REGULATORY UNDERSTANDING OF MINIMAL RISK Discussion: Gary Ellis, Ph.D. DR. ELLIS: Thank you, Mr. Chairman. Good morning. Can I have the slides on, please? I'm going to respond to the question that, you asked me to define and describe the regulatory view of minimal risk. In order to do that, I need to give some background as to when the term applies, who applies the term, and you'll recognize that this is because of the structure of regulation that we have. (Showing of slides.) DR. ELLIS: So the Federal policy for protection of human subjects contains the term minimal risk and it is defined, so it applies to 17 government department and agencies' research portfolios. (Changing of slides.) DR. ELLIS: Similarly, the regulations of the Food and Drug Administration contain the term. It is defined in the exact same way as the Federal policy for protection of human subjects. (Changing of slides.) DR. ELLIS: And so the term minimal risk that I'm going to use and define applies to research funded by any of 17 departments or agencies, regulated by the Food and Drug Administration, or voluntarily pledged to the regulations of the Department of Health and Human Services. (Changing of slides.) DR. ELLIS: There is no mandate that is applied to research not conducted by the aforementioned departments or agencies not regulated by FDA or not pledged to 45 CFR 46. This is very important. You've heard me say this before, you've seen these slides before. You heard Alex describe these yesterday. It's very, very important. (Changing of slides.) DR. ELLIS: Minimal risk means--this is the regulatory definition--that the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life, or during the performance of routine physical or psychological examinations or tests. That's the black-and-white definition and it's been more or less unchanged since 1981. It was changed in a minor way in 1991. Now, who applies this definition? In general, a quorum of the Institutional Review Board applies this definition. So in any case, that is at least three individuals, which must include a non-scientist. So again, minimal risk is not the judgment of any one individual, ordinarily, it's the judgment of at least three individuals, one of whom must be a non-scientist, by regulation, in the domain of research that I described. Beyond the domain of research that I described, none of this necessarily pertains. Let me stop there and say that I think that in practice the way that minimal risk is applied is, IRB members know it when they see it. I'm not certain that too many IRB members -- well, I shouldn't speculate. We don't know if IRB members could quote this definition, we don't know if they could pull it out on a laminated pocket card, but we are confident that they know minimal risk when they see it. Perhaps they could not explain it in the terms of this definition, but they bring their good sense to the table and they have a feel for what is greater than minimal risk. I'll give you an example so this is less abstract. Let's suppose that you, as IRB members, are considering a protocol that involves lumbar puncture. So you may have a visceral reaction and just determine in your mind that lumbar puncture is greater than minimal risk, or you may ask some questions or seek information, what are the risks of lumbar puncture itself. I think physicians or health care professionals might say, well, there's the risk of infection, there's the risk of nerve damage, there's the risk of headache from upsetting the cerebrospinal fluid, and the extreme risk of paralysis. Others who are physicians may agree or disagree with that list, but that would be a reasonable thought process for an IRB member to go through. Then there is a judgment. So this is a more sophisticated judgment than the first judgment I described, which was a visceral response to everything you know, or think you know, about lumbar puncture. Now, you have specific risks of harm or discomfort attached to the research procedure and you make a judgment as to whether the probability and magnitude of those four specific harms or discomforts are greater than they are in daily life. Let me go forward. (Changing of slides.) DR. ELLIS: On this slide I have not added to, nor subtracted from, the definition of minimal risk, I've just displayed it in a different way so that we can work through what the more sophisticated IRB members or analysts might actually work through. On the left side of the not greater than side, it says, "the probability and magnitude of specific harms or discomforts in the research," so this is not abstract. You are now, as IRB members, considering a specific research protocol and we can know, or at least estimate, what the specific harms or discomforts conveyed by this research might be. Then we can estimate the probability and magnitude of each of those harms or discomforts. Then we would compare, and I'm moving to the right side of the equation, and we ask the question, is the probability and magnitude of these specific harms or discomforts not greater than the probability and magnitude of those specific harms or discomforts in daily life or in routine exams or tests? If you conclude that that probability on the left is not greater than the probability on the right, then you would have something -- a proposed research is not greater than minimal risk. One remaining question on the right side of the equation. It says, "in daily life," and so you may have the question, in the daily life of whom? It's not stated in the regulation. The regulation says just what it says on the slide, "in daily life." Now, I know it's not the daily life of healthy persons, because that trial balloon was floated in the 1991 rule making process and the term "healthy persons" was explicitly omitted from the rule. So this, we know. Well, is it the daily life of patients, is it the daily life of people who may be less than healthy? One could proceed under that interpretation but it would lead one to the conclusion that people who are in harm or discomfort, the patients, can actually be subjected to greater harm or discomfort than another ordinary person. And that would be, I submit to you, an unacceptable conclusion. Let me restate that. If you proceed with that interpretation and on the right side of the equation you have the person in extremis, you could do just about anything to that person and you'd come to the algebraic conclusion that this is not greater than minimal risk because the person is in such bad shape anyway. That would not be a positive conclusion for the protection of human subjects and research. So our office prefers to interpret the concept of daily life as meaning the daily life of all people, which includes the research subjects, which includes healthy people, includes people who are less than healthy. So if you proceed in that manner, you would not ever come to the conclusion that you can inflict harms or discomforts on people who are in considerable harm or discomfort because it's no worse than they are anyway, and it would be most protective for human subjects. So to conclude, I just want to restate what others around the table have said before me, using different words. Minimal risk is not moderate risk, it's not intermediate risk, it's not medium risk, it's not midway risk, it's not so-so risk. We take minimal to mean least, smallest, limited, minor. Minimal risk is just what it means, minimal. So this is a narrow category of research that is, as it says, minimal risk. I'll be glad to answer any questions you may have. CHAIR CHILDRESS: Thanks very much, Gary. Trish? PROFESSOR BACKLAR: Thank you, Gary. I'm a little confused. You're saying that this risk is not experienced by healthy people. Are you saying they're ordinary? DR. ELLIS: I'm saying all people, which includes healthy people, less than healthy people, subjects of research. That's what I'm saying. PROFESSOR BACKLAR: All right. DR. ELLIS: I know that it's not the daily life of healthy people. This I know, because that term was explicitly omitted after being floated as a trial balloon in 1981. PROFESSOR BACKLAR: Then would you say, using your example of a lumbar puncture, that this would not be minimal risk, since most of us don't experience this in our day to day lives? DR. ELLIS: I think four out of five people would conclude that lumbar puncture is greater than minimal risk. I think there may be a commissioner or two here who would disagree with that. Perhaps not. PROFESSOR BACKLAR: How would you deal with this then if you're doing research on somebody who, for instance, has schizophrenia and their risks of their everyday life are far greater than yours and mine. So what kind of baseline do you have in mind here, because it's still a little bit fuzzy for me in the way you've described it. I had in mind that it would be ordinary people so that if one were going to describe risk of somebody in a population, for instance, someone who suffers from schizophrenia, right away you would be able to -- the very fact that they're being in research, may be for them riskier than it would be for you. DR. ELLIS: Let me answer twice, first in lay terms and lay language from instinct. I know that I can't come to the conclusion that, because the person has schizophrenia and is in worse shape in some ways than the healthy person, that I could do more to that person or with that person than I would with a healthy person. So I don't think I used any regulatory terms there and I announced I was speaking in lay terms from instinct. Now let me speak as a regulator. If I look at this equation and I say, what is the probability of magnitude of harm or discomfort in the research on the left side of the equation, I suppose I could put the individual with schizophrenia, the prospective subject with schizophrenia, on the left side of the equation and say, well, what's the probability of magnitude of harm or discomfort X, Y or Z for this schizophrenic patient? That's one way to work that person into this equation. But I would avoid putting the individual with schizophrenia on the right side of the equation and saying in the daily life of the schizophrenia, because that could lead me to the conclusion that, in my first statement, I found unacceptable. CHAIR CHILDRESS: Diane? DR. SCOTT-JONES: Gary, I have a question about your reference to the daily life of all people. That sounds as if the point to which you would compare the person who's a prospective research participant is an average, and then you are then referring to healthy persons, aren't you? It seems that in the end the standard is the healthy person. If you're saying all people and then you somehow take an average of all people, that would be a healthy person. DR. ELLIS: If your assumption is that the average person is fully healthy, then I would disagree with your assumption. I think that, if I look at all people, that the probability and magnitude of harm or discomfort X, Y or Z, is real and is measurable in some number of those people. So you and I might be at odds as to whether, with regard to the probability and magnitude of specific harms or discomforts, an average person equals a healthy person. DR. SCOTT-JONES: Well, it seems that the definition is fraught with problems as long as it stands the way it is. Is there the expectation then that the decision rightfully belongs with individual researchers, with specific IRBs? Because it seems that as long as the definition remains this way you will always have instances in which you need to discuss particular cases to decide whether there is minimal risk, a minor increase over it, an increase over it. It seems that there is no way out of the problems that exist with this definition. DR. ELLIS: Let me give some background again on the purpose to which this definition, this term, is used in the regulations. You maybe overestimate the problem or you may be looking to the concept of minimal risk to add a use to the term for which it wasn't intended. The term "minimal risk" is used in the Federal Policy for Protection of Human Subjects, in the common rule, essentially for three purposes. One, as a cleaver to decide what can be reviewed by other than a fully convened IRB. I'm talking about an expedited review process. So that's one important use of the concept of minimal risk. Research that's greater than minimal risk not be found on a list of 10 items must be reviewed by the fully convened IRB. So, as you say, it must be discussed. Minimal risk is also used as a cleaver to decide what research can proceed without consent. And minimal risk is also used as a cleaver to decide when documentation, a consent form, may be omitted. So those are the three principal uses in the common rule. There's another minor use. One element of informed consent says, for research greater than minimal risk, certain information must be conveyed to the subject. But I've described the three main uses of the concept of minimal risk. If you are looking for a cleaver for other purposes, I guess there's two choices. One, is to redefine minimal risk. I don't know that I would advocate that. The other, is to invent some new cleaver to serve your purpose. CHAIR CHILDRESS: Alex. MR. CAPRON: I guess my hope in having you make the presentation today would be that we would get some sense of whether there has developed a kind of a common law of this. That is to say, that in the IRB guidebooks, in IRB educational materials, we have a fairly rich set of examples of the sorts of things that if you were called for your advice and someone said, well, we have a questionnaire for someone to fill out, well, is it a sensitive subject? No, it's not a sensitive subject. Well, that's an example of something that's not -- You're going to do a needle prick to get a little blood. Is that? No, that's not. In other words, we're going to do venipuncture. Through the years, all the different kinds of things that are done. Is there any sense of the way in which that term is filled out? I mean, there are many terms that the law uses, the reasonable person and so forth, that remain sort of, each case, a matter of the decision of the jury. There are outer limits where judges will say that something is, on its face, negligent and no reasonable person would have done that. But the term remains elastic. There are other terms which become terms of art where we have, through case law and so forth, a sense of where you could say, well, what does consideration mean here or something. Where are we on this? I guess I was assuming that part of your presentation might be that you could really give us a sense, particularly as it relates to the kind of impaired subjects we're talking about here, where the minimal risk line would likely be drawn, recognizing, as you say, that, strictly speaking, it's a decision of the majority of any IRB. Or it may be, in some cases, the IRB administrator or IRB chair who says, I sign off on this, through expedited review; I'm convinced that it meets the minimal risk. DR. ELLIS: Well, I understand the question. I have no slide. I was going to show a blank slide to illustrate that I have no answer for the question, but that didn't work. (Laughter) MR. CAPRON: Important data showed up on this slide, so I can't do it. DR. ELLIS: Alex is asking for the frequency distribution, where we have arrayed ordinary research procedures that repeat over and over through the years and around the country, a labeling on that frequency distribution of how often an IRB found this to be not greater than minimal risk, or greater. That information was not something that's ever been collected, so there is -- let's call it a folklore. It's not even as formal as the common law. I think that at the extremes there would be 100 percent agreement among IRB members, probably among researchers, among observers, that a needle prick at one end, or something dramatic at the other, is either less than minimal risk or greater. In the middle, IRBs will come to different judgments. On lumbar puncture I thought I could split this group, but nobody spoke up. So the best that we can do as administrators of this large system is to say, well, we're going to put the judgment, under ordinary circumstances, on at least three people who are close to and understand the research site, which means the researchers, the expertise, the prevailing values and ethics of the community. That's as far as we've gone, is just to say, well, we trust that system. That's the best that we can do. Now, why haven't we collected data on that system, is a good question. We heard before that there is a general lack of evaluation of the system. Dr. McKay came before you in January of 1997 and said he'd be back in March 1997 with a results of a 191-question survey, and I for one am still very anxious to see the results of that. MR. CAPRON: Right. This wasn't -- let me be clear. In raising this this way, this was not in the least a statement on my part of reminding us that we have so little data about the system. I actually thought that, through your educational programs and so forth -- I mean, you get -- IRBs are not plants that grow in the jungle, they are groups of people who go through processes. Part of those processes, as you suggest, are local processes and then part of them are educational processes. So if you have new members of the IRB you are more likely to want to have them do an educational program so they get their bearings. And I just wondered what the bearings here were. I thought there might be something at that level. There was one other thing, but there's not, so I'm dropping that. There's one other thing that surprised me, what you said, and I may have misunderstood you. When you were looking at the chart that you have up here, you were asking that the -- you were thinking that the IRB would be comparing the magnitude and probability of specific harms or discomforts that arose in the procedure with those same likelihood -- the probability and the magnitude of those same things arising in ordinary life. That surprised me, from just my own experience with IRBs over the years, is the sense that I had always observed what seemed to me to be more of a trade-off. That is to say, well, what's the probability that people fall, break their legs, ski into trees, whatever it is? I think that that's sort of a distribution. And those risks of dying unexpectedly, being injured unexpectedly, and so forth, are the risks of daily life. Now, one may object that, unlike average income, it doesn't make a lot of sense to talk about those as, what is the average person here, because the distribution is so dramatic. It's sort of like average income in a country in which there's a very unequal distribution of income, a lot of very poor people and a few very rich. Is the average income $20,000 or should we really be drawing on something else? But, I mean, I took that to be some way in which we can say, well, what are the probabilities you're going to have some bad thing happen to you? But not that you would specifically have the same bad things happen to you that you would have from the research. That is to say, what's the probability that you will have a headache or be paralyzed, which are the two major risks of lumbar puncture, but is the kind of discomfort generally or the kind of risks generally there more than what happens to people, on average, in ordinary life? That's what I thought was going on. But you seem to say, no, it's really, you're looking for these specific risks and saying, do those happen to the average person in ordinary life. Did I understand you correctly? DR. ELLIS: You understood me correctly. MR. CAPRON: Is there some regulatory explanation, I mean, some commentary of an official sort that OPRR or others give to tell people that that's how they're supposed to read this? DR. ELLIS: I've shown this slide several times. (Showing slide.) DR. ELLIS: I don't think there's any commentary beyond this. I think what you say, actually, is probably quite true, is that most IRB members, for the right side of the equation, use a more vague or a more grand average of daily life. And I'm not disagreeing with that. In fact, that was the sense of my opening remarks, is that I think most people sort of apply this by instinct and never get to this slide at all. But if we sit down and we try to map out what this black-and-white letter of the regulations say, I think you would actually map it the way that I did. Obviously, I sat down to map it and I came up with that next slide. You may disagree. I think, in practice, most IRB members actually never think that specifically about the risk of harm or discomfort X, Y or Z in daily life. MR. CAPRON: Yes. I mean, the phrase there "harm or discomfort," to me, is different than the phrase "the harms and the discomforts anticipated in this research." Harm and discomfort are like pain and suffering, they are broad categories. But, I mean, I'm not arguing that your interpretation is wrong. Again, you're in an official position to interpret and I'm not. What I'm sort of wondering is, what do we bring in? If we're using that term here, I hate to use the term again, common law, but what sort of received understanding do we bring in here? Yours would be one which I would expect to be a very influential received understanding, particularly if it's been reduced to writing, if it's been used in IRB educational materials and lectures and so forth, it's likely to influence the way our IRBs go about their business. I mean, in my own sense, going back to the Daumel paper, Daumel was -- correct me on that paper; I can't remember. But way back in the time of the National Commission, there was a paper published in the New England Journal which looked at research and argued that most research, in fact, does not have greater risks than ordinary life. And they were not just looking at the research, the occurrence of specific incidences of research, and saying, do those things occur. They were looking generally, as I recall the article, at the risks of ordinary life. They had some broad statements about risks of accidents and so forth. I've always understood the term to be derived from that source and to reflect that very, as you say, sort of generalized understanding of what are the risks and discomforts of ordinary life. CHAIR CHILDRESS: Okay. I have Eric, then Arturo. DR. CASSELL: I don't want to tie too much into this, but the definition says, "Ordinarily encountered in daily life -- extraordinary -- of a risk, the population we're talking about now does not have the usual perception of the world around them because they are sick. So our problem is that what we consider to be an ordinary risk, clinical risk, like a physical examination, may be seen by somebody who -- our problem is how to -- outside of them at the same time recognizing -- so we have a minimal risk category, but we also try to protect them -- CHAIR CHILDRESS: Gary, did you want to respond? DR. ELLIS: No. CHAIR CHILDRESS: Arturo? DR. BRITO: I've been trying to assist the debate throughout the hearings. I'm one of those people who feels that lumbar puncture is really not much, if at all, minimal risk if it's done in a correct fashion and in the right hands. When you were initially describing the four different risk factors of doing a lumbar puncture I thought your point was going to be that, in ordinary life, your chances of getting an infection are going to be greater than in all the lumbar punctures that have ever been done, in a percentage. Your chances of getting paralyzed are going to be greater than all of the people who have ever been paralyzed secondary to lumbar puncture, even in research -- especially in research protocols. You obviously made the other point. So I'm thinking more of percentages. I'll give you an example of something that is considered minimal risk by most, is venipuncture. They showed in studies that children that have had venipunctures in research protocols, by far, suffer less psychological consequences of having that venipuncture than those that had it in clinical circumstances. So the point there is, in ordinary life, somewhere down the line you're going to get your blood drawn, probably. The research, by doing it in a research protocol, it actually reduces the chance of any harm being done. My point here is, and this is what I was trying to say earlier, that it is so difficult to make a blanket statement or draw the line somewhere of what is minimal and what is moderate. In certain situations, something that appears to be higher than minimal risk may actually be minimal risk. I think I heard Laurie say earlier, somewhere we have to maybe describe a bit more in the sense of gradient and be very careful in not excluding people from research studies that may involve them in what appears to be something that's greater than minimal risk. CHAIR CHILDRESS: Other questions, comments? MR. CAPRON: I don't disagree with that, but I want to underline one thing that the discussion has made clear to me. Which is, if we begin moving away from the standard that we have and the draft as it now is and we start saying, well, when there is only minimal increment to minimal risk, we are adding on a vague notion on top of a notion which, as written here, I think is almost incoherent as it is now being applied and obvious has a utility, and it can be used and is used all the time by IRBs, but it's not a very fixed point. It isn't like average income, the average household income of the United States. What we can say is, that is $28,272, and a moderate increase over that would be $2,000 or less. That's moderate. DR. BRITO: As we begin to draw additional categories on something that is as vague as this, we're beginning there -- I would agree with all the comments yesterday when people were saying don't make too many categories, because we're making categories which are like wet spaghetti. I mean, it's just -- DR. BRITO: Exactly. So I guess what I'm saying is, let's not make the categories. I think the effort should be more concentrated on the informed consent process and the explanation and communication, et cetera. I think it's impossible to make these categories. I mean, somebody even mentioned PET scans. Well, someone else may say, well, the psychological harm that can come from that is much greater than minimal risk. So there are just so many interpretations you can have from that, whereas somebody else -- you know, I would consider it no big deal for myself, but someone else, particularly somebody who has a psychiatric disorder, may suffer even worse by being put through a PET scan. So the point is, I think we have to be very careful not to categorize it so neatly because I don't think it can be so neatly categorized. CHAIR CHILDRESS: Diane, then Jon. DR. SCOTT-JONES: We have a big problem in getting this report done, because we have a notation on page 143 from Jonathan that we need to decide what we're going to say in this particular report about minimal risk. I think we may have a problem that may be practically unresolvable if we're required to use the definition of minimal risk that's there, because it implies a quantitative judgment, as Eric has just pointed out to us. From what Gary has said, in practice, people make a qualitative judgment. That is, they recognize what minimal risk is, what greater than minimal risk is in an intuitive way, and they're making a qualitative judgment that they couldn't quantify if their lives depended on it. So we're treating this as if we can somehow make a quantitative judgment and talk about increase over minimal risk, a minor increment. Those are all quantitative terms and we are not able to do that. Also, the notion of daily life in that context is absurd, given that Americans' daily lives vary so dramatically, with some people on a daily basis being exposed to enormous risks, ranging from gunshots to being run over by a truck; other people's lives are more sheltered and they're more protected. So we are just being irresponsible if we say, well, it's all Americans' daily lives, when any person knows that some Americans' lives are extraordinarily poor and other Americans' daily lives are wonderfully protected and safe. So I think we have two big problems. One, is we are jumping from qualitative to quantitative judgments, and the other is that we are imagining that Americans have some homogeneous life that is relatively benign or an ideal life when, in fact, that's not the case. We need to do something about this definition. CHAIR CHILDRESS: I don't disagree, but we have to ask what we can do for purposes of this report. To do something with it in the larger sense, in terms of trying to change the common rule or, a much slower process, helping to change the interpretation of this particular category in the common rule, I think we will all be dead before we finish this report. DR. MORENO: Gary, I sometimes wonder what would happen if the definition dropped the first disjunct which is the one that everybody always talks about, namely, those ordinarily encountered in daily life, and only use the second disjunct to the right side of the -- namely, the performance of routine physical or psychological examinations or tests. In other words, part of my question may have to do with what you understand as a regulator to be the nature of the "or." Is that, first of all, an exclusive "or" as logicians say, in other words, it's one or the other but not both, or is it an inclusive "or," "and/or," as we recognize in ordinary English? In either case -- well, if it's the former, then might not IRBs be able to decide which criteria they would like to apply? It seems to me, to take the example of the LP, that lumbar punctures might qualify under the left side of a disjunct, but probably would not qualify under the right side. That is to say, I don't think that lumbar puncture is part of a routine physical examination, at least I don't want to go to a doctor that says it's routine. So then my question is, I guess, several-fold. How much flexibility -- in your view, do IRBs have in deciding which disjunct to apply? Materially, what would be gained or lost if one were to use only the second disjunct? DR. ELLIS: Well, I can answer your question as a matter of reading the plain English. The clause, the "or," to use your words, I think, is exclusive, meaning A or B, it's not an "and," it's an "or." DR. MORENO: Ordinary English is usually taken to be inclusive. So in other words, in order to make it -- DR. ELLIS: Let me put it this way. You can have one or the other. DR. MORENO: But not both. DR. ELLIS: You don't need both. DR. SCOTT-JONES: But you could have both. DR. ELLIS: You could. DR. MORENO: In ordinary English, usually to make it exclusive people say either A or B. DR. ELLIS: Yes. I read it as "or," not "and," because it would say "and" if it was intended to be "and." DR. MORENO: Well, it would say "and/or." DR. ELLIS: But it doesn't say "and/or," it says "or." DR. MORENO: So you consider it to be exclusive. DR. ELLIS: Let me go back to my first point. I think that minimal risk and greater than minimal risk is what a majority of the quorum of the IRB finds to be greater than minimal risk. MR. CAPRON: Why isn't the IRB administering -- excuse me. Into the microphone. If you're dealing with expedited review, isn't that usually something that the chair signs off on? I don't -- DR. ELLIS: If you're dealing with expedited review, yes. MR. CAPRON: Well, that is, in my good sense, the major use of it. Yes, if it was occasionally used to avoid the documentation for consent, you're doing a face to face interview with people in public places and you don't make them sign a consent form. Why? Because you're asking them questions which are not risky to them. Occasionally you do that research without any consent at all because you're doing observational studies. The major use is expedited review. DR. ELLIS: I think you're correct. MR. CAPRON: And that can be done because the chair signs off, it wasn't more than minimal risk. I sign off and I approve it for the IRB. So you don't need a majority. You could have a single physician, the chair of the committee, looks at the lumbar puncture and says, this is not more than minimal risk. DR. ELLIS: No, that's incorrect because lumbar puncture isn't on the list of 10 categories for expedited -- Let me go back to the main point, that the IRB, in its wisdom, under certain circumstances a single member of the IRB, as Alex points out, for certain procedures that are listed determines what is greater than minimal risk. Now, those individuals do that with reference to this stated standard and I don't think, in practice, that there's the level of dissection of this stated standard that we've just gone through around the table, in all honesty. So if you are interested, for a certain population of prospective research subjects in creating a cleaver, is the word I've used, to decide what research can proceed, what research can proceed under certain circumstances, you may wish to create some new term, some new definition for that term that serves that purpose because the purpose of this term, as Alex has described, is mostly to determine what can go forward for expedited review secondarily, tertiarily, when consent can be omitted, when documentation of consent can be omitted for research that is covered by the Federal departments, policy, regulated by the FDA or voluntarily pledged. So you still have the issue of research beyond that. CHAIR CHILDRESS: Are there any other comments? I know Trish is waiting to get in. PROFESSOR BACKLAR: Well, the problem is, I see that we can't seem to get away from this, indeed, rather relative concept, the way it's dealt with. It's an interesting idea, Jonathan, that you brought up about, which side of the "or." If you went to the physical exam, would that be for a healthy person or would it be -- in the same box? I think the real problem is that average person as opposed to the healthy person. If you had a healthy person, would that give us a clearer baseline through which we could then go into, depending on the population that you're dealing with, that somebody, for instance, again, with schizophrenia maybe having a PET scan might be more difficult than it would be for me to have a PET scan. CHAIR CHILDRESS: Rhetaugh? DR. DUMAS: I think our dilemma lies in the tendency to be too specific or to try to go to a higher level of specificity than is possible in situations such as the ones that we're discussing. It might be that what we need to do is to think in terms of parameters and general principles. I've said this before. There are some things that must necessarily be left to the judgment of the people who are making that decision, and the best that we can do is to give them some guidelines for making the decision, not to make the decision for them. Now, that's one of the points. The other has to do with the same kind of thing about the report. I don't think that we are going to come to agreement on all aspects of the content of the report, but I think we do need to agree on the basic points that we want the report to reveal. If we could do that, the most important points that we want to make in that report, we could come to a decision on that, then we would have to leave it to the writer to convey that. I don't think that we could get all mixed up in the context of this because we'll never finish it. CHAIR CHILDRESS: Any last comments for Gary? MR. CAPRON: I'm sympathetic with the point that Rhetaugh just made. This is really one of the fulcrum issues of this entire report because, and I sense there is a division, a division which may be dramatic in the sense that we may have an 8-10 vote on the Commission, one way or the other, as to whether or not it makes sense to say, because of the value of the research process and the potential findings from research, we want to allow research to go ahead without the consent of the individual, with someone else's consent--I mean, we are still talking about other protections; there would be an IRB reviewing it, there would be some surrogate decision maker--which involves more than minimal risk. So it then becomes important that we have some sense of what we're talking about there. DR. BRITO: But parameters determined by whom? DR. ELLIS: Well, it is going to be determined by the IRB. But there are limits to what IRBs can determine, and there may be -- I'll put it this way. If we discover there is not a common understanding that within the context of this report we should go into some detail, and the writing we'll leave to others, Rhetaugh, I agree, but we should have a discussion of the kinds of things that we believe that term to mean when we use it here, otherwise we haven't said anything. DR. SCOTT-JONES: Could I very strongly agree with what Alex just said? I think we have to decide, even if it's no more than saying that these are problematic, but this is how we're using the term. I believe we have to have some statement in this report or what we have said is going to be meaningless. I think a definition that is left wide open allows for the possibility of mischief when that definition is used in the real world and people are trying to get a research project under way and stay on schedule. I think we have to aim for as much clarity and agreement as we can muster among ourselves. I think this is critical. We cannot just use language to avoid the problem of deciding what we need to say. PROFESSOR BACKLAR: Right. We have to have some kind of baseline that is understood. DR. DUMAS: But you can't exhaust all the possibilities that would fall under that category. DR. SCOTT-JONES: Right. I agree. CHAIR CHILDRESS: Jonathan, then we're going to move to a break. DR. MORENO: At the risk of repeating myself, this draft attempts to deal with this problem by establishing some examples of minimal risk and greater than minimal risk interventions--not research, interventions--for these kinds of populations. The language is on page 146. It's Number 6. We can tweak that for a while as a group, or individually, if you like. There is discussion around pages 90, 91, 92 on this issue. So it doesn't seem to me that there is no basis for this discussion in the current draft. CHAIR CHILDRESS: And what I would urge is that we all look very, very carefully at this and, not that we'll have a chance to do it thoroughly today, but decide exactly how we want to proceed. It may well be that we'll look carefully at this, and a couple of people who have paid a lot of attention to the debate about minimal risk, for example, Alex and anyone else who would like to join in, might propose additional language for our consideration. Bette gets the last comment and we'll take a break. MS. KRAMER: I hate to take the last comment, but I thought it might be helpful to the committee to hear from somebody who is listening to the discussion for the first time. As I've listened to you, and having read the report just recently for the first time, I think that the reality is that what you're talking about, just plain and simple, does not permit an objective measurement. Therefore, it really becomes a question of trust and, you know, how paranoid do you really want to be? I think if you believe it's appropriate to be totally paranoid, then you just don't allow any research at all to go forward where you can't get a true informed consent from the potential subject, and otherwise I think you have to rely on the nature and the character of the narrative. And, as I said, having read the report for the first time, looking at it fresh as opposed to having reworked it and reworked it, and listening to discussions, I really want to compliment you all on it. I think it's beautifully written. I think it expresses great sensitivity. I think it's a document that, in general, the Commission can really be proud of. CHAIR CHILDRESS: Okay. Thank you, Gary, for joining us. We appreciate your help. Okay. Let's take a 15-minute break and resume. (Whereupon, at 10:00 a.m., the meeting was recessed.) AFTER RECESS (10:17 a.m.) DISCUSSION CONTINUES ON RESEARCH WITH DECISIONALLY IMPAIRED SUBJECTS: DRAFT REPORT CHAIR CHILDRESS: Okay. Let's get started again. Okay. Jonathan wants to say something. DR. MORENO: Just very briefly. I just spoke a few minutes ago to a relevant section of the report that speaks to attempting to array examples of minimal and greater than minimal risk, is not on pages in the 90s, it's in the 70s. It starts on page 73 and goes on for about 8 or 10 pages. CHAIR CHILDRESS: Let's pick up our discussion and see if there's anything else you want to say about minimal risk. We've noted that the problems, the difficulties, in defining it and specifying it. What I would urge people to do, since this does play a crucial role in the document as you have it, is actually to look over those pages very, very carefully and let's do some e-mail exchanges. I mean, let's really now pick up along the lines of the cloning report, movement toward modifying this in a way that can get us to a final draft. Those who feel particularly strongly about things, let's come forward with proposed language and let's move it. Now, connected with that, I see Laurie and Jonathan had a conversation over the break about interpretation of benefit. We do concentrate on the risk side in our discussions, but obviously the benefit side is also important, where we are talking about the probability and magnitude of benefit parallel to the probability and magnitude of harm or discomfort. So let's have a few comments about that since I think their discussion, as I understood it, was potentially instructive, potentially beneficial to our group. Laurie or Jonathan? MS. FLYNN: Well, the comment that I made was, I continue to have real reservations about the structure that was laid out here in terms of greater than minimal risk with no potential benefit, in part, because my understanding of the concept of potential benefit is pretty direct, pretty immediate, and pretty readily and likely to happen for the individual who is the subject of research. That's what I thought our text was saying and that's my understanding of potential direct therapeutic benefit. Jonathan, I think, has a view that is different and appears to feel that the definition may be somewhat more elastic and more broadly applied in the real world than the way I'm seeing it. I think it's useful for us to understand, how is that term defined, what is meant by potential benefit to the patient? I think we really had no conversation, no inputs from the research community or others, as to how that term of art is used when IRBs make decisions. CHAIR CHILDRESS: Okay. DR. MORENO: Laurie has expressed, in essence, what I said to her during the break. Namely that, without endorsing this view, my experience as an IRB member is that the notion of potentiality is, indeed, quite elastic and that investigators are given a relatively large amount of leeway in identifying what could conceivably be of benefit to the subject, including even simply a closer monitoring of the subject. In the experience with the early HIV studies, for example, this was a very common point that was made by investigators, that potentiality of benefit for subjects could include simply getting better health care. That gives rise to other issues about access to health care and so forth, but we're putting those aside for a moment. So what I was saying to Laurie was that, perhaps in practice, more kinds of studies can be captured by the concept of potential benefit than one might at first think or one might think is philosophically ideal. CHAIR CHILDRESS: Jonathan, since I don't have the document fully memorized at this point, I can't remember how well we do it in the document. DR. MORENO: Probably not as well as we ought to do, because the document does try to walk the straight and narrow philosophical line that potential benefit ought to be -- a relatively compelling case ought to be made for potential benefit for the subject. But what I was saying was that, in practice, the way this washes out in the real world is that there is more breadth given to the concept than is done in the textbooks. CHAIR CHILDRESS: Could you take as a task to elaborate in appropriate places on that and we'll have further discussion on it. Other points to be made? Let me, before we -- two other things should be mentioned about minimal risk. One, is the FDA has a statement on minimal risk and that sheet will be provided and circulated. So it will be sent to the NBAC office and then will be circulated to us. Then, second, but we won't pick this up until Alex comes back in, there's also a research project under way at NBAC in looking at the literature of trials involving decision impaired subjects to determine, here again with the uncertainties about definition, those that involve more than minimal risk, and then with an effort to look at some of the consent forms related to those research projects. So we'll want to say more about that, and both those points are connected with minimal risk. DR. CASSELL: On the issue of benefits yesterday when we were having that argument back and forth, there is a benefit to people to be treated as though they were normal persons, to be allowed to do what normal persons do. To be altruistic. One of the things that normal persons do is to be altruistic, and that that is a benefit. However, I do not want you to think that I think that's a benefit under the terms usually meant by benefit versus risk. The benefits we mean are direct, usually therapeutic benefits, not the benefits of belonging to humankind. DR. MORENO: No. But what we're -- and what concerned Laurie was not the notion of directness, but the notion of potentiality. That is the issue that was of great concern to Laurie, and how the likelihood of benefits that might accrue to being in a study -- if there's 100 percent likelihood of feeling altruistic, I suppose, though I agree with you, that's not what I would, as a professor of medical ethics, consider to be a direct benefit of being in a study. What Laurie was concerned about was the likelihood that this diagnostic test or this therapeutic intervention that was being examined would be of direct benefit to me as a subject. CHAIR CHILDRESS: I thought it went beyond that, that this might well produce something that would be of benefit to me as a subject and not simply limited to -- if we go the direction you're going in, Jonathan, it seems to me then that brings it much more clearly under what we would ordinarily think about using as traditional language, that we've gone beyond the therapeutic trials. But I would take it that Laurie is looking at the review that, even in what we tend to think about as non-therapeutic trials, a possibility of developing something that would be beneficial should be included on the benefits side. Laurie, am I misunderstanding? DR. MORENO: That's an accurate description of her thinking, just to be clear. What I was saying was that in the real world my experience is that much of what you and I sitting around an academic seminar table might think of as non-therapeutic is often construed as having benefit, not just the psychological benefits, but being observed by good doctors and nurses as part of the study might accrue to your well-being -- your medical well-being. MS. FLYNN: Again, I was focusing on many of the kinds of basic neuroscience studies that are not intended or designed to provide immediate therapeutic benefit that are looking at the underlying etiology and process of disorder. There's no immediate likelihood that my clinical condition, if I am a subject, is going to be enhanced. So I would agree with all of these discussions through the very narrow definition of benefit. DR. MORENO: By the way, also in the real world I'm sure you've all seen on consent forms -- often one sees a consent form as a statement. One of the benefits to you for being in this study is being more closely monitored, having your condition more closely monitored. Many people would consider that to be a potential benefit. CHAIR CHILDRESS: As we approach this and think about the revision of the document, one has to worry about excessive elasticity at this point. Diane, then Trish. DR. DUMAS: But knowing about that elasticity just increases my resolve that people for whom the risk is conceived to be greater than minimal should not be included in research projects. There's another point here, too. That is -- DR. MORENO: Just to be clear, you mean, should not be included in research projects without their consent or -- DR. DUMAS: Without their consent. DR. MORENO: -- without some analogous process. DR. DUMAS: Without their consent. DR. MORENO: Would you permit legally authorized representatives to make -- DR. DUMAS: Yes. There would be exceptions. Yes, of course. But I think a general rule -- DR. MORENO: Because that's the framework right now. DR. DUMAS: The general rule is that people should be informed about the research. We should make every effort to make sure that they understand what they're consenting to in that process. Now, if there is some reason why that can't be obtained through the regular process, then the conditions under which there would be exceptions should be defined. But there is also a mention in the document about benefits accruing not only to that individual, but to the population. I don't know whether we want to deal with that or not. If the benefit is to the population for which the person belongs, are we interpreting that to be a benefit to the individual? I think that distinction needs to be made. DR. MORENO: I think we're quite clear that that is not considered to be a benefit to the individual. DR. DUMAS: As long as we're talking about potential or likelihood, I'm comfortable. I don't think we can promise anything more. CHAIR CHILDRESS: Diane, then Trish. DR. SCOTT-JONES: I was just trying to look in the draft, Jonathan, to look back and review where you talked about benefit and what it means. I am just trying to see how far we're going to go with this notion of quantitative judgments because we're sort of suggesting somehow that you balance the benefits against the risk and that you have some favorable ratio of benefits to risks. I don't know if we want to do more in that regard than we've already done, and I'm not sure that that was the point of the comment that maybe there are more benefits than we've acknowledged in most research projects. Is that the point, so that somehow the benefits side will have more points on it in relation to the risk side; is that the thrust of the comments? CHAIR CHILDRESS: Well, first of all, we've just not looked at the benefits side. If we're going to include the benefit/risk ratio in the determination we at least need to say something about it. But, second, there was also a question about -- DR. SCOTT-JONES: There's quite a lot of it. CHAIR CHILDRESS: That is in our discussion. DR. DUMAS: Oh. Okay. CHAIR CHILDRESS: Our discussion is focused only on the risk part. Then there's the question about whether it can be defined narrowly or broadly. But I think -- either risk or benefit, it can't be purely quantitative because there is the qualitative element that enters in in even defining something as a harm or discomfort, et cetera. So it's going to be much more complicated, even if there is a quantitative sign. CHAIR CHILDRESS: Trish, then Rhetaugh. I'm sorry. Diane, first. Sorry. DR. SCOTT-JONES: I was just going to say, here is already at least acknowledgement of persons saying that there are indirect benefits, such as diversion from routine, the opportunity to meet with other people, to feel useful and helpful, greater access provided to professional care and support. I think we've done a lot already to acknowledge these. CHAIR CHILDRESS: Well, the point was, not in our discussion. DR. SCOTT-JONES: Oh. Okay. CHAIR CHILDRESS: Our discussion here. What we need to do is identify, since we don't have a lot of time, areas that we want to go back and now look at the report and make sure that the report does what we want it to do, and then Alex and Eric can just come in. Then really take a Dali-like approach to this, namely, over and through e-mail and faxes over the next several weeks, really push forward areas where we want to make the kind of revisions so that we can come up with a draft that we can really go through very carefully and see whether that reflects what we, as a subcommittee and as a Commission, want to hold. I have Trish, and then Rhetaugh. PROFESSOR BACKLAR: I want to back up -- very important when we go to this. We know there's potential benefits, just as we know there's risk of harm. There is that balance going on there. I also want to reiterate the subjective aspects of these personal benefits are hard to quantify. The other thing which I really actually believe we have in the report, that some of these benefits which Laurie is alluding to come about because the actual care for many of these people is inadequate. Some people come into these protocols in order to get something they just don't get outside, just like people do who have AIDS. There are all kinds of research protocols going on with different diseases where this occurs. CHAIR CHILDRESS: We'll take Rhetaugh's comment, then we'll turn to the issue I raised about the research project on minimal risk research that the NBAC staff is conducting. DR. DUMAS: What I'd like to do is share with the group what I've said to some individuals, and that is that we need to give greater attention to issues of the characteristics or the constellation of IRBs because you can't quantify the factors that are important to consider. Ultimately, the people who sit on the IRBs will have to make judgments. We need to think very carefully about, as best we can, how those boards should be constellated to get the kind of judgments that we believe that they need to make. CHAIR CHILDRESS: Alex, if you'll make your comment, we want to then talk about the research. MR. CAPRON: Yes. I want to follow up directly on what Rhetaugh just said, because I was just having a conversation with Gary Ellis and I think it would be useful for Jonathan to take a look at the language about the special composition IRBs when they're dealing with research having to do with prisoners because, as Rhetaugh has emphasized, particularly when we're dealing with these vague standards, membership is going to be important. Without having to get into the whole subject of how adequate IRBs overall are and what their composition is and their education, certainly an emphasis on a membership that would have a representative of the relevant patient populations that would be perhaps more heavily balanced towards lay people and outsiders rather than fellow researchers and physicians, or physician researchers -- for this, would be a way of giving us some comfort that the process beyond the consent issue, which is so difficult for us, is adequate to the particular needs of this population where we have a history. I want to just put on the table something. After our last meeting, I was sent a consent form for one of the studies of people who testified. I thought the testimony had been very interesting in emphasizing the quality of the consent process, and so forth. The consent form didn't come up to that standard. I wrote the investigator asking for some clarification because I was afraid I was misunderstanding what was represented in the form. The staff is now engaged in the project of looking at studies in this area that seek to involve more than minimal risk and where there are questions about the subjects being exposed to risk without real consent, and so forth. We'll be following up to try to get some more consent forms to see whether they could usefully address that aspect of the issue, because I agree with what many people have said about the importance of consent here. We all recognize that the consent form is not equivalent to the consent, but certainly a consent form which itself has problems is not likely to be well remedied by aspects of many undefined -- about that. I mean, that's what the UCLA people said. Well, yes, the form was no good, but we had a conversation in which all this came out. I think that the concern about the membership of the IRB is one way of addressing that because I think the more disinterested IRB would have looked at the form that I saw and said, wait a second, what does this mean, why are we saying this, is this accurate, is this conveying what's really at issue here? So perhaps we can address it and perhaps you could get some ideas from other areas of the regulations that already specify special make-up. DR. MORENO: Could I just -- I want to make sure that I have good guidance right now from committee members. Alex, are you suggesting that I should draft further recommendations to the effect that not only the discretionary authority that the IRB now has to add consultants and other members for specific studies involving vulnerable or special populations, but that those ought to be required for certain kinds of studies? MR. CAPRON: Yes. DR. MORENO: Okay. I just want to predict that people will raise questions about the impact of that requirement on the capacity of institutions to do studies with these populations. I can hear some folks whispering in my ear, perhaps not in this room, that the analogy to prison studies would constitute a significant drag on the ability to do research with these populations. Now, as a draftsperson I'm only pointing this out to you. I'm trying to anticipate an issue that this will -- MR. CAPRON: All protections of human subjects are a drag on the ability to do research. DR. MORENO: Yes. But when we're talking about prison research we're talking about a relatively high threshold, as you know better than I. That is, again, something that this body needs to consider. I'd be happy to draft the language -- MR. CAPRON: Why don't you draft something and we'll consider it when we have a draft. DR. MORENO: Okay. MS. FLYNN: Let me just ask a question, because I feel very strongly about this. And I appreciate very much your comments, Rhetaugh and Alex. My organization several years ago drafted a policy that specifically requests guidance to IRBs who do review a great deal of psychiatric research, that they have as members of the IRB no fewer than two representatives of the subject population and that IRBs who do not routinely review this research have an affirmative obligation to bring on as consultants not only experts who are physicians and researchers, but those who represent the community who are the subject population. I guess I'm not clear what the burden is. DR. MORENO: That language that you just used doesn't vary greatly at all from what is currently at the discretion of the IRB. What I heard Alex suggesting was that something along these lines, some proportion of the IRB, not only membership, but a further question is, should they actually be present for the discussion of that study. Very often these folks, as we all know, don't show up. By these folks, I mean, community members have a hard time attending, very often. So it's not only a matter of having them as members on a piece of paper, but also having them actually sign off on the study. MS. FLYNN: Yes. Yes. Yes. Absolutely. DR. MORENO: Okay. That helps me. DR. DUMAS: I feel very strongly that our best bet for getting change is through the IRB. If people in our communities don't show up at IRBs, we need to understand why. In some communities they do and they are very active. It's not comfortable for the scientists. Most often, the groups have more scientists than other members. So if you've got one community member and they feel overwhelmed at not having a voice, I can see why they don't come. But we need to change that. Well, I don't think I need to say anything more about that because the assumption in the past has been that the IRB is a scientific evaluative committee so it should be comprised of people who are involved in research and who have a commitment to the development of science. I think that that is only partially true, that it should also include people who have some interest in the general welfare of those who are being involved in this process. CHAIR CHILDRESS: Okay. Let me Eric to come in. Alex has to leave shortly, right? Would you like to comment on the research project? MR. MESLIN: Sure. I'll just be brief about this and tell you where we are. A couple of stand-back are with us now and we can benefit from any input that the commissioners have. Following the last meeting when Alex had expressed some interest in staff pursuing this we engaged in a number of search strategies, inductive search strategies, designed to identify those projects published in the peer review literature that seemed to meet this generalized concern of studies that involved greater than minimal risk for which not only the consent form or consent process might be an interesting indicator of whether or not protection was adequate, but also more substantively whether or not the research design itself raised any particular ethical questions. So what we are now in the process of doing--and it's a very intermediate process, there's nothing to present to you today--is we've identified probably several hundred abstracts that seem to meet this general threshold of concern. We would love to hear maybe a bit more comment from commissioners as to what they would really like to see, because the next step in this process is to contact the investigators, identified obviously by authorship on the papers, and ask whether they wouldn't be prepared to share with us a copy of both protocol and consent form. This will serve a couple of, I think, very useful purposes. One, since this isn't an investigation into unethical practices but merely an effort to understand what the nature of this research activity is, it would, I think, meet our public obligation at the very least, but it would meet, I think, the more substantive obligation to understand just what is going on. Now, we realize that the publication of a study is not identical with our ability to understand all of the nuances of what goes on in the preparation of a protocol and how consent forms in the process might be carried out. At this point, that is what our strategy is and we would hope to be able to complete a summative, if not formative, analysis of that within the next few weeks. CHAIR CHILDRESS: Any comments on that? (No response) CHAIR CHILDRESS: One other thing, before Alex leaves, I'd love for us to decide, and that is whether we want to meet in February. MR. CAPRON: Well, I'm not clear from yesterday's discussion we didn't come away with the impression that, if we're dealing with a topic in Los Angeles the next meeting, we ought to all be dealing with that. So if the Tissues Report is in a position where it ought to be discussed, I would hope we don't have Tissues or Genetic Subcommittee meetings in which the rest of us would then come in and be presented again with something which would require, for Genetic Subcommittee people, to go over that ground again and either feel frustrated that we're all so naive and unsophisticated or that they've gone off in a direction which others are not happy with. Likewise, I would hope we don't go much further on this report. We had some good feedback from the other commissioners yesterday and it helped to make clear for us areas where the report needs to be worked on. But from now on in, aren't we thinking that we're going to be meeting as a committee of the Commission instead as of a couple of subcommittees? If so, Eric, Jim, I mean, it's really a matter of saying, how much are we going to have from our various work products that are ready for further discussion to be mailed out two weeks from now, which is really what you're talking about if you're going to have a useful discussion. So part of the agenda may be this report and part of the agenda may be the Tissues Report, and the Federal Agencies Report, and whatever. CHAIR CHILDRESS: I'm quite open on this. I understood from the discussion that evolved that the Genetics Subcommittee felt the need to meet in February to move their report. MR. CAPRON: I'm just saying, we shouldn't let them meet by themselves. PROFESSOR BACKLAR: Right. I second that. MR. MESLIN: Sounds like we're going to L.A. in February. You will be hounded for your calendar availability, since we are currently trying to secure two dates in February. The two dates being either February 5, 6 or 6, 7, and not everyone has responded to that yet. It would be very helpful, since the Genetics Subcommittee knows what it will be able to get accomplished within the next couple of weeks, i.e., within the next two weeks so that documents can be circulated in more than sufficient time for all commissioners to receive and think about them, it is not an entirely revised Stored Tissue Report, it is some specific aspects of that report that will be required for a focused discussion. It would be very helpful if this subcommittee could also make the same kind of request of staff, or of Jonathan with us, for what it specifically wants to have on the agenda for the February meeting. CHAIR CHILDRESS: Could I throw out some possibilities? MR. MESLIN: Please. CHAIR CHILDRESS: One, is we've had some things identified that we need to work through. Some of those having to do with minimal risk and benefit, for instance, can be -- the addition of -- materials that we've not talked about. Basically I would say our discussion with the whole Commission did not talk about the report. We only focused on a couple of recommendations. So I'm not at all concerned about not having something to do. I think we could have a very profitable discussion with the whole Commission about this report. That, at least, is my sense. I don't know what others feel. We should really go through it and think it through, with the changes that will be made also. But not that we have to have made every single change we think would be important at this point. DR. CASSELL: And in these two weeks we'll be doing back and forth. The two weeks before our document has to be produced we'll be going back and forth on e-mail. CHAIR CHILDRESS: I should hope so, if people are willing to commit to that. I think we could have a document that would be just a step or two short. But we have to obviously get the whole Commission's agreement on certain kinds of things, and some of that will come in February. DR. MORENO: I just need to be clear, Jim, on what we can do and what I can humanly do in the next two weeks. Is your theory that the whole Commission will be working from the current draft? CHAIR CHILDRESS: The current draft as modified, which would include any material -- any changes we can make in the discussion of minimal risk, et cetera -- the recommendations based on the discussion yesterday and today, doing the kinds of -- making the kinds of changes that we're committing ourselves to working on over the next several days and exchanging on e-mail. DR. MORENO: I can certainly make some headway in modifying the current draft. I am a little concerned, though, that there will be confusion if I make -- some of the modifications are substantive, quite substantive, and that the full committee will then be at a disadvantage in not being able to keep straight which is -- MR. CAPRON: Do a cover memo. Just do a -- DR. MORENO: Yes. What I've done, and so forth. MR. CAPRON: Read these pages for that, and this is new material and very -- and we're all -- discussing it for the first time. DR. SCOTT-JONES: Could I add to that that Jonathan already did some of that by noting points, like on page 143 and 144, issues we would need to discuss, things that are not in the draft. I think doing that type of thing, and also bolding the additions so we would know the things that had already been done in response to previous concerns. I think all those kinds of things helped us to be able to -- CHAIR CHILDRESS: I agree. And we are going to have to have a discussion with the whole Commission on this document. I should note that the outside critics have had less to say about--and internal critics--about the first several chapters. It's really only at the end where most of the problems have come, but we need to think about how all the things integrate. So I think we really need to have that study -- having that with these modifications in February, if that would be suitable for -- PROFESSOR BACKLAR: I think the Genetics Committee is going to be very interested and very involved in the discussion -- same issues. DR. SCOTT-JONES: I think, in addition to the cover memo, Jonathan, or I guess any one of us, perhaps you, Jim, could lay out for the whole Commission what these issues are -- in addition to their having them pointed out in the actual draft, because I think the discussion might be more productive now if it's really focused and not so wide-ranging. CHAIR CHILDRESS: I agree. Jonathan, Eric and I will take the lead on that, but we'll circulate materials to you to review, that is, what we are going to propose along these lines. DR. CASSELL: Just for clarification -- not making any changes in the hard copy before -- e-mail -- CHAIR CHILDRESS: We need to set a closing date for this. Let's look at the calendar and see exactly when NBAC needs to send out -- MR. MESLIN: May I make a suggestion, at the risk of helping Jonathan organize his work schedule. You all have his draft from today. I don't know whether everyone has given Jonathan any comments, written or otherwise, based on that text. If you are intending to do so, please do that as soon as possible. If you are also going to be providing additional materials based on the sort of homework assignments that seem to be coming out, please do that within the next week, i.e., within seven days. DR. CASSELL: We are using as our baseline draft of December 22, 1997. MR. MESLIN: Correct. DR. CASSELL: Unchanged, at least until that week is past. MR. MESLIN: Correct. It would be staff's hope -- DR. CASSELL: The baseline draft is this draft until seven more days. MR. MESLIN: Yes. Right. And it would be staff's hope that two weeks prior to the full Commission meeting, or sometime in the week of -- I'm just guessing here -- DR. CASSELL: The 19th. I believe the 19th. MR. MESLIN: Thank you. The 19th of January. We will be sending out the briefing books or have the briefing books being prepared with these revised materials, giving the full Commission at least, and hopefully, two weeks with directions for how to make their way through the materials, cover memos, et cetera, for what needs to be focused on. I mean, I'm pleased to say that with some of our additional staffing now that's something that we can do much more efficiently, and that you will come to the Los Angeles meeting prepared to discuss those items identified in that cover memo. The full Commission will receive all materials from this point forward. Is that what seems reasonable? CHAIR CHILDRESS: Any dissent to that? (No response) MR. MESLIN: This is a good time to talk about the dates. CHAIR CHILDRESS: Okay. MS. HYATT-KNORR: The only other issue I would like to raise is a very simple one, namely, which date would you like to pick. The 5th and 6th would be Thursday/Friday, the 6th and 7th would be Friday/Saturday. We have all agreed on the 6th already, the question is just, which day would you like to add at one end or the other for yourselves. DR. CASSELL: Would we have to start first thing in the morning on Thursday if we started on the 5th? CHAIR CHILDRESS: Could we start early afternoon? I think that would be helpful for -- DR. CASSELL: We can travel out. You want to use the Thursday to get out there anyway. It's just a question of getting an earlier flight. DR. SCOTT-JONES: I can't. I'd have to do it Friday and Saturday. I teach on Thursday. CHAIR CHILDRESS: Friday and Saturday. MS. HYATT-KNORR: Thursday and Friday. PROFESSOR BACKLAR: It doesn't matter to me either way. DR. CASSELL: Thursday/Friday. MR. MESLIN: What we will likely have to do, is we will have to take one final poll with the rest of the Genetics Subcommittee members as well, and we'll have to make a decision that allows everyone to obviously be there on the 6th, which will end up being a full day. Some will be able to come for the half day, which may turn out to be the way we do this, either on the 5th or on the 7th. So I hope you will appreciate that as we're moving into this new arrangement towards full Commission meetings with everyone participating, that every effort will be made to attend as much of the meeting as possible. We realize that this is difficult, and we're making these dates on the fly with previously existing commitments for your day jobs already in place. Hopefully by February forward, we will be able to schedule the rest of the Commission meetings along the lines that we had discussed in the planning bucket yesterday. So no one should take it personally if your preferred dates are not the dates that the Commission will be meeting in Los Angeles. CHAIR CHILDRESS: But it sounds as though everyone can make the date that had been previously scheduled, and that's very important. Okay. Any other discussion of what we need to do on the report, because it's almost 11:00. (No response) CHAIR CHILDRESS: We do have two people who have indicated that they would like to offer public testimony. If anyone else is interested in doing so, if you would indicate to a member of the staff. Jack Schwartz and Bill Freeman, could you wait until after the public testimony? We only have two people who are planning to testify, we can go ahead and do that since we planned to do that at 11:00, if that will be all right. Okay. First, is there anything else we need to say about how we're going to proceed on the draft report? I think we may have covered everything we need to. But let's plan to be active and revive the e-mail exchange program and move very quickly on this. All right. I know some are having to leave, Alex in particular. Let me just thank everyone at this point for being here and for a productive day and a half. The first person presenting in public testimony is Mr. John Cavanaugh-O'Keeffe, who needs no further introduction. He is with the American Bioethics Advisory Committee. And you know there's a five-minute rule, I'm sure.