DR. SHAPIRO: Let me now turn to the Human Biological Materials Report. We'll interrupt ourselves as other things become available. And let me turn now to Tom to see how we want to--what issues you would like to proceed with first. Tom.

DR. MURRAY: Thank you, Harold. I'd like to begin by putting to rest once and for all the terminology we're going to use about identifiability/unidentifiability, etc. We have been around this particular hill a number of times, and I just (UNINTELLIGIBLE). We should have exhausted any possible nuances, yet we always seem to be finding new ones. The section in which these definitions are given begins on page 57 (UNINTELLIGIBLE). If you want, you can look at Kathi's memo of the 12th of November, where basically Kathi just asks us to decide on these issues--the section of the report she gives on page 57. The central material begins really on 58, and continues on through with some very good examples, I believe, to about 65. Now, I don't want to do line-by-line editing; I want to know if we are comfortable with the concepts, the definitions, and the examples.

DR. GREIDER: The definitions as given in the section that you're talking about I don't have big problems with. But when we get to the recommendations section the wording is different. And therein lies my problem. I can delineate exactly what that problem is if you would ....

DR. SHAPIRO: Why don't you give us an example?

DR. GREIDER: I think that the most straightforward way to define these samples is to first say how the samples exist in the repository, and then say how they are then used. If a sample is identified in the repository, then it is an identified sample. That sample might be used in a different manner, but I have a hard time with the language on page 181 that says "truly unidentified samples," etc., etc., that is, the sample, "the repository may retain identifiers." I don't see how we can say that "truly unidentified samples" have identifiers. And so this issue, if we separate it out as to what the samples are and then how those samples are used as we had done in previous drafts, then that's fine with me.

DR. MURRAY: Even the language, I think, on page 58 seems to be self-contradictory. It would be really handy if we had perfectly clear, plain English concepts that would handle all of our difficulties here. That's not available to us because the terms--the nouns that one could apply to the biological materials as they exist in the repositories--are the same nouns that would apply to the biological materials in the hands of the researcher. You can use them. Now, what we propose on page 58 is to refer to the materials at the repositories as specimens, and the materials in the hands of the researcher as samples. That's not a common English distinction, but it might be useful if we could employ it. Would you think it useful if we employed such language consistently, which we do not now do? Would that at least help us to understand what we were saying?

DR. GREIDER: Yes. I think that the terms that you want are "samples" and "materials."

DR. MURRAY: So you don't want "samples" as it's used on page 58?

DR. GREIDER: I'm just reading what's here: There's "samples," and on 59 there's "materials." The samples are the physical things, the materials are how they're being used, if I read that correctly.

DR. MURRAY: Well, all right.

DR. GREIDER: No, now we're....

DR. MURRAY: That applies quite differently.

DR. SHAPIRO: David wanted to say something.

DR. COX: Well, I do believe the language is very important. But I don't know if we agreed on the concepts, and that's what I would like to try and get a feeling for first. If we don't agree on the concepts, the probability that we'll agree on the label is zero. So that's the first thing I would like to get a feeling about. The concept, to me, at least as I understand this, is that so long as anybody can basically take a human biological tissue sample and have it still associated with the person, then that's an identified sample. However, it's still associated with the person. On the other hand, if that sample is in a repository or wherever it is has been, had those identifiers taken off--i.e., you still have clinical information but you don't know who the person is--and you can't go back to that person, then it's not identified. That doesn't mean that there's not some hunk of that sample still back at the repository. But it's the fact that that particular sample no longer is hooked up with the person. Now the language here is very important, but the concept is a simple one. And I want to know if people agree with that concept or not, because if people don't agree with the concept, then we have a real problem. Because behind it is the sense that we don't have agreement.

DR. MURRAY: I want to recognize Eric and Bernie, but I want to insist on one thing first. Since other approaches haven't worked, let's focus on one of the two statements. Let's focus first of all on what the repository pulls. Now here we seem to be pulling these two terms in the report draft--one is "specimen," one is "materials." I would prefer "specimens," because "materials" clearly applies to (UNINTELLIGIBLE). But that's what I want to focus on right now. In the repository these human biological materials exist, and what we said in the report is that they can exist in two possible forms: identifiable, or identified, and unidentifiable. And can we focus on that for a bit? I don't know if Eric or Bernie wants to address that or not. Then we'll get to what goes to the researchers. Okay. What's in a repository?

DR. CASSELL: Well, the first step is the division into the repository and whatever the investigator uses, whatever name you're going to use. And the second step is what's in the repository--it is either identified or not identified. And there's another step that goes....

DR. MURRAY: The third step is how do we describe the various possibilities of what goes forward to the researchers.

DR. SHAPIRO: Tom, excuse me for interrupting, but could I just ask folks, just on the issue we've looked at--that is, what's in the repository--what's at the bottom of page 59? It uses the word "materials," which is fine with me, I've got no problem with it. So we're not going to use "specimens" for that; we'll use "materials," is that agreed? That's fine with me, I have no problem.

DR. MURRAY: I've no particular...(UNINTELLIGIBLE) have terms of meaning which was so clear (UNINTELLIGIBLE) [SEVERAL TALKING AT ONCE] But we have to define it.

DR. SHAPIRO: All right, so that's just fine. I just want to make sure that's done.

DR. MURRAY: Actually, I have a preference for "specimens."


DR. MURRAY: Because the report is about human biological materials, and that includes them both in the repository and in the researchers' hands. "Specimens," at least--you could at least stipulate that it refers to those things held by the repository.

DR. MIIKE: Tom, perhaps it would also be simple by simply moving the parentheses that says "the sample" to the end of the sentence so that it's clear that "the sample" is not referring to material but to material that is then sent on to ....

DR. MURRAY: Line 12 on page 58.

DR. MIIKE: Yes. And I also prefer "specimen." "Materials" is too general, as you say. I would think "specimen" means that it's that original hunk of whatever it is sitting in the repository.

DR. SHAPIRO: I have no view on this, I just do people feel? Is "specimen" all right?

DR. DUMAS: "Specimen" is fine with me.

DR. MIIKE: It's fine.


DR. SHAPIRO: Tom: "specimen."

DR. MURRAY: "Specimen" it is. Eric, did you have more you wanted to say? Okay, Bernie.

DR. CASSELL: If some specific thing has been settled, I wouldn't say a word. [LAUGHTER]

DR. SHAPIRO: Can I put that on tape?

DR. MURRAY: We know where Eric lives, he's just being him. Bernie?

DR. LO: I want to pick up on David's comment, so if we're just sort of trying to clarify the terminology, I'll defer.

DR. MURRAY: Well, Eric did a beautiful job of parsing out the conceptual steps. Step one is, do we accept the distinction between whatever (UNINTELLIGIBLE) materials we're now calling "specimens" in the repository and materials that have been forwarded to the investigator? Do we accept that as a key statement? Everyone clear about what that distinction means? Okay.

The second thing is these things in the repository, which we are going to call "specimens" consistently throughout the report, and it may make the--the language may not reflect that at every step, so we'll have to make sure we change the language appropriately--that the specimens as they exist within the repository, for our purposes we will distinguish between those that are identified and those that are unidentified. Is everyone clear and comfortable with that? Okay. So then the last step is one that David had begun to address, and that is what goes forward to the investigator. And we list them. We have, at this point, four descriptive categories we apply to this. But let me hear Bernie's comment.

DR. LO: I just want to echo David's point. I think it is important to try and clarify the terminology so it's consistent throughout the report, but I think the real ethical policy issue is these samples that are identified in the repository, passed on to the researcher in a coded fashion so the researcher can't decode it, but the code is kept by the repository, and therefore the potential exists for the researcher to go back to the repository and either ask for additional specimen--additional material from the same specimen--or to get updated clinical material information about the person from whom that specimen was obtained. And I think, as I understand from previous discussions, that this is a crucial issue for many investigators, and given the way the regulations play out, whether we call those specimens--sorry--whether we call those samples identifiable or not from the researchers' point of view has a big implication for informed consent and things like that.

DR. MURRAY: Bernie, I think you're moving us to the content of the recommendations. We will, I hope, go there very shortly. But I want to make sure we just have the concepts clear in our minds. We have tripped over these so many times that I think we're on the verge of breaking through here, and I ask Carol to carry us forward.

DR. GREIDER: I agree with the terms on page 61, using the terms "samples," "unidentified samples," etc. And again, my problem is not with this section but then how we use this section in the recommendations, because we do not use this terminology--or not even terminology--don't even use these concepts. I'm happy to agree on these concepts, but they're not likely to be used in the section on the recommendations. And that's the entire gist of my uncomfortableness.

DR. SCOTT-JONES: I have one question about this that has to do with the assumption of the division of labor, that the repository will have the samples and will be responsible for giving them out to researchers, and that researchers will make requests and get those samples from the repository. But in the example on page 62, of the researcher studying malaria, the example reads with the researcher being the person who collects the specimens, and then the researcher would do the labeling and so forth. And are we assuming that in almost all cases there is this division of labor where the repository has materials and maintains materials, and the researcher makes the request rather than the researcher making the collection and being responsible for how the collection is stored?

DR. KATHI E. HANNA: There is probably not the best example there.

DR. SCOTT-JONES: It's not.

DR. HANNA: I mean, I think we probably inserted that one because, from our questioning of repositories and their behavior, we couldn't find very many repositories that themselves collected materials in that way. It tended to be more the clinical researcher who was just collecting materials for a specific protocol. So it's not a good place for that kind of example.

MS. KRAMER: Kathi, that example might hold if the wording was changed such that the blood was--the researcher went to the blood bank and got it.

DR. MURRAY: It's probably worth taking another minute or so just to look at the definitions on page 61. Now, speaking about these--is the audience, people in the audience, do you know what we're talking about?


PROF. CHARO: Tom, I got the sense that, actually, in the end everybody did understand and agree with the use of the categories that Kathi laid out, but that there are some places in the report where the terminology is not being used absolutely consistently. And that seems to me to be a text-editing thing that we need to be doing by handing it in directly to staff so that they can make those changes. Because this has been through so many drafts that it's likely there will be errors from previous versions that we've all contributed to. So it doesn't sound like it's a conceptual issue at all; it's a matter of just handing in text edits.

DR. MURRAY: Well, I wish I could agree with you wholeheartedly, Alta, but my experience has been that there has been persistent, skeptical disagreement. It sounds like it's dissipated, it sounds like we're all together, that we accept at least that the four categories of samples are the appropriate categories, and can carry that forward in the discussion. Yes or no?

MS. KRAMER: I have one question, looking ahead to the recommendations. When we talk later on about collections that are sent from the repository stripped of individual identifiers but the repository knows which hundred are in that batch, is that now--are we going to call that "unlinked" or "coded"? The repository cannot identify an individual, but ... that's going to be "unlinked." Okay.

DR. MURRAY: Unless the language actually says--look at page 61, lines 18 through 21, which I think addresses your concern.

MS. KRAMER: No, because that's exactly where the confusion is in my mind. That says, "retains information linking the code to particular human...."

DR. MURRAY: Or "where the extent of the clinical or demographic information provided is sufficient that the investigator, the repository, or the third party could link the biological information derived from the research with material from a particular person or a very small group of identifiable persons."

MS. KRAMER: Okay, so then what's a "very small group"? If a batch is a hundred, is that a small group?

DR. MURRAY: That's entirely in the context.

MS. KRAMER: Well, I think this could provide confusion later on.

DR. MURRAY: David.

DR. COX: I have a proposal, that because of this, in my view, it's not a matter of words, but the words basically make it unclear whether we disagree on concept. It's the commissioners who have strong feelings, and I'm one of them, about this--use their own words, write it down on a piece of paper and send it around so that there's no confusion from their point of view in terms of what that language is. Because as a group, the probability that we're going to work out the language issues is zero, since we've tried it about 200 times.

DR. GREIDER: Can I just say something? I think I'm the one who's responsible for this feeling among people that we're not--at least I'm partly responsible--for bringing this back up recently as an e-mail issue. And I don't have any problems with this section that we're talking about right now. Where I have problems is how we then translate this into the recommendations. And so I'm not sure that there really is a problem with the language or whatever. The thing is being consistent and then taking that forward to the recommendations.

DR. HANNA: If I could summarize where I think the disagreement or confusion continues, it is in the two top categories--I'm sorry, it's in the unlinked samples and the coded samples--on page 61, those two categories of samples. When we get to the recommendations, it seems that some commissioners want to put the unlinked samples into the unidentifiable category, and some want to put them into the identifiable category. That's where there's disagreement. I don't think there's any confusion, it's just where people want that category to go.

DR. MURRAY: Larry?

DR. MIIKE: Yes, that's the gist of it. And I don't think, whether you put it as "unidentified" or "identified," that we're differing about how you treat it in terms of the review process. But apparently, if you call it "identified" it goes through a completely different review process. As I said in my last e-mail conversation with Carol, the bottom line was that it really didn't matter to me which way it ended up, although I prefer to call the unlinked "unidentifiable." It didn't really matter as long as the regulatory rigor applied to these is about equal no matter what you call the category, because that's the bottom line about what we tried to do.

DR. MURRAY: So I just want to see if I understand correctly, Larry, that in terms of the concept, this set of four concepts works for you.


DR. MURRAY: Loud and clear. When it comes to policy decisions you may wish to combine them, or different people may wish to treat them in slightly different ways. That's fine. If we get the concepts clear, that's a very, very important first step. Alta?

PROF. CHARO: I don't believe that the concepts, as you put it, can be made clear in a way that's isolated from their consequences. Words don't have absolute meanings. They have a meaning and a context. Here, the significance of calling something one thing or another is to use that word subsequently to trigger different consequences. Otherwise, you might as well call them the same thing. The only reason we distinguish red from purple is so you can sort your clothes into red ones and purple ones. Otherwise, it doesn't really matter. Therefore, I think it actually would be productive to focus on the policy questions rather than the words, and then work backwards. For example, the overall issue here is how one wants to see the stream of research proceed. Everybody knows that a large portion of the research is going to be benign, and some small portion of it is actually going to be somewhat threatening or risky. Therefore, the question is how do you design a series of holes in the system where you can stop, think, and perhaps put in protections, and where do you want those places to be? Do you want one of your holes to be that most things have to go through a body that gets a first eyeball, and then you have a fairly easy process following it because most things are going to be minimal risk, and da, da, da, da? Or do you want something where very few things wind up going through a regulatory process you try to prescreen, and then once they're in there they get a very heightened level of scrutiny because you've already prescreened for things you think are going to be problematic? It's like looking at a pipe with little narrow areas and you want to find which of the areas you're focused on. The words that we use here are primarily aimed at that first chokehold, which is, does it go before a peer review body in the form of an IRB? That's what these words are designed to accomplish, is to sort things out for into review, even if it's going to turn out to be expedited review, no consent, etc. But do they get a first review or not? And so I don't think it's actually ever going to be possible to get a kind of intrinsic, inherent, pure definition of these concepts isolated from their uses. I just don't think anything in this world can be isolated from its uses.

DR. MURRAY: Bernie?

DR. LO: I want to continue this line of thought that the categories are important but the reason they are really important is the policy implications that flow from them. And I think one of the things that we're doing here is using categories that already have pre-existing regulations and consequences attached to them. I think we've identified what the tough cases are, and I would actually prefer that we take a look at a tough case--one I mentioned before, for example--and try and decide how we want that regulatory impact to flow. I think that I'm concerned that we're using the pre-existing categories, trying to stuff things into one category or another and settle the question of whether we think certain types of review ought to go before an IRB, ought to be able to be done without specific consent or not. And I'd rather we talked about specific cases and said what do we think is the right thing to do, and then see whether it fits the existing concepts, categories, and regulations.

DR. MURRAY: Carol?

DR. GREIDER: I agree with Alta that one of the issues is the policy, where the policy comes. And I thank Kathi for pointing out that really where the rubber is meeting the road here is the middle two categories, whether you go up to the top one with the second one or down with the second one. That's something we should discuss. Again, I'm not worried so much about what language we use, but that we are consistent throughout. And I really don't have a problem, I don't have a particular direction they should go, up or down, but what bothers me is the fact that we're very inconsistent. This whole language is laid out on page 61, and in the recommendations there is no restatement of these kinds of categories. The words that are used would suggest that category 2 that we have here on 61, unlinked samples, is now called "unidentified." I think that that terminology is obfuscating, and investigators can say they are working with unidentified samples when in fact it is possible to identify them. So I just want some kind of clear language that you can't have investigators pretending that something's unidentified when there might be some way to identify it. Then the policy decision is fine; we can talk about those. I don't have a particular bias one way or the other. It just bothers me to put in language that is unclear and so it can seem like you're working with one thing when you're actually working with something else. So if we just take this whole text on 61 and stick it in the recommendations and then be very clear about what we're doing, that will solve all of my problems.

MS. KRAMER: I basically want to say the same thing, except I'd like to carry it one step further. And I think that before we go on to the recommendations we ought to adopt, say, a working proposition: let's decide what we're going to call that second category--either we're going to call it "identified" or we're going to call it "unidentified," and see when we get to the recommendations if it works. If it doesn't work, then we know where we've got to go back and correct it. But I myself don't understand when you--if the investigator requests the repository to strip all of the identifiers off of a batch of specimens before they're sent on, I don't understand why that still remains "identified." Yes, I know we've heard the arguments that....

DR. MURRAY: It's not. It's "specimen" in the repository; if it was identified, it's an "identified specimen." If everything is stripped and then sent on to the researcher, it is now called an "unlinked sample."


MS. KRAMER: Not as far as the recommendations.

DR. MURRAY: If our definitions don't....

MS. KRAMER: Now wait a minute, hold on. Now what about a situation where the repository knows which hundred samples it sent but doesn't know which one is which?

DR. MURRAY: That's still the "unlinked," unless--read lines 19 through 21--unless it's so small. Unless there is enough information accompanying the sample that some party could perhaps reestablish the identity of the person providing the sample. Then we'd have to count it as a "coded" sample, according to our terminology.

MS. KRAMER: But that's where it gets very unspecific, like how much is enough information.

DR. MURRAY: Right. We don't quantify that.

MS. KRAMER: Other than that it's going to be--all right, it's going to be "unlinked," it's going to be "unidentified." "Unlinked" is, therefore "unidentified."

DR. MURRAY: That's not what I said. It's "unlinked." Treat it as linked.

MS. KRAMER: It's going to be treated as "unidentified." Oh.

DR. MURRAY: And that's what we'll talk about in the policy discussion. Now, Harold?

DR. SHAPIRO: It seems so me, Tom, what I'm hearing is that it would be a good working proposition right now just to accept these pages as written, quite aside from the examples you might want to change. And at the appropriate moment, when you're ready, just go ahead and start looking at the policy issues.

DR. MURRAY: I agree.

DR. SHAPIRO: And see if it works. If it doesn't work, we can circle back.

DR. MURRAY: I agree. I do actually think that this morning's exercise so far has been helpful in getting things straight. At least we have a shared understanding the concepts we wish to use. Eric?

DR. CASSELL: Well, I think I'll say something similar. I think you have to establish, and I won't buy into any agreement on concepts and possible language before you go to consequences, because I listen now to this discussion go around and around because of a confusion of a level about which people are talking. And unless we settle that this is the end of this level and we make sure about it, then you can't move forward to consequences. Things are what they are apart from their consequences. And things like words are very difficult, if not impossible--they are not definitions. It's either impossible or it is not impossible. If it's not, it's possible. And it's that sharp definition we need at this stage so we can accept it and then move on to consequences. Or one says it will never be impossible, and then that's a definition. But it has to be precise language at this point or no precision is possible at any further stage. It's just like the identification of an organ or a tissue or anything else--you've got to have language that positively identifies it or concepts that identify it before you move on. I can't see how you could do it otherwise, and I think the experience of this report is the evidence of that.

DR. MIIKE: It's clear in my mind, I think. What we're talking about is that "unidentified" samples and "unlinked" samples are going to be treated the same; "coded" samples and "identified" samples are going to be the same. That's what we're talking about. So the definitions hold, it's just how we apply the regulatory review process to those two categories.

DR. MURRAY: Okay. Are we ready to move to the next level? Kathi has something to say.

DR. CASSELL: That means you're taking out difficult, but not impossible?

DR. MURRAY: No, it doesn't.

DR. HANNA: I just want to add the reminder that part of the confusion is because we're trying to look at how these materials are defined in the context of research, because the regulations apply to them only in the context of research, not in the context of how they sit in the repository. The regulations have nothing to do with how they sit in the repository. So just as a reminder, it's the research use, and that's maybe why there's some confusion between this chapter and what shows up in the final recommendations--because the recommendations really only talk about their use in the research, and therefore the regulatory setting.

DR. MURRAY: Right. If you look back at Kathi's memo, do you want to describe what you were after in your point 2?

DR. HANNA: Well, I think that 2 refers back a little bit to what Alta was talking about earlier, and that has to do with that there's been some concern on part of commissioners that we aren't presenting a kind of big picture of this area of research. We're not communicating through the report whether in fact the Commission feels that by and large most of this research is going to be minimal risk, or conversely, that a lot of this research is going to be above minimal risk. There needs to be something in the report that communicates where the Commission stands on this area of research--the reason being that if the Commission feels that a lot of this research is above minimal risk, then that's going to dictate how elaborate a system of protections you want to put in place. So everything else falls out of that. The discussion and the report right now on minimal risk that appears in Chapter 5, staff have worked on it. We've tried to figure out what to say about this, and what you want to say about the concept of minimal risk and rights and welfare in the context of this kind of research, which is different from minimal risk or risk issues when you're doing invasive research or the kind of research that you're talking about in the Capacity Report. The concept of minimal risk and rights and welfare concerns is different when you're doing work on materials that are stored and far removed from the source. So we would just appreciate some clarification on what kinds of overall statements you'd like to make about this area of research and what kind of language might be useful to an IRB that is trying to decide whether this is minimal risk or not.

DR. MURRAY: Kathi, I'll just look for guidance here from the commissioners. Would you want to discuss this issue in generous terms, or would it be better to turn to those passages in the context of Chapter 5, which addresses the issue of minimal risk? Is there a sense from members of the Commission as to the most efficient way to proceed? Well, hearing none, do you want to talk about the issue in general terms or a given interest in getting them down to brass tacks? Do you want to turn to the passages in Chapter 5 in our recommendation (UNINTELLIGIBLE)? That addresses the issues of minimal risk.

DR. HANNA: Can I just add that the reason why this is important following on the previous discussion--and I think you have to have this discussion before you can make your decision on number 1 in my memo--is that you have to decide how protectionist you want to be? And how protectionist you want to be will tell you whether you're going to put unlinked samples into identifiability or unidentifiability. So the two discussions really do feed on each other.

DR. MURRAY: Bernie?

DR. LO: I think it is very important to have a general sense of whether we think most research involving stored tissue samples is minimal risk or not because it obviously is a key term in the regulations. I would like to suggest that the answer is yes, but with a big but. I think that most research is minimal risk, but there are a lot of big buts. And I think if we could agree on that and try to define IRBs and the types of research they need to watch out for, we will have done a big service. I mean, if you think about most of the things that are done, samples from persons with specific conditions are looked at for certain conditions. Often the people who donated the sample have the actual condition; sometimes they don't. But my sense is that most people don't think that type of research per se is particularly risky. But there are certain types of research that are, and I think we tried to introduce this concept of sensitive studies. I think that my concern with the report as it now stands is that in our effort to say that most of this is minimal risk we downplay the types of research that probably aren't minimal risk. So I think that if we can agree that it's mostly minimal risk but we ought to define more precisely those areas where IRBs and investigators ought to have a lot more caution, we might have pushed things a big step forward, because as it is now there's just a lot of confusion. You heard, again just yesterday the notion that, well, you guys seem to think that any type of DNA-based research is more than minimal risk. And I think that that's such a sweeping statement, but it really does color what a lot of investigators and IRBs now think.

DR. MURRAY: Bette and Alta.

MS. KRAMER: Bernie said what I wanted to say. I think we ought to adopt a statement one way or the other and then proceed from there.

PROF. CHARO: I agree with Bernie that most work in this area is likely to be of minimal risk to the people whose tissues are used. I think there are going to be several different ways in which that low risk can be identified, and it's probably worth our while to list them. Some of them are topical--that is, you're dealing with characteristics that themselves are not particularly controversial, stigmatizing, or otherwise upsetting. You're looking for things that have to do with coding for hair color; I doubt that it's really going to be significant in the context of risk to anybody. And a lot of research is that type. The second way in which things become minimal risk is not based on what you're working on but on how you do it and how you make sure that certain risks don't come to pass. That is, you work on the probability rather than the magnitude of possible harms. So on this score it's a little bit like with the Capacity Report: there's a toolbox that can be used in research protocols to ensure minimal risk. One is the creation of appropriate rules ahead of time about how you're going to decide if you would ever go back to the original tissue source to tell him or her something that you had found. Most researchers certainly don't intend to do this, but occasionally some result comes up that raises questions in the researcher's mind about whether this needs to be done. Prospective planning about when you will or will not do that lets an IRB assess whether or not there's a specific chance of this happening. David Cox has spoken often about the value of repositories, even helping in this kind of endeavor, since often to go back to the tissue source would involve cooperation from the repository anyway because they're the only people who will hold the key to the links between the researcher's sample, the repository's materials, and the name and address of the tissue source.

The second thing has to do with the kinds of protections against breach of confidentiality of the work that the researcher is doing. And that's a real issue because there are many institutions in which medical records have to have test results recorded, regardless of whether they're in the context of clinical care or research care, so that research results are being intermingled in a record that's available to other people. And this is the kind of thing where the Joint Committee on Accreditation of Hospitals would actually be able to do something useful in order to help sort out that problem and allow research information to be isolated in a way that maintains privacy. Finally, you can take a look at the kind of information you're generating and the kind of population you're studying. If some of the harms that you're worried about have to do with things like a breach of confidentiality that leads in turn to loss of insurability for health insurance, for example, you're dealing with a population that's drawn from a group that is covered under a group policy. The risk is then much lower than if you're drawing from a population insured by individual health policies. And most people are covered under group policies, but they're not individually rated. Some degree of attention to that I think would be important. These are all the types of things that can go into a protocol that can make something that otherwise might not be minimal risk become minimal risk because you paid some attention to ways that can be accomplished. If we list those kinds of tools we can also suggest that most protocols can be rendered minimal risk in one fashion or another.

DR. MIIKE: I think that through the course of this study we've been distracted by how we treat the materials and we've not paid enough attention to the informed consent process. I think if we're talking about greater than minimal risk, that's the area where you put the protections in. I personally think all this issue about confidentiality insurance is overblown. Everybody is worried about that, but there's very few real cases to me in a systematic fashion that makes me worry that it rises to the level of primary importance in this area. So that when we talk about minimal risk or greater than minimal risk, the way I would view it is, of course, we deal with the way you treat existing specimens; but I've said from the beginning that we've got to address the issue about the current informed consent process in clinical collection of specimens. And my proposition has always been that the easiest way to do it is you sign twice. Just pull out that general authorization for clinical use that's buried somewhere in that clinical consent form, stick it at the end after you sign your clinical consent form, and sign again where it says, "In general, I agree to make my tissues collected available for research."

So I think that if we're going to be talking about protections and levels of risk we've got to turn back toward the informed consent process. It seems to me, and you can correct me, the scientists in this group, that the areas in which we're going to be dealing with greater than minimal risk are basically going to be in those areas where people are going to have their specimens collected in a research protocol and not in a clinical setting, and that's the primary area in which people's really valid informed consent can be obtained.

DR. MURRAY: I want to just see if I understand some of the points that have been made in the last couple of minutes. First of all, there seems to be a sentiment that most of the research involving human biological materials either is minimal risk or could be made to be no more than minimal risk with appropriate care--Alta's toolbox. Larry is then talking about one of the means by which we protect the rights of subjects, that is, by informed consent. That becomes a policy response and a means of protection. Those are separable points, both important. Am I clear? Am I capturing what was being said? All right; I just wanted to make sure about that. I know Steve had his hand up. Anyone else? Steve, then Bernie.

MR. HOLTZMAN: What's been somewhat unclear to me in this line of discussion we're going down is the following one of thought: the way we've used our classification with respect to identifiability results in the overwhelming majority of samples in what I believe are the overwhelming majority of studies being considered identifiable samples. Hence, the way the regulation operates is it puts you into the gambit of the reg. We're now saying, "Hmmm...but the majority will be minimal risk," and I think that's probably true, but you still are in the pathway where you have to go through the four-part test.

So all that minimal risk gets you is the potential for expedited review. It doesn't get you outside of the issues of whether re-consent is necessary, the practicability tests, and whatnot. And therefore it is striking that in Kathi's letter she's got it exactly right--if you're heading down this pathway you then ask yourself about the consequence, and you say, "Maybe I've got to get rid of the practicability requirement, because if I leave the practicability requirements, this will be tantamount to having to go back and re-consent." If you look at our recommendations on pages 203 and 204, you will find that that's where it comes out. So I'm not sure what this gets us by focusing on the fact that they are minimal risk unless you're going to draw a consequence from it.

DR. SHAPIRO: That's point 3 in Kathi's letter, as I recall.

MR. HOLTZMAN: That's exactly right. So again, it comes back to that it doesn't matter what you call it, and I think Alta is exactly right: it does matter what you call it because these are the consequences of calling it the way we've called it.

PROF. CHARO: Steve, I absolutely agree. That's why one of the very initial questions that needs to be answered is whether you want to use a system that refers a large bulk of the research to an IRB for a pre-review. Right? Because the question is how worried are you about the subset of cases that really deserve some extra protections and some peer review. And it may be that we can't answer that question, we can't balance the burdens of having IRBs review things that in fact turn out to be fairly risk-free as opposed to the value of having them catch the ones that are risky. We may not be able to answer that until we get further down into determining exactly what level of protection will be imposed on the ones that go through the system, including protections that may be excessive by virtue of the way the regulations are phrased.

So I don't think we can actually get back to the first question of whether or not we should have them all go into the IRB to begin with until we see how flexible it is at the other end and how efficiently we can clear out the problem-free protocols.


DR. MURRAY: Bernie, then Carol.

DR. LO: I want to try and add a couple of points to the discussion, which I really agree with. I think people are pointing out that there are a lot of key points in this and minimal risk is one, whether we're going to get consent is another one, and whether the practicability criterion is going to be retained or modified. I would like us to focus on what's going to be our bottom line in terms of what kind of oversight and what kind of regulations for what types of research.

I want to try and point out that in our two reports it's important for us to be consistent in the way we think about minimal risk. With the other report on persons with mental disorders we took a very strict view of minimal risk. We said there's going to be minimal risk and not minimal risk, and things that are a little bit more than minimal risk but aren't minimal risk. I think there are going to be some attempts, because of what flows from the regulations, to try to put things in that category that on first glance might not fit in that category.

One of the things I think we should think through is to what extent do we feel obligated to retain the current regulatory structure with certain concepts being absolutely crucial in terms of what gets reviewed, what needs informed consent, and the like. There are pragmatic arguments and there are conceptual arguments. Pragmatically, we started out many meetings ago saying look, just sort of try and rewrite the regulations. It's a herculean task. To the extent that we can use the existing framework, it's going to be a lot simpler. On the other hand, it seems to me that if the existing categories and the way these are linked to regulatory provisions really aren't quite right for DNA testing on stored tissue samples--remember, these regulations were written for things like reviewing medical records of your last 50 cases of a certain type of operation--it's not to me automatic that those categories, as helpful as they may have been, are going to be exactly the ones we want to use to tie to certain regulatory things here.

My own concern is that by being wedded too tightly to existing categories and the way those categories play out in the regulations, we're going to end up with putting things in boxes where they don't really belong, because at the bottom we don't want them to be in the category of "must get full informed consent." I think we have to think through whether the gist of this report is a conceptual report to help IRBs and investigators who are truly perplexed about these issues--what are they supposed to do, do I have to go to the IRB, do I have to get informed consent--to help them think this through. Is that going to be more valuable than saying, look, we can tinker with the regulations so that you can solve most of the problems?

I think that if we can reflect back on our experience with the other report, we ought to sort of see if we can learn from that how to make the second report of the two go a little smoother. But I would just be a little concerned that we not feel ourselves too tied to concepts and the links between those categories and regulations that may be counterproductive at this point.

DR. GREIDER: I agree with what you said, Bernie, and I agree with what Alta said, and I agree with what Steve said. Here is my problem. Alta says that we should think about what the consequences should be. So if I think about these four categories that we have of our samples and how they're treated, I'm happy to take the first two categories and treat them one way and the bottom two categories and treat them another way. But in order to do that with our current regulatory system, what happens is that our recommendations now say that those top two categories are called "unidentified."

I think that giving the message to investigators that these two samples are the same and are "unidentified" makes them think in a certain way--that they can fool themselves that these samples really are unidentified when they're not. And I would like the investigators to realize that they are really two different things and yet have the regulations come out the same way. And so that's my problem: that the way I want the consequences to be, it's difficult right now to find language to fit those two things into the same thing without making it clear that they are very different things.

DR. SHAPIRO: Carol, I just want to make sure I understood what you just said. It was that if we take the first two categories of samples, currently called "unidentified" and "unlinked," that in your own judgment you would like to treat these in the same way, but have investigators conscious of the fact that they aren't quite the same. That's the aim, as I understood what you said.

If that were the case, it seems to me there's a simple answer to that problem--namely, you just never combine them, you just keep on using two words. So you just say "unidentified" or "unlinked" have these regulations, "identified" or "linked" have those. That seems to me a reasonable solution if that were the problem. I just want to make sure I understand.

DR. GREIDER: That's my major problem.

DR. SHAPIRO: Thank you. I just wanted to understand.

DR. MURRAY: I think that clarifies for me Carol's concern. I think, Harold, it's a very elegant solution, really, to just keep labeling clearly at every step each of the categories we think belongs in each particular policy response.

I heard a different concern expressed--let me see if I can try to put it concisely, and tell me if I understand it correctly--that given that most of the research with human biological materials will either be minimal risk or can be made minimal risk with appropriate, readily available measures, and given the current regulatory scheme, so long as they are either in our categories of "coded" or "identified," an investigator would be put through a fairly extensive process in order to receive approval for the research or might be made to go in and take measures that might be disproportionate in order to get, for example, re-consent in order to be able to use those samples. Do I understand that? Is that the concern that I've heard expressed I think by Bernie, maybe by Steve, and maybe by Alta?

MR. HOLTZMAN: It's precisely that. If you're getting specimens from the Corials of the world, in our terms those are "unlinked" samples. They also, for that matter, may or may not be "unidentified." But in the majority of instances, when you're going to the pathology department what you're getting is a "coded" sample. Now what we have in our report is OPRR's interpretation that a "coded" sample is "identifiable" according to OPRR and therefore triggers the entire consent process.

Six months ago I asked whether or not we could ascertain whether most of the researchers in the United States share that interpretation. I don't know if we ever got an answer to that question. So, therefore, I don't know as we're writing this what the practicable implication is because we never, to my knowledge, found out what the practice is.

DR. MURRAY: Kathi?

DR. HANNA: We actually did ask some of the big repositories.

MR. HOLTZMAN: Kathi, the repositories, I'm familiar with their practice. I'm talking about most of the stuff going on, which comes from the pathology departments.

DR. HANNA: And your question is, do we know whether they're being forwarded to the investigator as "coded" samples?

MR. HOLTZMAN: Yes, number one. And if so, are they being subjected to IRB review and meeting the four-part criteria? Do we know that?

DR. HANNA: No. We would have to do a survey of investigators to find out, in fact, how they submit. We have no way of knowing from the IRBs either, because if it doesn't come to the IRB they have no record of it.

MR. HOLTZMAN: That's right; you'd have to go to the pathology departments.

DR. HANNA: Right. I would just add one other thing here, which is that there is another consequence of calling "coded" samples "identifiable." It doesn't necessarily mean that all of those protocols have to go to an IRB. It could also mean that the investigator can make a decision to unlink the samples. Yes, request the samples in an unidentified way, whereas before he or she might have not thought about whether it mattered to have them coded or not.

MR. HOLTZMAN: That's certainly true. My question is about research as conducted now.

DR. MURRAY: And Elisa Eiseman was nodding knowledgeably there. I don't know, Elisa, do you have anything further to add in answer to Steve's question?

DR. ELISA EISEMAN: No, I agree with what Kathi said, that that's a really hard question to answer.

PROF. CHARO: First, I think there may be one easy way to get a partial answer to the question, and that's to contact PRIM&RB, that is the Public Responsibility in Medicine and Research Board, because they work directly with investigators and IRB members and can probably give us a fairly good idea of how the regulations are understood in the world so we would know how much our advertisement of OPRR's current understanding is going to shake things up out there. But in some ways this is not the main focus of our discussions, because we do not control OPRR's current interpretations; they can change them if they want. But since they're the lead regulatory office in this area, for better or for worse, their interpretations are going to be given great deference.

What can be within our purview is to suggest ways in which the current regulations that don't have much interpretation could be interpreted, as well as to make recommendations for specific changes. For example, having something go to an IRB for a first prescreening does not necessarily turn into an incredibly burdensome procedure if (1) it's handled in an expedited fashion, and (2) if the protections that flow from those things that can be rendered genuinely minimal risk are not disproportionate. And that means a focus on the meaning of consent and, specifically, whether what was described to us at one of our meetings as an opt-out as opposed to an opt-in procedure is an adequate substitute for consent. It's not the same thing as consent, but it's an adequate substitute in light of minimal risk in that it answers the question of paying respect to people's personal choices but is less than the ordinary kind of consent that we associate with things. That might be one avenue to work on.

The second is an understanding of practicability that takes into account costs, time, response rates, etc. We've got some possible avenues for discussion.

And one final comment on the point about whether or not opt-out as opposed to opt-in is an appropriate level of respect for people, where opt-in is what we ordinarily call consent and opt-out is clearly a new beast, not consent, something else. I'd point out only that for those of us in law, we're familiar with the history of the doctrine of informed consent. It grew entirely out of a set of circumstances having to do with physically invasive phenomena; that is, I touch you without your consent in a way that's harmful or offensive. That's the origin of the doctrine, and its extension into non-invasive areas such as purely informational areas even in the medical malpractice realm was a very substantial expansion of law and has created theoretical problems that we're coming up against here. And then in the regulatory regime in research we saw the same thing--the same notions of consent and the same notions of entitlement to give consent were given to both invasive and non-invasive research.

Non-invasive research is the new wave. There are a lot of privacy concerns out there, may be best dealt with under the rights and welfare language, but I think it's up for discussion whether an opt-out procedure is an appropriate level of personal respect and opportunity for choice in non-invasive areas, like research on excised tissue.

DR. MURRAY: Alta's comment actually brings us to point 3 in Kathi's memo, where she asks about practicability and opting-out. So Kathi, would you say what you'd hope we do in response to that inquiry?

DR. HANNA: Well, the issue of practicability actually came up about six months ago in staff discussions, and we weren't clear the direction the Commission was going in terms of labeling and how large the flow was going to be to the IRB. When we went back and looked at the four conditions that have to be met for waiver of consent, we thought that one way of trying to decrease the volume, if that's in fact what you want to do, would be to say that even if you're going to send all these, because if you do call "coded" samples "identifiable" you are now going to be sending more protocols to IRBs, because that is clearly not the way the entire scientific community is viewing those protocols. So you've already increased the volume of protocols going to the IRB. Now they have to make a decision about whether consent is required and they have to meet the four criteria, and all four have to be met. And it occurred to us that if, in fact, in this area of research--that is, using biological materials--if it is minimal risk and there are no concerns about rights and welfare, then would it make sense to then drop the practicability requirement and instead offer an opt-out mechanism, so you would actually waive consent after the first two conditions were met?

And then for those studies where you might have concerns about the nature of the research, it for some people might be objectionable, then you would give the opt-out mechanism just as an extra measure of protection. But the opt-out mechanism kicks in only after consent has been waived. We just floated that on e-mail to see how people reacted to it because, as Steve said earlier, of the direction the report is going in, and it might be the way you want to go, but you're building the volume exponentially of protocols that are going to go to IRBs that are going to have to not be able to waive consent even if they are minimal risk because of the practicability requirement, therefore requiring consent or re-consent on a huge number of studies. The question is, is that what you want to do?

DR. MESLIN: Yes, Steve?

MR. HOLTZMAN: I think you're right, Kathi. And I want to make clear to the Commission that from my perspective this is a very textured and layered landscape. As we think about going forward in the context of major medical research institutes, where people recognize that that which is collected in the clinical context is likely to be used for research, you're going to see much more robust consents, and I think we will all applaud that. I'm thinking of a relationship we set up with the University of Pittsburgh Transplantation Center, where we knew we would be establishing a tissue bank--very varied layer of consents.

But you have to keep in mind the whole landscape of research here. There are large numbers of samples that are just coming into community hospitals that have tissue banks, that will be brought in where you're not going to have all of the apparatus involved, where you're going to just have the local doctor and local pathologist and you're going to be getting those samples.

And so I just want to caution us to keep in mind the broad range of examples not only on the go-forward basis but also in terms of what we're saying with respect to a repository that currently exists with millions and millions and millions of samples. What when we're finished with this will be the consequence in terms of cost and practicability of doing the kinds of research that most of us would say are minimal risk and are not a problem, and which I believe we heard in a non-scientific but nevertheless perhaps meaningful sampling of public opinion, will be that most people thought it was good that those sort of samples were being used to that end.

DR. HANNA: Let me just add that this suggestion only applies to existing samples, obviously. So don't get confused. Obviously, you can't obtain a sample from a living person without their knowing you're doing it. This is only for existing samples.

MR. HOLTZMAN: No, I realize that. But there will be stuff that falls in the category of existing in the future, Kathi, right?

DR. MURRAY: Further thoughts about this issue? Bernie?

DR. LO: I think this is a very important topic and I'm glad we're pursuing it. I wanted to make a couple of brief remarks relating back to what people have said and then try to introduce some new concepts. First, with regard to Alta's reminders about the history of informed consent, while I agree with what you said about the development of the doctrine of informed consent in a treatment setting, I think the research setting is really different and that it's not just physical harms but being a research subject without knowing about it. Having been involved with some investigations of the human radiation experiments, in which people were subjected to radiation in really trivial doses that was not a physical harm in any meaningful sense of the term--but it was an offense in that they were used without knowing about it and without their permission, and they were outraged. So I think that in a research setting we should be paying more attention to non-physical harms than we would in a treatment setting.

Second, Steve brings up a really important point about existing samples and future samples. One of the things that concerns me is that we should really be looking toward the future and encouraging investigators under IRBs to develop consent forms that are really more meaningful than current consent forms. I think Larry brought up the really important problem of what to do with samples that are going to be collected in the future in a primarily clinical context and what we can do to get away from these blanket consents that are signed on admission or as part of the surgery consent form.

I'm willing to treat existing and future samples quite differently. I think Steve's point, that there's a lot of samples there, it would be a shame just to not use them by making people get specific consent. But what I would like to see linked to that is a real commitment to saying let's make consent in the future much more meaningful than it is now. There's a lot of exciting work going on out there on how to do that and that's not in our report now and I think it's a real lack. It's actually not taking up an opportunity to really take the lead here.

Finally, Steve brought up a point about community hospitals participating in repositories. I remember we heard many meetings ago from women with breast cancer saying that if they went to their community hospital for a mastectomy, it was important for them to know that their sample might be used in future research and they didn't want to be excluded. I think that's a good point, and I laud them for their altruism. But I think what they need to understand is that we're not just talking about using their samples for breast cancer, we're talking about using it for Alzheimer's, drug addiction, and a whole bunch of other things. To me, that's a misconception about what's going on. I think for people to think that it's going to be used to help researchers find the genetic cure to their specific illness is not what we're talking about here. I think Steve was very eloquent in giving us a sense of the big picture here. We're talking about lots of other diseases, some of which are diseases they'd probably say, "Yes, go ahead and use my sample for hypertension or something," but there also may be researchers who by the same process, unless we can be creative here, might want to use it for research on aggression, research on drug addiction, research on all sorts of other things that people might be a little less comfortable with.

So I think it is important, as we think about trying to remove unnecessary regulatory burdens from the majority of protocols that are proposing to used stored tissue samples, that we also be very clear about the number of situations where we really want to make exceptions and to get researchers to think very hard to make sure that they're not in one of the exceptions.

DR. MURRAY: Bernie, just to bring this around back to the conclusions and recommendations. We do try to identify a category of research that would be--we've used different labels for it, controversial, sensitive, I don't know that we have the right label for it, nor do I want to spend a lot of time deciding on what the right label is--but we do want, I think, to signal that such research does happen, is possible, but also that it's likely to be relatively--my conviction, tell me if I'm wrong--likely to be a relatively small percentage of all the research projects undertaken. Is that a reasonable empirical presumption or not?

DR. LO: Yes. I'm willing to agree with that. I don't have any better facts than anybody else. But I think that if the gist of what we're saying is that we only remove unduly burdensome regulations from the vast majority of projects, it seems to me it becomes very important then to be very clear that on the other hand it's extremely important to make sure that we've fleshed out those categories where we don't think the streamlined process is appropriate, and then to decide what level of oversight we're taking. For a lot of this, it seems to me it's just consent. If there's a sensitive, which is one of the adjectives we've used, topic, maybe an opt-out really isn't good enough and you have to use specific consent for the types of research that we've listed. So we have a lot of, in Alta's metaphor, tools in our toolbox. My concern is that we just identify a big category of saying we've got to take these, consider them apart, and then decide what sort of additional precautions are triggered by things in that exception category.

DR. MURRAY: We have a couple of policy possibilities there; we have more than two, but just two obvious ones. One is to say, look, we think this is likely to be so infrequent and to be offensive to so few people that we're just not going to create any special rules to deal with it at all. That's not the direction we're heading. The direction we're heading is to work somehow into the process a signal that would indicate that sensitive research is at issue and that it may require some different sort of reviews and different sort of response. Are you happy with that second track, which I believe is the track we're trying to take?

DR. LO: So, for example, just to be very concrete, if we're going to use for existing samples the clinical consent form as meaning anything, we probably should say it doesn't apply if it's a sensitive topic. That it's presumed that you would consent to have your breast cancer specimen used for investigation of breast cancer or other cancer or other diseases that affect women, but not for the genetic and ethnic bases of violent behavior. That's a totally different area.

DR. MURRAY: Right. Rhetaugh?

DR. DUMAS: I think I agree with Bernie. I'm not quite sure. It seems to me that there is the issue of rights and prerogatives of the donor and then there's the issue of the potential for harm or discomfort. And I think we need in this case to separate those two, because I would be less worried about potential for injury, harm, or discomfort in a sample that's been disconnected from its donor for years. I would have a hard time really deciding what, in addition to stigmatization or bad press, could be included in that. But I resent having people use part of my body, my being, without my permission and without my even knowing that they stored that sample.

So I think that the issue of rights and prerogatives of donors is something that we need to make sure that we give attention to. And I think we have. I think the issue of informed consent is a very critical issue in that regard, knowing full well that there are some cases in which this is not going to be possible. I think we need to spell out very carefully the conditions under which informed consent is possible and where we would insist that it be obtained.

PROF. CHARO: Rhetaugh and Bernie both, I'd like to ask you to consider the following and tell me how you react to it. Imagine that somebody wanted to use an opt-out procedure in lieu of consent, so what they did was send letters that had a notice that guaranteed that the letter was actually received. This way there's not an issue of letters that never arrived where they were supposed to arrive. Okay? This may be unrealistic because of cost, but just imagine it. So they send a letter that says we need to use your tissue for the following kind of research--obviously, it's your prerogative to say no--please contact us at our expense by returning this self-addressed, stamped envelop to say no. Would that be sufficient? Or are you advocating more than mere notice and an opportunity to decline, but an actual entitlement to give an affirmative yes?

DR. DUMAS: I have two answers to that. In relation to the letter, I'd want to know whether or not when that sample was collected I signed the consent form.

PROF. CHARO: No. This is in a setting in which we're going to assume that you've never prior to this moment contemplated or given authorization for some kind of research use. This is coming out of the blue to you.

DR. DUMAS: Yes, the letter would be adequate.

DR. MURRAY: Bernie?

DR. LO: I would say it depends on the study. If I had had an operation for pancreatic cancer, which runs in my family, I would be delighted to have that sample used, and for any other type of cancer I would probably say why did you even bother, go ahead and use it. But I can think of a lot of studies that I would have said no, I won't give affirmative consent, I want to hear more about the project. So I think it's very dependent on the nature of the study. I'm willing to say to most of them that's fine, or that consent form that was buried in the surgical consent was probably okay. But I want to hold out the exceptions.

PROF. CHARO: Do you think an IRB is capable of making that judgment of when it would be appropriate to use opt-out as opposed to a full consent?

DR. LO: I think they would be greatly assisted if we could develop both some examples and guidelines. I think just to throw it back to the IRBs is asking them to do a lot, and I think they're saying this is tough. But I think we can all put our fingers on things. If someone was going to use that sample for combining my cells with cows to be cloned, I would be upset that they didn't tell me about it and didn't give me a chance to consent.

PROF. CHARO: But it's not about not being told, it's about whether or not you opt out or opt in.

DR. LO: Yes, I would want to say that you shouldn't--because we all know, I leave all kinds of mail. I don't return my driver's license reapplication on time, so the fact that I didn't return it doesn't mean I didn't want to do it.

PROF. CHARO: Got it.

DR. MURRAY: Remind us of that the next time you offer to drive us anywhere. [Laughter.] Kathi, then Steve.

DR. HANNA: I just wanted to remind the Commission that a long time ago you made the decision that you were going to assume that existing consents that were obtained in the clinical setting were inadequate, inappropriate, non-existent, or whatever. And so the reason you I think then progressed in this more protective fashion was based on that assumption. We've actually seen some consents from institutions that collected materials 10, 15 years ago in a clinical setting and they were quite clear, and I would say an IRB would say it was very clear in there that it was a separate line they signed or whatever. So all of this has been based on the assumption, which might very well be true, that existing clinical consents are inadequate. But I heard Alta say that in lieu of consent, well there was technically a consent form signed, we just don't know the adequacy of it, and in fact an investigator could pull those consents and present them to the IRB if he or she felt that they really were applicable.

DR. MURRAY: Kathi, just to amplify that. I looked at samples 15 years ago of such consent forms for research I was doing then about gifts and tissues, and there were separate lines, there were signatures on separate lines, the language was relatively clear that you were donating your tissue, usually it was for research or education or both, not just for research. But it was also pretty clear that it was extremely generic and I had considerable doubt whether people even carefully read what they were signing when they were signing it. I have some close family experience where someone signed such and then immediately after had no idea they'd signed it. So the moral significance of these, even though there may be signatures that would look like clear pieces of paper, are, to put it back in the category, that we shouldn't assume that they were the full sort of fleshed-out consent that we regard as ideal, but perhaps not necessary for our purposes. Steve?

MR. HOLTZMAN: I had a response to Alta. But on the second point, I've given at least a dozen talks to various audiences in the last year on this subject, and I always start off with, "How many of you have had tissue taken in a surgical or other kind of medical context?" Over half the audience, it seems. "How many of you remember signing a consent to research?" Nil. So.

Alta raises the point of respect for the individual and their choices, and the notion that even if we are not our body parts there is a sense of identification with how they are used and in wanting to know how they are used so that you would not be complicit in kinds of research that you think would be offensive. And I think we all acknowledge, and in fact the regulation acknowledges, that that is an important, important value. What the regulation also acknowledges is that there are two sets of values at stake here--those, let me simplistically call them autonomy rights, and the social utility rights. And the way the regulation struggles with it is it says if I can bring down the potential for harm sufficiently through rendering the sample unidentifiable, then the social utility value will trump the autonomy right. Okay. So if we are going to now say with respect to existing samples, against a backdrop in which those consents for all intents and purposes don't constitute true consent, that we are going to use a concept of identifiability that is very broad, effectively what we are doing is saying the autonomy right now trumps the social utility right.

DR. MURRAY: Let me just tell you what our parameters are. We have something like nine minutes left for the conversation at this stage, at which point we're going to take a break and I'm going to turn it back over to our chairman. Kathi has an issue she wishes to get as clear a statement as she can on from the commissioners, so I'm going to ask her to put her question.

DR. HANNA: As you know, this next draft is the draft that will go out for public comment. So although it won't be perfect, we'd like it to be as close to where the Commission wants it to be as you can get at this point. What I really need to hear is where people stand on this practicability issue, because the other discussion can be changed in the draft now to reflect Carol's concerns and confusion about the language. A change in issue number 3 having to do with practicability would require that we change some of the recommendations in Chapter 5 and then reflect those changes throughout the report. So I need to get a sense of whether we should go ahead and try that approach before public comment or not.

DR. MURRAY: Carol?

DR. GREIDER: This is just to clarify that what we're talking about is on page 220, the flow chart, when you're talking about waiving the practicability when you say those four items. So the question is, will the research in its entirety involve greater than minimal risk? No. So this is now minimal risk research. And then the first thing is, is it practical to conduct the research without the waiver alterations? That's the one that we're talking about suggesting we should not have for this category. Is that fair?

DR. HANNA: Right. But that would not then drop you down to the rights and welfare argument. The way this flows....

DR. GREIDER: So that would just be gone, and then it would just go directly to rights and welfare?

DR. HANNA: To rights and welfare, right.

DR. MURRAY: Bernie?

DR. LO: Steve pointed out that any time we're talking about regulating research we're balancing conflicting values--autonomy versus long-term benefits to society. I would rather see that balance made not on whether it's practical or not, but on--and it's called rights and welfare--on how important is it that I knew I was going to be a research subject and did I have a meaningful chance to say yes or no. I'm willing to say that I think that's the key consideration. And if it's on a topic that is really benign and straightforward, we shouldn't burden people with the practicability requirement.

But when I come back to whatever protection was in that practicability requirement I would like to see a beefed-up "rights and welfare" that really looks at certain types of topics with a lot more scrutiny. But I think it's misplaced to think that I'm getting protection, because it's going to cost the investigator a lot to send out consent forms. It seems to me that's a very awkward, cumbersome, and misdirected approach to trying to protect subjects.

DR. DUMAS: I agree.

DR. MURRAY: You want to say more, Rhetaugh?

DR. DUMAS: No, I just wanted to agree.

DR. MURRAY: We have a yes from Rhetaugh. Larry?

DR. MIIKE: Well, on the specific question, I think we should just send out the draft the way it is without alteration of the practicability issue. It seems to me that if we go down the flow chart, the troubling one to me is rights and welfare. It is such a nebulous concept that I don't know where you draw the line on that. What is the meaningful application of that? I think that's where we're going to get hung up.

Overall on this project, I look at it the following way. We've made our decision about what is "unlinked" and "unidentifiable." It turns out, from what Steve says, that that just excludes a very small piece of the universe and the rest of it is still going to have to go through the review process. So what I'd like to do is to send this draft out and see what kinds of reactions we get in terms of what we're trying to do within the current regulatory structure and whether that is a feasible way of protecting individual rights and still allowing research to go forward. And then I think our choice is going to be, can we still tinker around with the current regulations to make a better balance or are we just going to have to dump the current paradigm of the regulatory structure and come up with something of our own? I think the only way we're going to know that is to send this draft out and see what kind of reactions we get.

DR. MURRAY: Larry, I actually came to a different, for many of the same reasons, I've come to a different conclusion. And that is, to find a fully fleshed-out public reaction, this might be a particularly appropriate time to plug something new that we want talked about--to see whether people are keen on it, hard on it, or think it's a wonderful idea. If they reject it, that should tell us that maybe we need to rework the whole structure. I guess I've been thinking, what's the purpose of the public review, and it's to give us feedback about what we think the most appropriate steps are.

DR. MIIKE: But what is your major change aside from dropping the practicability issue? What is our major revision?

DR. MURRAY: There will be other changes. The notion of dropping the practicability requirement and perhaps substituting some sort of opt-out, or at least offering the possibility of an opt-out procedure, is novel, as I understand it. And I would actually be very interested to know both how the public responds to that and how investigators respond to that. I'm not committed to that one way or the other. I'd be interested in what other commissioners think about this. Bernie, David, then Alta.

DR. LO: To follow up with Larry, I agree with you that rights and welfare is a pretty nebulous concept. I think one of the things we can try to do is flesh that out with some general guidelines and specific examples. I'm wondering if we should try and have a compromise, because this report has been gestating a long time and it's getting to be almost past due now. I thought Kathi's memo was very helpful in terms of signaling things that we should think about. And if we put this up on the Web, it should have a cover sheet saying these are particular topics that we would like public feedback on. So if there's a way to try to do something with the practicability issue that says this is a proposal that we're just thinking about and we'd particularly want your thoughts on it. But I thought the discussion today was very rich and ought to be incorporated in whatever gets put out on the Web.

DR. COX: I'm responding specifically to number 3. Kathi asked whether the practicability requirement for waiver might be dropped for studies using existing samples deemed minimal risk and posing no threat to rights and welfare. I support that approach.

DR. MURRAY: And David, on the issue that Larry and I were discussing, would you want to see the notion of dropping practicability and introducing the notion of an opt-out? Would you like to see that in this next draft, or would you rather leave it out?

DR. COX: I support number 3 in the next draft.

PROF. CHARO: I'd love to take the idea out and see how people react to it. I also think realistically that, once again, we shouldn't constrain our imaginations but we should constrain our expectations when it comes to changing regulations. It might be valuable to put out in the draft two things: one that says we're very interested in this idea that would actually require a regulatory change, but short of that, there's a second idea we'd like a reaction to, and that is that within the current regulatory structure--which will remain for some period of time an interpretation of practicality that acknowledges that if an investigator plans to use a population that is likely to have a substantial portion of it difficult to find or with exceedingly low response rates, not that they are dissenting but that we just can't find out what they want--that these constitute the basis for a finding of impracticality that the IRBs can work with and that the IRBs might want to then impose an opt-out notification letter rather than simply waiving consent. That's at their own discretion.

But I'd love to be able to run both those ideas up the flagpole since it may turn out that it makes sense to recommend stages of things--one is an interpretation of current rules for IRBs to use while regulatory change is being planned. Finally, on rights and welfare, Larry, I think fleshing it out is important. I did a literature review and found virtually nothing on it. But at a minimum, I think we can add the following things to the content. First, there are rights that people have by virtue of state law that the Federal government is not necessarily aware of that the local IRBs need to be aware of, and if something violates their rights as given under state law, clearly that's relevant. For example, there might be a medical privacy law that affects the ability of the researchers to continually go back and ask for abstracts of medical records. We've actually not found one that was a complete obstacle, not one that couldn't be passed. On the welfare, I think that's a good place to pick up some of these stigmatization things that have been talked about. And maybe those are the two ways in which we can flesh out those terms and give some guidance to IRBs.

DR. MURRAY: Carol will have the last word in this session, except for Harold.

DR. GREIDER: I just wanted to point out that the first thing that Alta said was that it might be impracticable to drop impracticability. [Laughter.] And the other thing I wanted to say was that I agree with the idea of sending out the draft with this dropping of the impracticability and a cover letter, etc.

DR. MURRAY: Yes, I thought the cover letter idea was an excellent one to point out the things we particularly want people's comments on. Harold, do you have any instructions you want to give us?

DR. SHAPIRO: Yes. Let me just tell you, we're going to take a brief break now. We really do have to keep it to 15 minutes; otherwise there's going to be no possibility of doing the things we absolutely must do this morning. When we return, we will go first of all to look briefly at the rewording, so to speak, of our recommendations we approved yesterday; that is, that memo you have is an attempt to put into language what we approved yesterday not always using very specific language. Jim will go over that and highlight any particular points where there might be some change that wasn't fully discussed yesterday. I want to remind everybody this is not an opportunity to rewrite these recommendations, much as you might like to do so in ways that might please you. This is solely trying to make sure that we haven't seriously misunderstood the issues that were approved yesterday.

I do want to say in that connection that there were three particular issues that came up that are not in the recommendations but will be in the final text, which we will distribute, that I just want to mention so that we don't have to deal with them again later. One is the question of how our recommendations relate to the waiver issue. That we discussed yesterday, and it will be discussed more explicitly in the text. The same thing is true with respect to the regulations regarding children and so on as we discussed yesterday. And, of course, also how these recommendations affect those institutionalized as mentally "infirmed," to use a term of art that has some history. Those will all find their way into text in appropriate spots as indicated yesterday. They do not find their ways directly into our recommendations, as we discussed yesterday.

We will also then move to discuss, I hope I'll have a draft by then, the letter to the President to see how people respond to that. We may be able to finish that this morning; we may not be able to finish that this morning, as I indicated before. In whatever time is left we will return to the Biological Materials Report if for no other reason than to decide what really our next steps are. The discussion has been very helpful this morning and I think we can make some useful next steps.

So it is now almost a quarter after. I'm going to turn to Jim precisely at 10:30. Your absence here indicates that you have no concern about this issue and therefore I will take your proxy. And so 10:30. Thank you very much.