DAY 2 CALL TO ORDER - 8:17 a.m. WELCOME AND OVERVIEW OF AGENDA - Dr. Harold T. Shapiro
DR. SHAPIRO: I call todayís meeting to order.
Iíd just like to remind the Commissioners of the general scope of our agenda here today. We are going to spend our initial few minutes this morning revisiting rather briefly the issue of the proposed scope or nature of what this Commission might address itself to with respect to international research issues. We had some presentations on that yesterday. Weíve had some very brief discussions at previous meetings about that. And over the next little while we do have to define a task for ourselves in this area thatís compelling and interesting to us. And I like us to begin that discussion. We donít have a lot of time to spend on that this morning. I would then like to return to the issue of the use of human biological materials which we discussed yesterday. A number of things I have on my mind there and other things which other members of the Commission might wish to address. Weíre then going to spend a good part of the morning looking at some cases in this area.
We do have two speakers who will be with us from the National Human Genome Research Institute and theyíll be discussing a particular case, in fact a very interesting and fascinating case, and I think it will be helpful to us to listen and understand and try to think through what we would feel comfortable with in a case like that. Also, David has some cases which we might look at, and Steve I know provided Kathi with the material which formed the basis of a memo Kathi wrote, the material basis of issues that Steve brought forward. And I think it just might be very useful for us to consider these cases and go back and forth a little bit between how we want to sort of abstractly deal with these issues and sort of test these ideas out in the context of some particular cases. That will probably use up most of the time this morning, weíll just have to wait and see. We have some time reserved for that this afternoon if it still seems at that time that itís productive for us to continue conversations in this area.
And then, of course, we want to go to research involving persons with disorders affecting their decision making capacity, which is always a mouthful to say and Iím always never quite sure if Iím getting it out correctly. But in any case, we did have an interesting draft to review and a lot of issues there to be resolved also. And we will get to that as soon as we can. I know that itís always difficult to retain enough of us here as the afternoon wears on because of the imperatives of travel schedules, plane schedules, other kinds of commitments, so if we do have a capacity to get to the that particular report for which we have a draft earlier, weíll take advantage of that so we can go to it somewhat earlier and have as many of the Commissioners here as possible for as much of the discussion as we can.
In that context, Eric spoke to me yesterday, he has something that he would like to speak to us about regarding the Saks paper which some of us have seen. And we can describe that and Eric has some views on that and others may have also. Weíll get that more generally distributed as soon as we can.
So thatís the general nature of our discussion. We will adjourn no later than 5:15. We probably wonít last that long, but, in any case, we will certainly go no later than that.
FURTHER DISCUSSION OF INTERNATIONAL RESEARCH ISSUES - Dr. Harold T. Shapiro and Commissioners
DR. SHAPIRO: All right. So letís go to the first issue on the agenda, which is really left over from yesterday when we ran out of time, with respect to international issues. Let me turn to the Commissioners to see what ideas you have, what things you think might be an appropriate scope or nature of anything we might do in this area. There is of course a lot of other activity going on in this area. And as I announced yesterday, Iíve asked Alex to take some leadership here in helping mobilize our efforts in this area and Iím very grateful to him for agreeing. And to repeat what I said yesterday, any Commissioners who would like especially to work on that area, please let me know. We would be most anxious to accommodate you.
I have some ideas in this area, but I would like to hear from Commissioners also. Alex says heíll be all ears since heís got to listen and mobilize our agenda in this area. Let me get started here.
Oh, Bernie, Iím sorry, I didnít see your hand. Bernie?
DR. LO: I think this is a really important topic. My concern is that itís very, very broad and sort of nebulous. And unlike the other things weíve worked on where we had both a very clear focus and I think a clear audience that was interested in what we had to say, Iím a little concerned here about who are we going to be hoping will read our report and act on it. I guess personally I am not very enthusiastic about trying to work towards a revision of international codes for a lot of reasons, but, basically, Iím not sure people are going to pay much attention to them.
I do think it may be worth trying to identify what are going to be the hot issues regarding international research, particularly in an environment where I think weíre going to be seeing more of it rather than less of it. I think we donít want to focus on specific issues, like these neonatal HIV prevention trials, but the whole notion of placebo controls and standard-of-care in other countries and how that effects the design of studies. I think thatís going to keep coming up.
I guess my caveat is provided we think thereís some assurance that what we say will not fall on deaf ears, I think we should try and identify what we think the pressing issues are or are likely to be and provide sort of an analysis, sort of an approach to it rather than trying to sort of make specific recommendations on how the Helsinki Declaration might need to be amended or whatever.
DR. SHAPIRO: Okay. Iím going to turn to David and to Arturo in just a moment, but I did neglect something right at the beginning I intended to do. We have a former colleague and guest with us this morning, Dr. Zeke Emanuel is here with us this morning primarily to discuss the issues regarding human biological materials. We will ask him to join our conversations at that time. That is to occur very briefly. So, welcome back.
DR. EMANUEL: Thank you.
DR. SHAPIRO: I just want to indicate to everybody that this is not an extra Commissioner or call-back Commissioner but a guest here this morning to help us with one of our discussions.
DR. COX: I share some of the same concerns that Bernie just brought up. And so I asked myself from what perspective do I really want to address these issues. I guess in the process thereís two perspectives, there are two things to look at. One is, are there general ethical principles with respect to research in international research that can apply across all different cultures and all different countries? Thatís the international code. Itís not likely weíre going to change it. Itís a much more difficult question then, what are the principles that apply in American society and culture? In fact, we are the National Bioethics Advisory Commission.
So to look at those two different things because I believe that the utility of this investigation into the international things is going to basically be to inform us about how other cultures and views look at things other than the United States and it will have great utility for us addressing things with respect to the United States. In fact, itís not so much us giving pronouncements for the rest of the world as the rest of the world informing us. So thatís what I mean about perspective.
On the other hand though, thatís very parochial if itís just what can you do for us. And so I think at the same time we can say out of those things that are useful for our own deliberations with respect to types of research, what are the overriding issues that do cut across different cultures. And there are going to be some of those, but itís not going to be nearly as much as how do other people look at things that may differ from our viewpoint. And the AIDS AZT research is a classic example of that because it was an example of American viewpoints that differed with other peopleís viewpoints perhaps. So itís a perspective issue. It doesnít help with the exact things weíre going to do, but itís the perspective that weíre coming from.
DR. SHAPIRO: Arturo?
DR. BRITO: I agree with David that we do have a lot to learn from other cultures in looking at how they do research. But my understanding is that what weíre going to be looking at is international trials, or we should be looking at is international trials that are U.S.-sponsored either by NIH or other entities in the U.S. and seeing how well the U.S. sponsorship of teams comply with even our basic codes.
There was a memo that the staff sent out to the Commission members and I have some points that I think are important. It particularly addressed the AZT trials. Thereís a line in there that the recent decision to cease the use of placebos in such trials render such an approach moot. Iím not convinced that all the trials have stopped at this point. And even if they have, even if they have, thereís still some what allegedly would be inappropriate research has occurred recently. I think this would be an opportunity to use this as a basis for how U.S.-sponsored trials can go awry.
I think that weíve brought up before that there may be cultural differences, biological differences, etc. But it seems to me that we need to look at why the decisions were made to stop the placebo-controlled trials, what was the basis of that, and maybe use that in a positive end. And then thereís also a line in there, "The Commission should consider addressing the issues in both developing and developed world." Well, that goes without saying. But what weíre really emphasizing is that making sure that the criteria used for research in the developed world is also being applied in the developing world, particularly with any U.S.-sponsored or Western-sponsored trials. But, obviously, weíre going to be addressing the U.S.-sponsored trials.
But I think there should be no distinction in how codes are upheld with either private or publicly-funded research.
So, in essence, I think this is an important topic we should address. I think that the HIV, the AZT trials should be used as a starting point just as an example, and that what we really need to do is also what we need to get from the international community is basically cultural differences and interests from there and how they may apply to U.S. sponsorship.
DR. SHAPIRO: Thank you. Alta?
PROFESSOR CHARO: Based on yesterdayís presentation by Tom Puglisi and the comments from Bernard Dickens, it struck me that if we wanted to take a fairly narrow focus that builds directly off the AZT trials, we could say that what we would like to do is examine the actual practice of U.S. collaborative trials abroad with regard to four kinds of topics.
Given that we have the CFR already governing for many circumstances some of the procedural requirements that the foreign institution and foreign investigators have to meet in order to collaborate with the U.S. investigator, there are still substantive questions about the actual distributive justice questionsóabout subject selection, notions of vulnerability and potential exploitation in that local culture, and in the particular kind of risk-benefit balance that is permitted for the protocol overall as well as for the construction of the control group. Those are things that are not answered by the existing regulations which focus on the procedure for decisionmaking but not its content. And this is where the CIOMS guidelines are a beginning for the discussion. But we have yet to decide for ourselves if weíd like stronger guidance for U.S. IRBs about whether or not they should permit their own investigators to collaborate.
The second, which is in fact addressed by the regs but perhaps is subject to further discussion and even change, is in the area of the nature and quality and evidencing of informed consent. Because of the frequent problems with notions of personal autonomy, legal status of certain persons, particularly women, in many cultures, there is frequently a problem in the quality of the ability to obtain informed consent. And there is a U.S. requirement for a physical evidencing in the form of a signature or even an X. The signature actually becomes a problem in some cultures and we see many requests to waive that portion of the requirement. I suspect that many times it is being waived inappropriately in kind of a sotto voce way. And we could revisit what it is that we want in terms of both the nature of the consent and how itís evidenced to meet both our needs and those of the local culture.
The third would be what had been focused on yesterday in the questioning, which is the enforcement mechanism. Regardless of the actual authority that we have, what is the ability on the ground to get cooperation from foreign institutions to investigate or to have site visits and is it sufficient, and how can we improve that kind of cooperation, which is going to be very much about local culture and about U.S. relations with that culture. And it wonít necessarily be that itís developing countries that are the problem; I suspect that it will be our colleagues in Europe who have got well-developed systems of their own who may turn out to be the least interested in having the U.S. come in and play enforcer.
And the last, which Tom was emphasizing in his responses yesterday, is probably the most difficult because we havenít done a really bang-up job yet in the U.S., and thatís the problem of educating investigators into the culture of research ethics that ought to apply in the course of a protocol. Since thatís really the most important protection for human subjects or human participants in research, to the extent that weíve figured out how to educate our own PIís, some thought about how one might try to quickly transfer that education to our foreign counterparts as part of a collaborative protocol would be interesting. And that would be an agenda just for the narrow how do we do U.S. trials abroad kind of approach.
DR. SHAPIRO: Thank you. Larry?
DR. MIIKE: I guess this is more for Alex as he does his investigation. Expanding on David Coxís comments, I would be interested to see what other developed nations see as deficient in our system. It is sort of the way of what Alta was talking about, is that if the criticism is that we donít, say, have universal health care, it may back us up into the issue about compensation for research subjects. But what sort of a mirror back at us about what do people in other developed countries see as deficiencies in the way that we do things.
DR. SHAPIRO: Thank you. Yes, Laurie?
MS. FLYNN: I would just want to reinforce the last two points that Alta made. I think itís critically important that we recognize the culturally-relevant context in which this research goes on, and that if we have concerns, the ability to have site visits, and I understand the negotiations that would be involved. But I think it would be important in terms establishing kind of relationships that would lead to greater assurance that ethical standards are being met.
And secondly, I think it goes without saying but perhaps needs to be said regularly that the work that needs to be done before we can think of anything else is upgrading and enriching the education for investigators, the understanding of the dynamic of ethics and their ability to participate much more fully than I think some have. And thatís an issue that we have to address here in this country I think much more strongly than we have before we can imagine exporting it effectively. So I just want us to remember with some humility how far we have to go here.
DR. SHAPIRO: Thank you.
MS. BACKLAR: I just would like us to remember to be very, very sensitive to the colonial aspects of this discussion and thatís all.
DR. SHAPIRO: Alta?
PROFESSOR CHARO: It is, depending on how it is structured, but if it does focus though on U.S. collaborative research, not even necessarily on U.S.-sponsored research, but U.S. collaborative research, U.S. investigator and foreign counterpart, we can direct the comments very much to the circumstances under which our own researchers are permitted to collaborate. Not a matter of telling other countries how to do their own research, but a matter of telling our own investigators whether or not theyíre allowed to participate in it. I think that avoids some of those problems.
DR. SHAPIRO: Thank you. Any further comments from Commissioners on this?
DR. MURRAY: I think it has come up at least indirectly, but I wouldnít want us to loose sight of the primary issue that in the past year or so has brought this to the fore, and that is when youíre looking at lesser developed countries that do not have the resources and the infrastructure or the standards of care that we have in the developed world, and when it is proposed to do an investigation, one or more of which treatment conditions would be a standard-of-care less than that would be provided here. I just think we need to address that. Itís been called a placebo group. It need not be a placebo group; it could be an older form of care thatís a lot cheaper. But the key thing is when youíreóand the bite of moral criticism that I recall in the debate weíve had in the U.S. recently has been to remind us that we should never expose human subjects to a standard of treatment less than that which they should otherwise receive. But that has not been contextualized in an appropriate way. And Iíve heard some very good arguments on both sides. This is the sort of issue I think it would be worth our delving into more.
DR. SHAPIRO: Thank you. Other comments?
PROFESSOR CAPRON: I would like to hear in the weeks following this meeting any further ideas people have about issues of that type. I think Bernie began the discussion by saying that the placebo control, and as Tom has said, is a slightly broader question than just the placebo control. But the design of experiments, to what extent are there other "hot issues" that are not procedural issues of the type that weíve spent most of the time on, which I think we have to figure out how to get a handle on those, and I found this a very helpful discussion, but if there are other issues of that sort. And we can ask, as I think has been implicit in several of the comments, are there issues we think that exist domestically for which looking abroad becomes a way of looking at them and almost diffusing them a little bit. Itís as though we were talking about a hypothetical, and then turning back and saying are there ways that, after we look at them abroad, that we ought to actually be concerned domestically and what effect would they have on the U.S. regulations as well.
Iíd be happy to get any of those. And I will try sending an outline in the next week or so of these and discuss with staff how we might go about on a continuing basis in the next few meetings having input that will help us to pursue different avenues.
DR. SHAPIRO: If I could just say a word about this, as we wind up this small part of our agenda today. Picking up on some comments I think that some of the staff made and Alex made yesterday. I think the issue that Tom points to or issues like that are very important to address in some way. But, on the other hand, Iím hoping that as we form our agenda here that itís a little broader in context. That is, my own sense of it is it shouldnít be just collaborative research we do with less developed societies. If you looked at the NIH data yesterday, in fact, most of it is not there. Most of it is in the U.K., and Canada, and Australia, and so on, which are hardly less developed places. And so weíre going to have to have a perspective that includes, in my view, something beyond this special case, which is important enough, I quite agree with what Tom said and he raised a lot of issues in this last year.
I also think that we need to at least consider going beyond Federally-funded projects. That is an issue that Alex raised yesterday, if I recall. That is, thereís an awful lot of U.S.-sponsored research in this area going on abroad that, first of all, it doesnít go through NIH or HHS, it goes through some other government agencies, but thereís an awful lot of private research. Certain kinds of trials are typically held abroad. And I think we might want to understand what the scope of that is, what the nature of that is, why that is, and whether that raises or doesnít raise any particular problem.
So Iím hoping that as we begin to focus down on the agenda we can have a sense of this dealing not only with the key issues, one of which Tom has raised, which are very important, but get ourselves informed about this broader concept and see whether that raises any issues for us. Until we know more about it, itís hard to say. I donít have any perspective one way or another, but I hope we can take a broader look at it. Eric?
DR. MESLIN: Just very briefly for the Commissionís information. This subject is not limited to what report we might write, but also the way in which the Commission itself is being perceived and looked to internationally. Our reports will become part of the international dialogue on bioethics which is increasing apace. You heard from Dr. Alexander yesterday about one of his roles as the U.S. observer to the Council of Europe, others have played a similar role at UNESCO meetings. And there is an increasing interest amongst the worldís national bioethics commissions of the way in which they can have a common dialogue on issues of mutual interest.
So whatever we come up with will serve an educative function iteratively, both they learning about how the U.S. National Bioethics Advisory Commission functions and speaks to these issues, and how we can learn from those other commissions. Several meetings ago Dr. Shapiro mentioned that in November there is a planned second summit of the International Association of Bioethics to take place at this point in Japan. And that may be an opportunity for whatever the agenda we are putting together, which will form the basis of our report, to be raised as our perspective. This is something that I think the Commission needs to keep in mind.
DR. SHAPIRO: Thank you very much. Any other comments on this issue before we move on to the next item on the agenda?
FURTHER DISCUSSION OF HUMAN BIOLOGICAL MATERIALS REPORT - Dr. Harold Shapiro, Dr. Thomas Murray, Dr. Kathi Hanna, and Commissioners
DR. SHAPIRO: Thank you very much. And let me thank Alex once again for agreeing to take leadership on this issue.
Well, we had a rather long discussion yesterday including a number of presentations in the general area of the use of human biological materials. I think, at least my own sense of our conversation, is we came to some kind of quasi resolution yesterday that was, in fact, really quite productive. Iíll wait and look at the transcript to make sure that I havenít sort of selectively listened to what was going on. But it was my sense that we really had taken our discussion a step forward.
I wanted to say two things which I think, at least for me, helped us take the next step forward. One is, although I think that our focus on what we have called the boxes, and that means a lot of different things, has been extremely helpful to us in formulating our ideas and so on. I think finally itís come to really get in the way of finding a resolution. Iím going to propose that, in fact, as we go ahead in our discussion, and Iíve discussed this, as I mentioned before, informally with a number of Commissioners after our meeting, that we really try to look to frame our discussion around something which might be a decision-tree approach or a flow-diagram approach, depending on how you call these. I think it just leaves us a lot more flexibility. At least as I visualize it right now, if you had a "decision tree" approach to trying to partition all these various characteristics, at the bottom of the tree would be the protections that NBAC suggests in each individual cases. I think, in fact, that will help us work our way through a number of the issues that we discussed yesterday.
I donít know if Carol managed to put them on overheads, but I mentioned this to Carol last night at dinner and she came in this morning with a decision tree worked out. So she will present that in just a moment just to give you an idea of how that might work and see if we think thatís helpful or not.
Also this morning, and I think you all have your place, Alex took the initiative to listen carefully to what weíve been discussing with regard to definitions and came up with some alternative definitions. This was the last page of Chapter 5. Iíve only taken a quick look at this and not carefully yet, but it does seem to reflect from my quick look what ó
PROFESSOR CAPRON: One major typo.
DR. SHAPIRO: Well, I didnít see the typo.
PROFESSOR CAPRON: Under "unidentifiable materials," after the word "which" should be the word "no."
DR. SHAPIRO: Yes, thatís right. And if we have a chance, we should also perhaps revisit this at least very briefly. But it does seem to me to summarize really rather nicely the nature of the discussion we had yesterday.
PROFESSOR CAPRON: That reminds me. I called on a student once and she gave a very elaborate answer to the question. I looked a little skeptical, and she said, "or exactly the opposite."
DR. SHAPIRO: All right. So I think that, in fact, our discussion moved ahead quite substantially.
But I think it might be interesting to just see what Carol came up with overnight just as an illustration of the kind of way we might sketch it out. I donít know that Carol wants us to take it all just exactly as it is. Alta had also taken a shot at some decision trees yesterday which I saw which havenít looked at carefully. You may want to say something about that as well, Alta. And as I said, after this, as soon as we see this and see if that sort of helps people think things through, if thatís useful, we will, of course, work it out in greater detail, but then we will turn to cases this morning.
DR. SHAPIRO: Carol?
DR. COX: Carol, excuse me. Can I just say that I really like the revised wording in these definitions because I think itís exactly what we talked about yesterday and it clarifies some ambiguities that were, in my view, in the previous wording. So I really like this very much.
DR. SHAPIRO: One of the other conventions, I would say, that these seem to incorporate, these definitions, is we decided, or at least it was suggested, I think it was, Iíve forgotten, Altaís suggestion, somebodyís suggestion, that in our discussion we reserve the word "samples" for what it is investigators have and use and we stop using it for many other ways it could be used in this context. I think that actually helps in the discussion and it helps clarify our thinking and our writing in this area, and thatís reflected in these definitions here, at least as I understand it. So, Carol?
DR. GREIDER: I gave my overheads to Henrietta to make copies for everyone and until sheís back retrieving those from the photocopy machine, Iíd like to just make one comment about the definitions that were passed out just in terms of the language, although I agree with most of what is written in these definitions. The term "unidentifiable materials" seems needlessly long to me. Canít we just call it "unidentified" and "identified" in the top two definitions?
DR. DUMAS: No. It makes a difference I think.
DR. CASSELL: Unidentified is the state, unidentifiable is the process.
DR. GREIDER: But in the repository, the material is, in fact, unidentified.
DR. DUMAS: That might be true, and it might also be unidentifiable or it could be identifiable.
DR. GREIDER: All Iím talking about is the first two definitions. In the repository there is either identified material or unidentified material in the first two definitions. It just seems overly cumbersome to say unidentifiable material when, in fact, itís sitting without any, nobody knows anything about it. It is, in fact, unidentified.
DR. SHAPIRO: Is unidentified you think it cannot be identified?
DR. GREIDER: If thatís the definition that weíre making for those first two classes of material that are sitting in repositories.
PROFESSOR CHARO: Carol, besides the extra syllable, what is it thatís cumbersome, so I appreciate what youíre trying to get at?
DR. GREIDER: Iím just trying to simplify the language because I found, when all the previous discussions that we had about identified, anonymized, anonymous, all of these sorts of things, there are very subtle meanings that are tacked onto suffixes and prefixes, like identified anonymized. And Iím just trying to simplify it so that you get to exactly what you mean in the simplest possible words so that nobody can read anything additional into what you might be meaning.
DR. MURRAY: Simpler is better. But I think calling them unidentified leaves open the possibility that somebody could then go in and identify it. This is an unidentified lost object. Well, weíve now figure out who it belongs to. Unidentifiable indicates that even if you made an effort, your efforts were not likely to be fruitful. So I think actually there is a denotative difference.
PROFESSOR CAPRON: Why donít we all think about Carolís suggestion? Itís worth playing through the alternative.
DR. GREIDER: And maybe we can discuss the actual language thatís going to go in there a little bit more later on.
PROFESSOR CAPRON: The purpose of putting something on paper was to have something to shoot at. Itís hard when we have these generalized oral discussions and then we donít know where we are.
DR. GREIDER: So from our discussion yesterday, we had discussedóthis is now just for the stored material, not for the future materialówe had discussed that there are two types. And here Iíve used the term "unidentified," and we can have the discussion about how weíre going to call that, "unidentified" and "identified." That this is how the material sits in the repositories.
The unidentified wouldnít go any further. And into this box here we would put what the protections would be that we would want to give to this particular kind of sample.
Then there is the identified sample. And from these identified samples we broke it down and said there are three ways that you can treat this. One is that it can be coded so that it is not traceable, and, again, Iím using the old language, we can change the language in this box but I think that weíll have to agree on the actual meanings. The other is coded so that it is traceable in some manner. And this is going to have other possibilities attached to it. And then the third possibility is that it is actually identified.
So the one that breaks down then is coded so that itís traceable in some manner. And Iíve given this molecular biologistís "wedgie," we call this little thing, to indicate that thereís a continuum of different kinds of protections that you might give to this material that is coded. Iíve only written down two of them along this continuum. We can discuss various other kinds of protections that might go in. But the two that we talked about most in the subcommittee are that it would be encrypted in some manner so that you could have feed forward information coming from the physician, say, to the researcher, but the researcher cannot go back. And the other would be that it would be encrypted in some manner so that you would have feed forward and walk back capability. So thatís why this arrow is pointing in both directions. Maybe we can discuss this.
And then Iíve also done this very much an analogous one for the future samples. And I can put that up afterwards if we want to discuss it.
Iíll let Harold handle the questions.
DR. SHAPIRO: Yes, Bernie, Alex.
DR. LO: Carol, I like this very much. Visually, it helps me to understand it better than having just a list of definitions. Iím trying to make sure, I know the terms are not exactly the same, I want to make sure the boxes are the same. So under what youíre calling "identified stored material" which the sheet of definitions we have calls "identifiable," it seems to me that the farthest right hand box on the next level down of the samples, what youíre calling "identified" is meant to be what the sheet calls "identifiable." So theyíre readily directly linked to a person.
DR. GREIDER: Right.
DR. LO: Okay. Then the middle box, the coded traceable, what weíre calling "coded samples" and what youíre doing is introducing a further branching of that category.
DR. GREIDER: Correct.
DR. LO: Which helps me because I think there are important distinctions in that category that the definition here doesnít quite make stand out.
And then the box on the left, the "coded but not traceable," is that meant to be the same as the "unlinked" samples?
DR. GREIDER: Yes.
DR. LO: Okay.
DR. GREIDER: And we could change the language in here. Itís just that Alex and I didnít get together on the definitions.
PROFESSOR CHARO: Carol, a question also about the decision tree. "Coded not traceable" is what we had been discussing as the situation in which a code was attached so that information could flow forward on a collective level. What is the point of "coded not traceable" in that left-hand box if in the middle section youíve got a version where you have encrypted feed forward?
DR. GREIDER: Right. So these two I think are actually distinct and it depends on how you do the coding. You could come up with a three random number generator where the middle key is thrown away and so that nobody can ever go back and get any information. I think that is distinct from there being some sort of a code and whether encrypted and who knows the code is debatable. But if there is a code and you can go back, there is a distinction between those two cases.
DR. SHAPIRO: We have a lot of people who want to speak. Alex?
PROFESSOR CAPRON: What I had hoped we would be moving to as we get to a flow diagram would be what this will permit, which is the next step of asking what protections and then you have yes/noes that come out of this. And it may well be, to carry that thinking through, that rather than spinning out further and further definitions as such, we ask the question about things which are coded in a way that there is a link between the code on the sample, you donít know looking at this whose it is but that code is attached to some means. The question would then be, can the laboratory, the repository, or the information system provide further information to the researcher as it is accumulated about the subject? If the answer to that is yes, then weíre moving into what you call the "encrypted feed forward," and there would then be certain questions.
Because each of these categories is potentially different only if we think that a risk arises there. And the only thing that I see immediately that I donít see up here was the point that David made yesterday, and that isóand I think Alta gave him part of the example or someone else gave him part of the example that led to thisówhen we talk about something "encrypted feed-forward," we also have to think about the fact that what that means is that the repository knows how to link its material with its identifiers on it to the sample. It is just that the person who has the sample doesnít know how to link the other way. So if the person who has the sample comes up with research results which they attach to a research sample which they supposedly can never know who it is, and the repository, the person who is running the repository has that information, that person can make a link. And so itís not to say that we shouldnít allow that to happen, itís just that raises a concern which I hope that this division doesnít obscure.
Because by looking at the feed-forward side, it doesnít recognize that there is, in effect, a feed back way where the repository can, you might call it a pull back instead of a feed-back or walk. Itís not a matter of walking back, itís a matter of my, on the repository end, looking over at the data and saying, "Oh, well, I know who that is even though you donít know who that is, Mr. Researcher." Anyway.
DR. GREIDER: Can I respond to that?
DR. SHAPIRO: Yes.
DR. GREIDER: If I can just give my interpretation of the history of where we went with the genetics subcommittee. Zeke had started out with this very full matrix that we were discussing all of the different boxes. And then as we started thinking about what protections we would fill in, we started eliminating a number of the categories because the protections were the same in the individual categories. And then what we brought to the full Commission was a much smaller matrix than we had initially started with. And that caused all kinds of confusion on the Commission because people didnít understand why we had eliminated some categories that one would logically think of.
So Iíve now come back around to thinking we should have a framework or a flow diagram that encompasses all of the different possibilities and, even if the protections are the same that weíre going to fill into these different boxes, we should leave them there because other people looking at what we did will then be able to understand from a logical point how we got there. And so I donít want to run into the same problem that we ran into going from the genetics subcommittee to the full Commission going from the full Commission to the world not being able to see where our logic was.
PROFESSOR CAPRON: I have no argument with that. Thank you.
DR. SHAPIRO: Let me just say I have a lot of people who want to speak. Let me tell you what the list is before I make a remark. David, Rhetaugh, Steve, and Larry, those are the people I have on my list. Zeke, also. Zeke, in fact, was the next one on the list.
But I do want the Commissioners to understand this is not a proposed final issue. This is just to show you how such a scheme might work our way through. Of course, at the bottom of all these trees or diagrams would be a set of protections, which has been the key issue. So that would have to be worked out and maybe it would be this scheme or maybe it would be something like it. We ought not to get too focused on the exact nature of this yet but just whether we like that way of thinking about it. Zeke?
DR. EMANUEL: I just wanted to make two brief points. First, to complicate things, there are two elements of materials here usually, and those of you who do research a little more with this stuff than I do correct me. One is the actual biological material, the slide, the sample. The other is the clinical material which is distinct from the biological material. It is either, in case of a clinical sample, the patientís clinical history, whether they relapsed, or, in the case of research studies like the Physiciansí Health Study or the Nursesí Health Study, the ongoing data collection that is being updated all the time.
It seems usually, again, you have a one-time sample, the biological sample, and then the issue is the continuous clinical update. And so thereís two kinds of materials that need to be thought about here. Itís not that you usually have a continuous update of the biological material, but of clinical information on that.
The second thing I would like to say, now having talked to a variety of groups, I think the emphasis, the real issue for clinicians out there and researchers out there are the bottom two over, "coded so traceable." Thatís the real divide. The encrypted feed forward so you cannot walk backwards, not only canít the researcher walk backwards, but even if the repository wants to pull information back, it canít get the result back. I donít think thatís right Alex.
PROFESSOR CAPRON: That was Davidís example.
DR. EMANUEL: Well, I think that falls into the "encrypted feed-forward and walk-back." If anyone can get that, attach the name to the result, thatís walking back. If no one can do it, then thatís feed-forward only. Thatís the way I had understood those kind of boxes.
It seems to me the real emphasis from the practical standpoint, where are the majority of research studies, where is the majority of the problem are in those two boxes. I would just urge the Commission to reallyóthatís where the money is, as it were.
DR. SHAPIRO: David?
DR. COX: Actually, Iíd like to follow up on exactly where Zekeís going and attempt to be as clear as possible here. With the present regulations and speaking as a researcher, from the perspective of a researcher, that a desire to use tissues but at the same time have protections for human subjects, the way the regulations are written now, if weíre in the box of "coded but not traceable" thatís okay with the present regs. And thatís how researchers have been doing business for a while.
But even from the researcherís point of view, although the researcher can get the tissues, itís not scientifically the best. And the reason why itís not scientifically the best is because it gets rid of other types of information that are very valuable scientifically. And itís this clinical and extra information, not necessarily the clinical, but additional information of which clinical information can be one type that goes along with the sample.
And so as a researcher, one says how can we maintain the protection for the subjects and at the same time get this extra information. And thereís only one way it can happen. It doesnít work if the repository scrambles all the information. Somebody in the repository has to be able to keep track of what information goes with what sample. There has to be some way of doing that. And thatís why the coded and traceable is important because, as a researcher, if itís not traceable, then I lose information. And so speaking as a researcher then, I want the repository some way to feed me additional information and at the same time being protective of the human subjects.
Now not speaking as a researcher, but now speaking as a research participant or a patient is that the researcher may not care if that information canít go back to me but I care if can come back to me because if thereís no way it can come back to me, I donít get any possibility of direct utility out of it. So it depends on whose perspective youíre looking at in terms of if it makes a difference of whether itís going forward or back. And I would say as a research subject that if itís my protections that are being looked at, then it is not only discrimination against my material, but itís also the utility to me in terms of the use of it. So the point Iím making here is not looking at it just from the point of view of the researcher, of which I am one, but trying to look at it from the point of view of the research subject, too.
And so right now it is absolutely true that the research community and the public are one with the idea that making things not traceable seems like a high cost to pay for protection. And is there some way, and this is the punch line, is there some way that we can keep things traceable and still protect people? Having said that, once theyíre traceable, then what are the protections?
So, to me, the issue is whether theyíre traceable or whether theyíre not traceable at the repository level, thatís why I like this conceptualization so much, then Zeke, after the fact, if theyíre traceable by the repository, then we start talking about what type of information, how much, and when it goes forward or back. I think a rigid statement which is nothing will ever go back is not practical. Itís practical from a researcherís point of view, but I donít think it considers all the possibilities from everybody elseís point of view.
DR. EMANUEL: Can I just respond with two things. And I may be completely out there, but, as I understand it, the real issue and the real potential harm is when the result goes with the name. Thatís the key issue of traceability. Does result Q, BRCA1, yes or no, go withócan someone link those two pieces of information. Because if they canít link them, then they are not traceable. Because the key issue isnít did you know that this sample was in that group. Thatís not the issue I think. The real harms come with the result being linked to the name. And that I think has to be where we keep focusing on.
The second thing I would suggest to the last comment, David, is, again, remember what the person from the National Breast Cancer Coalition said. They are willing to give up that traceability for more research. So you keep telling me what you think the research subjects believe, that they want that information back to them. At least one person who testified to us doesnít agree with that. It seems to me what we need to do is give researchers and subjects the choice, which box do they want to be in?
DR. SHAPIRO: We have a lot of people who want to speak. So letís please have some discipline in our mutual selves here.
DR. SHAPIRO: Rhetaugh, youíre next.
DR. DUMAS: Itís very interesting because I think people are speaking to different aspects. I want to go back to the diagram and change my mind, Carol, about the not identified and identified samples. Because if theyíre stored, I agree with you, they are either identified or not identified. And what happens after that is a different story. So Iím with you and it helped a lot to see it up there.
Now with the identified material, you have "coded not traceable," "coded so traceable." It seems the other category would be "not coded."
DR. GREIDER: Thatís "identified."
DR. DUMAS: Itís already identified.
DR. GREIDER: That is the other category.
DR. DUMAS: Yes. Itís already identified. And if youíre going to have three categories of identified material, this might be nitpicking ó
DR. GREIDER: Oh, youíre talking about the language?
DR. DUMAS: Iím talking about the logic of the diagram. You have "identified," "coded traceable," "coded not traceable" and the next one would be "not coded."
DR. GREIDER: Thatís what it is. Thatís what I meant by the identified goes to "identified." Itís not coded, itís ó
DR. DUMAS: Itís not coded. Okay. What I donít understand is the difference between "coded not traceable" and "encrypted feed forward."
DR. GREIDER: Because you could have a mechanism of encoding something where nobody can ever go back. Imagine three different computer programs generating random numbers and you throw away the middle one. So the researcher canít go back and the repository canít go back.
DR. DUMAS: Is that not true of the "coded not traceable"?
DR. GREIDER: Thatís what the "coded not traceable" is, is that nobody can ever go anywhere with that information. Itís impossible.
DR. DUMAS: Okay. I understand now. I got it. Your "coded so traceable" can be changed so that it becomes essentially what you have ó
DR. GREIDER: And thatís "encrypted feed forward" or "encrypted feed-forward and walk-back."
DR. DUMAS: All right. I got it. Now one of the things that I think we have to make sure that we do, and Zeke reminded me of this, is to be able to separate out how we think about the material from how we think about the information, both the information about the subjects and the results, too. I think we can get confused there how we think about the materials, the samples, and then how we think about all of the information that would be associated with that.
DR. GREIDER: One of the questions is in a lot of these categories there is no information associated with it. That was the point. So the "not identified" and the "coded not traceable," there is no information.
DR. DUMAS: In the "not identified" thereís no information about a priority ó
DR. GREIDER: The information comes in the box that starts off "coded so traceable" and "identified." Those are the only two boxes where information becomes an issue and the boxes below them.
DR. DUMAS: Okay. And then what Iím saying is that how you handle the material and how you handle the information needs to be distinct.
DR. SHAPIRO: I have really four other members of the Commission who want to speak, then weíre going to end this part of our discussion. We can rejoin it later in the day. They are Steve, then Larry, Tom, and Alta. So, Steve?
MR. HOLTZMAN: A couple of different points. One, as we engaged the language of other statements just for the staff to think about. In our nomenclature here of "not identified," something in a repository could be not identified because it never had personal information ever associated with it or that personal information was irrevocably removed. And that sometimes is how those statements use the latter as "anonymized." Sometimes they mean it is removed for the purposes of the study. So we should just be clear about that.
The second point goes to something Zeke was saying and leads to a third point, is I think we need to be clear about information, whether weíre talking about information which is the paradigmatic personal identifier or information sufficient to identify the person. And I put that together as distinct from clinical and biochemical information associated with the sample. Whatever one means about not identified or no information, etc., it is the very, very rare study that is interested in just a hunk of meat with no clinical information associated with it. All right?
The third, and this is not meant to be more complex but it really struck me as we were talking here ó
In other words, the results of the research can be hooked up with the individual from whom the sample is taken. So, it may be hard to do at your place. But what I found myself doingóin the identified bucket on the right was saying, "Well, now, it goes out to an investigator. It either is or is not provided with personal identifiers." Those were the two buckets that were really important. Now, again, first of all, identifier could be name; it could be sufficient information to point to the individual. The same is taken from three people who live on thus-and-such block, etc. If it is not provided with personal identifiers, then it is either possible to link your results to the person, or itís not. Okay? And this kind of ties ó Alex made the assumption that it was possible to get feed forward information, than by definition. You also had to be able to get back to the person, and that is one of the things weíre asking. So, if I find myself saying, itís either provided with personal identification information, or itís not. If itís not, you either can rehook it to the individual, or you canít. And within the bucket of you canít rehook it to the individual, you either have this snapshot of clinical information you get today, and thatís it; or you can get a forward flow of information thatís clinical, but not hooking you back to the individual. So, and I can redraw this and give it as a break. But I think that we may be confusing ourselves a little bit with the traceability, because the traceability we were interested in the feed-forward is flow of clinical information, but not anything that would be personal information.
DR. SHAPIRO: Thatís helpful if you can write it down. Thatís helpful. We can look at it, and think about it carefully. Letís go to Larry next.
DR. MIIKE: Clearly, the game is in the two right extremes ó identified and an encrypted, feed-forward, walk-back. I, for the life of me, I donít understand the difference. They seem to be basically the same, except there is the repository person that is keeping the name. I donít know what you mean by "walk back." If it means that a person can get any access to anything over there. So ó and even if we are in the identified stage, I donít think weíre envisioning any research or being able to go and call the patient up and say, "Let me see your records, etc." So, to me the only difference between the identified and the feed-forward walk-back, is that there is another filter in there somewhere, which is the repository person saying, "Iím not going to give you the name." So, it depends on what we mean by the extent of the walk-back, how current that update is. So, I think weíre getting already into what safeguards. So, to me the only difference between those two is that the repository filter of the safeguard between the two. This brings me back again to some of the issues that we had talked before in the subcommittee meetings, which is that, from my personal side, I would want the same protection for the feet forward and walk back, as it is for the identified. As long as they are fooling around with my information, at my individual level, I want the same protection. What other researcher has my personal name on it?
DR. SHAPIRO: I think a lot of these trees are going to end up with similar, or sometimes the same, protections. Let me go next to Tom.
DR. MURRAY: That feeds nicely into my next point. We began with boxes. Was it a millennium ago? It was a while ago, we started out with those other boxes, as a visual metaphor for what we were trying to do. This presents essentially the same information in a different visual metaphor. We were actuallyóI think we had worked ourselves into a box a bit, using the boxes. So this gets us out of it, set a pathway now, a walkway. I could have let that one go. The point I want to fix on is what I think Larry ended with, and, that is, this is just an effort to capture conceptually the major options. Okay? We could actually make a much more elaborate set of paths. There is no question about that. The key issue is: Does this capture the main sort of choice points in deciding from the options? We have yet to decide what we would do in terms of protecting patients, or sources of human biological materials. Some of those, it may turn out, will do exactly the same thing, or two different ones. But what Iíd like us to do is say, okay, this scheme is good enough for us to work with. Letís start talking about what protections go in each of these kinds of cases. If we decide that it fails to capture some important distinction, we can go back and we can refine it. But I would really like to see us, after we have the next talk, begin to work with this and talk concretely about policies and protection.
DR. SHAPIRO: Thank you ó Alta.
PROFESSOR CHARO: Two points. One is that I find this particular schematic close, but not quite yet for me, as clear as I need to understand the scenarios at all moments, and I look forward to working away on this. The box called "coded, not traceable" still confuses me, because it seems to me this is about "not possible to go back or forward on an individualized level," at which point, I donít understand what the code is there for. It looks to me like itís simply uncoded or unlinked. And, at most, the repository has recorded which hundred people materials have been sampled.
DR. GREIDER: But remember our distinction that we are distinguishing between how it exists in a repository. So, the point is that it exists in the repository as identified.
PROFESSOR CHARO: Which you have already indicated above.
DR. GREIDER: We have indicated above, but we have then removed that information, so it has to be distinct from the not identified, because if it exists in a different state in the repository...
PROFESSOR CHARO: This we can work through on paper over time, but this particular discussion led me to wonder if it would go more to the heart of the matter, if instead of focusing on the mechanisms, codes, encryptions, etc., what we did was have the scenario flowcharts flowóbe identified, basically, in terms of information flow. So, we have identified materials. There will be a category of samples that are provided to researchers, in which there is no ability on an individualized level to go back or forward. Whether itís due to codes, or encryptions, or whatever, you canít go back or forward. There will be a second category which you can go forward only, and a third category on which you can go forward and back. And by focusing not on the mechanisms, but on the information flow, we might be able to get closer to the set of concerns that we have, which is "How does the information flow relate to the outer parameters of risk and benefit to the people whose stuff is being used?" Which leads to the second, and this will be brief, because I know weíre closing. When Zeke was suggesting to the Commission members that the only significant kinds of harms that we need to be concerned about are those that are associated with identifying a particular person, and linking that person to a particular sample, I found myself disagreeing, because I have been involved with several situations now, where collections of people have been identified as a group for whom there is a risk that they, in fact, have some characteristic. And the question that has been raised is: How does one approach members of that group to ask whether theyíd like to be further tested to see whether or not they indeed have this characteristic? In some cases, it was paternity issues; other cases, it was disease carrier. And thatís because there has been an investigation that revealed something about a high frequency of a phenomenon in a collective group. And the anxiety that can be engendered by just being asked whether or not you want to be further investigated is real and Iíd like us to keep in mind that thatís something to consider as we look through the risks and benefits of information flow back to people, even when itís not yet been linked.