The pathologist only knows, yes, John Jones was in that study, but the result of the study, right, defective gene or not defective gene, is unknown to the pathologist. Thatís the key element.
MR. HOLTZMAN: Yes, but this is why we need an encryption expert, okay. Because the notion that sample 1, John Jones, sample 1 in my hand, then goes through a random number generator and becomes 467 in your hands, then there is no way back. But if the next day you want more information, how can it go ó
DR. GREIDER: I think that Zeke is right, that such things exist. You read about them in Wired magazine and computer people do these things all the time.
DR. MURRAY: One virtue of the terminology, not just the terminology, but the conceptual scheme I was proposing is if, in fact, such encryption schemes exist such that nobody can untangle it, even if you can pass some information forward but neither the possessor, the researcher doing it, nor the possessor of the tissues can ever make the linkage between the two, then those are samples that are unidentifiable and with identity not recoverable. Okay? So it fits in category B. Okay? And if such encryption schemes are the mere fantasies of computer experts, but I donít think they are, then they donít go in category B. Then they are linked and they are in category C. Do you follow me?
I donít think we need to speak about whether these encryption schemes exist or not or the precise details. I think we just need to understand what we think the implications would be if they could successfully interpose the kind of barrier that would not permit identity to be recovered no matter what. Thatís the key, isnít it for our purposes? Alta looks pained.
DR. SHAPIRO: Alta, then Bernie.
MS. CHARO: Yes. Because Iím still trying to make sure I know what weíre talking about. I hear frequently from different people the phrase that "the researcher canít go back." But I want to make sure that they understand that if the researcher can go back with the assistance of a second, or two, or three, or four other people, if a collaborative effort can allow the researcherís result to go back to that individual, then that is an identifiable sample. It may be coded, we may be determined to never, in fact, identify the person, but it is identifiable.
So, Bernie, in your example of somebody who wants further demographic information for filling out additional fields, the only way to accomplish that is if the researcher, in fact, is able to say I want more information on this sample sitting here and can communicate to the repository which sample that is. Which implies some kind of code, which means that the repository, in turn, can go back to the person. If I got it wrong, thatís just a piece of performance art for why it is that I canít follow the discussion yet.
DR. LO: I think youíre right. A lot of these schemes depend on a bunch of different people who are unlikely to get together by accident or itís going to take a lot to put the people together to walk backwards. But youíre right, it is possible to do. In fact, a lot of these schemes that weíre talking about, these one-way schemes, it is often argued that theyíre also good because if you found something clinical back here in the research you could walk back. But I think you canít have it both ways.
MS. CHARO: No, no. See, Iím not trying to argue for a particular policy position here. Iím simply trying to point out if any number of people can collaborate together and make the result link to the person, there is almost certainly going to be a situation in which we are tempted to ask, "Gee, is this the time we should do that?" We may have set up any number of firewalls and the reason may turn out to be because we want to do more research or because we want to send clinical information, but some situation will arise where weíre tempted to go back.
DR. EMANUEL: I agree with you. But just take the scheme where you get number 1 equals 486 by a computer generation, not by people in the room. What the researcher would have to say, he couldnít say go back to sample 486 and give me the additional field on that patient, he would have to say to the pathologist, "I need the following field, toenail size, on all of your people because I donít know which one 486 is."
MS. CHARO: Okay. Thatís right. And that would genuinely be different.
DR. EMANUEL: That is the scenario that I think is the right one. Itís not you get five people in the room and they all compare their codes and, aha, they can figure out who it is. It is, in fact, that you can actually send it through an encryption scheme that all the person can do is say, "I need everyone," you feed it into a computer and at the other end you get the information. And no one actually can walk back. Even if you get the pathologist and the researcher in the room, the pathologist just has sample 1, the researcher has sample 486, and they donít know if 1 is 486, only the encryption scheme knows that.
If thatís possible, and I think we do need an encryption expert to tell us itís possible, as I understand it, it is possible, thatís what weíre talking about.
MS. CHARO: But was it Carol or Tom, that was the point being made, that we really donít need to worry about whether an encryption scheme exists. It is if it is possible for human individualsónot computers, human individualsóto get back to an identifiable individual, thatís one category. If it is not possible, whether itís because the links donít exist or because theyíve been encrypted in a fashion thatís not capable of decryption, thatís a second distinct situation. But up until now, what I perceived the argument to be was whether or not, for example, a coded sample where you could break the code qualified as unidentifiable under 45 CFR. And the answer is, it doesnít.
DR. MURRAY: Right. Thatís why Iíd like to do away in our discussions with the concept of coded right now. It just means too many things.
These are the four categories that Iím trying to suggest encompass the important distinctions. Now, itís not clear to me that we need ... A and B, in particular, I think, with the possible rare exceptions, we can probably treat as if they were the same for most purposes in our policy. C is the case, weíve talked about C a lot, weíre reestablishing identity as possible either because codes exist to which human actors have access or because of the context you might be able to walk back. And D is identified. We all agree that if itís to be identified, consent is required. What I just want to make clear is does that capture the relevant moral categories for us. If it does, then we still need to decide how to treat the different categories and which may be combined or not.
DR. SHAPIRO: Bernie, then Steve.
DR. LO: Let me just put in one complication. I really second everyone saying we need to have an encryption expert here. Iíve heard talks where people say B isnít really what youíre interested in. What youíre interested in is unidentified with very, very, very, very small possibility which would take a conscious effort. And the difference between B and B-1, which I just talked about, is enormous to encryption experts. What they say is if you want absolute guarantees, thatís one thing. If you want a system which is very, very, very, very difficult but still possible, thatís a whole different technology and itís a lot simpler and so forth. So I think we need to be clear that we really want no possibility. But Cóone possibility is I can just call up my buddy in pathology and say, you know, I really would like to find out who 486 was. And he says, well, Iím really not supposed to but that sounds pretty plausible and here it is. I mean, I would be extremely uncomfortable with that. But its a very easy possibility which is fraught with sort of human coercion in an institution may be morally very different than very difficult because an encryption scheme that requires getting a lot of people together in a really sort of upper level.
DR. SHAPIRO: I understand that C contains a lot of different possibilities in it. And the cost of reestablishing it would be very different in different circumstances, and it may be that we need to address that. I would leave that aside for the moment. But I think, Tom, I hope Iím not misspeaking, if you look at A and B, those are clear possibilities. Whether you desire them or donít desire them is a whole different matter. But itís clearly possible to have an A and B, and where establishing identification is impossible, literally impossible, for one reason or another, whatever the reasons are. So there are real things that go on in A and B. The same thing with C, and thereís a wide variety of issues in C. And D is, I think what we all know what D is. So it seems to me that this is useful to describe it in this fashion. Alex?
MR. CAPRON: To the extent that what weíre saying here is not just trying to set up categories but comment a little on them, and I know Kathi is listening to this and is going to have to write the report, I would say that in C, I am much less worried about a CIA conspiracy view of this, that a bunch of people are going to be getting together and crack a code who shouldnít be doing it, than the situation in which someone comes forward after some research with what seems to people like a very moving case for going back when you thought you were setting it up that they werenít going to go back. Because we just have to recognize that we might want to go back because as people think is much less hard than, "We have this data that could save Mrs. Jonesí life, if you would just tell us who she is." That still has all the problems that Alta talked about. So I just want us to be clear that when weíre talking about something thatís encrypted but is breakable it isnít just people sneaking around to break it, itís people coming forward and saying let me get back to her, I need more information about her, itís crucial, or I need to get more information to her, itís crucial.
DR. SHAPIRO: Tom?
DR. MURRAY: As I was saying when we got into this about a half an hour ago, I have this completely unobjectionable, simple categorical scheme here.... We have at least the categories clear. But I think Alta has usefully added that A and B we might treat the same but there are these casesóthey might be very rareówhere we might want to think about them differently. Thatís useful.
Bernie, I think, makes a valuable conceptualóitís not just a conceptual point, itís a practical pointóthat experts on information privacy will tell you it is almost always not a matter of is it private or not, itís how hard and how many resources would it require to disrupt privacy. One can imagine scenarios, fairly outrageous ones even under B, where somebody breaks into the lab, steals little snippets of tissue, and does DNA fingerprints on all those in order to make the link. One can imagine it. Not thatís extremely remote, people arenít going to do it. But I think nonetheless this captures a good deal of what we wanted to do.
Now, we have some hard choices to make. Iím not going to propose specific ways to do it right now. Iím just going to say some of the options we face are, for example, these. We could ó well, I canít read my own notes on number 1, so Iíll go to number 2.... One thing we could do is we could place the burden of proof on an investigator, for some of the reasons that Alta laid out, that people want to be protected against discrimination. Place the burden of proof on the investigatoróthis is just a possibilityóas to why reestablishing identity should be permitted at all. So the default presumption might be, our advice to IRBs might be that the investigator ought to put it in category B, "no reestablishment of identity possible," unless there is some good reason why you would need to have C instead. So a kind of default presumption.
And if we had C, we then might require additional safeguards, such as description of protections against unapproved reestablishment. Letís get somebody else to figure it out. Description of circumstances under which reestablishment might be sought. Procedures for review of request for reestablishment. Apparently, in your case, they went back to the IRB, which might be what we do. But we have to think about what we want there.
Now Iím just going to sort of live out two other issues different than this that I think we also need to attend to today. I hope we can get to both of them, we need to get to both of them.
The second is the whole notion of community consultation. That includes both what we would regard as the appropriate standards and procedures for determining when and what community is implicated. I donít think weíre going to do this in detail, but thatís the kind of thing weíll need to say in the report.
And two, we need to provide guidance for determining what constitutes adequate community consultation, which may include both identifying representatives from the community and saying something about what we think consultation actually means.
And can I say the third thing, Zeke, then Iím finished. We want Carol to go through the matrix. It might be that, weíll see how the discussion goes here, it might be that weíll get Carol to do it right after. Weíll have a break earlier maybe and then have Carol pick it up when people are a little bit fresher.
The third thing is we need to also talk a bit more about consent for research with samples to be collected in the future. Weíve had some discussions about that. Do we wish to treat samples gathered in the course of clinical care differently from samples gathered in research for the future samples? Itís a possibility. What level of consent would be required and/or permitted in these? People have talked about layered consent, general consent, specific consent. We need to spend a bit of time thinking about those.
Those are three key issues that I hope we can cover today.
DR. SHAPIRO: Thank you. Alex?
MR. CAPRON: I wanted to suggest a way of using the idea of community consent which is different than what you use and maybe we should just use a different term for it. Itís the community being consulted not because the community as a whole has a collective interest, but because youíre doing the same thing you do whenever you use a surrogate decision maker. We use a surrogate decision maker when the person from whom we would otherwise get consent canít give consent, and thatís usually because theyíre comatose or a child or mentally impaired. But in this case, weíre using it because we donít have direct access to the person. And we could use the community, that is to say the generally described group from whom the samples came, representatives of that community the same way you all were using your focus groups. It would be most relevant, it seems to me, in the C situation where thereís a possibility that down the road weíre going to have some reason why we might want to walk back with information or ask you to walk forward with some more information. It strikes me that the analogy is not farfetched.
In case we ever start using the terminology about community consultation, I want to note that this is a different reason and a different way perhaps of consulting the community, not asking an identifiable community do you mind being put at risk because weíre going to come up with information about characteristics of the people in your community, but presuming that your sample might be one of these samples, what would you feel about being put in a situation where people had information about you that they were disclosing or, conversely, you were confronted with potential information that would cause you to go through a process of facing something that you donít otherwise have to face.
DR. SHAPIRO: Okay. Tom, then Zeke, then Carol.
DR. MURRAY: Two very quick points. One is I could see that as a kind of alternative justification for why we would do community consent.
MR. CAPRON: Yes, thatís why I brought it up under this heading.
DR. MURRAY: Thatís good. But secondly, I think it actually pertains to A, B, and C, not just C, because as long as there is a community identified.
MR. CAPRON: Okay. It became more acute to me in the situation in which itís more likely that there is a potential risk and an identifiable individual somewhere down the line. But I donít disagree at all if you think it could be used more broadly.
DR. SHAPIRO: Zeke?
DR. EMANUEL: Just a point of institutional memory here. If we actually collapse A and B up there and we have three categories, we once in our Subcommittee, once, for many months had three categories. We got rid of three categories. The reason we have two categories on the framework is because we actually collapsed the categories. So we may be reinventing the wheel. We should think again the urge to think about the safeguard implications of making these divisions and which way theyíre going to fall.
The second thing I would comment on ó
DR. COX: Can I ask a question about that just for point of information? So you meant that C and A and B were collapsed into one thing? When you talked about being collapsed, you meant A and B were collapsed, right?
DR. EMANUEL: No, no, no. We collapsed A, B, and C into one thing. I just wanted that to be really clear. A, B, and C collapsed into one thing.
MR. CAPRON: And we blew them back up again.
DR. EMANUEL: I have no idea where itís going to go. Thatís part of the advantage of deliberation. All Iím saying is we shouldnít forget that fact because it may be that we want to revisit those notes. The staff may want to revisit some of that.
As regards what Alex says, I think itís very important. In some cases, what you say is the community will be identifiable. But in most of the studies where, for example, in the framework we have individual known communities like the Physicians Health Study or the NHANES study, or in most of the studies that actually have brought us to this point there is no identifiable community. What do you go to, the physician leaders? Youíre going to go to the AMA and ask them about consent? Or in the NHANES, itís people from all over the country.
So, your idea works already in the category that we had thought about community consultation in the other categories as sort of surrogate, it doesnít, for individuals, if thereís no community youíre already looking at that has some genetic traits to it.
MR. CAPRON: No, thatís the point. It isnít a community with any genetic traits where youíre going to come up with any statements about that community. Itís just a question of do you have some people who share enough characteristics ó if youíre looking at the tissues from males between the ages of 30 and 50, can you get together a group of males between 30 and 50 who have had tissues sampled at this hospital or wherever the samples are coming from and say to them, "This is the study being done, we have an IRB that generally approves it, they could use your advice as to whether you have any thoughts about this?" It may not even be a matter that you give that group the same full rights that a surrogate has, but youíre trying to take the temperature of people, saying "Does this worry you?" or does this seem ó I mean, itís what you did with your focus groups that came back with a lot of people saying, no, this doesnít really bother them.
DR. EMANUEL: Itís very clear ó that is to say under individual, no community linkage, you are now going to have community consultation as a requirement, which we never had thought of before. Thatís what that suggestion amounts to. We may want to adopt that, but one should be clear what youíre saying. Where there is no community linkage possible in the result, you now want to add community consultation as a surrogate? We have not held that position. We have always said we should not require that.
DR. SHAPIRO: Okay. I have some people on the list here now, and then I think weíll take a break after that. Eric, Carol, and Alta.
DR. GREIDER: No, Iíll withdraw my comment.
DR. SHAPIRO: Okay. Eric?
DR. MESLIN: I have one comment and two questions to help staff organize the work that will likely come out of this discussion. The comment is to remind you that weíve contracted with Professor Alan Buchanan to prepare a paper that lays some of the moral terrain out, but not in a highly theoretical and abstract way, but rather in a very concrete way that compares the interests at stake when we err on the side of protecting access to these samples, and the interests that are at stake when one encourages freer access to those samples. In the course of the paper that weíve asked Alan to write, he will be considering both harms to individuals, to communities, and others in a way that I think the Commission will find helpful. We can ask Professor Buchanan to come to the March meeting and present that. His paper will likely be ready within the next week or so, and we will obviously distribute that well in advance for your benefit. Thatís the comment.
The two questions are I donít want to leave this notion of encryption, which has been mentioned by many. I would be anxious to hear the sense of the group as to whether (a) you would like us to identify such a person and have them simply communicate with staff the factual basis for some of these issues, and that can be fed to Kathi and she can incorporate that, or (b) do you think that this is an issue of sufficient gravity that you would like a commissioned paper and a person to come? The second question relates to IRBs. Zeke alluded to the NHANES study, and we know that there is some discussion going on with the CDC in the use of the NHANES data. That is one of two IRBs in the country that Iím aware of, and maybe others know more, who spend some, if not all, of their time looking at genetic studies. The other is a separate IRB at the Mayo Clinic that Chris Hook chairs. Does the Commission wish to ask staff to identify information from those IRB chairs in the same way that I have suggested about encryption, or would you just like to let that pass?
MR. CAPRON: Is there a third alternative that they might actually be a useful witness?
DR. MESLIN: Yes. Really, I was collapsing the categories. You could pick A, have them give us information, or B, come to the meeting in March, which is already becoming a very full meeting.
MR. CAPRON: Or C, ignore it.
DR. SHAPIRO: Bernie?
DR. LO: My response is I think the encryption can probably be handled by staff in the paper. But I would certainly want to get input from those two IRBs just because I think the clearer idea we can have of what the issues are now and are likely to be, as people who are experiencing it can best predict an uncertain future, itís going to help our deliberations. Weíre grappling with theoretical categories. I think it would really help us to sort of try it out on some of the tough cases that IRBs have either faced or will face.
MR. CAPRON: Yes. Give them our schema at wherever it stands, then we say how does this fit with your experience.
DR LO: Yes. What cases have you had that are tough and does this schema help you any better than what guidance is out there.
DR. MESLIN: Just so that Iím clear. They will have that luxury anyway when we send out the report in its draft interim form. Obviously, we will direct it to as many of those kinds of individuals as possible. But would you like to have them before that point?
DR. SHAPIRO: I think so. I think that would be a good idea.
Carol, then Eric, the other Eric.
DR. GREIDER: This is just to address that specifically about these people that might come and talk to us. If they could bring a set of cases that they find illustrative of some of the issues that have been difficult for them, rather than just having us ask them questions, to bring two or three to lay before us so that we can put them in our own matrix might be useful.
... What has to be clear about the last hour and a half is that thereís been a fair amount of disputation over categories. And I think you have to be careful about making it more complicated again. It was beginning to simplify clinical cases as a different situation. Bring in experience like Carol suggestedósomebodyís casesóbut if youíre going to bring in people who will tell you thatówhich they willónothing can be encrypted permanently or we have a scheme, youíre going to get into trouble.
DR. SHAPIRO: I think thatís right. My own sense of that is thereís not a big encryption issue here at all. And that there are encryption problems out there but they donít happen to relate to this by and large. And so I think we donít need to do much in that area. Letís take a break now and I think a relevant pick-up, particularly just where we are, Iíd like to go to Carol as soon as we come back. Letís look at this scheme and see how it fits into what weíve said so far.
BREAK: 3.29 PM
DR. GREIDER: When Tom asked me to go over the matrix that we had been discussing in the Subcommittee, first I wanted to kind of back up a little bit and ask myself a question: Weíve had this framework a long time, why havenít we gotten through it, and what have we learned along the way? And I came up with a couple of things which we have touched on here today but I just want to go back to them a little bit as a sort of preamble before we go back through it. And what I started thinking about is what are we really trying to do in this framework matrix that weíve laid out. And it seemed to me that it was a very practical way of thinking about the kinds of recommendations that we might make about the use of human biological materials. And thereís been a little bit of a conflict, and one of the reasons that we ran into some problems is that there was a conflict between sort of global conceptual frameworks and practical reduction, what are we actually do. And that we keep running into these things every time we talk about this matrix, but that weíve done a lot of hard work in going through that, and so it was useful. But to think about it in the terms of a sort of practical document, at the last meeting I think it was Harold that suggested that another way of framing the issue that you could draw a different kind of a matrix, and I know that Eric Meslin has alluded to this and Iíve heard rumors about a three-dimensional matrix with risks, benefits, and what the third mentionóI havenít actually written it out...
DR. CHILDRESS: Types of protections.
DR. GREIDER: ...types of protections being sort of a three-dimensional matrix were a different way to frame the problem. And so in thinking about that, I think that that way of framing the problem really gets at a lot of the more global issues, the sort of higher level kind of questions, whereas the matrix that weíve been dealing with is dealing with more of the practical issues: What are we actually going to make recommendations for. And then I go back and ask, okay, what are we actually supposed to be doing? And from my standpoint, one of the major goals of NBAC is to sort of lay out, clarify, and articulate what the ethical issues actually are as a sort of first educational goal, to state them very clearly. And then second, to suggest practical approaches. Thatís my personal view.
So having come that far, then I ask myself what next. And I think that the framework that Zeke did lay out for us is very useful in the practical approach and weíve gotten part of the way through it, and so I think we should continue that analysis while recognizing that we need to articulate very clearly in the actual report weíre writing some of these other more global issues that have been highlighted. Okay, if thereís any discussion about that, if anyone else on the Subcommittee feels any differently about what weíve done, Iíd be happy to hear about it. Otherwise I will go and put up an overhead. Okay, so youíve seen a number of different tables, and the only change that I had to what I actually got directly from Zeke for his framework was that I added numbers so we can all refer to the ones that we have in front of us rather than just having names there. So you should have gotten this by fax, this is Table 2. And I think itís a good starting point for some of the issues that we need to discuss.
From the discussion that we just had, we can already see that thereís going to have to be a certain amount of change, but let me just go through some of the what I think are the relevant features that are in the outline of this framework.
The first is that we separate out the previously collected samples from the samples collected in the future, which we just discussed and there seemed to be some agreement on. The second is that we have two categories going across these rows, an individual is implicated or a community is implicated. And I think at the last full Commission meeting we did discuss that this is just going to be one row across here. We had collapsed down the previously-collected samples. Instead of separating them into clinical care and research studies, had collapsed them into any existing samples and that was the discussion that we just had also earlier that the actual recommendations that you might put into these boxes probably wouldnít be any different if they were separated into these two different categories.
This chart that Iím showing you is somewhat different from one that went out in the original briefing book that was sent around in that it does have in the samples to be collected in the future, clinical care and research studies separated out. And just very briefly, the one that Iím talking about that you may have seen is this, where this is collapsed down. From my recollection in the Genetics Subcommittee, we had not reached complete agreement. There was a lot of discussion about whether or not we should keep these separate or collapse them. And so I think thatís probably the starting point that we should revisit here, is whether or not we should keep this. So Iíll put this one up now for the rest of our discussion so that we can talk about what weíre actually going to recommend in the different boxes. And then we can revisit this issue about whether we collapse these down again.
Just let me get to one more thing. So my interpretation of what we just discussed over here with the A, B, C, and D would be that each one of these boxes would have a line or two lines going through it because as we discuss this, as it says here, these are previously collected samples and this is how theyíre going to be used, in an individually unidentifiable manner. Weíre changing the word anonymous to unidentifiable. But as we just said, there are more categories than just that and so one of the discussions that we should have here is how to bifurcate these and whether or not these are two separate issues.
What, to my mind, we didnít really ever get around to doing in the Genetics Subcommittee was ever articulating the reason we put in here 1A, 1B, 1C, 1D is so that we can write down in the report we think that in case 1A these should be the recommendations; in case 1B these should be the recommendations, etc., etc. Now, Zeke had given us some proposals about what he thought we should think about and those went out, again, as recommendations. But my memory is that those were just proposals and weíd never actually hashed through that in our Subcommittee. And so all of those are revisitable.
I think thatís all I have to say about the actual framework. Maybe Iíll just leave this up here and then we can have a bit of a discussion about it. I know that Steve had something to say.
MR. HOLTZMAN: Okay. And just very simply, our nomenclature up there to be used in an individually-anonymous manner encompassed what is sitting up here as A, B, and C. We did discuss it, maybe we didnít discuss it thoroughly enough, maybe we really do need to discuss it. But as we work through what would be the practical policy implication of how you would handle A, B, and C, what we found was they all came together; hence, we ended up putting them into this bucket of to be used in an individually-anonymous manner. So I think thatís one point. And certainly we should be discussing that again if people are uncomfortable with it or go through the logic, thatís one point.
The second point is among the handouts, thereís Table 5, and again I just want to call attention to this. In Table 5 using this one said what we thought was the current policy, okay, and by current right on existing samples. Table 5 in what was faxed to everyone. All right. And so what you will see is that it was at least the interpretation which has been called into question whether the current policy of "no IRB necessary" applies to all of A, B, and C. What I have heard is there is agreement that it applies to A. I think maybe thereís agreement that it applies to B, but not agreement that it applies to C.
So again, this is not arguing, this is just making sure we all know exactly what has been...whatís implied in whatís been handed out and to identify where we need more discussion.
MS. CHARO: Point of clarification...
DR. SHAPIRO: Alta....
MS. CHARO: Yes, yes, yes, I know. Just as a matter of clarification, could you just help me understand what you mean by no community linkage versus community?
DR. GREIDER: The idea was that an investigator plans a study and determines that there will be no implications of any kind of a community here, like the proportion of people that have attached earlobes versus nonattached earlobes looking for a gene for attached earlobes. We canít think of any particular community that this would have an effect on. And so the investigator has to go...one of the proposals was the first thing that happens is the investigator says, I think my proposal falls in box 1A. Thereís administrative IRB review to say yes, it does fall in 1A, youíre correct. Or maybe the IRB would say no, there is a community implicated in that study of earlobes, and so you need to go out and do whatever is in box 2A rather than 1A.
MS. CHARO: Point of clarification two. The researcher gets what you called and administrative IRB review to check what box he should be in.
DR. GREIDER: Right.
MS. CHARO: What is an administrative IRB review?
DR. CASSELL: Well thatís another issue.
DR. GREIDER: Thatís another issue...we havenít...somebody...the only point is itís not just the investigator that determines what box theyíre in. Thereís some sort of review to say yes, thatís correct.
MS. CHARO: Okay, you werenít suggesting that thatís an existing mechanism that youíre...
DR. GREIDER: No, no, no. My starting point here is weíre making...
MS. CHARO: I understand the words youíre using.
DR. SHAPIRO: David.
DR. COX: So Iíd like to make the distinction betweenóand weíve said this a while ago but just to make it againóbetween how samples were used versus whether itís possible to go back and do any identification with them. So distinctions A, B, C, and D refer to the ability to go back and do any linkage with individuals. But how theyíre used can group any of those. You know you canít use D in that but it will be possible to group A, B, and C, and to use C without having the identifiers even though you could go back and look at them. But that doesnít mean that B and C are the same.
MR. HOLTZMAN: No, David, I think itís very important to be clear here. If you look up here, A actually refers to the sample. If it is the case that the sample is of such a nature then it must be the case that when you use it, you use it in a nonidentified manner.
DR. COX: I agree.
MR. HOLTZMAN: I think we all understand that thatís a matter of logic, right?
DR. COX: Exactly.
MR. HOLTZMAN: B and C, the first two words, unidentified, refers to how it is being used.
DR. COX: I understand.
MR. HOLTZMAN: Okay, and then we are talking about after that. How itís been made such that the in its use it is not...the individuals are not identified.
DR. COX: I completely understand, and youíre correct, both B and C, the unidentified means that thatís how itís being used, right?
MR. HOLTZMAN: Right.
DR. COX: But for the rest of the world, it makes a difference in terms of how it was made unidentified. Because for the rest of the world, and including the rest of the regulations, if itís been made unidentified so that there is no way for anybody to identify it, thatís one thing. If itís made unidentified so somebody else can identify it, thatís another thing.
MR. HOLTZMAN: Thatís B and C youíre talking about.
DR. COX: Correct. I mean thatís all that Iím saying. And in terms of all of the professional society statements and also with respect to the regulations, it makes the distinction between B and C.
MR. HOLTZMAN: Okay. And all Iím saying is implicit in us coming to the framework we came up to there is number one, we said that the distinction effectively between B and C was not salient, and second off if you look at table 5, there was a difference of opinion about what the current reg says.
DR. COX: I understand. But what Iím trying to understand is why the difference between B and C isnít salient.
MR. HOLTZMAN: Why we reached that conclusion?
DR. COX: Correct. Thatís what Iíd like to know the answer to.
DR. EMANUEL: The only answer is when we looked at the safeguards weíd like to put in in those boxes, for A and A-prime, if you will, we came to the conclusion that in fact they would look the same for category A and B and category C. So one of the suggestions is think of the kind of protections and safeguards we put in or have available to them put in place: IRB review, individual consent, community consent. Those are the three flavors, unless you want to add some more.
MR. HOLTZMAN: I do.
DR. EMANUEL: Okay. And when we thought about those three flavors, we had collapsed it. It could be wrong and upon reflection, or it could also be something where the subcommittee agreed and the whole Commission doesnít agree. Both are....
DR. SHAPIRO: Jim.
DR. CHILDRESS: Of course another possibility for presentation at least when weíre putting this out if not now, it might be helpful to go ahead and list all of these and go ahead and list the protections weíre putting in place. It doesnít matter if they overlap. If itís clear to people that weíre talking about these different matters, so wouldnít that be one way to handle it?
MR. HOLTZMAN: No, one other thing some of us discussed is that itís very important to engage the categories that have been out there by the other societies, alright, and make sure that we show how weíre thinking about all of those distinctions, even if we conclude with respect to policy that certain of them collapse is unimportant.
DR. EMANUEL: I just go back to the suggestion that our subcommittee chairman made was simplicity. One of the reasons was collapsing them, at least, was conceptual simplicity.
DR. CHILDRESS: But clarity in communication is another important criterion.
MR. CAPRON: It does seem to me that what this comes down to is our discussion about C, because what you are saying operationally isóalthough Steve has doubts about thisómost all of us seem to think that under the present regulations, C is in the 1B box. And if thatís the case, it gets full IRB review, full consent, and thereís no community consent process yet. And if you are saying that C belongs in the 1A box, thatís where the difference lies. We really arenít departing from current regulations as to A and B; weíre not departing as to D; we ought to focus our discussion simply on C. And we ought to see, as David has just suggested, are there things like a surrogate consent process or full IRB discussion even if you canít get individual consent, or a presumption that a first attempt be made to go back to the people in the tissue sample and send them a letter saying weíre now proposing to use your tissues in a research, or in a series of research protocols about genetic screening, do you agree to this? We, our plan now is not to have the people who do the research know about you, but the design would allow us to either come back to you and ask you to plug more information into the system for us, or conversely us to feed something back to you if we find out something that might have some clinical relevance to you. That is different than the way that you were proposing to treat A and B on todayís A and B list, right? And so Iím not even convinced that as of now, besides Jimís very good reminder, that we might want to present C differently even if we had the same rules. Iím not inclined to think that there will be the same rules. And I would specifically, if we want to get the ball rolling, I would specifically move that we not allow such research without full IRB review rather than just administrative review; that we not allow it without some form of surrogate consent; and we not allow it without a presumption in favor of an attempt to establish agreement by the subjects to participate in research. The latter does not say research could never go forward, but as we heard from the cancer people when they were here (the breast cancer group), they have done that in certain cases. And in effect applied their prospective framework to retrospective samples. Weíre really talking about trading off dollars, of the difficulty of doing the research, versus protection of subjectsí interests. Thatís all weíre talking about here.
DR. CASSELL: I actually understand that, and thatís wonderful because I was worried about this creeping dementia that must be ...
DR. CASSELL: Itís only temporary.
DR. SHAPIRO: Bernie, and then Steve, and Carol.
DR. LO: I think another way to ask that question is why are many researchers trying to argue that C ought to be considered in box 1A rather than box 1B. And a lot of it, I think, has boiled down to the itís going to be too hard to do the research or prohibitively expensive or something. I guess the ...the question is what kind of project would you design under C but not B? What would be the benefits be? And it seems to me we have to think of different kinds of studies. And I donít...how would you classify a study where right now Iím using existing samples but next year or two years down the road I want to get updated clinical followup thatís going to be part of a computerized medical record, will require no contact with the patient, and at the time I could probably say well, theyíre existing records now so I could do it? But itís not existing now. It seems to me that kind of study is, to me, a little different, or actually significant different, than a study that says, next year I want to go back to the repository of the data and have them get a little bit more information, maybe from a doctor or something as to what kind of clinical followup. Is that the same thing? And it seems to me clearly itís going to be different if Iím actually going to contact the patient for additional information, because thatís a new study it seems to me. But itís not clear to me. I mean the arguments Iíve hard from the advocates of putting C into 1B really stem down to if we...Iím sorry, put C in 1B it will be too difficult, all this valuable research wonít get done because itís just too hard to do. And I guess Iím trying to think of what is clinically behind that and what are they really gaining by designing studies to B and C rather than in D?
DR. SHAPIRO: Steve.
MR. HOLTZMAN: No, I think I can give you an answer to that question, okay. Let me deal with something first. Iím not trying to, in terms of the interpretation of the current reg, I donít know whatís right and Iím happy to defer to your folksí interpretation that C does not fall within the exemption. It does strike me that others whoíve been dealing with this a lot longer than I wrote this piece of paper about what is the interpretation of the current reg. And Iíd be very interested in staff having finding out how most people out there are interpreting the current reg and what the coded studies are considered to be subject to the exemption or not. Okay, so thatís one point. With respect to the motivation for collapsing B and C, I think it was two-fold. I think we focused on the notion of the harm, and that if the individual was not identified then there wasnít a harm. That was one sort of piece of it. The other piece of it was that it wasnít prima facie evident how under B, you could have followup information flowing through.
DR. CASSELL: You canít.
MR. HOLTZMAN: You canít. All right. Now, what Zeke is suggesting is that followup information with an appropriate encryption scheme could be flowing through. But if you start with the assumption that thatís not possible, that if thereís going to be subsequent information that connects this to this, that it is logically impossible for there not to be a path back, then that gives you the reason for wanting to say Iíll collapse C into B provided there are sufficient safeguards. That provides the motivation.
Now if in fact thereís a straightforward way in which, while not maybe not logically impossible itís physically impossible under an encryption scheme to achieve B and yet have the followon information flowing through, then the motivation for splitting them goes apart because B and C parse off into physically-impossible to really get back in here in any meaningful way versus you can get back. Okay, that was the motivation. Was that clear?
MR. CAPRON: Steve, itís clear, but you keep assuming that one particular design exhausts category C, which it doesnít. There may be people who say I donít want it to be that hard, I donít think Iím going to need to talk to these people but I might need to. And so I want to set up the encryption scheme in a way where someone can decrypt it.
DR. CASSELL: Break the code.... But I want to get permission. And when I go through the IRB I want permission to go back.
MR. HOLTZMAN: But our assumption, I think, was thatís exactly when it would trip it over into the 1B.
MR. CAPRON: That would make it identified.
DR. SHAPIRO: Carol, Alta, then Zeke.
DR. GREIDER: So I agree with a lot of what had just been said. When we set up the two categories there to be used in an individually-anonymous manner and to be used such that identification is possible, a lot of that was done in the absence of this robust discussion on walking back and what does it mean to walk back and what are all the different scenarios. We now have had a lot more of that discussion and I think Iím coming around to the point where instead of having two categories there, I would propose that we have three categories there. Instead of A and B it would A, and weíll call it A-prime for now, and then B. And weíll renumber them number. So then the question is which one of these three categories?
We just had a long discussion about whether B and C can be collapsed into each other and I donít think that anybody thinks that they really can, or maybe Iím wrong. I mean I think maybe I hear a lot of people saying that they donít think itís appropriate to collapse B and C. What about collapsing A an B? And then weíre left with three categories.
DR. CASSELL: From a regulation point of view?
DR. GREIDER: From how weíre going to fill in the regs here and that sort of stuff. And then we would be left with three columns or rows. Three columns, rather than two. So A and B have now become one. Weíve done something.
MR. CAPRON: Well, let me just say about that. It seems to be that thereís...when you start off with A, I guess the idea is that you simply have a "gamish" of samples. And while you may have a little bit of data about each one of them, you donít have any identification of the individuals at all. Whereas in B, the ... you have that identification and youíre going to strip it before you pass it on. And the question is is the possibility of the fact that you donít strip it well enough a way of distinguishing A or B? Iím not trying to be difficult, Iím just saying weíre dealing with human error and human...
DR. SHAPIRO: It seems to me if you donít strip it well enough, youíre in C.... Or D, depending on how badly youíve botched it, right?
MR. CAPRON: And the question, Harold, is in that situation, if weíre dealing with a combination of the abilities of the researchers and the source of the data and the IRB to make sure that the design actually belongs in 1A rather than 1A-prime as Carolís now talking where we put C for the moment, or Iím not sure where C is. Anyway, so Iím saying, yes, I think Iím basically...but Iíd like to do it with kind of an asterisk saying it is important to note that when this is done from a sample source that has identifiers, care must be taken that they have truly...I mean someone may say, well, Iíll just use initials, I mean that strips the identification.
MR. SHAPIRO: Right. I agree. Itís important to know what youíve got and not what you wish you had or something. All right, letís go to Alta, Zeke, and then Bernie. And I have a proposal on this matrix here, but letís....
MS. CHARO: Number one, in answer to Steveís repeated question of how is it possible that everybody in the world is misunderstanding this interpretation except for Alex and Alta, itís entirely possible that Alex and Alta are the only people who are right. And hereís how Iím going to show you. Iíve been involved in two OPRR investigations. And in both cases, so out of this very small sample size we have a 100% positive rate. The PIs confused the concept of unidentifiable to them because there was a code that hid the name and address and personal identities with the notion, "unidentifiable" because nobody could actually get investigations approved for other purposes. This confusion was unearthed. it gives me the impression itís a commonplace confusion. Which gives me the impression itís very easy for a lot of people out there to have also had it.
Secondly, because of the ambiguity of words like anonymous, itís possible for a lot of people to be writing using the word anonymous and reading one anotherís stuff as meaning one thing when it was intended to mean another. So I think itís entirely possible that only Alex and Alta and Melissa in this entire planet really do understand these regulations. And I hope Iíve proved to you that we are right.
MR. HOLTZMAN: No, but you said B is included. Melissa says B is not included in the current regulation.
MS. CHARO: I never said B is included in the regulation. I said C is included in the regulation, which I was calling coded samples.
MR. HOLTZMAN: Iím sorry. Theyíre included in the exemption.
MS. CHARO: C is not included in the exemption. Anyway. Second, I would like to urge that in light of the suspicion that as a full Commission there will be a number of people who are at this point of the opinion that the rules governing C have to be different than the rules governing B because of the variety of walk-back scenarios that we not jump the gun on C nor on the A versus B thing. I think itís very possible that A and B are going to wind up having the same rules, but the experience of having seen just a situation in which B opened up possibilities that were different than A, in which B opened up possibilities for epidemiological studies that identified...made identifiable a relatively small number of people who could be approached for the possibility of individual testing without having its own complications, and there were two or three examples so that itís not just a matter of using a newspaper notification, makes me want to take the time to thrash through. So I would simply like to ask for the time to thrash it through as an entire group.
DR. CASSELL: Whatís the difference between A in that regard too? Epidemiologic study with A might do the same thing.
MS. CHARO: But in A, even the tissue repository wouldnít know who the people are from whom the tissues were taken.
MR. HOLTZMAN: Newspapers are the only way, then.
DR. EMANEUL: Not true. Let me give you ... Guthrie cards are completely anonymous, right? You can nonetheless, if you know the year in which theyíre collected, right, you could then say every birth registered in this State in this year weíre going to mail out to. So I donít think thatís the case. And furthermore, if you have DNA databanks in the future, not too distant future, youíd be able to in fact do this.
MS. CHARO: We have DNA databanks in the future there wonít be any concept of unidentifiable and we need to be aware of that. This is a transitional stage.
DR. SHAPIRO: Excuse me. Arturo, then Zeke and Bernie.
DR. BRITO: Alta, if you can...when youíre talking about identifiable for this small group, and maybe your experience with OPRR the two investigations, are you talking about identifiable for the individuals by means of exclusion, or are you talking about identifiable of a community of individuals because they have a certain disease?
MS. CHARO: Neither. What Iím saying is that in two out of two investigations on other topics, we found that investigators who were using samples that had just codesóthey got a sample and it was coded XYZóviewed that as unidentifiable and viewed the use of those samples that something that did not require getting consent from the tissue source. Or IRB. That was incorrect. And we know it was incorrect because we were working with OPRR on this. Another source of fairly definitive understanding of what the significance is of a coded sample, where the personal identity of the tissue source can be tracked back. But they, because they didnít know who these people were, assumed that therefore it didnít matter about getting consent. Right? And so it seemed to be a commonplace confusion.
DR. BRITO: So there was a possibility of identifying from the onset? Of going back? So is there...going back to the original...I think someone just mentioned it. Is there a possibility where you have A, you have no possibility?
MS. CHARO: Absolutely. If I went around here today...if I went into a street and I didnít even know who was passing, and I just snatched hair from every person who walked by, I would get arrested.
DR. SHAPIRO: Okay. Zeke?
DR. EMANUEL: Can I just...Iím all in favor of expanding the framework again to analyze the protections, because I do think weíre not going to make any progress until we expand them, figure out what the protections are and where our disagreements are. In light of that procedural suggestion, I would make the further procedural suggestion that we actually begin with the future collected samples because there, I think, weíre going to actually have a lot more agreement. Because I donít think weíre going to have the same level of disagreement on this. I think the kinds of protections, the kinds of informed consent are things that we have some models for, etc. Thatís merely a procedural suggestion.
DR. SHAPIRO: Bernie?
DR. LO: Well if weíre going to go to the future samples, Iíll pass, because I was going to make a proposal with regard to seeing how it sort of fits in with 1A and 1B. And I would argue that itís different from both 1A and 1B but itís not clearly in B for some cases. But if weíre going to go to the future samples to get some consensus, letís just do that.
DR. SHAPIRO: Eric, did you have something?
DR. CASSELL: Iím sitting here trying to see all of this. Iím trying to protect the human subjects and the individual persons who happen to drop a piece of meat on the floor or something like that. On A and B, they cannot be known and they cannot..they donít need protecting without another study being done in which the newspapers or whatever may be involved. Thatís another study required. In C, the way a study is written, they donít need protection because a study is written in such a way that they cannot be identified or the samples have been dispensed in such a way they cannot be identified. Now they found this remarkable thing and now they want to go back. Thatís a separate study and they have to come back to the IRB. If anybody wants to know who those people are, they must come back to the IRB and thatís a totally different thing. That, we are now in D. Whenever they want to do that theyíre going back to the IRB in D. D, of course, is the other thing. And I donít see...I mean with all this discussionóit must be complicated. But I really donít see why thatís so complicated.
MR. CAPRON: Let me try to answer you why I think...why I think itís complicated. Because IRB and an investigator ought to know at the outset whether or not that bridge will ever be confronted, even if they havenít yet fully committed to how theyíll cross it when they get there. Thereís a difference in saying Iím going to develop information about you and you and you. I wonít know itís about you and you right away. But if the information is interesting enough, Iím going to want to get it to you or Iím going to want to find out a lot more about you.
DR. CASSELL: But they canít do that for A and B.
MR. CAPRON: But they can do it in C.
DR. CASSELL: So A and B is taken care of.
MR. CAPRON: A and B is taken care of. Iím just trying to say...
DR. CASSELL: So we have only one category.
MR. CAPRON: We have one category for A and B to me with an asterisk saying you better be damn sure youíre really in B and you havenít slid over to C by mistake.
DR. CASSELL: Now youíre now in the one where the person could be at risk.
MR. CAPRON: Right. And it seems to me...I suggested to you before something which is, I think, in line with what Bernie said a moment ago, I think that C isnít in 1A and isnít in 1B, itís in something in between where the protections ought to be greater than they are in A but probably donít have to be quite as great as they are in 1B, on the chart up there. And I tried to suggest to you what those would be. I said in addition to you donít have individualized consent in advance but you do go through a process of trying to turn those retrospective samples into prospective samples. You tell people we want to do research on these samples of this type, are you agreeable to having your samples used. And the individual researcher may say, with this set of samples thatís impossible. These people are too mobile; weíll never find them, or whatever. And the IRB has to make a judgment, okay, weíll waive that this time. But they have to have full review which they donít under 1A. And secondly, I would insist upon if youíre going to do that having a surrogate consent group, a surrogate group for the community that participates with the researchers and so forth and figures out is this reasonable as a person looking at is who isnít a researcher but who is basically in the category with the people whose samples are going to be studied. So Iím acting as a surrogate for all these people who we canít contact, it turns out after all. Thatís a concrete difference. I then end up with the question, which I think Steve posed, does the example he gives in which there is a system which allows normal hospital data thatís still accumulating about this person to flow through to the researcher because of a clever encryption scheme, is that C or is it B? Is it basically that the researcher...is our only concern that the researcher canít ever go to the IRB and say please, please let me get back to them, I either need more from these people that isnít flowing in automatically, or I need to tell them something, I have something very urgent to tell these people, please weíll be doing the humane thing if you let me go. You know, thatís the question. And thatís only ... thatís possible under C. Steve was trying to say the way heís designed his hypothetical study thatís not possible and therefore we should treat it like B, as I took what he said.
For all intents and purposes, that is really a B situation, even though there really is a linkage going from patient through to research. If the researcher goes in on Day 10, the record may look different for code #75417 than it looked on Day 1 because sheís come back into the hospital and theyíve done some more routine tests on her, and oh my God, theyíve got more.
DR. CASSELL: Then he has to go back to the IRB.
MR. CAPRON: In Steveís hypothetical...
DR. CASSELL: No, your hypothetical, "I want to save the human race and go back and find out more...."
MR. CAPRON: Yes, yes, he has to go back... Theyíre different enough that he should tell the IRB right up front, and the IRB ought to look at that differently than they look at something which is really in the B category or he can never go back.
DR. SHAPIRO: Let me...I want to make a couple of comments, and also remind you that we ought to avoid just talking back and forth. Thereís a lot of people who want to ... participate in this conversation. As I listen to this conversation and look at that framework thatís up there represented in that matrix, there is an aspect of that matrix which I think the Subcommittee felt justifiably was new and that is this issue dealing with community issues, not in the surrogate sense which you introduced which may also be very important and find a role here, but in the sense that the information coming forward had something of some relevance to that community and one needed to address that in some way. And I think that is an important issue; both of those are important must...weíll have to deal with it. However, for purposes of trying to work out our scheme, and for filling in the boxes and so to speak, my suggestion which is simply a tactical, not a big issue of principle, is that instead of putting...distinguishing between individual communities you go down those rows, that those rows should really be these here. And then weíll come back as we go through and lay over the community issues .... Instead of individual community/community, youíll have A, B, C, D. And you will have to deal in the boxes with these community linkages but youíll have to deal with them in some way. I just believe that itíll just give us a framework in which we can work out the simple problem and deal with the community issues as we go along.
DR. EMANUEL: I thought those were columns actually.
DR. GREIDER: Theyíre just another way to do it, right, which is to split them.
DR. SHAPIRO: Correct, thatís all I meant.
DR. MURRAY: But what would be in the column category then?
DR. SHAPIRO: You could use the same thing in there as you have right now and then you can decide whether to collapse them or not.
DR. MURRAY: I think if I understand what Harold was suggesting, first, let me just clarify. Do we all agree that right now this is at least A and B? Over there belongs here, is that right? And thatís D, right, because identification is possible. And we may put...C may go in the middle. So Haroldís suggesting this. We sort of turn the array around 90 degrees and now each row, B1 representing A, B, C, and D. Thatís all, right? Thatís what is new. No mystery here.
DR. SHAPIRO: It seemed...I mistakenly thought I was clarifying something. I withdraw that idea, clearly not correct. Were I an artist I would try and redraw that, but I canít.
DR. MIIKE: Can you move that exhibit a bit, Iím having a hard time seeing. [LAUGHTER FOLLOWS]
DR. SHAPIRO: Alta.
MS. CHARO: First Iíd like to second Zekeís suggestion that we focus on prospective, perhaps, because going along with what Alex said, I think if we had a common set of rules about prospective collection, and we then encouraged all of the large archives to try to contact people and reconsent them along the lines that weíve developed for prospective collections, we would reduce the number that exists in this retrospective with no idea what these people want because theyíre either refusers...well, theyíre nonresponders. That would reduce that size and they would be refusers, and weíd know these people really donít want to be used. And that might be helpful.
But more importantly, in response to Ericís question of why this is still complicated, the experience that Iíve been having sitting on IRBs in the area of walk-backs is varied. But hereís what I imagine happening in the future, and Iíd love some guidance on this. Thereís going to be the discovery of more and more oncogenes of various sorts that are part of a multigenic, complicated, environmental genetic complex that lead to certain kinds of cancers. Any one mutation is unlikely to have a clear clinical significance, but neither does it have no clinical significance. In addition, various tumors are going to be identified as genetically distinct so that there will be interest in tracking the reaction of various patients to various forms of chemo, radiation, and combos, and tracking that in conjunction with the kind of tumors they have. So youíll both be looking at peopleís predispositions to cancer in a complex array of mutations and the forms of cancer they have in a complex array of mutations.
Any one single bit of information you develop about any single piece of tissue is likely to be interesting, intriguing, but not definitive. Weíre moving into a world in which most genetic informationís going to be highly ambiguous, rather than the old Mendelian model of highly-penetrating, single-gene disorders where if you have it youíre going to get it, this is what itís going to look like, and now deal with it. Itís going to be totally different.
There are going to, therefore, be thousands of situations, Eric, where if you permit the first part of the study, which is to go ahead and look at the tissue, right, I can predict for you that you are setting yourself up for 16 visits back to the IRB for touchy, sensitive, complicated, balancing acts about whether or not this is information that justifies recontacting for further followup of those original tissue sources, or contacting these people in order to send clinical information back down. Either scenario.
And so I think itís important that we not just say oh, well, itíll be a new study, thatís no problem, because we are setting the IRBs up for a very large number of very difficult scenarios, each to be handledóand it might make more senseóat the very beginning when you can see this is a study which, by virtue of the potential for a walk-back, can open ourselves up to 16 requests, to think about it, anticipate it slightly, and because each one of those requests is going to come up in a seemingly compelling fashion. But over time you begin to recontact people multiple times with ambiguous pieces of information, and you really are running the risk of driving people completely out of their birds. And I would just like us to not put ourselves in situations where weíre on kind of a runaway train in the recontact world.
So thatís why Iíd like to treat C as something more than just no problem because itís a new study if you want to go back to these people.
DR. CASSELL: But, can I just respond? Just briefly, itís really brief. I accept everything you say... and thatís why in the protections for future sample collection, we have to make provisions for that. But that does not mean that it applies to the protections for existing samples, or the complexities that you just introduced. You can solve that problem in future samples, but you donít have to do the same kind of complexity for existing samples. And if you say, well, we may miss a scientific opportunity, that may well be the case.
DR. SHAPIRO: David.
DR. COX: Yes, I think Alta has put her hand on, or her finger or whatever it is, on something important here. Because the ... it does become a nightmare if you think about the researcher going back and saying, oh, and I forgot to ask about the big toe and I forgot to ask about Aunt Millie. One of the things that the Breast Cancer Coalition people said to us, and a word that we havenít heard mentioned once today, is standardization. And itís extremely, I believe, important if something like this is going to work. So that itís not, in my view, or itís possible but itís not something that youíd like to see happen, that researchers could go and ask for any kind of information that theyíd want back. Thereís, in my scheme, there would be a standardized set of information that would come back, period, thatís it. There could be a menu of stuff that the researchers could ask for that would come back. It wouldnít allow them to identify the person in C. It couldnít identify the person; theyíd be using the information in a nonidentifiable way. And then, if they wanted to go and do a new study, thatís over and above that standardized set of information, then there has to be a mechanism by which they can contact then, or list those people for other research.
Now I think itís a conflict of interest for them to contact that person, and thatís why I really like the idea of the surrogate group thatís not only protecting the rights of the patients from the researchers, so the surrogate group could do that. It could also be the group, as Alex suggested, that would deal with the issue of community, because itís the community of people who the samples are, thatís what weíre talking about. And furthermore, that surrogate group could predict, could protect all the other players from conflicts of interest of one or another physician that had more than one role. For instance, a pathologist that was involved with the clinical care of rooting out the samples and at the same time involved with getting the samples for research: one person playing both of those roles. thatís not a "for sure" conflict of interest, but itís certainly an apparent conflict of interest. So the surrogate group could be looking, protection each other for dealing with these things. And if you have one standard set of information that can come back. And it can also be longitudinal, so if you that this thing, that this piece of information will be updated each year, youíre not going back. Thatís whatís set in there.
The .. but itís a menu that the researchers can do but itís not an unlimited opportunity to go the kitchen and ask for a completely different meal. Itís like a restaurant. So, and I have...if we ever get to it, some practical examples of the existing this that meet this criteria right now.
DR. SHAPIRO: Bernie, then Zeke.
DR. LO: Two points. First, in some of our comments, Iím concerned that we donít want to set out guidelines that provide rewards to people who are either sloppy, stupid, or ethically obtuse. So that I wouldnít want to say to an institution that actually has good records, is able to go back and contact patients, youíve got to go mail them a postcard and get consent for their old samples, whereas if Iím running a really third-rate organization and canít contact people, weíll thatís okay, I can just go ahead and use their samples.
DR. EMANUEL: So you donít want to penalize the Mayo Clinic.
DR. LO: Right. I donít want to put burdens on them that I wouldnít put on institutions that just arenít as well, sort of, set up. And similarly, I donít want to give rewards to investigators who havenít thought through the first-time around what is my research question, what am I asking, what if weíre saying, well if we keep nickeling and diming the IRB: Can I do this, can I do that?
My other comment has to do with I think we need to build into the protocol for these kinds of studies on existing samples of genetic tissues some prior thought as to how the investigator proposes to handle foreseeable dilemmas regarding recontacting patients in either direction. And I think thereís, again, ample precedent. Any time we do a study that, for instance, deals with psychosocial issues, our investigators are told, or at least we teach them or try and teach them, theyíve got to in their design think of what happens if I identify someone whoís severely depressed, whoís a victim of domestic violence. How are they going to handle the confidentiality? What backup do they have in place? And so I think part of what we need people to think about when they design the study is try and anticipate what dilemmas may arise in the course of your study that may...under which you may seek to recontact patients either to give them information or to try and get more information. And tell us how you propose to deal with those situations rather than having people run back in six months, then in a year and then two years.
So I think also the way to get around your problem is to sort of start to develop almost a standard of practice as to what are the types of information that warrant going back and warning patients in this multigenetic, incomplete-penetrant sort of model, and what are the ways in which more information from patients ought to pass to the investigator in a one-way sort of walk-through without necessitating full individual consent from patients.
DR. SHAPIRO: Zeke.
DR. EMANUEL: I want to make a suggestion. I am at one with Alta on the wish to avoid this sort of constant recontacting in the scaring people for the susceptibility genes that arenít really predictive. Now I think we can take one of two approaches. It seems to me if an investigator wants to do that kind of research on stored samples, with the possibility of going back because they might find something, we should treat it as identifiable. Thatís what they want to do. I am all for, in some sense, ruling out category C altogether. I have always been for that, which is you donít go back. And you ... if you want to use the sample in an anonymous manner or an unidentifiable manner, you donít have the possibility of going back. Itís just excluded from you. Now, what is the usual what happens if we find something that is serious. Serendipitously we find a serious...you know weíre doing some controls and we have the Huntington sheet in there, we find someone. Those are always the questions. I think itís very clear for us...we need to be very clear, either way somebody is going to end up being harmed. Whether we permit C and weíre going to have a violationówe should be clear about thatóor we donít permit C, we exclude C, either you go and make it an identifiable study or you can never walk back, in which case we are sometimes going to find something on sample 486 which we canít go back and identify. And the only way itíll get out is when we publicize our research objectives and people have to go decide for themselves. I think that...my own view is I think that minimizes the harms. And especially the harms of this constant recontact, constant additional information that may be very unwanted separate from a full-blown study where you get to decide whether youíre in or out. And as I, again, heard the Breast Cancer Coalition, thatís the way they wanted to do it, too.
I will, however, put on my other hat which is when I frequently propose this idea at various institutions, people who are clinical investigators, both clinicians and researchers, get very nervous about it. And their clinician hat rises up. I think we have to recognize that and if we come out...if we rule out C, we have to decide that.
DR. SHAPIRO: Tom, then Carol.
DR. MURRAY: Zeke, my intuitions track yours very closely, and I think I was wholly in favor of ruling out C till I went to the mini-hearing. And I heard a person, at least the one I heard and apparently this is true of other hearings, they, you know, it seemed to me they wanted to leave open the possibility that they might benefit. Now they also worry about discrimination so that would favor ruling out C. But they also felt like if theyíre going to have their tissue used, they would like to see if thereís...if they might benefit directly from that, theyíd like to see that happen. So that made me rethink whether C ought to be kept alive as a possibility. Thatís all.
DR. EMANUEL: Benefits there turn out to be the key problem, right, because knowing that you might have a five percent increase risk of cancer, is that a benefit? And so when you pose it to them that youíll benefit, I mean who would say no to that information? The problem is that the quality of the information, as Alta I think has correctly pointed out, is going to be completely different...than what we previously or what weíre used to thinking about.
DR. SHAPIRO: Carol.
DR. GREIDER: Just to get back to this issue about whether or not we delete category C and just make it not happen, to make it be actually B, if I hear what my colleagues, David Cox and Steve Holtzman are saying, that is like currently the largest category. And so we should just be aware.
DR. EMANUEL: Thatís the largest category? I though B, I thought B was the largest category. David tells me repeatedly that C is the largest category and so we just have to be aware...that youíre shutting the door on the largest category of maybe itís not whatís going on currently, but this is where are things are going in terms of genetic research. And so ...
DR. EMANUEL: David, are you saying Cís the largest category because of the continuous feed of more information? Or are you saying Cís the largest category because you want to go back to the individual samples?
DR. COX: Because itís the existing largest category. Pathology departments donít have all their samples with all the identifiers stripped off of them sitting there waiting for somebody to ask for them. Samples are sitting there with peoplesí names on them.
DR. GREIDER: But you said that people want to use them in a way that they can then go back and find out more information. This was what I hear you from you...
DR. COX: Thatís exactly what Iím saying.
DR. SHAPIRO: Bette, and then Bernie.
DR. LO: Let me make a specific proposal which I think addresses concerns Iíve heard David Cox and Steve Holtzman make. Thatís the situation of a investigator who wants to study, do DNA testing on a large sample, large number of samples, trying to find a hundred or so people who have a mutation that she will then want to study in more depth. Obviously, once she identifies those hundred people, sheís going to have to go back and get specific, individual, thick, informed consent for further studies. But that first-pass study, which is taking advantage of a large number of samples and doing tests, sheís really only going want to do without having to contact the individual patients for a number of reasons. I would like to suggest that under some situations, those kinds of studies ought to be permitted with full IRB approval, without individual consent, with some sort of community surrogate consultation as Alex was talking about, provided that thereís some, and also that those kinds of studies be allowed to feed onto the research in a one-way direction, clinical information thatís, clinical information that is gathered from the patient in the routine course of clinical care and fed into a computerized data system so that you can get follow-up information on a patient on such things as, you know, relapse and something, or clinical follow-up, not, sort of, other bits of information. Provided also that the investigator and the IRB ahead of time work out some system for dealing with contacting the patient or setting out the parameters under which they might find it permissible to contact a patient for really, really definitive clinical findingsówhich I agree with Zekeówill unlikely be from that research but other serendipitous findings that would really have a clear-cut dramatic impact on a patientís health.
DR. EMANUEL: Can I clarify one thing Bernie? Why, I mean, in yours, as youíve just described it, why couldnít you make it look like B in the following way: Iím going to take a thousand breast cancer women, right? Iím going to get the clinical information on the thousand, Iím going to do tests for gene Y, okay? A hundred of them are going to be positive, and Iíll have the clinical information on that hundred. Iím never gonna go back and contact anyone, itíll be completely anonymous. And Iíll get, and Iíll get continuous feedback.... But in an encrypted manner so I canít go back.
DR. LO: I could do that, but then, but thatís not the study I want to do. I want to be able to, if I identify those hundred, contact them to invite them to enroll in the next generation study, knowing Iím going to do that very carefully because of the concerns Alta raised about, you know, jeopardizing their insurability. But I would plan to go back to them once Iíve identified them to get full informed consent for a next-generation set of studies. So I want that possibility of reestablishing identity after the study is done, and I donít want to have to mail out postcards to a thousand people, because I really want to get those hundred. If I only got fifty of them, my study canít be done. Now I, Iíve sort of tried to hear from what Dave and Steve have said, that this is a strategy that is the sort of one of the strategies that is likely to be very fruitful in future genetic research. And so I think we need to look at it closely. And Iím just concerned that if we say you really can only do this if you have individual consent from everybody, you may not really do the research in the, just, your sample size isnít big enough to get the genetic variation.
DR. COX: Thatís correct, and thatís exactly what the community is concerned about.
DR. LO: Well then, then I think we need to address that, because Iíve heard it from enough research whom I respect I want to be able to say letís letís just try and address that problem.
DR. SHAPIRO: Eric, then Alta.
DR. CASSELL: But, Bernie, letís suppose weíre not talking about future specimens?
DR. LO: Totally different.
DR. SHAPIRO: No, no. Just for the moment, itís the same, itís future specimens. And you, should you be asking permission for the people those specimens are coming from about just the study youíre describing? It may be the case that investigators will wish to recontact you, blah, blah, blah. Is that the case?
DR. LO: Absolutely.
DR. CASSELL: Fine. So when you start your research youíve already declared that thatís your intention, and the consent form for it since you must have that in it in the first place, right? But this material doesnít have such a consent form. And so to solve that problem, you need permission from whom to go get that consent? You have to ultimately get it from the person, donít you? So really what you need is the ability to get back to a hundred people and get their consent for your further studies. Is that correct?
DR. LO: Absolutely.
DR. CASSELL: Right. And that, should that be, the only question I have is, I have no trouble with that. Should that be part of your original design, I will desire to go back.... In which case, youíre already talking about people who are, in essence, identified. You are not interested in the nine hundred that you, right? But you are interested in the one hundred. Therefore itís a study about people who are identified to start with.
DR. LO: Right, but the question I have is knowing all that, and by being honest about it and being straightforward, can I do my first-cut study with the thousand without getting specific individual informed consent from all thousand on their stored tissue samples?
MR. HOLTZMAN: So I go, go to Harvard Community Healthcare Plan, okay? And, and I think itís important to keep our minds wide in terms of what you might be looking for, right? So what we said to them is, "Can you go through your records and identify how large a group of people you have with high HDLs?" That is, good cholesterols. Weíre looking for the healthy folks here because we want to figure out those genes, okay? Do we need informed consent from everyone in the plan for them to go through and look at it? Our intent is, if there are enough folks in there that we could launch a study we would then go and enroll those people in a study.
DR. COX: But there may not be enough.
MR. HOLTZMAN: But there may not be enough. Okay. But clearly, in my mind, if weíre then going to go and enroll those folks, youíre going to get involved. Now, on the other hand, letís take it further, right? So suppose they come back and say yes, we have N, and N is a large enough sample to do it, and it so happens we have in the fridge bloods from all of them, okay? Now. Question. Under what conditions can I do a study on those bloods without consent? And those are, theyíre current, theyíll be sitting there. And since youíre continuously getting more information about these folks because theyíre part of your plan and theyíre going in for their annuals and itís going to take us a couple of years to get to the gene, can you feed us forwardóI donít want to know, I donít want to go back, but just as part of their regular health care, can you feed us forward any additional information about their HDL status, or whatever, thatís changing? So when David was saying the future of genetics, okay, and does it mean you have to go back and mail the individuals or what. You can imagine these scenarios where you donít have to talk to the individuals, you donít have to know who they are. Someone is in possession of information.
DR. COX: Do you need their names?
MR. HOLTZMAN: I donít need their names. I donít need, then, well let me, again, the question again comes back to in what weíve described and I thought was the motivation was that it was unclear that you could be, be B and get the go-forward information. Okay? The clinical follow-up information. So when you say itís C, I donít know, does it need to be C or not? So, but those are some real-life cases. I also want to say we shouldnít be so focused on genetics because, in the sense of "the mutation" and "the genetic study," most of what we envisage here in terms of particularly the cancer is not going to be looking for germ 1 mutations itís going to be looking at differences in RNA profiles, transcriptional differences, and protein differences, which may not be indicative of inherited genetics.
DR. SHAPIRO: Thank you. David?
DR. COX: Although it would be really nice to make this case very simple, that itís not sort of laziness on the part of the researcher not to sort of declare that he or she, you know, has this in mind to begin with. But it really depends on what that initial sample looks like. And why this is a real problem is this is exactly the way NIH is setting all this up. They have these samples that were done with these detailed informed consents. The tiered informed consents, thereís lots of samples collected that way now. And researchers want to go in and initially use those in this sort of unidentified fashion, a C-type fashion. They want to make sure itís in a C-type fashion because they donít want to go to the work of getting the informed consents for everybody to begin with. But, if it looks like a sample thatís going to be worthwhile to them, then they do want to go in and do the informed consents. Some of those samples, they can go through a lot of them. Letís say that thereís ten different sets of heart disease samples and that you find out itís only one of them that really has the groups that youíre interested in. So, thatís the one that youíll go in for the full IRB approval. Now Iím not saying that this is the way it should be. Right? I mean Iím agnostic about what we should be. Iím just saying the way that the research community is thinking about it now. Some the way Steve said, others the way Iím saying. I donít want to argue which is going to be more.
MR. HOLTZMAN: There will be both.
DR. SHAPIRO: Bernie?
DR. LO: Iíd like to repeat a session Iíve made before. I would find it immensely helpful if we could get a chapter or mini-chapter from scientists saying, "These are the types of studies we think are going to be really fruitful in the future," just to ground us and make sure we have in mind the kinds of studies that, at least in the short to medium term are likely to be proposed and raise the dilemmas. Also, I think that for the public at large, I donít think they have any clue that these are the kinds of studies that we really have in mind. I think it would be important to add some sort of real-life description to our analytic categories to make people understand whatís going on.
DR. SHAPIRO: Okay, we have a few more people on the list here. Weíre going to have to draw our discussion to a close this afternoon. Weíre obviously going to have to do some staff work here to try to take this discussion and give it a framework which seems sensible to people. Weíre not going to hone that down this afternoon, we just donít have time. But I have Alta, then Eric.
MS. CHARO: First, I want to say that the examples that Bernie and Steve gave are extremely sympathetic examples for why youíd want to be able to make sure you can go ahead and do the research. Iíd also like to note that retaining the requirement that there be some form of consent does not necessarily preclude doing this research. For example, you might actually get the consent. Or, you can have a version of consent that is essentially an opt-out, and that handles the problem of the now missing people. Itís a letter that goes, "We are planning to do this kind of stuff and if you object, please get back to us," with the presumption being that those who donít get back to you are either actively consenting or weíre going to simply draft them in. Because this is in the realm of minimal risk. Right? And indeed the exemption is written to anticipate that if you reasonably canít get consent from people and itís minimal risk you really donít have to worry about consent. Weíre talking now about a possible change in the regulation where maybe if itís not minimal risk youíd want to debate whether or not an opt-out is appropriate. But nobody here is suggesting that we shut this research down. The question is, how much effort do you make to allow people an opportunity to be aware that theyíve been made into research subjects while this goes forward. And although the examples you give seem completely innocuous, the problem as Iíve said, is that there are unexpected things that seem to crop up. Youíre looking at healthy people with high HDLs and then a lab halfway across the planet in Nagano, Japan comes up with something that links high HDLs to, uh...
MR. CAPRON: Schizophrenia!
MS. CHARO: Schizophrenia.
MR. CAPRON: So we ought to put our two reports together.
MS. CHARO: Thatís right. [Laughter] My point simply is that if itís possible to work out a system by which we make a serious effort to notify people and get some consent or at least a lack of objection, we can go a long way towards making it easier to live with ourselves when these situations inevitably arise down the road. And we can talk about how when we do it. This is a national issue, there are 228 million samplesófine! Let NIH with its new expanded budget finance a $100 tax credit for every person who say yes on a checkoff on their IRS tax form. I mean weíve got national-level endeavors we could talk about that would allow you to get out at least one blast of alert and notification or something. I mean these are nonsense ideas at a quarter to five but Iím not willing to abandon the idea that youíve proven that these studies wonít if we try to live up to our ideals about not roping things into, roping people into things that they didnít know about and putting them at risk of getting phone calls they didnít expect or spouses who see the letter or get the phone call saying, "I never knew you had breast cancer," or "I never knew that you were once at Harvard." Or whatever it is that the, the recontact incidentally tells other people in the household about: your past and your medical past, your social past.
DR. SHAPIRO: Talking about that very last risk of never knowing you were at Harvard, I repeat an anecdote that occurred to me that I witnessed in an elevator in New York, in the elevator. One man is saying to another "All three of my sons went to Harvard." To which some women in back said all four of her husbands had gone to Harvard. [Laughter] No consent, no anything! [Laughter] Eric?
DR. CASSELL: Well Steve, I hear your case is an excellent case, and one of the questions we would ask you is, "Do you need consent from those people to do the study as it exists now?" We can make a case that you do not, or no harm will come to those people and the data will never get connected to them, and so forth, and thatís the issue. If the data cannot get connected to them and you cannot go back, cannot go back, then we donít think you need consentóthe specimens have already been stored. Now the, and what I hear again and again is "Yes but angst! Because look, it will turn out that schizophrenia..." Well then thatís the way it will turn out. And you canít go back. Period! You cannot go back. And, and if we understand that then things become easier. If, in the future, you want consents gotten that allow you to go back, thatís a totally different thing. And the, and the fact that scientific progress may be slowed down doesnít move me at all. Iím not moved at all by that.
DR. GREIDER: Not by, not a bit?
DR. CASSELL: No. Not a bit. Not an absolute bit. Progress is only one value.
DR. LO: But Eric, how about clinical then, if itís the patient?
DR. CASSELL: Clinical benefit to the patient also! Because remember, it isnít clinical benefit to the patientóitís clinical benefit versus harm! And since you have a number of people, to the patient against how many harms? Thatís like when you say about an in ICU thing, "Well he might live, well he might live!" How many people do you keep on respirators, that one person might live? Those things have tradeoff. Itís easy as long as youíre concentrating on "The benefit will comeóweíll be able to show that schizophrenia and HDLs are intertwined..."
DR. LO: No, no, Iím saying, no, Iím, see I think we really have to keep clear...
DR. CASSELL: And weíll get that person treated and theyíll never have a break, whereas if we hadnít done this work they would have gone ahead and broke it.
DR. LO: No, Eric, I think we have to really keep clear. Wanting to contact the patient for research purposes either to get more information or to get them to, invite them to enroll in a future study versus contacting a patient because serendipitously in the course of your research youíve found clinically relevant information for that individual patient. If you found it on an employment screening exam you would feel obligated to tell that patient that he has tuberculosis or...
DR. CASSELL: I know that but youíre doing the same thing. Youíre isolating it as though itís this example. We may benefit this patient rather than the wider screen of all similar studies. All studies done with that caveat built into it. You see, if you look at that one patient, look at, at the injury. But if you realize that weíre not talking about one patientóweíre looking at a spectrum of studies of which thatís one example. So yes, you can make a persuasive case for that one patient. But if thatís the way all studies of that type are designed then remember, youíre protecting an awful lot of people. And, in fact, some people do get injured when you protect a lot of people, so Iím not moved by that.
DR. MIIKE: Can I interrupt?
DR. CASSELL: Okay, Larry.
DR. MIIKE: I agree with Eric on that. We either have to fish or cut bait on some of these issues, and we canít let the individual cases sway us on the overall. The second thing is that Steveís example about wanting to go back and go back, I look at that and say "What if I was a patient?" It seems to me the fact that thereís some tissue or some blood stored is irrelevant. I would feel offended as a patient if I knew, if I didnít know and was not informed that they were continually tapping into my medical record with my never, ever knowing it. So to me, I would call that, and I, I would, I donít know how you deal with that but I certainly wouldnít want to give my consent on that.
DR. SHAPIRO: : Thank you. Weíll take a couple of more comments. Then weíre just going to have to break and try to...youíll have the last word in a moment. Eric, you wanted to say something?
DR. CHAPPELL: No, Iím okay.
DR. SHAPIRO: Okay. Alex?
MR. CAPRON: I actually have two questions now. One relates to the exchange earlier between Steve and David. And that was the notion of a person doing studies on a whole bunch of different samples and one of them turns out to be the one of interest. My understanding of that exchange was those were all studies being done of the "B" type. That is to say, you didnít have the linkage and you didnít get consent in advance, and so forth. Having then identified this group, you then wanted to do a "C" type. Is that a correct understanding?
DR. COX: No, that was Steveís. We mixed those. It could either have been by the "B" type, and then you have to look at the whole group. Iím particularly interested in those being of the "C" type, where you actually knew, not from the outset, but you would by looking at the group. You wouldnít have the links as a researcher. Youíd have all thousand people. You would identify samples 23 and 32 and somebody else could have told you who those were.
MR. CAPRON: Yes. Okay, thatís "C" type.
DR. COX: And there are two, clearly very different things. Because one of the things if you wanted to go back, youíd have to go back to the whole group, right, if you wanted to inform them. The other you could only just go back to those two people. So, that it would be sort of much more cost-effective from a research point of view. But, the risks, as Eric has pointed out, for those two people increase considerably, so...
MR. CAPRON: And the second is to follow up a question on what Larry just raised, because maybe everybody else saw this before, but a little while ago Steve was describing a study, and we were trying to decide whether it fit in "B" or "C" and it was the one in which there was a one-way flow of information from an ongoing patient into a database and then the researcher was looking at it. And Larry just put his finger on something which has been my sense about it all along, which is that sense of sudden shock and a little bit horror to discover that all your stuff was flowing in, it wasnít just your doctor that was looking at it, but someone was doing research on it. Are we clear that thatís referred to as a prospective study, or are we, are we trying to bundle it under retrospective? Because you start it off looking at existing data and the next time you look at that data itís been supplemented, but at that moment that you look at it, that new data is also "existing data" even though youíve set it up, to allow yourself to constantly get, as it were, prospective data. The data is existing by the time itís, because "data!" But are we judging it, in other words, from the point where the research taps into it or at the point at which the researcher begins the study? Because Larryís comment makes me think what I originally thought before I sort of put it out of my mind, which is we ought to treat that as a prospective study at that point. Are we in agreement about that? Okay.
MR. CAPRON: ...youíre saying "as you come in and supply new data I wonít know who you are, but I will know your new data." You know, I canít treat that as a retrospective study.
DR. SHAPIRO: Rachel, did you want to say something?
MS. LEVINSON: Yes. I have ten yearsí experience working in a pathology lab on tissue. And I have to say that "C" is the by far the biggest category. And I couldnít call it prospective after the first cut either, necessarily. An example might be where you have a hypothesis that normal people (this is something I worked up) normal people have thyroglobulin in their retro-orbital muscle. And some people develop an autoimmune disease that causes their eyes to bulge out because theyíre reacting to the thyroglobulin in their, their eye muscle thatís there with everybody. So I go and I get 200 samples of retro-orbital muscle and I look for thyroglobulin and I find it. So I know that these people have it. Then I want to know something about thyroid function. I go back to medical records at that point. And I didnít have the patientsí names, and I didnít care about the patientsí names. I got the tissue and I had numbers of the people. So thereís a record in pathology that says "this is autopsy tissue from "A"...98-137. And I can go back and get from medical records from that number their record of thyroid function. Itís still old, existing data in the same medical record. Then, I find something thatís a little different and I want to go back again and look at, still, existing data. Itís normal people, still, nothing about disease function, to try and get more details to understand how the variability would come out. Today, we would look at the genetics of it. But, itís probably the largest type of a study. The most frequent type of studies that are done. And you never need to know the names, ever. You can do it all by numbers.
MR. CAPRON: But itís still "C."
MS. LEVINSON: Itís still "C." But...
MR. CAPRON: It isnít prospective, because itís all...
MS. LEVINSON: Itís not prospective, itís all existing data.
MR. CAPRON: Itís all, youíre looking at it, just on the day that you, you start the study.
MS. LEVINSON: Exactly, youíre just cutting it different ways and going back and asking questions.
MR. CAPRON: Whereas if you were having the patients at the same hospital were coming in for annual physicals and their eyes were being examined, and that data was flowing in to the data banks, that would become a prospective study.
MS. LEVINSON: That could become a prospective study.
DR. LO: The real question is do we want to get full consent from each individual for the second study but not for the first study? Because thatís a big difference in how feasible that research is and how much effort. And I think itís not how you categorize it, itís what kind of protection you think is appropriate in each of those two situations.
MR. CAPRON: Yes, is my answer, where youíre going to be tapping into new data, the person whoís supplying may really become a subject in your research and they ought to know it. And the opportunity is there. Theyíre coming in, they could be asked. This isnít one of these things where you start wringing your hands where you say "theyíre dispersed, we donít know where they are, they might be dead, they may be," right, whatever. These are people who, they only are relevant to you because they are still coming in. And, they are becoming current subjects in your study, as people, not just as tissues, theyíre not just tissues anymore, they are people coming in.
MS. CHARO: But youíre acting as if the retrospective study wouldnít require consent, and if you link medical records, as I understand the rules, you need to get consent even if theyíre existing medical records. If I have a piece of stored tissue here and a medical record in a different room, and I want to do research that involves linking information between the tissue and the record, or if Iíve got two different recordsóIíve got a dental record on avenue "A" and an opthalmological record on avenue "C" and I want to link them. My understanding, under the current rules, is that if, if consent is possible I need to get it. Itís one of the most commonly, if Iíve got it rightóI think doóbecause itís one of the most commonly misunderstood things, along with confidentiality versus unidentifiable, that weíve run across in our PIs. Because it seems so totally harmless. Because they donít care about the patientís name. And theyíre shocked, shocked, to find out that they need to get consent. And yet, Iíve, this has come up endless. So we donít want to have this discussion about prospective versus retrospective as if it means different rules, as far as I can tell. Itís the same rule! Youíve got to get consent.
MR. CAPRON: And they say, "of all the IRBs in all the world, why did she walk into this one?"
DR. SHAPIRO: Okay! [Laughter] Thatís right. I think we ought to move to adjournment now. This obviously, itís been very helpful, but I think what it tells us is that we have to get back to this group. Tom, Iím going to turn to you in a moment. But get back, try to assimilate all this and find a structure that seems to allow us to begin building the kind of protections we want. I actually think myself that as we start articulating which protections belong in which box, however you do these boxes, that a lot of this is going to seem much more straightforward. That itíll be pretty easy in a lot of the boxes, and then there will be some very difficult boxes to decide. Just whether we need informed consent or donít, in certain... But I think itís really quite doable. Tom?
DR. MURRAY: Thanks. A first quick word of thanks to Carol for presenting the matrix and for helping me get my own thoughts clear, and David was also very helpful in that. To Harold for chairing the meeting with characteristic graciousnessóIíll let Harold say the final words about staff. And Alex for acting as our host. But I have to say Iím shocked to disagree with Alta about something. Not what you last said but your comments about testing for schizophrenia in Nagano. [Laughter] Iíll have to tell you right now that, you know, at the eve of the opening ceremonies for the winter Olympic Games, theyíre not testing for schizophrenia at the lab in Nagano, theyíre testing for anabolic steroids, stimulants, diuretics, and beta-blockers.
MS. CHARO: And Sudafed!
DR. SHAPIRO: Well, Iíve actually discover, Iíve discovered something about Tomóthat heís really big on these athletic analogies. [Laughter] And weíre going to have to investigate this, where this comes from, that enthusiasm. But, we really thank everybody today. Alex, thank you, itís great to be here in Los Angeles. It doesnít look like itís raining too hard out there right now. So, thank you all very much.
ADJOURN 5:25 P.M.