UNITED STATES OF AMERICA ADVISORY COMMITTEE ON HUMAN RADIATION EXPERIMENTS (PUBLIC MEETING) The Madison Hotel Executive Chambers 15th and M Streets, N. W. Washington, D.C. Friday, March 17, 1995 8:00 a.m. ADVISORY COMMITTEE MEMBERS PRESENT: RUTH R. FADEN, Ph.D., M.P.H., Chairman ELI GLATSTEIN, M.D. JAY KATZ, M.D. PATRICIA A. KING. J.D. SUSAN E. LEDERER, Ph.D. RUTH MACKLIN, Ph.D. LOIS L. NORRIS NANCY L. OLEINICK, Ph.D. HENRY D. ROYAL, M.D. PHILIP K. RUSSELL, M.D. DUNCAN C. THOMAS, Ph.D. REED V. TUCKSON, M.D. STAFF MEMBERS PRESENT: DR. JEREMY SUGARMAN NANCY KASS DR. STEVE GOODMAN SARA CHANDROS GAIL GELLER ANNA MASTROIANNI DAN GUTTMAN MONICA SCHOCH-SPANA A G E N D A PAGE UPDATE ON SUBJECT INTERVIEW STUDY Jeremy Sugarman, Nancy Kass, Steve Goodman 511 UPDATE ON RESEARCH PROPOSAL REVIEW PROJECT Sara Chandros, Gail Geller 561 Break RECOMMENDATIONS: LOOKING FORWARD 620 Lunch RECOMMENDATIONS: LOOKING FORWARD (continued) 699 Break MEETING ADJOURNED P R O C E E D I N G S (8:10 A.M.) CHAIRMAN FADEN: We are a little late but we're going to go ahead. We are having a contest between one side of the table and the other. Oh, you're sitting on the wrong side. Okay. Now, we're even. Good morning. We'll start right away. Steve, I can't recall if you've sort of been formally introduced to the Committee members or not. DR. GOODMAN: Once indirectly. I don't know if they remember. CHAIRMAN FADEN: Well, we're going to start the morning with reports on the two empirical contemporary projects that are ongoing. We've got Jeremy and Nancy whom all of you may be familiar with and we've been joined by -- well, I know you're familiar with Steve Goodman, who is an epidemiologist and pediatrician and statistician and -- have I missed anything? DR. GOODMAN: Good guy. DR. SUGARMAN: Whom we've co-opted into helping us deal with the data from the subject interview study. We're really very lucky. And he's like all the rest of us who thought this was something you could do a few hours a week and now it's taking over his life. So, we appreciate Steve's allowing us to snooker him into doing this, along with Jeremy and Nancy. Okay. We have stuff to talk about; right? DR. SUGARMAN: We have stuff. First of all, I'm basically going to walk through the handout that we gave you yesterday at about 4:15, so if you could find that, it will be helpful as we go through this material. Basically, I'm happy to report that of the 19 institutions that were selected for participation in the subject interview study we have succeeded in getting IRB approvals from 16 of those institutions. They are balanced in a way better than we could have hoped four universities, four VA hospitals, four community hospitals and four governmental hospitals. The three institutions that did not come on board, Baylor and Dallas, didn't come on board because the oncologists voted that they didn't want to participate. And the Seattle, University of Washington, are tied with the same IRB in the person who is designated as the titular PI at that site. His mother was sick, as I described last time, and he tried to do an expedited review over the last few weeks and that didn't fly. So their IRB approval, sometime during the next meeting of the Advisory Committee, and that was a little late to get data. In terms of the brief survey, surveys are being completed or in progress at 13 of the 16 institutions. Since three of the institutions' IRB approvals just came in this week, we have conducted as of yesterday 1458 interviews, the brief survey, and we're going to report later on today on 943. In terms of the in-depth interviews, realizing that these follow the brief interviews, 18 of the 100 in-depth interviews have been completed and we will be giving you some information about the process of the in-depth in just a minute. We did proceed with doing some on-site observations to see how the surveys were being conducted in each of the institutions. Some of the Advisory Staff went out and with their Tony the Tiger glasses on and sat in waiting rooms around the country and they observed the clinic atmosphere, how clearly the brief survey was explained, how people were recruited, how informed consent was obtained, the privacy of the process -- so it was almost helpful if they couldn't observe some of these things -- and the relationship between the RTI, the interviewers and the clinic staff and with the patients. Overall, they found that the interviews were conducted well, they found a couple of instances where things could be done better. More private space, for instance, might be needed. We gave that feedback to the contractor and we've been assured that they're making the corrections in each of those institutions. In addition, we called some of the people who said they were willing to be called back and asked them what they thought of the process. And overall, the results were very positive. We called 10 people at least from each of the five geographic sites and they seemed fairly happy. Their only complaint is that this five to 10 minute interview is more like a 10 minute interview or a 15 minute interview and they would have liked to have been told that up front. And that was a fair request. And so, we've asked that in the future, for recruiting folks for this study, that they actually tell them -- give them a more realistic time estimate. With respect to research determination and assessment, Pat Perentesis on the staff visited with the site coordinator at each of the five sites. She helped them design an institutionally specific mechanism for making the determination of research in the way that I outlined during the last Advisory Committee meeting and they are in the process now at each institution, clinic by clinic, going through and trying to determine whether people are research participants. The next hurdle we have is to now get an abstract of the protocols from each of the studies that people are enrolled in, whether they knew it or not, and that's going to be something we're going to be concentrating on over the next couple of weeks. What we anticipate doing is calling the investigators and asking them to send us those and following up by letter. We then will come up with a mechanism for assessing these protocols in a much more abbreviated fashion than the research proposal review project. Basically, what we need to know is what kind of study it is; is it therapeutic, diagnostic or epidemiologic or other; where it took place, which one of the medical clinics; what was the approximate level of risk to participants; what was the level of benefits to participants. In terms of analysis, we will present sort of some frequency analyses today but once the interview phase of collecting the data have been cleaned, RTI will deliver data tapes to us and Steve Goodman will be supervising an analysis of those data, consistent with the analytic plan, and he'll describe that in a minute as well. Do you want to give an update on the in depth? MS. KASS: Yes. The only addition I will make to what Jeremy said related to the qualitative part, the in-depth part, two things, actually. First of all, I would like to introduce -- CHAIRMAN FADEN: I was going to say can we introduce Monica? Yes. MS. KASS: -- to the Committee, Monica Schoch-Spana. If you could stand up for a second? CHAIRMAN FADEN: This is another person that we seduced and snookered and misled into joining us, joining the enterprise. MS. KASS: Monica is an anthropologist who is going to help us with the qualitative piece, who's now going to work full- time for the rest of the Committee's existence to help us with this component. To tell you how quickly all of this is moving, from the time when this memo was written until now, there actually have been many more in depth interviews done. We now have done 79, even though your memo says 18. CHAIRMAN FADEN: 79? MS. KASS: There's 79 that are completed. CHAIRMAN FADEN: In-depth interviews? Sorry. MS. KASS: In depth interviews. Yes. CHAIRMAN FADEN: That's terrific. MS. KASS: Which we're very pleased about. And these are from 11 different institutions. We wanted for some of the Advisory Committee staff to do some of the interviews so that we would have even a better handle on the data so that we would have first hand experience of going into the hospitals, doing it in the settings or doing it in the patients' homes. And so we decided that among us we are going to conduct 20 of the interviews. And so the subcontractor will probably only conduct a handful of the remaining interviews because we now have changed, as it says in your memo, to do 100 total, rather than 125 total. Shall I go on with the recruiting scheme? Okay. The other major thing that we have done is to try to figure out how we are going to code these interviews. As any of you will know if you've worked with qualitative data before, the main way you analyze these data is to try to figure out what kinds of themes keep emerging, and then group the quotes from each of the transcripts by those themes. So the first step of the analysis is that Monica is going to read every single interview transcript front to back so that she has a sense of the overall data. Then we have picked out 10 codes or themes that we think, from having read the first 10 interviews, are the kinds of themes that keep emerging and reflect the kinds of things that we hope we have learned the Committee is interested in. And I will run through these with you. They are also in the handout. I guess this is also a time to tell us if there are particular things that you want to make sure that we look for that aren't included in this list. And remember that these are broad codes. The way that it works is that coders are hired to read the transcript. And whenever a particular passage seems to be associated with one of these themes, that passage is coded to be labeled with this theme. And a particular passage could be coded with several themes, as several themes are included. And then later, with the help of a computer, the computer spits out all of the quotes that had to do with, for example, voluntariness or all the quotes that had to do with consent. And that way one reader can look at everything that had to do with the particular topic and get a feel for what was mentioned. So, the codes are, first, a general appraisal of research. This is any time anyone talks about attitudes, about research in the big picture, sort of in the abstract. CHAIRMAN FADEN: Nancy, if we could have everybody directed to the diagram. It's in the middle of the fat thing that you have. I'm sorry. I didn't mean to interrupt. DR. SUGARMAN: It's attachment 3. MS. KASS: Yes. It right in the middle of the large handout that you have from us. CHAIRMAN FADEN: And it starts, "In-depth interviews, global focus." DR. SUGARMAN: It's before the table shells. And if anyone filled in their table shells correctly, you'll be getting some free Danish. MS. KASS: Okay. Thanks. So the first code has to do with when someone talks about research, not in terms of their personal experience, but in what they think research is general. If they talk about their attitudes, if they think research is a good thing or a bad thing, if they think research helps to advance science, something like that. The next code is their personal experience with research, particularly if they say things like I felt this way when I was in the study or they treated me this way. The third code is their reasons for participating. There are specific questions about this, but also if in the course of the discussion a participant says something like, well, I was really hoping that this would be my chance to get better or my chance to have a cure or the doctor really recommended it so I thought it would be a really good idea if I went in. Anything like that will be coded with this term, reasons for participating. The fourth code is voluntariness, which obviously has a lot of relevance, I think, to the Committee in terms of the history of why we are here. And this both reflects the choice to join the study, whether there was a choice, the decision to participate in terms of the choice versus pressure aspect. And also, any choice or pressure to stay in the study. So, any time there's discussion about whether or not they thought they could leave, whether they thought that there was pressure to join, whether they heard about it and it was really their own free will by which they decided to join, all of that gets coded with voluntariness. The fifth code is consent, and that has to do with the consent process. It has to do with the form itself, but obviously it's broader than that. It has to do with someone from the study team talking to them, giving them information, what they were thinking about. The next code, which is somewhat related, is their own personal decisionmaking process. And this actually is a code that we added after having read through the first 10 transcripts. It seemed like, from whatever conclusions you can draw from a small number, that there were some people who thought about it, weighed the options, needed more information, and there were other people who acted. The information seemed not to make much difference. For whatever their own complex of reasons was, they knew they wanted to be in the study. And so this process and how they thought about it is what this code reflects. The next code which also emerged from having read the first set of transcripts is trust. There were many people, even in the first set of transcripts, that said things like, "I trust my doctor" or sometimes, unfortunately, I think, in terms of accurate understanding, "I know I couldn't have the placebo. I trust my doctor. He wouldn't do that." But things that reflect trust in the system or "I couldn't be harmed in research. They wouldn't do that to me." Something that reflects I have faith in the people who run this kind of thing or I have faith in the medical profession. So there's a code that reflects this issue of trust. The next code we are calling, for lack of a better term, blurred boundaries. The main reason we put this is was initially a concern that we had I think both from the literature and also from a few things that we had read that often people don't distinguish clearly what is research and what is treatment. Obviously, particularly, for clinical research. We have included in this anything similar to that that we would call a blurred distinction, such as the doctor versus the investigator, being a research participant versus being a patient, being at a research institution versus a non-research institution, side effects of the medical condition versus side effects of a research intervention. So anytime it seems to us that those things are being blurred in a discussion, we want to capture that and look at it separately. The last two codes are, first terms. As you know, this is part of the brief interview that we asked people to distinguish among four different terms. And we already have gotten a few interesting things that fortunately consistently have shown up in the brief survey, which Jeremy will talk about in a minute, and in the in-depth. But there really do seem to be differences in the way people understand these terms and we want to capture that. And then the last one is radiation, obviously. Any time anyone mentions the word radiation we're going to code it and look at the context in which it was raised, whether it was simply descriptive, whether they tried to express some kind of reaction that they had that they think perhaps is attributable to the radiation. Any time it comes up we're going to flag it and look at it. CHAIRMAN FADEN: This has probably provoked enough that maybe we should take just five or 10 minutes, Nancy for questions on this coding and on the qualitative and then we'll return to the plan. Is that okay, Jeremy? DR. SUGARMAN: Yes. I think so. I think it would just be helpful for the folks not familiar with -- and tell me if I'm wrong -- with qualitative research, which these codes do and how they're used. And then why the data are coded. Would that be helpful? CHAIRMAN FADEN: Sure. MS. KASS: Okay. Again, what we will do is take all of the 100 or 100-plus transcripts, read them in their entirety and block off sections of text that we think apply to any of these codes. And again, portions of text can be coded with nothing if it's just sort of extraneous stuff. That, again, gets captured in the total read but we think doesn't apply to one of these. It could be coded with one code or it could be coded with several codes, again, just depending on what it is that the participant says. That all gets entered into a computer with these handy new software packages. We then call up any code that we're interested in. And again, if any of you has an interest, if you want to read everything that someone said about radiation, for example, or anything anyone said about voluntariness, we'd request that from the computer. And if there was a section in an interview 2 and a section in an interview 6 and a section in an interview 12, all of that gets grouped together. It's put in a printout. It actually is also printed out, if anyone cares, with the other codes that that particular passage was coded with. And then you have a whole set, a printout that is anything anyone said in the entire part of this part of the project about that particular subject. After that, the analysis starts to happen and we try to draw some conclusions, both from the overall picture and from these particular components. CHAIRMAN FADEN: And I think the point that really needs to be underscored is that these are very broad. MS. KASS: They are very broad and they are deliberately broad. There are different philosophies about coding and different mechanisms for doing it. We decided, both because we're under time pressure and because we want to get some of these broad areas covered that we would do this broad type of coding. Another philosophy is that you have about 100 codes and, for example, the 15 possible reasons that may be mentioned about why people participate each would be given its own code. And we want to look at it in the aggregate after we make these broad distinctions, and that's why we did it this way. CHAIRMAN FADEN: Ruth? DR. MACKLIN: This is really just a very brief question. Did any of these codes -- and I think particularly in the consent and the voluntary -- capture the subject's perception of alternatives different from whether they had a choice not to participate, the coercion factor, but that is legitimate standard practice or what other things come in? I didn't hear you say it, so I'm looking at those. MS. KASS: Yes. No. That's a good -- I think you're right. I think actually we should add that as a completely separate thing. Even though it will probably come up in some, to highlight it, to see whether they either repeat that it had been mentioned by an investigator or they were thinking of it themselves. DR. MACKLIN: Well, from the terms being used -- I mean, in the follow up to the research in the lengthy interview, is the term used by the interviewer or does the subject have to initiate the language? MS. KASS: Because the questions don't follow a rigid set of questions, it doesn't necessarily come up but it is in their guide so they are supposed to cover it. It sometimes will come up in the course of conversation even before the interviewer initiates it when the patient is going through is or her decisionmaking process. The patient may say, "I was thinking about joining the study because what I would have had otherwise I've been through before and it didn't seem to have worked." Something like that. And then that hopefully would be coded alternatives because that's how the patient is conceptualizing it. That's a good suggestion. CHAIRMAN FADEN: Nancy and then Sue. DR. OLEINICK: Is there any way from this exercise of discerning whether the subject's perception of being informed is in fact -- the fact that they would have been informed sufficiently to make that decision? In other words, you're going to get some information, some of the phraseology that's going to talk about yes, it was explained to me and I agreed to do it. But I don't know exactly how one would do this but I wonder if in any of this information we would expect to see phraseology that would suggest that it was a misperception. Does that come out of that or does it come out of the kinds of questions in the short interview where you're asking them to describe the study? MS. KASS: Well, if I'm understanding you correctly, it sounds like part of what you're interested in is some kind of validity check. DR. OLEINICK: Right. Exactly. MS. KASS: And that is a piece that we are not doing except the piece that we have is we will have abstracts of the proposals. So that will tell us what the proposal is about. However, we won't have a tape of the conversation. And in certain ways, if this were an absolutely complete study, what we would have is a tape of the interaction between the investigator and the potential, at that point, participant. But instead, what we will have here is the piece where the participant is recalling what he or she had heard and had been exchanged. CHAIRMAN FADEN: I think that's important to emphasize that the study can't speak to the quality of the information that was provided. It speaks to the status of the understanding that the subject has. DR. OLEINICK: And the perception of understanding. CHAIRMAN FADEN: Right. That's right. DR. OLEINICK: Whether the subject thinks he or she understands. CHAIRMAN FADEN: That's right. And also if there was a gross -- like if the person said, well, I'm in the study because I think it could cure me and from looking at the abstract, we could pick up some misconceptions if they were very gross. And from the abstract it's clear that it's research that's not possible to offer a prospective benefit. We don't know. We will never know whether that the subject's overlay or whether they were somehow led to believe that. That we wouldn't be able impact. We would simply be able to see that there's some problem here because the patient has -- the subject has a discrepancy. But that would be the only -- is that a fair characterization? I figured we would do this. We're probably never going to get done, so we've got Sue and Duncan and maybe one or two more and then we'll go back to the quantitative. DR. LEDERER: Do you have a sense that the subjects have given any thought to what would happen if a bad outcome were to occur? MS. KASS: In the transcripts I have read so far, not at all. DR. LEDERER: Because something you said made me think of that when you said that nothing -- I mean, my doctor wouldn't let anything bad happen to me. I mean, there's certainly an outcome of that. But if a bad outcome were to occur there's not much -- MS. KASS: Have you seen any discussion of that? CHAIRMAN FADEN: Monica, could you come to the table? Thank you. MS. SCHOCH-SPANA: Of the first 10, there hasn't been any commentary specifically to that issue, so we might have to postpone discussing that. MS. KASS: Yes. I think that's a good question. What has been overwhelming so far, and I'm almost hesitant to say this because it is 10, but it really is the opposite. It is the trust that comes through so clearly and very positive experiences. Again, obviously, it's a bias. We are selecting people because they are in research. We are not selecting people because they've rejected being in research. DR. SUGARMAN: Also, the code of personal experience with research would pick up those sorts of things. So if you think some of those experiences will be good and some of those experiences may be bad or adverse in some way, so it will be the interpretation of that in context of that person's interview that we'll be able to get at that. DR. LEDERER: I guess I was thinking of the language of some consent forms that say explicitly that the university will not be held -- will not pay for treatment if they don't get outcomes. MS. KASS: I'm glad you mentioned it and we'll certainly look for it. CHAIRMAN FADEN: Duncan? DR. THOMAS: These coding schemes seem to be, at least at this stage, basically used as a sorting device. MS. KASS: Exactly right. DR. THOMAS: Nothing more than a big pair of scissors. Smart to compare scissors to it. MS. KASS: But it's a lot more convenient to have it considered. DR. THOMAS: Did I understand you to say that now the analysis piece begins? And the question is does that analysis piece entail attempting to assign codes to what people actually said in a manner that could then be linked with the short interview to provide us more insight into an analysis of actually what happened. DR. SUGARMAN: We're going to illustrate that for you, actually in the next section here. When we review the quantitative, we're going to give you a hint at how that might work. CHAIRMAN FADEN: And the fact is, I don't know what Jeremy is referring to, Duncan, but if that doesn't work, we'll have a speaker come back. DR. SUGARMAN: Yes. Because we're going to have a section. What we hope to do is provide you with a review of the brief data, the sort of very preliminary data, and then talk about analysis while Steve is here. And then, once we've seen the sorts of analysis that we're going to do, maybe we could deal with the whole analysis questions together, if that would be all right. MS. KASS: the one thing I can tell you briefly in direct answer to your question is that when we get a complete transcript that's come from the transcriptionist, it comes with what's called a contact sheet that has on it eight to 10 demographic variables, so that at least that particular transcript is being read knowing some of the demographics of the person. And again, qualitative data has a lot of analysis done in the reader's head, and so part of it is understanding -- okay, this is an African-American man in his 60's who's saying this and you read it knowing that. And the next one is a white woman from Texas who's in her 70's and you know that. And you start to make some conclusions by reading these chunks of data that you know come from this person and that person and this person and that person. And that is on initial way that the data are linked from the two types of surveys. DR. THOMAS: It isn't evident to me why you want to do this that way. In other words, we're not particularly interested in this case in knowing whether or not race is a factor in how people respond to these things. But supposing there were, that would seem to me to build in certain biases in your analysis. And that we'd be better off doing that coding blind and then seeing whether or not there's an association. DR. SUGARMAN: Yes. The coders won't have access to the brief interviews when they're coding. DR. THOMAS: No. We're talking about the in depth interviews. DR. SUGARMAN: Right. DR. THOMAS: And why the coder ought to be provided this background information in the first place. DR. SUGARMAN: Should be provided. So you're making an argument that the code should -- MS. KASS: Should not. DR. SUGARMAN: Should not or should? DR. THOMAS: Should not. DR. SUGARMAN: Okay. They're not. DR. THOMAS: But they are being provided the demographic information and I'm just trying to understand why you do even that. CHAIRMAN FADEN: No. I think we're distinguishing between the coders and the professionals who are analyzing the data. Monica could speak to this better than I could, but it's my understanding -- obviously, when you're doing ethnographic work, you will know who you're talking to. It's a different -- you've got to suspend, think of this as an anthropologic project. It's ethnography. We're not sitting here trying -- this is not quantitative data we're trying to -- you know, sort of pull out the variables and then stick them in and model this. This is -- when an anthropologist talks to his or her respondent, you know who you're talking to generally. MS. SCHOCH-SPANA: Correct. CHAIRMAN FADEN: And you're forming impressions in a gestalt fashion. MS. SCHOCH-SPANA: Right. Well, to speak to your concern, the coders are going to be coding the transcripts blind. That is, they won't be focusing on the demographics of the respondent. I'm the staff member that's been entrusted with reading the transcripts in their entirety and I do have the contact sheet associated with the transcript that includes demographic information. But I think because we're using multiple tools to both code and analyze the data that includes both being blind to demographic information and then being attentive to it, that we're getting a nice balance and trying to control the detrimental effects of bias and still be sensitive to differences across income groups and age groups. CHAIRMAN FADEN: Maybe if it's all right, if we don't hear, let's go on with the quantitative stuff in more detail and then try to put everything in. DR. SUGARMAN: Okay. In order to facilitate a quick review of the quantitative information, we've provided you with the frequencies put directly onto the survey forms so you wouldn't have to keep bouncing your heads back and forth. We're going to actually start on page 21 of the survey instrument form, which is the demographic information. Although this is the latter part of the interview, we thought it would be helpful to tell you who it was we were hearing from. Let me just emphasize as I go through this information that these are preliminary data. The data tapes have been cleaned somewhat. They're not in their final clean form. We are going to be receiving another whole bunch of data and we shouldn't even pretend to leap towards conclusions based on the data that are presented here. And it's -- I know you always like to dive in to do that and try to make sense of all these numbers, but if you can try to hold back for another few weeks, that would be helpful, because it's harder to unlearn those things later. Basically, what we're finding is that the mean age is about 60 years old. We have a good balance between men and women. There is representation from various groups. We have black or African-Americans, 139 of these respondents, and 757 whites and 45 Latino. These data don't completely reflect the sampling in Texas and we anticipate that we will be able to provide more Latino representation based on those data. We actually have a highly educated sample. If you take all those confusing numbers under F-5 and lump them into at least four things instead of however many are there, 11, about 118 of those folks don't have a college education, so about 10 to 15 percent have a high school education; 281 have finished high school or some kind of vocational school; 225, about a quarter, have some college; and about 25 percent are college educated or beyond. People tend not to be employed about 60 percent. DR. MACKLIN: [Off mike.] DR. SUGARMAN: I think that's a reasonable way to interpret these data. I wouldn't want to imply causality from one to the next yet, but that makes sense to me. Let's see. What else. Most folks believe that their health is good or fair and they tend to be insured. Now let's flip back to the beginning of the survey instrument to Section A. And you'll recall that Section A are general attitudes towards research. And we find that overall most people feel pretty positive throughout and that's summarizing the items on pages 1 and 2. We then ask people to make distinctions between some of the terms. Now, there are four versions, as you'll recall, of the survey instrument, each one asking about a different term, so each respondent compares medical research to something else. But what we find over the group is that medical research seems to be different than clinical investigation, clinical trial and medical experimentation. At the risk of doing what I said not to do, clinical investigations and clinical trials seem to be perceive to be the lowest risk or sort of the most beneficial in the group; medical research in the middle; and medical experimentation to be somewhat riskier. What do you do with these data? Well, Nancy now will give you a couple of excerpts from -- these are unlinked to the particular respondents to this, but these are just our first transcripts back, to show you what some of the people said about each of the terms. MS. KASS: I'll give you quotes from two different in depth transcripts about the same topic of terms. The interviewer says -- there's a card that the respondents are given with these four different terms on it and the interviewer says, tell me if you see any difference among them. And the respondents said medical experiment would be medications more than research as such, and there's a little bit more questioning. And then the interviewer says, if a doctor said to you, look, we've got these four different kinds of medical research happening, which would you like to participate in, the respondent very quickly said the study. And then the interviewer said, and why would you feel that way? And the respondent said, less risk, parentheses, laughter. And then the interviewer says, so you think there are - - there's one with more risk? Which one would probably have more risk? And the respondent says that would be the medical experiment. And then, similarly, another person said medical experiment means that you don't know the results or what you're testing and that's what the word experiment means. And that you have an idea or theory or hypothesis and you're trying to prove or disprove it. Clinical trial is another stage of that. You've got some results and you've got some information. It's based on a very small scientific sample and you're trying to see whether those results hold. CHAIRMAN FADEN: That's a very sophisticated person. MR. GUTTMAN: Who were you interviewing? Dr. Katz? (Laughter.) MS. KASS: The only thing that I'll say about the reassurance -- you know, I assume most of you have conducted research. When you get your first set of data and you're actually really anxious because you go in sort of -- you've asked the questions because you expect that you might find something and you're not really sure. And when both the brief survey and the in depth survey had really consistent results in this, it was for us personally very reassuring. DR. SUGARMAN: The other reassuring part skips to page 4 where there was a huge discussion back in July and August when we were initially in the process of designing this experiment about if we went into these particular waiting room, would there be anybody who was in fact a research subject. Now, what I can tell you is what people perceive. And from the data we have so far, it's that 12 percent of the 943 respondents believe that they are currently participants in research. An additional 15 percent believe that they have participated in research in the past. So that gives us about 25 percent or so of the population that has some experience to base their thoughts and attitudes on and we can see if those differ with the other groups. That breaks down in terms of what types of research project. And this is from the patient's perception. One hundred fifty-two of the respondents of the 943 believe that they are in a treatment trial; 40 of those people believe that they are in some kind of diagnostic trial or study; and 63 believe that they're in a epidemiologic study. So we have no reason to suspect that those numbers, the proportions, will differ greatly later. So, we're going to skip several pages now through these items which then explore what people think of their participation based on treatment, diagnosis and epidemiologic study, and generally, most people seem to be positive. Again, some of them -- most of them had altruistic motivations for participating in research. And although the urge is to dive in and go through each of these items, we're going to let you do that in the privacy of your home or office because I think really going much further with these data would be quite tenuous because the numbers get extraordinarily small. But the patterns generally are revealing that there may be now -- there are minorities of respondents that may be highly significant, but the overwhelming trends seem to be quite positive and we'll just need to wait to explore that further. DR. KATZ: Jeremy, can I ask -- DR. SUGARMAN: Sure. DR. KATZ: Sorry. Ask one quick question. I didn't quite understand. All these people that you interviewed of course are participants? DR. SUGARMAN: These are people who believe -- well, everybody who -- DR. KATZ: Is in the research project or not necessarily? DR. SUGARMAN: The overall 943 are people that were in waiting rooms, either in cardiology, radiation oncology or medical oncology waiting rooms. And one of the questions that we're talking about, when we asked them about these particular reasons for participating, are the group that suggested or believe that they are research participants. DR. KATZ: So later on you'll tell us something about whether their perceptions are correct being -- DR. SUGARMAN: About research. Yes. DR. KATZ: That's still to come. Okay. DR. SUGARMAN: Yes. That's still to come. DR. KATZ: Okay. CHAIRMAN FADEN: And everybody in the qualitative interview believes they're a research subject. Is that correct? DR. SUGARMAN: Correct. MS. KASS: That's right. CHAIRMAN FADEN: So everybody in the in depth part of this thinks they're a research subject. Whether they actually are or not is something -- DR. SUGARMAN: Skipping to Section E, reasons for not participating, these were a group of people who didn't answer the first set but had been asked to participate in a research project before but they said no. And we asked them some questions about why they decided not to participate. And the only generalizations I'd like to make now is that most of those folks thought it would be inconvenient and they didn't like the uncertainty or the inconvenience of participating in research. They wanted to make their own decisions with regard to care or have their physicians do something like that. I'm going to stop right there and let Steve talk about analysis. DR. GOODMAN: Yes. I'll direct your attention to the table, the shells, that are in the latter half of this. It's Attachment 4. As you see, we've completely eliminated any temptation to over-interpret the data by putting no data in these at all. This is obviously just the beginning of an analysis. This is just a welter of cross-tabulations by a variety of factors. And this is what the subcontractor will provide to us and from which we will take off on. Now, this is obviously restricted to lots of two-by-two comparisons and there are lots of questions being posed by this research that are going to involve a lot of substratification. That is, we'll want to know questions by whether they were in former research or current research; by whether they were radiation, not radiation, et cetera, et cetera. It's not going to be restricted to just these two by two comparisons, but this will begin to give us a sense of what the data look like. The parameters that we'll be using for the overall analysis will be the same sort of things we see here, just in combination. That is, the geographic site of which there are five; the hospital, of which there are four; whether they're in research or not; and among those who were involved in research, whether they're current and former; whether they're in radiation or no radiation. There are obviously a host of patient characteristics which are all listed here in the demographics; race, income, insurance, education, sex and age. And the outcomes are both the outcomes of the attitudes to the questionnaire, as well as the concordance, whether they know that they are on research or not. And then, of course, there's the relationship of some of these with each other. Now, obviously, the final analysis will not be necessarily in the form of these tables, which will be virtually impossible to interpret with a brief inspection. We will be using those horrible things called models to start to sort out the independent contributions of things. And, we'll go back and forth between both interpretable data displays and the models. The models will be used both as exploratory tools to try to sort out which factors are related to what, as well as what you might call confirmatory tools to sort of summarize very, very complicated patterns. Although, my experience is that in the end you can often sort of present a lot of the message in very unsophisticated ways. That is, you can have a final model but you can show how it looks in terms of some simple two by two tables. In fact, my goal in almost all research is to reduce all of the numbers to a single two by two table, so we will be trying to do that here, as well. Now, the one thing we actually had not talked about specifically which Dr. Thomas just brought up, was specifically linking the specific interviews in the in depth interview to specific brief interview results. And I think that's a very interesting suggestion. And we certainly, I think, will have the ability to do that. So I think we'll think about the exact logistics of that, but it's certainly not impossible. I would say in terms of the Committee, if there -- I mean, I've outlined the general sort of things that will go into the models. If for the purposes of your making recommendations there are certain questions that you want to make sure, absolutely sure that we have nailed down within a month of your final report that you need for those deliberations, of course, if you give those to us, you can absolutely ensure that they'll be addressed. I think we have just about every -- you know, we will look at just about every combination of factors we can think of that will be of interest, but we obviously want to make sure that we don't miss some. DR. SUGARMAN: If you express any ideas as you deliberate about policy that you would like to test, rather than just simply conjecture, we can sort of look at those specifically, if directed. DR. MACKLIN: I don't know anything about this kind of data analysis, so these may be very stupid questions. Well, the first question is stupid. DR. GOODMAN: I'm sure, they're not. If they're simple, they're probably very hard. DR. MACKLIN: What are these things called? Shells? DR. GOODMAN: Yes. DR. MACKLIN: On page 40 -- DR. SUGARMAN: Was that your question? (Laughter.) DR. MACKLIN: No. I know how to listen. I guess maybe it's 40, but the one that has two choices; radiation research patients and non-radiation research patients. DR. GOODMAN: Yes. DR. MACKLIN: The three categories are oncology, cardiology and radiation; right? DR. GOODMAN: Yes. DR. MACKLIN: So that you have lumped together in the non-radiation research people who would be in cardiology, cardiology patients and oncology patients. DR. GOODMAN: That's right. DR. MACKLIN: My question is if you find some kind of differences, significant differences between the radiation and the non-radiation research patients, how do you know without further division that there might not be a greater difference between the cancer patients and the non-cancer patients -- DR. GOODMAN: Well, obviously -- DR. MACKLIN: -- or would it matter? DR. GOODMAN: Well, it certainly could matter. And this is just an examples of the type of divisions. We could, of course, produce a table with that split out. And, of course, that will also come in in the models where there'll be a specific term for type of research. I mean, oncology, radiation oncology, oncology and cardiology, will be a separate term. If anything came up -- if we actually haven't produced a table of that already broken out. The thing is, many of these headings can be broken out into a number of subheadings, so we didn't want to produce every possible table here that we could possibly produce, but that is one of many very good points about subdivisions that we'll have to look into. Because obviously -- DR. MACKLIN: So we'll be able to look at it, even though you're not representing it here -- DR. GOODMAN: Absolutely. These are really prototypes. They're, A, not necessarily complete; and B, we will be going -- as I said, we'll be going back and forth between the models and these tables. And it may be that if we find that there is a particularly important contrast among non-radiation research participants, which is possible we would only see in a model, although we could see it here if we just produced that table. We would then go back and look at just the two by two, this type of cross-tab, to see what the raw data actually looked like. The disadvantage of any one of these tables is that any two by two contrast, that is, one thing by another thing, doesn't then control for all the other things that are different. So there's always a loss of balance between a loss and a gain in simplicity. DR. MACKLIN: One other quick question. And this is on the -- when you're comparing the current and the former research participants. DR. GOODMAN: Yes. DR. MACKLIN: Isn't there a problem about recall? That is, the longer ago in the past the person was a subject of research, the last recall there might be about some of these. And if someone answered, "Don't remember," that's one thing. But if the person thinks he or she remembers -- DR. GOODMAN: Right. DR. MACKLIN: -- then -- I mean, it's really a question of what do you do with that kind of factor when -- and is there just for example, any indication of how long ago the person was a research participant? DR. GOODMAN: Yes. I believe there's a specific question that addresses that. And it's a good point. We can include that, as well. Like within five years or greater than five years, and see if there's an appreciable difference between those types. Again, -- DR. MACKLIN: But in any case there's the problem of -- I mean, suppose you found some significant differences in the consent process between the current research participants and the former research participants. How do these mechanisms enable you to determine, if at all, whether the person is mis-remembering or just simply doesn't recall, or whether there was a clear consent. DR. GOODMAN: There is, I would say, based on this we'd have to use surrogate measures. There's no direct way of knowing that aside from perhaps getting clues from in depth interviews. We could use a length of time since the research as a surrogate and see if we see data patterns that suggest, that are inconsistent or whatever. Of course, you have problems associated with that, like people who were involved in research a long time ago are likely to be systematically older and have other characteristics that might be different. So, obviously, the degree to which we'll be able to sort things out is to some extent limited and we'll have to use very indirect methods to determine that. DR. SUGARMAN: And also, if you'd look at the types of items, the types of questions we're posing, we're not asking people to report to us what they remember about say the side effects of the medication or that they forgot some things over time. We're trying to be careful in the design of the instrument not to do what we know people do. We know people forget things. And so that would be -- we could prove a scientific sort of so what. And I think we weren't interested in that question. There is an empirical literature on informed consent that shows, gee, if you ask people what they know at the minute they can date for consent, do they forget things over time. And it's no surprise that they do. Likewise, we're not going to look and say did you think the consent form was readable. We know that consent forms are readable and that's been proven. So we've tried to eschew asking those kinds of questions. So there may be some recall bias but I think it's effect may be minimized by the statement. CHAIRMAN FADEN: Duncan? DR. THOMAS: There's a block of tables on the concordance of indicators of medical research participation. I understand from the script from the beginning that you're actually planning to code the protocols in terms of things like - - tied kind of like risk and benefit. Is there any plan to try to compare the concordance in terms of the patient's assessment of risk and your judgment of risk and did it have a benefit. DR. SUGARMAN: Yes. We can do that. The reason for that -- and it's an appropriate question -- is that these shells will be filled in by RTI when they provide us with the data tape. Advisory Committee staff are doing and coordinating the efforts of retrieving the protocols and then getting a mechanism outside of the contractors. We're keeping that in house. So we'll have a separate database which we'll be merging so that there'll be no possibility of having that analysis presented from the subcontractor. It's going to lag by a few weeks because we're going to have to do that. And that's the only reason that's not here. CHAIRMAN FADEN: Henry? DR. ROYAL: When we've been reviewing protocols, it's often been difficult to be very quantitative about the benefits and the risks with the information that we have. What information are you going to have to do this quantitation about the control in terms of approximate level of risk and benefit and what sort of semi-quantitative units are you going to use? DR. SUGARMAN: This is the stage that we are working on now. We are probably -- what we hope to do is do something like low, intermediate or high risk and to force consensus of a group or what I'm probably going to do is get experts in each of the specialties to do the risk/benefit calculus and to have them sort of do it independently and see what consensus is like. CHAIRMAN FADEN: I think Henry's point is all we're going to probably have is the abstract. DR. SUGARMAN: Correct. CHAIRMAN FADEN: So we may only be able to do a best guess of -- you know, more than minimal risk, minimal risk, or something. You know, higher, lower, relative. Because we're going to have very little information. And this is the roughest sort of a thing. The only agenda -- remember, this was stimulated by -- I forget -- DR. SUGARMAN: Committee discussion two months ago. CHAIRMAN FADEN: I know. But I'm trying to -- okay. So we can credit or blame one of us who suggested that it would be really interesting to know if people don't know or a wrong understanding, but don't know that they are a research subject. Whether that's more likely to occur in minimal risk studies, the studies that are not very significant consequentially in terms of people's lives. So that's really all we're looking for here is a rough cut to test -- to explore the hypothesis that if we have anybody who doesn't know they're a research subject who is one, which we don't know yet, whether that pool of persons is more likely to have been enrolled in a lower risk study than a higher risk study. So that's all we're trying to do here. And as a consequence, since the research aim is relatively modest, we don't -- you know, it's not a very precise sort of risk/benefit. It's not for the purposes that we're doing in the research protocol review project where we're trying to determine whether the research and the project itself is an ethical one. So I think that's important to emphasize and we should make clear that that's all that we're trying to do here. And therefore, it's not -- it would be nice if we had more information but we're trying to make a guess based on the protocol. DR. SUGARMAN: Yes. If you just found -- just to demystify a little bit. If you found that in these data that there were a group of people that were discordant, they were research subjects but in fact they didn't think they were, and if it turned out that all of those people were in survey studies, it's a problem we would like them to be aware of but it's not as big a problem as if they were sort of engaged in something that posed them at great degree of risk and there was some intervention versus a placebo or something. So that's all we're trying to get at there, so that we know what to do with those concordance and discordance numbers rather than just have them be out there with no -- not to hang them on anything. DR. MACKLIN: I just wanted -- just a quick point about what Jeremy said and who you're going to tell what the level of risk is. I can't cite the study or where or when it was published, but I know I remember something about it, and that is that experts in a particular area tend to rate the risks lower than non-experts in that area, even among physicians. So, for example, neonatologists who work with three pound infants will rate the risk of inserting some catheter in this teeny little infant much lower than someone who works with adult patients. I mean, just something like that, but among specialists and subspecialists. So that could skew the data if in fact that is correct. That could skew the level of risk if you pick the experts to make the judgment. MR. GUTTMAN: There's a whole science of expert bias which we have not yet called on. DR. GOODMAN: The division we've made -- I mean, this is a very rough cut, but even if we didn't go to the abstracts, the division into epidemiologic diagnostic and treatment is obviously a very rough cut at level of risk. And in fact, looking at the patterns of reasons why they -- that we've already seen in terms of reasons why they are in studies, we see exactly what you would expect from these sort of studies right now where issues regarding risk and treatment didn't seem to play any role in the people who signed up for what they perceived as epidemiologic investigations. DR. MACKLIN: Could I -- just sort of to understand what you meant, are you implying that diagnostic studies would or do in general carry lower risk? DR. GOODMAN: Than treatment. This is a trick question. (Laughter.) CHAIRMAN FADEN: Don't answer it. DR. MACKLIN: I mean, at least for some. I mean, I'm thinking of ones I've seen in my own institution. I'm also thinking that some that we've seen in the protocol review where they were purely diagnostic, no direct benefit to patients. They're sticking wires into people's arms and they're making them exercise on treadmills until they drop. I mean, -- DR. GOODMAN: I would say very rough, very rough. DR. MACKLIN: So some -- I mean, I understand what you mean, you know, a diagnostic study. But some of them in cardiology, and I don't know about oncology. Somebody could speak to that better perhaps. But I mean, among the things both that we've seen here and that I've seen as a member of an IRB, I don't think you can make a quick -- DR. GOODMAN: Oh, no. That was really -- I mean, when I said rough, I meant rough and on average. But I've seen screening studies that posed a much greater risk to participants than some treatment studies. CHAIRMAN FADEN: We probably could go on all day about this. The problem is, of course, we've got to do all our other work. I have to just say on behalf of all of us, I think this is extraordinary. We have how many? Fourteen hundred something, 1400 of the short interviews done and 79 of the long interviews, which is totally news to me. It's really remarkable. And when we started this, this sort of issue, there was the general view abroad this could never be done. So, there's an accomplishment in the process of the doing which is really worth noting. We're all very delighted that we'll have this information in time to use it for our deliberations. So we'll be seeing stuff presumably between now and the next meeting from the four of you and then at the next meeting we will have a go at maybe filled in shells as opposed to empty shells or the impressions based on 10. DR. SUGARMAN: If over the next couple of weeks you do have ideas for analysis, we do need to hear from you rather soon, like within the next week or so, so that we'll have time to plan for that analysis if you want to look again over the analytic plan now that the idea of making policy recommendations and the like is close approaching. We're happy to do any of those analyses. We're just going to need to know early. So just please send them my way and I will get them distributed to the right people. CHAIRMAN FADEN: Thank you all very much. That's great. DR. LEDERER: Is there going to be a draft, a chapter draft of this material due by our next meeting? CHAIRMAN FADEN: I don't know. We're shooting for April. What we don't know either is whether we're going to have this project and the project that we're about to discuss will be one chapter or two chapters. We'll see how that will go. We don't know yet. I think it's really -- we should -- DR. KATZ: Is it possible as certain sections or certain issues are being analyzed to a reasonably good extent, that this be faxed to us? CHAIRMAN FADEN: Anything you want. DR. KATZ: This could be part of the policy because then it can -- CHAIRMAN FADEN: Yes. Of course. I mean, I think the issue is -- DR. KATZ: -- come part of the forward thinking. CHAIRMAN FADEN: Yes. I think we have to think of a reasonable way to do this. DR. KATZ: Yes, yes. CHAIRMAN FADEN: Something that's provided to everybody. And then people have particular interests or want to help work. If Committee members want to work on analyzing particular themes or particular subsets of the quantitative data, that's terrific. Plus, we will need to be pulling stuff out and getting it to you quickly so that you can have it available as we think through future recommendations. But the bottom line is we will have input before our deliberations from these data and we will have the perspectives of people who are currently subjects of research, which was the goal of this whole enterprise was will we really be able to hear from people who are current research subjects without putting an ad in the newspaper and seeing who shows up. So we've reached out and we've found such people and we will have data from them. So that's just great. It's really great. It's really wonderful. Nancy is reminding us that the numbers that we've heard are the number of people who think they are research subjects. And the big piece of the puzzle is the confirmatory process; how many of these people correctly appreciate that they are research subjects. We'll see what happens, won't we? And the fact that we've got a very nice balance for university hospitals, for community hospitals or military installations or VA hospitals, allows us to be able to explore whether the experiences are different for people who are receiving their medical care and being recruited into research from institutions. We should underscore that one big limitation of these data with respect to the contemporary situation is that we are only then getting information about research subjects who are being recruited in context because they are getting medical care. So research with people who are healthy, the kind of research that's done on healthy subjects, we don't get in this pool. I don't know that we even pick up any quote in normal controls in this context. I doubt it. And certainly research that's done exclusively on healthy populations, community research or research where you're recruiting healthy people, we miss that entirely. So that's something that we're going to have to just acknowledge straight out. That this is focusing on clinical research and not on research involving healthy subjects. And that's very unfortunate because, as we know from our historical investigation, the issues are somewhat different and also important when the subjects are not patient pools, not coming from patient pools but coming from other communities -- not communities, other contexts. Okay. We're going to move on now to an update on our research proposal review project, where we are. We're generating the data as opposed to the customers or clients for the data. So, if we don't like the pace at which the data are being made available, it's our fault and no one else's. Sara and Gail are with us? Great. Now, we should look at a document that was distributed the first day. MS. CHANDROS: There's two documents. One is -- it has "handout" in the upper right-hand corner and it's going to be the basis of my presentation. And the second one is -- it lists the frequencies of all the responses on the coding form that we have to date. CHAIRMAN FADEN: Can we give everybody just a second to see if they can locate it there? MS. CHANDROS: Sure. CHAIRMAN FADEN: This is always risky, very risky, right? (Pause.) Okay. Sara and Gail, could we get started? thank you. MS. CHANDROS: Okay. Thank you. We have as of March 13th, which is -- as far as the analysis in this memo goes, we have 59 radiation reviews completed and entered into the database and two non-radiation proposals. Right now, -- and since then, I've also gotten five or six back that aren't factored into this analysis, and 20 are in circulation amongst reviewers. So, we now have a chunk of information that we could begin looking at numbers, but the bad news is that this represents only about a third of the proposals that the Committee planned to review itself. There is approximately an additional 48 radiation proposals that need to be completed and entered into the database and between 50 and 60 non-radiation proposals. In order to meet the stated goals of the project, something is going to need to change or we need to either change the sampling scheme, modify it to get done something reasonable, or modify the mechanism for conducting the reviews, or both. I want to briefly present two ideas to the Committee that you can discuss and decide how you'd like to proceed. In Table A on the second page of the update handout, there's a table, a familiar table. It now includes the numbers. The numerator is the number of proposals in each category by biomedical category and agency that have been reviewed, and the denominator is the total number available to be reviewed. The shaded cells, which I know are a little dark on your copies, are done. We've completed those and there's nothing more to do in those. One, our goal has been to fill each cell with between three and 10 studies. As a compromise, the Committee might want to consider at least prioritizing. Make sure we complete five in each cell with the hope that we could finish everything, but if we don't, at least we have some sort of even distribution and we can say something about each of the categories and have it to be as balanced as possible. Another possibility is to increase the number of reviewers working on this. The Committee has been dedicated to at least one person from the Committee reviewing each proposal. And what we could do is unpair Committee member who are currently working together and match them with a new member of the staff. We'd have to train and include more staff people. Now, maybe even hire new people with the proper expertise, because we need scientific -- people with scientific background on one side and ethics or IRB experience on the other side. But we could increase the number of reviewers doing these per week because we know they go slower than we originally anticipated. So that's the second option. Or, the Committee might want to consider doing both of these to get done something reasonable so that we can have -- so we can make conclusions based on a reasonable number of proposals. Moving on, based on the 59 studies that we do have completed, I can characterize those generally right now. And we don't wont to necessarily draw conclusions based on this, but I want to show you what the numbers look like right now. We've been using an overall rating system of 1 to 5 where 1 is excellent, outstanding proposals, and 5 is ethically unacceptable or very problematic and troubling. Twenty-seven of the 59 studies viewed as of March 13th received an overall assessment of 1. That's almost half. Seventeen of the studies were given an overall rating of 2; seven received a 3; five received a 4; and three received 5's. That means a total of eight out of 59 studies overall gave reviewers the impression that there are real troubling ethical concerns. When we look back at each of these eight, each of the eight involved greater than minimal risk to the research subjects. In general, concerns over these proposals revolves around the level of risk and the disclosure of this risk to the patients -- I mean, to the research subjects. So, still, these eight studies and any more that come up that receive ratings of 4 or 5 will be reviewed again by the subcommittee to first confirm this rating, to see what the core ethical concerns are, and then decide what to do from there. Again, based on these 59 studies, some trends have been emerging and a lot of them are consistent. The percentages have persisted. If you look at the second handout, these percentages are relatively constant with what I reported at last month's meeting. So we're finding -- with some confidence, we can say that we're seeing some consistencies. It's still too early to draw conclusions based on these, I would say, but I want to talk about some of these trends very generally. Some of the numbers that we see are percentages stand alone as being interesting and some of the reviewers' comments -- we also asked each reviewer to comment on their answers, and some are particularly poignant or consistent, and that's what I'm going to report on. In terms of the scientific merit of these research proposals, reviewers were unable to determine if 15 out of 59 studies were what we would say are worth doing. And we want to point out since IRB's and agencies are looking oftentimes at the same materials that the committee reviewers and staff reviewers have in hand and also have the same types of expertise, a question that comes out of this is what sorts of outside consulting do IRB's or agencies utilize in order to get at these scientific questions for expertise that they don't themselves possess. Another question of scientific merit that has come up is sample size. Whether the sample size that is proposed in these studies is adequate to get at the research questions. And in approximately five studies, the sample size was small because they knew that there aren't enough subjects to recruit into the study, but this might jeopardize the results that would come out of doing this research. And on the other side, so many subjects were proposed to be recruited into studies that reviewers felt that it was too excessive. Not all these people needed to be included in the research to get at the answers. So we're seeing those kinds of problems on both sides. Regarding the selection of subjects, some preliminary observations. Five out of 59 studies specifically stipulated the inclusion of economically disadvantaged research subjects in the population. And similarly, five out of 59 studies proposed that students would also be included in the research. Of the questions that are related to these populations, we could ask whether they're being overly persuaded by financial compensation to participate in research. So far, out of the studies that do offer compensation to research subjects, 23 out of 25 were deemed appropriate, so it may be that this question is adequately addressed in the proposal, that it may not be a concern. One number that stood out as particularly pointed by itself, 35 out of 59 studies explicitly exclude pregnant women from the research. Of nine studies that involve children who are old enough to read and therefore thought old enough to give assent, only five proposals include assent forms, so four did not include assent forms in the materials that we received, so they could not be reviewed. If they did exist, they couldn't be reviewed. And the question is do they exist at all. Ten -- fourteen studies were found to include subjects who have questionable capacity to give informed consent for various reasons and out of 10 of these, these limitations to give consent were not addressed at all or were not adequately discussed. And three out of 12 of such studies adequately discuss how consent will be obtained in these cases; whether proxy consent will be utilized. Now, an interesting point with the discussion of the balance of risk to benefits in the research proposal document as opposed to the consent forms. In approximately half, 17 out of 35 of research proposals, the balance of risk to benefits was partially or inadequately addressed. However, looking at risks individually, 41 out of 50, they were adequately addressed. And looking at the potential benefits, 35 out of 46 proposals discuss these adequately. So, somewhere when they're discussed together, it seems not to be as complete. And then, finally, in the evaluation of consent forms, which is a separate section of our coding form, reviewers felt the reading level, 31 out of 59 consent forms, was appropriate. And based on the reviewers' comments, there seems to be a fundamental conflict between including just the bare -- making it very readable and therefore not including enough information about risks and potential benefits and other information that would be relevant to the subject. And on the other side, in putting too much detail, telling everything possible. But then it's too technical and very difficult to read and understand and would also be intimidating. Also, a number of the consent forms were very lengthy, which would also decrease readability. And in several cases, there are also language barriers and ethnic specific barriers that may have been a problem in certain environments, in certain populations. Something I pointed out at the last meeting and seems to be consistent is the problem of the use of boilerplate or standard language on consent forms, literally in small print, on a smaller font. Some of the most important information is included on consent forms such as alternatives to participation, cost to the subject, confidentiality and that participation is voluntary, and these look like -- reviewers commented that these look like they could easily be overlooked and not noticed by subjects. In 23 out of 54 consent forms, reviewers were concerned that risks and burdens were not adequately addressed. Ten studies were identified as involving potential social risks. And the consent forms for these 10 studies, only one of them discussed that risk. In 13 out of 56 studies potential benefits to the subject are not adequately addressed and only 18 out of 40 adequately discusses the balance of the risk to potential benefits in the consent forms. Those are, in a nutshell, some of the major -- most important trends we see emerging that may now lead into what sorts of questions the Committee really wants addressed by the research proposal review project. And this is another thing. I want to encourage the Committee to discuss today or to keep comments coming in to us about what types of questions you need these analyses to address in order to be able to draw conclusions and make recommendations. We're at the point where we need to go beyond simply calculating the percentages and looking at reviewers' comments and deciding how they're going to fit together and what the core concerns are or what issues does the Committee want to place priority on. So, I know Jay wants to -- CHAIRMAN FADEN: Could we do this? I know Jay wants to -- in retrospect, I'm sort of sorry that we didn't stop after your initial discussion of the fact that we're behind schedule, and address that issue before we got into the suggested findings. If Jay would not mind and if you all would not mind, we can return to that and to the issue of how we're going to get focused. I know even these preliminary findings are very intriguing. We might want to pursue them and discuss them. Maybe we could do that after we hear from Jay. And they're sort of all of a piece, if that's okay, and take 10 minutes or five minutes to concentrate on what do we want to do about the fact that we are behind schedule in completing these reviews. On the one hand I think it's clear from what Sara's already suggested to us that the information we're gleaning from these reviews is potentially of great importance and we are learning from these reviews. And we would like to get this project completed so that we can have a high rate of confidence in what we're seeing. On the other hand, we're having problems getting this done at the pace that we would like to get it done and that's a human factor issue entirely. So there are two proposals that Sara briefly went over that have emerged in discussions by the staff and subcommittee and they're not mutually exclusive. One is -- and we don't have the table for the non- radiation research, but in a few cases, they are as well -- the potential number of studies that could be evaluated per cell is greater than five. So one proposal that's out there is to say let's concentrate first on making sure that we have five projects reviewed in each cell. If there are, for example, four left to do in that cell and we already have four, randomly select one to make five. And then if we can get five in each cell and we still have time, we would look at the remaining two in that cell or whatever it turned out to be. If not, we just won't look at them. We just will say, okay, it is now -- whatever. How many projects would that save us, Sara? MS. CHANDROS: Twenty studies. That would eliminate 20 from the sample. CHAIRMAN FADEN: For radiation or non-radiation? MS. CHANDROS: Just radiation. CHAIRMAN FADEN: And then the non-radiation, what would we guess? MS. CHANDROS: Possibly a similar number. CHAIRMAN FADEN: So instead of having a total of -- what was our goal originally? How many radiation studies did we want to review? MS. CHANDROS: We have -- CHAIRMAN FADEN: The total? MS. CHANDROS: There's now about a total of -- I think it's -- CHAIRMAN FADEN: 107? MS. CHANDROS: Yes. CHAIRMAN FADEN: Okay. The total. So instead of reviewing 107, we would review -- what is 107 minus 20? (Laughter.) MS. CHANDROS: 87. CHAIRMAN FADEN: Thank you. We would review 87 instead of 107 radiation ones. And if we pulled it off, we would go ahead for the whole 107, but if not we would randomly pull the ones that we did. And we'd have 87 in the pool as opposed to 107. And in the non-radiation, what? MS. CHANDROS: It would be about 15 in the non- radiation. CHAIRMAN FADEN: So what would the sample size go? From what to what? MS. CHANDROS: We have 48 or 50. About 35-40. CHAIRMAN FADEN: I'm sorry. How much was the original? MS. GELLER: The total was about 145 radiation. CHAIRMAN FADEN: No, no. In the non-radiation. MS. CHANDROS: Non-radiation? It's been 50 and 60. CHAIRMAN FADEN: We don't know exactly? MS. CHANDROS: Well, it may be as low as 48. We've had to pull a lot of studies -- CHAIRMAN FADEN: 48 minus 15 would be the worst case scenario. MS. CHANDROS: Under 35 -- 33. CHAIRMAN FADEN: 33. So we would have 87 radiation and 33 non-radiation? MS. CHANDROS: Right. CHAIRMAN FADEN: What would you say? That's too low on the non-radiation side. We'll just take the radiation side down by 20. Twenty would help. I mean, if we could eliminate 20 reviews, that's a lot. So that's one proposal that we should discuss. And the other one is right now we have paired, sometimes paired Committee reviewers and that turns out to be inefficient because if the position we want to take is that every project has to be looked at by at least one Committee member, we could decouple some Committee member pairs, assign you, if you are now currently assigned with a fellow Committee member, and team you with a staff member. And that would allow the Committee to look at more. So, this one, the second one, everybody seems to think is fine. Nobody -- I'm looking for body language. Nobody has any trouble with that one. So the second one goes. I don't know how much that will save us. I mean, how much it will save us from the perspective of Committee members having to look at -- MS. CHANDROS: That would give us about six extra reviews per week, based on what people said that they originally could do. CHAIRMAN FADEN: It's not going to solve the problem by itself probably, or maybe. We don't know. It depends on how quickly it goes. But we're all agreed that that one is okay? Okay. So, that one's all right. So now we're into the other proposal, which is do we want to lower our radiation sample. The non-radiation one may be too low, but for the radiation one, are we willing to say we will shoot for five in each cell and max out at five rather than go up to ten in each? Duncan? DR. THOMAS: I really can't answer this without knowing the timetable and what its impact on the timetable is. My big concern is getting a draft that we can react to, a substantive draft as opposed to just tabulations, that we can react to at our next meeting. Because without that, we're not going to be in a position to finalize it at the May meeting. CHAIRMAN FADEN: Right. DR. THOMAS: Now the subtext of this is if we're still doing reviews up to May 10th or whatever that date is, and at that late date we're trying to finalize the text and we learn new things from ongoing reviews, that's, I think, quite unacceptable. We have to decide that the data collection is finished before the report is finished. CHAIRMAN FADEN: I agree. I mean, -- so let's just do this out loud together, because I don't think it's real complicated. On the one hand, Sara has indicated that it looks like, at least so far, based on 20-some last time and based on 59 this time, we're not finding any differences, but you never can tell when something could happen. So, if we were to -- if the draft that we will have by the April meeting would not be based on all the reviews. That would be unrealistic. But if we closed out reviews by the end of April, that would give us four more -- how many more weeks? We could have a draft but it would be based on however many are done for April. How many more weeks are there? MS. CHANDROS: Six. CHAIRMAN FADEN: Six more weeks. So if we reviewed for six more weeks, if we go with the original end, how many would we have to do a week? And if we threw out 20 studies, -- Jeff's sitting there with his calculator. How are we doing? DR. SUGARMAN: Six weeks; correct? CHAIRMAN FADEN: Six weeks. DR. OLEINICK: It's impractical, though, to think about doing reviews the week of the Committee meeting because we have so much other reading and -- CHAIRMAN FADEN: All right. So we'll say five more weeks. So we'll say it's five functional weeks. How many are left, Sara, to do overall? If we go with the original end and then we'll knock 20 out. DR. MACKLIN: And the original end goal is what? CHAIRMAN FADEN: Take the 48 figure for the non- control. Jeff, it's 48 plus 107. MS. GELLER: 155. CHAIRMAN FADEN: 155. Okay. We'll just say 155. So 155 divided by 5 is 31 a week. MS. CHANDROS: No, no. 155 is the total. Minus 59. CHAIRMAN FADEN: Minus 59. Excuse me. 155 minus 59. MS. CHANDROS: So 94 is the -- CHAIRMAN FADEN: 94 divided by 5. 19 a week. We would have to plug out 19 a week if we are to do -- and if we subtract 20 from that -- DR. MACKLIN: How many have we been doing a week just to get a comparison? MS. CHANDROS: It's varied from week to week. MS. GELLER: The original plan was to do 20 a week. MS. CHANDROS: 20 to 25, but we haven't achieved that. DR. MACKLIN: There are two factors for being behind. One is that we started five or six weeks after the projected start date and the other, I guess, it's been a little bit slower. CHAIRMAN FADEN: I'm sorry we didn't do this calculation beforehand, but basically, it looks like if we don't reduce the sample size, we have to do 19 a week if we're going to finish these all out by the end of April. And if we took out the 20, we would have to do 16 a week. DR. KATZ: But you have to leave the slippage in the assignments because in addition to everything else in the next four weeks we have to read back chapters. CHAIRMAN FADEN: That's exactly right. DR. KATZ: And all other -- and think about things. And I'm sure, speaking for myself, only speaking for myself, but I'm sure probably for some of the other Committee members, too, we have other kinds of obligations. And in a sense, the final Board draft has to take some precedence. CHAIRMAN FADEN: No. Like for this. I realize that. So the notion is if we drop by three a week -- that may not seem much, but obviously I'm advocating doing this because I think there's a practical -- there is no magic to this. If you're drawing inferences based on 107 projects or 87 projects, I'm not sure that it matter a whole hell of a lot. Right? We're at still a fair number of projects that we're looking at in an unusual and unprecedented fashion. So if we can pull out and go three fewer a week, let's do three fewer a week. That's still 16 per week. That means that everybody here, if everybody were to pull their weight, would have to do one per week and a few of us would have to do several a week in order to get the 16 done, now that we're decoupling Committee member pairs. So it would mean that we're all here obligated to do at least one a week for the next five weeks in this collective fashion and we can pull off something I think worth reporting on. DR. OLEINICK: May I just make a comment from my own experience? The first few protocols that arrived, the pack of material was like such. I've discussed this already with Sara. There was just a huge amount. And much of it was redundant. But it took a great deal of time to go through and find out that it was redundant. Don't know -- even though it looks like it's the same, it's not necessarily the same. It has gotten better in the more recent ones, so I would encourage you please to make sure that at least we have a proposal. One package, as you know, came without a proposal. CHAIRMAN FADEN: Some came with two or three. DR. OLEINICK: And some came with two or three. But that saves the Committee and whoever is reviewing it, the Committee or staff member, a great deal of time. And I think -- you know, there are occasions where I could have done another review in the time that it took just to sort out stuff. DR. MACKLIN: Along those lines, another thing that takes a lot of time -- I mean, Sara has been doing a wonderful job, so this is not my complaint or I think anybody's complaint, and it is better after we made our initial complaints. There are still things that take too much time and make for a great deal of difficulty in sorting out the materials. And those are projects that we get that are either multi-center or program project grants. Because with the multi-center one, either we end up using more coding forms and doing one coding form for each IRB submission, which is really two different protocols in a sense. I mean, the proposal is the same, but the IRB's -- CHAIRMAN FADEN: We should just pick one. DR. MACKLIN: So I think we should pick one, if you get ones with several centers, or else what we've been doing is checking. I mean, those of us doing the coding forms have said, all right, the first column is -- CHAIRMAN FADEN: Petition A and -- I think you're right. We'll just pick one when we got one of those. DR. MACKLIN: So even if you got more, I suggest you just wipe one out. The other similar or analogous problem is with the program project grant where the protocol is a huge protocol that may have many substudies. Then you've got the substudies, all of which are being done by different people, and their consent form, their level of consent form is different. So, I mean, that, too. It's like having five different proposals when we look at things like the IRB application. So unless we are interested in covering that kind of material and reporting on it, which I don't think we are -- I mean, we'll have enough information about inter-institutional differences. I suggest here, too, it would just simplify it, because both reading it and then deciding with a co-review, what should we do about this, should we do all of them, should we do some of them, should we just use this one as the model -- takes a lot of time. MS. CHANDROS: As you said, we've been trying to do that and we'll continue to pull those out. In some cases with the multi-centered projects, deliberately we want to review two side by side. I think each of those counts as an individual proposal. CHAIRMAN FADEN: As long as they count individually we don't care because that's one of our numbers. If they get counted as one, we don't want to do it. That's basically what's going to happen. DR. MACKLIN: That has not been the process of individuation that I've seen so far. CHAIRMAN FADEN: So we're now into a thing where it's one study per review. And if it turns out that a thing generates two separate studies, send it to a different group so that people can get on it. It's a huge job for Sara and it's overwhelming. We're trying to do the best we can, but at this point we really - - every piece of paper we don't get is like 10 minutes time saved trying to figure out what piece of paper. And that's conservative. So, efficiency demands it. MS. GELLER: I know that this alters our random -- or efforts at random election, but is there any reason to consider consciously deleting from now on, if we're going to pick some in each cell, the ones that are program project grants? DR. MACKLIN: No. I thought the suggestion here was to pull something out of the program project grants rather than look at the whole thing. That makes it much more complex. Just pull one item out rather than eliminate the whole thing. Pull out one grant element. CHAIRMAN FADEN: I think if we're going to pare down, Gail, we should only do it by randomly collating. We've got four left in a cell which is randomly selected. Also, I think on the comparison one, we think the number is 48 for the non-radiation. We might, if it's all right with the Committee, and maybe we could just run it by Duncan just to make sure it's okay. If there is a case where there's like 10 in one cell and we don't have the table in front of us and we could go to six in that cell, we could get it down to maybe 40 comparison ones. That would probably be all right. But even eliminating eight of the comparison ones would make life a little easier. So if it's all right with the Committee, could we pare it down to 40 comparison ones and 80 -- whatever it turns out to be, so it's sort of still preserving something like a two to one ratio. Eight-seven radiation ones and 40 non-radiation is enough to give you a feel. And we'll just look at the cells from the non-radiation ones. That will take the number down to maybe 15.1 a week or something and save us a little bit. Well, it will take us down to less than 15 a week. Every one we can do and still feel like we have confidence in being able to say something. Plus, we have -- Jay's going to report on his own analysis on these same projects and we'll have a rich base. Ruth? DR. MACKLIN: There's one other methodological point and I want to hear what Duncan says about this. When I saw the preliminary assessments and the figures -- oh, by the way, let me just preface by saying that the least meaningful thing we're doing with these is giving the overall rating. There are many of this number, of this final number. And the reason I think it's the least meaningful is sometimes it may get a lower rating because the consent form and process are miserable but the research is fine. In other cases it may get a low rating because it's a risky protocol and the ratio, the risk/benefit ratio is not favorable. And those are comparing two very different things. CHAIRMAN FADEN: Well, we will obviously pull out the eight or 10 or 15 that fall into that category. DR. MACKLIN: Right. I mean, so the reasons matter more than the numbers but this -- actually, that was just prefacing my observation here. I was surprised to see so many out of the total that received an overall assessment of one, since among the ones that I've reviewed, which is nowhere near the number that Jay has, but it's somewhere in the vicinity of 20, I think, only two were done with my co-reviewer. And I should add that I'm not the one pulling them down. (Laughter.) In at least as many cases my co-reviewer has proposed a lower number. CHAIRMAN FADEN: I think what we should do is clearly emphasize -- DR. MACKLIN: So we need now to mix up the pairs, because I've done quite a number with three other Committee members. And now I think we have to separate those and fix it up a little bit. And I'm wondering if it destroys things or helps things to do it deliberately. In other words, if you could look at the ones done where you've got the guys who said one, and pair them up with the guys who had more of the lower ratings, would that help as a matter of methodology and statistical accuracy for you to rate a reliability -- CHAIRMAN FADEN: We're not doing that. I think more than that it's important for us to realize that the 1's and 2's should be smushed. That there's really -- these are global impressions. It would be very troubling to me if one person's 1 was another person's 5. But if one person's 1 is another person's 2, I really don't care. I mean, that's sort of my view about this. If one person's 4 is another person's 5, you know, big deal. The notion is are they more or less okay or are they more or less a problem. And I think that's how we'll need to report this. I think that's how we'll need to present it. And we probably should take a look to see if there is any, you know, real serious problems. We hope that the pairs would work that out. If indeed you thought something should get a 1 and your colleague thought it should get a 4, that that would precipitate -- you know. DR. MACKLIN: But that would lead to another review. CHAIRMAN FADEN: Right. That's what I'm saying. That's our mechanism. That if you had a disagreement that broad, our system was such that you were supposed to then take it back to the subcommittee and say, look, we really disagree about this. DR. KATZ: Has that occurred yet? CHAIRMAN FADEN: Has that occurred yet? MS. GELLER: Actually, in my experience, I gave a proposal a 2 and my co-reviewer gave it a 5, but I was completely educated in discussing -- CHAIRMAN FADEN: That's different. MS. GELLER: That's a different case. CHAIRMAN FADEN: I think that's a different matter. MS. GELLER: Right. CHAIRMAN FADEN: I mean, after you've discussed it, if you still disagree -- MS. GELLER: Right. CHAIRMAN FADEN: So the issue is have we had any instances. MS. CHANDROS: There's one study that remains to be re- reviewed. CHAIRMAN FADEN: Okay. So basically, if we're having disagreements, I think that that was the internal check. So if people are pulling it down a little bit or it's, gee, I didn't realize that was so risky. This is not my technical area. Or I didn't realize that here was an instance in which you needed assent. I didn't know about assent from children under 7. That is mutual education and that's what would go on an IRB and that's fine. Okay? Obviously, -- you know. So I think that that's how we should be thinking about it. I would hate for us to come out there and say, you know, 20 percent or 30 percent got A's and then a bunch got D's. I think when we report this out, it's the ones that -- might take a look at the 3's maybe to get a sense of it, but the 1's and 2's. The 4's and 5's we're particularly looking at to make sure that a larger group of people agreed that these are seriously problematic studies. And then the 1's or 2's I would report out as no major problems. Forty percent or 50 percent of the projects that the Committee looked at, the Committee saw no major problems and they seemed to be ethically acceptable and no major problems. Lois? MS. NORRIS: Are you finding on the overall assessment that most of the downgrading is being explained under comments? MS. CHANDROS: Yes. MS. NORRIS: Okay. MS. CHANDROS: People have been pretty good about talking about what the major concerns are and what caused them. And mostly, like I said, it was either disclosure of risk, which has to do with the consent process, or the actual risk in the design of the study, which has to do with the science of the study. So it has been both, as Ruth pointed out. CHAIRMAN FADEN: Duncan, and then I wonder if we could go to Jay's report. DR. THOMAS: Yes. I'm all for scrambling the review teams for just the reason you described. Unfortunately, we've lost an opportunity to do a proper inter-variability study. In part because it was my impression that we were each of us going to be sending back our original independent reviews first as well as consensus. Having lost that, it's difficult now to design a proper randomization scheme, setting aside the difficulties of -- you know, just the fact that we have to pair a Committee member with a staff member, ethics systems assignments and so on. So we can't do it properly at this point but it still should be subject to some sort of analysis when we're finished. CHAIRMAN FADEN: That was an intentional decision. DR. THOMAS: I had forgotten that. CHAIRMAN FADEN: We'd given up on trying to do that that way because there were a complex of logistic and another sort of reasons. Okay. If there's silence it's because we're all trying to figure out where we're going to do those 1.2 reviews a week, plus the chapters that we said we were going to get finished. MS. GELLER: What about -- do we have sufficient staff? CHAIRMAN FADEN: Excuse me, Gail? MS. GELLER: Do we have sufficient staff on the staff side? CHAIRMAN FADEN: We may have to hire some staff consultants on the staff side. And we would look for people with IRB experience and also the matching. So if Ruth's been coupled with science types, we have to -- science and physician types, to use her as an example on the Committee, we will be looking to either find within the staff or to hire a staff consultant person who has the right medical or science background to replace one of you who fits that category but hopefully who has IRB experience, as well. And we'll have to scramble. But the Committee judgment and staff is retained by the fact that every pair includes one Committee member so that every project is looked at and evaluated by a Committee member with a colleague who may be staff. Who from now on will be staff and in the past sometimes was staff and sometimes was another Committee member. We should have thought about this in the beginning and realized that there was not a good use of Committee resources to couple Committee member with Committee member and attempt to do these many reviews, given everything else we're asking of each other and the short time frame. DR. THOMAS: It's another thing you know for the next Committee. CHAIRMAN FADEN: Right. Next time we do one of these we'll know how to do this better. Jay? Do you mind if we just go to Jay's because I think -- then we can look at the substance issues the stuff suggested by Sara and Jay's findings, perhaps, of a piece. So, -- DR. KATZ: Look. As a general comment, I really think we are on top of it with respect to the evaluation of present practices and its implication for the future. I mean, before the afternoon is over, we talk about it and figure out what we can do about that. Because in response to Duncan's question, it will be late before this phase will be completed. With respect to my review, and I'll try to be as brief as possible. It may in part have to remain a private review by one Committee member because, of course, it has shaped my thinking about the pertinent implications for the future in light of the work that I've done. But I'm not sure whether I can really complete it because I've already spent an inordinate amount of time on doing what I've done. I've read 120-130 research protocols so far. Fifty of them, of which I want to briefly report to you, I've read two or three times or more and formed some judgments about them. Of course, with apologies to Duncan, on the next page I did a statistical analysis. (Laughter.) Okay. Fifty protocols. I identified 30 of them as being in a certain sense trivial experiments, survey studies, questionnaire studies, most minimal minuscule kind of risks or no risks. And we have 26 and 4. Four raised some minor ethical problems. But since they were the kind of study about which one could be quite forthcoming, everything seemed to be reasonably all right. It may be a testimony to the fact -- to two facts. One is that investigators are more careful now because it has to go through IRB review so they do their utmost to decrease the physical risk issues. And that's of course true throughout. And also, many of these studies are also tracer studies. And it seems to me, I get the impression that with respect to tracer studies, the radiation community has really developed standards and safety standards that are very carefully followed. And therefore, we don't have to be that much concerned about. Now, 20 studies to my mind created problems, except the first four. Four were very, very good. These were risk studies. They were complex studies raising questions, quality of life issues. Raised questions about should one leave matters alone, stay with standard treatment rather than becoming a participant in a research protocol. There were these kinds of studies which I will eventually try to specify more. Four were very, very good. Two particularly are outstanding. And I've never seen informed consent forms like that. That in a very complex kind of situation, the investigators were really able to present in understandable language risk, benefits, complications, alternatives. I've never seen anything like that before. Sixteen were problematic. Six of them according to our ratings I would approximately give a 2 or 3. Five I would give a 4, and five I would give a 5. So now my statistical analysis. (Laughter.) If you use a denominator of 50, 34 are problematic or 16 percent of them, a remarkable figure. And problematic -- 2, 3 -- 12 percent; 4, 10 percent; 5, 10 percent. If you use the denominator of 20, which I would use as my denominator -- CHAIRMAN FADEN: We discussed this, by the way. DR. KATZ: We discussed this. Yes. Twenty percent are very good; 30 percent are 2 and 3; and 50 percent are 4 and 5. I'm sure some of you will comment on my statistical analysis. Look. Time is short. I want to just give you a few descriptions of what I've learned from reviewing these protocols and I will try to be brief for the sake of time. Take one study. It is a chemotherapy study that tried to compare intensive versus milder treatment for Stage 4 low grade follicular lymphomas. The question was do milder treatments work just as well as more aggressive kind of treatments. In the informed consent form, the risks, side effects and discomforts arms of the -- it was a randomized study -- for both arms of the research study were combined. No distinction were drawn between the milder one and the more aggressive treatment. There was no discussion of the quality of life or even no mention -- when I say no discussion, there was nothing there - - of the quality of life issues of one treatment research arm compared to the other. There was no discussion of the medical discomforts which the randomizations imposed on the subjects. There was no discussion about the question of alternative -- of conventional treatments rather than participating in the experiment, even though in the research protocol it was noted that conventional treatments, some conventional treatments really had a very high success rate, 60 to 80 percent in some instances. And none of this was mentioned. I could tell you more but I want to go on. CHAIRMAN FADEN: Jay, just to give an insight, was that one that you rated a 4 or a 5? Do you recall? Just to give us some insight. DR. KATZ: Either 4 or 5. Yes. CHAIRMAN FADEN: One was definitely a 4? DR. KATZ: Or a 6. (Laughter.) One is a study is chemotherapy of cystomas. And let me only mention one thing about that. In an earlier informed consent form, it was mentioned -- and it used a very powerful chemotherapeutic agent. I'm trying to be careful and not identify agents because of the confidentiality issues. Highly toxic agent which they were giving to a maximum kind of dose. In an earlier consent form it was noted that there was a 10 percent mortality with that particular treatment. It was ultimately left out of the informed consent form altogether and just some general mention of toxicity. And in that particular protocol, it was one of the bigger ones that Sara sent us, there was one death report after another included, though it didn't really fully explain where it all came from. Another study, treatment of Hodgkin's disease, grade 122A, and children under the age of 18, a randomized clinical study comparing low level radiation therapy versus low level radiation therapy and an intensive chemotherapeutic agent. One of the chemotherapeutic agents causes -- has a 3 to 5 percent incidence of cancer within three to five years after administration and there was again nothing mentioned about the pluses and minuses of taking radiation alone versus radiation plus intensive chemotherapy, including the fact that in general - - and I have discussed it with three persons very knowledgeable in the treatment of Hodgkin's disease and research of Hodgkin's disease, they wouldn't use that one agent in their combination chemotherapy because of its incidence of three to five percent of causing leukemias. The general -- it was mentioned in the informed consent form that, of course, that malignancies can occur as a result of treatment, but nothing was said about this particular agent, which generally was the culprit for these consequences. Nothing was said about ordinary treatment, which by and large for children, as I understand it, whenever possible -- and it's not always possible -- is radiation therapy. They try to avoid particularly with younger children. Chemotherapy, the toxicities involved, et cetera, none of this in the informed consent form. Let me just give you one more. Actually, that was a frequent issue in various combinations and permutations. Talking about Phase 1 treatments, Phase 1 research -- I'm getting contaminated -- as if it were a Phase 2 or a Phase 3 treatment. In one protocol, which was highlighted both in the protocol and in the informed consent form as the frontline treatment for advanced breast cancer it was never described in the research protocol as research. Always it was treatment, treatment. Much investigation was used for a very interesting reasons because one of the drugs involved was investigational and therefore the insurance company wouldn't pay for it, so they wanted to make clear that the patient research subject would have to pay for that particular medication. That was the only mention of investigation in the informed consent form. Otherwise, it was a toxicity study. They were using a new combination of chemotherapeutic agents where it was known that using them in combination increased myelotoxicity and they wanted to find out what the MPD was with respect to this combination. That was the purpose of the study. It was described in the protocol -- I mean, in the informed consent form, as being treatment, even though they said in the protocol, this is not treatment. This is going to establish toxicity. Once we've done that, we will do a Phase 2 study to determine efficacy. Two of the commentators, probably members of the IRB, said, you know, there's nothing confusing about this protocol because this is not a Phase 2 study, it's a Phase 1 study. The methodology is wrong because it's a homogenation of Phase 1 and Phase 2 issues. And one of the investigators was concerned about it, not only for scientific reasons, but for fairness to the other investigators at the institution because they have been instructed that they must clearly distinguish between Phase 1 and Phase 2 studies. And therefore, they felt this group of researchers should also. Nothing was done about that. And neither of the two commentators who were concerned about the Phase 1/2 complication, made any suggestion that the informed consent form had to be changed to identify that issue. I could go on and tell you -- give you many more examples, but I think this gives you a flavor of what my findings were and what they are based on. CHAIRMAN FADEN: We are open for questions and they can go to Jay or Sara. DR. RUSSELL: I wonder if most or all of the ones, the five that fall into this general category of high risk treatment for malignancies, is that where our big problem lies in general? DR. KATZ: I would -- yes. I think probably four or five or maybe all five are within the area of malignancy. And there's some very interesting additional issues involved. Namely, how do researchers and IRB's deal with situations of hopeless prognosis. None of these I have now -- yes. So that is a problem. DR. RUSSELL: I don't think the numbers, whether they change or not for the next 50 are going to make any difference to the fundamental problem of the Committee on how to address this set of issues. And it seems to me a very specific set of issues around the quality of life, the issues that relate to adding one poison on top of another poison for these kinds of therapy. And I think from a philosophical and recommendation point of view, we need to wrestle that one right, because the numbers, if they go up or down, don't make any difference. The problem that has been identified is out there. DR. KATZ: But what should we disclose to the subjects of research in these kinds of situations. DR. RUSSELL: Well, I think there's two issues. One is what should be arrayed for the IRB in the protocol to make judgments regarding risks and benefits and so forth. That's one part. And according to this evaluation, half of them don't make the grade. And then the other is how do the risks/benefits issues get explicitly laid out in the consent forms. One of the things I see is, from past experience, is that the issues of risks and benefits are woven through a discussion. There isn't a paragraph that says these are all the risks and then these are the benefits, and then here's an analysis of the equation. That is usually not done. It's woven through. So, consciously making a risk/benefit analysis by way of science takes a little intellectual work. DR. KATZ: Yes. You can't identify the threads because it's so interwoven. DR. RUSSELL: They're interwoven. DR. KATZ: Yes. And that's the problem. And, by the way, you raise another important issue that I've also paid some attention to. The IRB's I think are not sufficiently informed by the investigators about what the issues are and the IRB's seem to accept that or not comment on it, by and large, and on the basis of incomplete protocols make judgments about the acceptability of the protocol. CHAIRMAN FADEN: Henry and Ruth. DR. ROYAL: I just wanted to say that I completely agree with Jay's comment about the quality of life issues. They are extremely -- to me they're even more important when someone has a limited life expectancy. I mean, if you're going to live six months, you'd like to know what those six months are going to be like if you participate in the research or if you don't participate in the research. The protocols I've seen don't give a very good description of what to expect. I think the problem with chemotherapy is that there is evidence of the more intense the chemotherapy is, that it in fact does help. And that's sort of the dilemma that they're faced with. When I say there's evidence, there have been some successes and so that's the motivating force. That even though you know that it might be an uncomfortable experience for the patient, it's possible that you might shift things around a little bit and have more survivors, less morbidity long-term. One of the problems that I didn't like is not only don't they describe the quality of life issues very well, but they also don't give the patients any reasonable expectation of what the benefits might be. Are we doing this intensive chemotherapy because we think that there might be a chance of a cure? If we think that there might be a chance of a cure, what percentage are we talking about? Are we talking about a gain of 2 or 3 percent or are we talking about a 50 percent chance of cure? If we're talking about prolonging life, are we talking about two or three months or are we talking about year? What's your expectation? I mean, I know that you can't answer it exactly but what would be a reasonable expectation. And maybe they're not even talking about extending my life. Maybe they're not talking about a cure. Maybe they're just talking about improving the quality of my life. But the benefit is really never explained in any way that you could make an intelligent decision about whether you should participate. CHAIRMAN FADEN: Ruth? DR. MACKLIN: Yes. There are certain things we cannot tell from this review about the IRB process. And I suspect that it's very, very involved and that in some cases -- I mean, Jay just made the remark that the investigator isn't telling the IRB about certain things. I don't think we know whether one of three things is happening. A, the investigator is telling either the IRB or a primary reviewer because we don't have any evidence about what a reviewer in the IRB who is assigned to review the protocol is saying over and above what kind of pieces of paper we have. So we don't know whether the investigator is saying more orally, if the investigator is present. B, if the investigator is saying something to the primary reviewer who then conveys it. Or C, even if these things are said, the IRB is approving it anyway. So -- even with the information. So, I mean, in a sense, we have to be agnostic about that. Now, just as a piece of ancillary information, I was struck, quite surprised to learn in a bio-ethics discussion group over the Internet that a distinct minority of IRB's have as their procedure that the investigator, the principal investigator, come before the IRB. I was struck by this since they do in my own, and I know they do in others, come to present the protocol and answer any questions. And the overwhelming response among the people who replied to this -- Jeff probably has seen the same thing -- was that it takes too much time, wastes too much time. Investigator comes; runs off at the mouth. Investigator comes and is disdainful of the IRB members as being a bunch of dummies who don't know anything about research. And among the respondents of this -- it there was a very small number. I think two out of 20 or so said that the investigator comes before the IRB. Now that's ancillary information to what we're having but it tell me something. And if it's so, it sort of may explain. I mean, they of course then go on to tell the primary reviewer -- the process of primary and secondary reviewers. But that's only going to be as good as -- if the people who think that too much time is wasted when the investigator comes to the IRB, they may also think that too much time is wasted. So I think there may be a huge variability out there and we don't know what to attribute. CHAIRMAN FADEN: I think that's the core issue. What we know is that these are approved protocols that people have been authorized to go ahead and do these studies based on the description of risks and benefits and the consent forms that have been approved. It's remotely possible that some of them have been revised, but basically they were approved and people were given authority to go ahead and do this to people, enroll them in these studies. It is a black box and we can all have inferences and guesses based on our own experience as to why when things have gone wrong. And in these eight cases or 10 cases or however we slice it, things apparently have gone wrong, why they went wrong. But we just had to be very clear that what we can say is these are projects that have been approved by IRB's in the format which we got them and we are concerned about these. We can all have educated guesses about why they ended up the way they ended up and maybe even enough so that we can make recommendation about how things might be improved. But we do have to be careful -- I think Ruth is right -- to say we can't know for sure why they ended up. And there may be different reasons every time. Jay? DR. KATZ: Well, I know one thing for sure -- a number of things for sure. I know for sure that the IRB are charged with the responsibility. And one of their primary responsibilities is to review the informed consent form and to approve the informed consent form. On the basis of my review, they're doing a lousy job in 50 percent of the cases. This I can document to my satisfaction. That we know. We also know -- I also know that if after all our majestic principle is principle one of the number code, then the voluntary consent of the subject of research is absolutely essential, that in the present day and age, that principle is not being implemented. And I'll leave for this afternoon or next time, but I hope we'll have some time this afternoon, to discuss what my views are on where do we go from here in terms of future recommendations. But it's a very important issue. CHAIRMAN FADEN: No. I think that however we want to slice the percentages, Jay, the point -- your point is well taken. What we have here are approved protocols. That's the power of this analysis. They have been approved and people have been authorized to go ahead and do this study with the consent form that we have, unless we've been given bad information, and with the risk/benefit balance as it's described. So this is not -- and that's powerfully important information. These are approved projects and they are allowed to go forward. People are actually doing them. And that's different from other kinds of contexts where you're looking at things in prospect. I wonder -- just real quickly. I know we have a lot to talk about. The four that thought were very good, were any of them complicated chemotherapy trials? DR. KATZ: Yes. One. CHAIRMAN FADEN: See, I think it would be very nice to put side by side to show to the world, look, it can be done well; right? It isn't being done well. And in important instances. But it can be done. DR. KATZ: I'd like to give you one of them and see whether we can circulate it to the Committee. I find it very impressive if we can sort of keep it and do that. CHAIRMAN FADEN: And that may give us insights into recommendations, too, like here. It can be done well. Yes? DR. RUSSELL: How many of the inadequate consent forms seem to you to result from this tension between readability and explicit specificity of all the -- you know, there's endless discussion on all -- and whether the argument comes down on the readability and simplicity and reasonable brevity versus the specificity and detailed exposition is going to determine whether the consent form is looked on by an independent evaluator as adequate or inadequate. How many of these seems to be a result of that in particular? DR. KATZ: I don't -- you see, I don't think so. And I've thought and written just a little bit about it. Most of the consent forms are three or four pages and double spaced. And the one that are nine and 10 pages are the worst ones. But the problem is, and that is that I would say that in defense of IRB's, though they do it all so slavishly, they are constrained by the federal regulation's requirement to go through A, B, C, D, E, F criteria. Even though I think many of them in my view don't need to be mentioned or need to be mentioned only most briefly, and the kind of issues I've identified, I think they can be written in two or three sentences to give the person who signs it an idea of what is at stake. So, I think a good informed consent form by deleting lots of unnecessary information and including some necessary information that would give the person an idea of what this is all about would not make the informed consent forms longer. But let me in two minutes and then I'll shut up, or less than two minutes, tell you an anecdote. Okay. Last week I talked to a distinguished medical research scientists and I gave him two hypotheticals based on my review and said I want to ask you three questions. Do you think that -- one, do you think the following information should be given to subjects of research. And he said, yes, of course. In order for them to arrive at a considered judgment as to whether to participate or not. And I gave him the information and he said of course, they need to know this. Two, do you think this information can be provided in simple enough language. The answer was yes. The third question was would you provide the subjects with this information. And he said no. And why not? Because too many subjects might refuse participation and it may take too long to accrue the requisite number of subjects. Then I asked him another question. Do you have any experience with this happening when you've really informed the subjects of research. He was very thoughtful person and he was quiet. And he said, you know, Jay, I've never thought of it. I've never tried it. DR. OLEINICK: Can I ask just one other question of Jay? CHAIRMAN FADEN: Yes. DR. OLEINICK: Of the protocols that you reviewed that you rated 4 or 5, I think you alluded to one and I'm just asking you is the number larger than that, of a research project that, even with the best consent form in the world, shouldn't be done? Do we have any of those? DR. KATZ: I have a number of them. I have a number of them in the other 50 that I haven't gone over yet because, you know, I've never had that experience of, in a relatively short period of time, really seeing a mass of -- reading a mass of protocols. And some reason or other -- by the way, these are consecutive. I didn't make any selection on the basis of -- because they seemed to be more problematic than others. The first 50 in order of -- that I received them. But I'm now in the second bunch, I'm getting more protocols that deal with situations of hopeless prognosis where the patient subjects are really very, very sick. And I wondered, after reading three or four of them, should these -- and these are really heroic treatments that the patients are being exposed to. There's no mention in the application to the IRB the question should we do this kind of research; should we leave them alone. There's surely no mention in the informed consent form about the alternative of no treatment except, you know, it's mentioned somewhere in passing, but in a meaningful kind of fashion. Because one might wonder if the persons really knew what is in store for them undergoing what the investigators had in mind in the hope of finding -- I mean, these are well intentioned people -- of finding a cure, then many of them -- a number of them at least, maybe not many of them, but who knows how many might say it's time to pass on. CHAIRMAN FADEN: I have Henry and then I think maybe we should take a break since this is break time. But Henry, Gail and Sue, and then we'll stop. Henry? DR. ROYAL: Jay made all of the points much more eloquently than I could. Thank you. CHAIRMAN FADEN: Gail? MS. GELLER: I would like to add to the list of things we don't know about the IRB's whether they've decided it's within their purview to make some assessment of scientific merit. And it's relevant because I think in some cases where some of the risk/benefit analyses are absent, it really may be -- and it's particularly true perhaps in some of these very complicated cancer treatment cases, it may really be because there's been some decision that the study section will decide. That it's just not -- I mean, I have certainly experienced it in my own institution this debate and I've certainly had discussion a lot with you, Phil, where something that strikes you particularly is the scientific merit issue. And I know that there are some IRB's that have decided that it's not within their purview. DR. RUSSELL: And there are situations where there's no other organization or system to lay it off on but not within the purview of the IRB and there isn't any funding agency that picks up that responsibility or there isn't an internal requirement within the institution to do it. You could envision the funding, the private source, would have no oversight of the science. If the IRB doesn't pick it up, there's nobody else. It will drop right through the cracks. CHAIRMAN FADEN: Sue? DR. LEDERER: I have two brief questions that maybe Sara and Gail could answer. I wondered if there's any distinction in the protocols which we have reviewed between research involving healthy subjects and those involving sick patients. And my second question is you note that the level of proposed payment is a concern. Is it a concern for the reviewers or for the IRB's? And secondly, is the absence of compensation ever flagged as a concern? MS. CHANDROS: I'm going to answer your second question first. When I've reported on those numbers, I think it was two out of 25 studies raised concerns in our reviewers. We don't always know how the IRB deliberations went. Sometimes we have correspondence and minutes but that wasn't the crux of what we asked for so we don't reliably know how they responded to the compensation. The absence of funding? I don't remember. I haven't really focused on it but I don't remember seeing that in any cases, but it's something we can look for and reviewers might want to, now that you've alerted it. Reviewers can keep that in mind also. Regarding the distinction between healthy patients or sick, we did the therapeutic diagnostic, that breakdown, but we know that doesn't always reliably -- therapeutic studies involves at least some sick individuals we would think. Diagnostic studies could be either. The proposals themselves, I think those distinctions are made when the subject population are reported. We have a tally. If you look at the percentages in the second handout I gave out, there's a tally that says how many studies explicitly state whether healthy individuals, whether hospitalized individuals are included. So we do have figures on those. CHAIRMAN FADEN: We haven't broken it out yet. MS. GELLER: And we certainly have the capability to do that if that's important. CHAIRMAN FADEN: This is the only source of information we have about research with healthy subjects. DR. RUSSELL: But the small numbers, have we identified any number of high risk normal subject protocols? CHAIRMAN FADEN: We haven't looked for it yet. What we need to do at this point is we need to very quickly take a look and see how many studies we have that involve normal persons. DR. RUSSELL: Not a lot of them. And I don't think -- DR. KATZ: I haven't found any. I've been looking for that in the 120 I've looked at. DR. RUSSELL: There aren't an awful lot. DR. KATZ: Yes. I haven't found a lot. CHAIRMAN FADEN: It may be that we'll do 100 of them and there won't be a study that has maybe a few normal controls, quote/unquote, but we may not have any. DR. OLEINICK: We're picking oncology and cardiology. CHAIRMAN FADEN: Well, not in the other ones we aren't. In this one we're just taking it -- DR. OLEINICK: Yes. That's right. DR. KATZ: We have a number of normal volunteers. CHAIRMAN FADEN: Volunteers. Right. So we have to pull those out and see. DR. RUSSELL: But they're mostly in the small, in the - - DR. MACKLIN: But Ruth is right. I think that the ones that have normal controls, there are some that have normal controls that do involve, at least I can recall one or two, that are risks that are more than minimal -- CHAIRMAN FADEN: To the healthy person. DR. MACKLIN: -- to the healthy controls, the normal controls within a study that is comparing the healthy controls to the patients. CHAIRMAN FADEN: And the epi studies may well have populations that are not hospitalized or not ill. But whether we have a study where it's only being done on healthy persons that involves medical like interventions, I don't know. We haven't seen vaccine trials or anything like that. DR. LEDERER: Well, the studies stipulate students or specify students and they presumably -- CHAIRMAN FADEN: So we need to focus -- that's the message. We need to pull that out and take a look and see whether we've got -- because again, looking at our history, we know that there are reasons to think that things may have been different in the past. So the question is are things any different. MS. GELLER: I would like to be a little bit clearer about Sue's point about cost. Are you interested in compensation? Not to the cost to the subject? DR. LEDERER: No. I'm interested in compensation. CHAIRMAN FADEN: So the issue is is there any one of us who said, "They should have paid somebody?" DR. LEDERER: Right. CHAIRMAN FADEN: It's like the flip over. How come they're not paying this person to do this as opposed to -- is that right, Sue? Rather than -- as opposed to the issue of they're paying them too much? DR. LEDERER: Right. CHAIRMAN FADEN: There's kind of a flip over as to that's a huge imposition and should they at least be paid for their child care or something. DR. LEDERER: Well, because it suggests that if they're getting a high rate of compliance, I mean, why are people agreeing. MS. CHANDROS: Actually, there is one study where the issue, the cost to the patient and the compensation kind of overlap. One reviewer noted that the subject was required to pay for the experimental medications, they or their insurance. So that was the flip side. But yes. Not only are they not being paid but they're being asked to pay. And it's particularly problematic, I think, in these very complicated high risk cancer treatment protocols where cost becomes a part of the risk/benefit calculus. I think greater prominence if you have four months left to live and you're asked to spend everything you have. CHAIRMAN FADEN: What has happened clearly is the group - we need a break. We're breaking down into too many two-way conversations. Thank you all very much. This is clearly important and we've made a dent in it. (Whereupon, a recess was taken.) CHAIRMAN FADEN: Do we have any -- yes. We have some Committee members, but not many. I wasn't paying attention in terms of the agenda. We have to return to the backward looking recommendations or the recommendations to the past, but I think this experience, the discussion this morning, has us all thinking about the future and the current situation. And I'm inclined to think that maybe we should spend some time on contemporary, future oriented recommendations since we're all thinking that way and then just make sure that we return to the discussion about situation 1, 2, 3 and 4 that we were having yesterday after lunch. I just think people's minds, at least my own mind right now is so filled with thoughts raised by Sara's and Gail's presentation and by Jay's presentation especially that I kind of think it's weird. So does everybody -- that we focus on the future ones for right now? Again, remembering that these are initial passes, quick cuts, ideas being thrown out and mostly to stimulate discussion. What did I do with my copy of it? Here we go. It's something called Final Chapter: Coming to terms with the past; looking ahead to the future. And if we could just -- it starts on page 21 and the format is there are headings and there's a little rationale and then the draft Committee recommendation is in bold. I think the purpose now is not to nitpick about language but basically is this general thrust appropriate. Is this an area about which we want to make a recommendation and is this framing of the recommendation going in the correct direction. And the headings -- we start with recommendations with respect to openness. Those recommendations don't flow directly from the discussion this morning. I'm wondering if we should skip ahead while we're thinking and go to page 27 and then go back to the openness recommendation, because we're all thinking about the conduct of research, based on the discussion this morning, a discussion of what people would propose, remembering that this is just a very rough, very rough cut and we don't have our findings findings but we've heard some preliminary findings now from the contemporary projects. All right. So we're on page 27. I don't know how to do this except by sort of marching through. March through some of these and then if people want to stop at some point and say this is okay. But what I really think needs to be here is something more along the lines of this or this is inadequate. We can start to discuss ideas that haven't been written down and see if there's a Committee sense, a Committee feeling that that idea is worth pursuing and then we'll try to get written language either from the Committee member who proposes it or from the staff. So, we're on page 27. The first area -- this is under the heading Preliminary Recommendations for the Prospective Review and Conduct of Human Subject Research, so this is right on the point of this morning's discussion. And the first recommendation that's proposed here addresses the question of -- addresses the importance of finding mechanisms to more clearly distinguish research from treatment in the process of soliciting consent from potential subjects. The specific proposal is kind of ironic because we heard from Sara this morning concerning the tiny boilerplate. The argument here is the opposite, massive overplate boilerplate that would be required which is very plainly signalled to anybody looking at it this is not like the consent form you sign for surgery. This is not a consent form you sign for admission to the hospital. This is something different. This is a consent form for -- and then based on the subject interview study, whether the term should be medical research, medical experiment or clinical study is something that is in itself worth debating. And we could wait for the results of the subject interview study to get clear on what we want to say, but we already know that if you call it a clinical -- we already suspect, based on the subject interview study, that if you call it a clinical investigation you will get a different reaction from people than if you call it a medical experiment. And so we have to be thinking about that and there may be recommendations about educating about the public about what these terms mean and so on. This is a recommendation that's very particular or boilerplate. It would be for the opposite purpose of standardizing the message to potential subjects about whether this is research or this is treatment. Henry? DR. ROYAL: In the footnote, it says that you want to clearly communicate that the primary intent is research to advance medical knowledge and not to enhance the welfare of a particular patient. I think that, yes, that's the word we want to choose. But the other thing that I was hearing about the subject interview study was the amount of risk was also varied, depending on what word you used. And it's not clear when we select the word, how that factor is going to fit in. Is it better to pick a word that makes it sound more risky or is it better to pick a word that makes it sound less risky? CHAIRMAN FADEN: I don't know. I mean, I think we have to think about that. I don't know that we can prepare that right now. Or maybe part of it is we need a massive educational campaign that goes out to people in some way to educate people that these terms don't really mean anything differently. I don't know, but that's a very good point. What we do know is that it doesn't all mean the same thing. DR. OLEINICK: But maybe we should be using more than one term. That it should be saying: "This is a research project. An experiment is described here which will involve a clinical investigation," or some such as that, just so that whatever term they use, it's there. CHAIRMAN FADEN: Another recommendation might be get rid of all these terms. Call them research projects and don't let people use words like study, which tend to be more reassuring, or clinical investigation. That sounds more reassuring. And just emphasize that the key issue is to communicate to people clearly what's in that footnote. That this is primarily being done to address the scientific question and not to treat you. And that if there's a potential benefit to you that might flow from that -- but rather than pick the right term, simply say don't use any of them unless we have a standardized thing that everything is called a research project. DR. ROYAL: I'm wondering if in that standardized heading that says "This is a research project," whether it should go on to say that has minimal risk, substantial risk, right in the title. CHAIRMAN FADEN: In the big bold stuff at the front? DR. ROYAL: Yes. So that it clearly communicates that it's research and it really gives people some idea right up front whether we're talking about something trivial or something that might have significant risk to it. CHAIRMAN FADEN: It's worth considering. But is there some general sense of agreement that there should be -- that this recommendation is worth pursuing with respect to distinguishing research from treatment in some standardized way that's bold, that makes the form look different and doesn't have obfuscating - - this is a clinical investigation study; welcome. You've been chosen. Sort of like when you get -- I keep thinking about the Sweepstakes. I haven't been fortunate to be selected by somebody for a one in 10 million chance of getting a condo or some swamp - - (Laughter.) So, we need to make sure that this is treated at a much more -- and I think it is generally. I don't mean to be so facetious. But that general sense that we have to be real clear about this. Yes. I see Lois and then Phil. MS. NORRIS: Yes. This is really pretty picky, but I think sometimes language which is expressed at the top of a form in bold face tends to be overlooked. CHAIRMAN FADEN: Oh, really? MS. NORRIS: People go immediately to the body of the form and look for the things that apply to them as individuals. So I don't -- maybe that's my own way of doing things and maybe other people don't do it that way, but people tend to overlook the titles and they tend to overlook the captions on the top of the form and go to the guts. CHAIRMAN FADEN: I think that's a good point. And obviously, we can suggest that somebody empirically test this. Just like the subject interview studies are empirically testing that these terms mean something different. But we could have a recommendation that says, look, whoever this recommendation is directed to, this is the objective and you figure out the best way empirically to accomplish this objective. Here are some suggestions the Committee has. We don't have the time to run these little tests but we've established, as other people have established, that you can approach answers to these questions empirically. Figure out which would work. But something that had a boilerplate instruction: This is consent to a research project, not for a -- and then in the body it's repeated again. The purpose of this is -- what a research study is. This is the purpose of which you -- but whatever. I think your point is well taken. We should probably resist making very particular recommendations unless we're sure that that very particular recommendation is exactly as it should be. Lois, I think you're right to say that we can lay on somebody else that the recommendation is to figure out how best to do it. This is the problem. Here are some suggestions worth trying out. The message is clear. Figure out a way to make sure that people are not going to be confused about the difference between research and treatment when they're approached in the context of clinical care. That's great. That's very important, Lois. Thank you. Phil? DR. RUSSELL: I'm a little behind the curve here. I was wondering how -- what the intent was in terms of operationalizing these recommendations. Who are these recommendations to and are we making a recommendation to all the advisory committees of the world or are we making a recommendation to a specific federal officials for operational -- I mean, what's the operational context for these recommendations? CHAIRMAN FADEN: It looks like Ruth wants to speak to that, and also Jay. Let me just say that I think we can direct it to whomever we want. DR. RUSSELL: Yes. But to be effective we have to -- but the onus for operationalizing it -- CHAIRMAN FADEN: I agree. DR. RUSSELL: -- on some individual, whether it's the - - CHAIRMAN FADEN: So we need to be thinking about that. But I'm just saying by way of backdrop, there's a way in which all of this is delivered obviously to the Interagency Working Group and to members of the Cabinet that we know about which agencies they are, but we can also be more particular and specific and go outside of government or within government, too. And that's obviously part of what we need to be thinking about. But we're not constrained. We can recommend to whoever we want. Whether they listen to us or not is a separate order of problem. DR. RUSSELL: I'm just concerned that we -- CHAIRMAN FADEN: Right. I agree. DR. RUSSELL: -- are specific when we make the recommendation, not just throw them out for the world. CHAIRMAN FADEN: Somebody out there, please fix this. Right. Somebody out there please fix it would not be a good idea. Ruth and Jay, I think. DR. MACKLIN: I had the same question that Phil asked but I think we should be more specific since we can address anyone. But what underlies this question, this is not a question that applies only to this one, obviously. It's the next one, communication of medical benefit. In all of these we're recommending something about the consent form, which is a piece of paper. I mean, we can say something about the consent process, but the piece of paper. I think we have to ask whether -- it could be to OPRR or whoever that we place in the federal regulations. But I think the underlying question is not only to whom, how it would be implemented and to whom, but also whether we are taking a stance that there be uniformity in all federally funded research, which moves things a bit beyond where they are right now with the IRB process, which is presumed to be semi-autonomous. Now, we're calling for more consistency among IRB's, and particularly in light of some of these findings. And I think we have to recognize that the implications of that are more than -- I mean, in addition to the implementation are that there be a kind of higher level uniformity that meets certain standards between and among IRB's in order to be acceptable. And that does take us beyond what the current situation is with IRB's and it may be not very pleasing to some people who think there should continue to be that kind of autonomy. CHAIRMAN FADEN: Jay and then Dan. DR. KATZ: Well, Phil just raised what to my mind is the most important question and I've thought a little bit about it. I believe -- I would answer your question that the federal regulations need to be radically revised. I think they are inadequate. They are cumbersome. They put requirements for IRB's that I have questions about and they don't emphasize sufficiently the important points that to my mind they should emphasize. I've made the suggestion, and some of you have read it, that we really need a national human investigation board that really wrestles with these issues of informed consent forms, of giving better instructions and continuing instructions to IRB's, that reviews at times what they are doing, that has some overall administrative function. That's the direction in which I would go. And these recommendations are couched in terms of, many of them, in terms of the IRB should do X, Y and Z, but I don't think that's going to be too helpful because why should they accept our recommendations. And who will see to it that they follow whatever we may wish to recommend? CHAIRMAN FADEN: Dan and then Phil. Did you want to respond right away? Let Phil respond. DR. RUSSELL: I think that I'd like to make two comments. One, a search for uniformity across the federal government is more likely to bring down the average than bring it up. (Laughter.) And it will prevent leadership. I think we've found excellence in the system. Trying to make the system uniform is, I think, probably hopeless to begin with and almost certainly don't bring the total thing down. The other -- and I tend to say the same thing about adding another centralized level of the bureaucracy. That I don't think it's going to solve the problem. DR. GLATSTEIN: No one wants to pay for it; right? DR. RUSSELL: Well, again, that's an issue of political acceptability and the reality of the times, too. So, while I understand your intent, and I fully support it, I'm not sure that operationalizing it in that way is exactly the right choice. DR. KATZ: Do you have an idea? DR. RUSSELL: Not yet. Not one that I'm going to lay out on the table. (Laughter.) CHAIRMAN FADEN: You know, Jay, I think it would probably be helpful if we circulated to all the Committee members your article and I think that lays out the major case, the case for the position that you're proposing, well. And we should all take a hard, hard look at it, because I think there's an awful lot that is meritorious of what you proposed. And maybe you want to take a look at it, too, and see if in the light of these findings, you would like to supplement. That would be very helpful. We could circulate the article, plus whatever in addition -- DR. KATZ: I'll try to get something to the Committee. CHAIRMAN FADEN: That would be very critical, so that we can pursue this further. Dan and Eli. MR. GUTTMAN: Yes. And Anna made a comment which probably deal with this more carefully. One of the things that was quite interesting when these were discussed on the staff through E-mail, was there were a couple of comments saying it's really interesting. It jumps out that all these recommendations are that government should do less. You know, we should have a new centralized this or more regulations, whereas this is all about individual -- VOICE: -- behavior. MR. GUTTMAN: Right. And none of them were citizens should do X. So it may be Pollyanna-ish, but just to think about a supplement, not certainly exclusive, but you know, maybe anybody who would go into an experiment may want to ask the following questions. You know, just to cast some of these in that -- as a think directly at -- if we're talking about who the audience is; right? And if it is the public as well as the Secretary of the agency, what a citizen might look at as a recommendation to say, you know, this is what you should do if you're going to be involved or your family member. That kind of stuff. DR. RUSSELL: There are some things that the federal government does very, very well and there are some things that it does very, very badly. I think we ought to just differentiate between the two. CHAIRMAN FADEN: I know what you're talking about. Eli and Sue? DR. GLATSTEIN: Well, along the same line, it seems to me that the key to being able to supervise some of this is to tie conditions to the funding of some of this research. It could be done through structures like the NCI or American Cancer Society whereby funding would not be granted unless the institution can show that it has these kinds of programs in place; educational programs for the IRB. And there should be probably an ACS type of national conference on responsibilities of IRB's, a function of that sort of thing. I think it can be done. The problem of trying to do it through the government is that in a time of reducing the budgets, there's not going to be any money to hire new people to carry out these kinds of additional functions. And in the case of the institution, NIH, it's not been a regulatory agency. That's not its function. And that sets up for some real problems. CHAIRMAN FADEN: So that goes to some core issues. DR. GLATSTEIN: But if you tie it to funding and put the pressure on the institutions -- CHAIRMAN FADEN: You also, then -- and this is later. Then you also have to tie it to some kind of outcome performance measure to be able to -- there has to be some way -- DR. GLATSTEIN: That, I think, can fly. It is not perfect but there isn't going to be a perfect solution for this. CHAIRMAN FADEN: Okay. Sue and Ruth. DR. LEDERER: My question is actually for Phil. His answer, I think, would be useful to helping me think through some of these issues. Do you think that the federal regulations that created sort of the IRB system are not effective in improving the conduct of human experimentation? DR. RUSSELL: No. I think the work. DR. LEDERER: So you said -- well, I guess I was going back to your comment about -- DR. RUSSELL: The question is -- we have a system in place and the system clearly works when it's being run by a concerned and educated and affected people because some of the outcomes is very, very good. Then the question is what about the bottom five percent or 10 percent or 20 percent of high risk? Why isn't the system working in those instances? And the question then comes, is it a -- can you change the outcome by tinkering with the system, by putting additional bureaucratic constraints on it or bureaucratic pressure on it. Can you change it by changing some of the rules and regulations? In other words, can you fine-tune the system to make the outcome better or is there something intrinsic about the operation of the system, the people and so forth, where the target is. And I tend to believe that any more regulations -- simplifying regulations, I'll go along with. Adding more regulations and adding more bureaucracy is probably counterproductive at this point. We need to figure out how attack the problem of educating the people and putting more responsibility into it. It's already bureaucratically onerous for a lot of the people involved. The time issues that they -- DR. KATZ: Phil, I would exempt 50 percent of protocols from review. I think we can specify -- DR. RUSSELL: And figure out how to cut out the workload and focus on the risk/benefit issues for the important once. There's ways of doing that. And simplifying the regulations, changing the focus and so forth, that's certainly probably a productive way to go about it. But I think the education at the operational level is equally as important. And how does the Committee reach out to that world and get that message through is what Eli addressed here. CHAIRMAN FADEN: We haven't mentioned education recommendations that come in later with the certification proposal, et cetera. DR. RUSSELL: But they're totally related. CHAIRMAN FADEN: It's all of a piece. I think this is all of a piece. And the issue is how much can we -- how specific can we get as a Committee in our recommendations versus -- DR. GLATSTEIN: Well, most of those IRB's are comprised of people that want to do a decent job but there's a tendency to get carried away because the workload is really enormous. And there's also an underlying sympathy within the IRB for the investigators. You know, everybody's got it's own work that they want to carry out. CHAIRMAN FADEN: Sure. Absolutely. DR. GLATSTEIN: And there's an underlying theme that the study is so good, you know, we've got to make a little extra allowance for this. Sort of ends justifies the means kind of thing. I didn't honestly think there was this much of a problem until we started this protocol review and I'm surprised it's as pervasive as it is. But that's the way it is and I think that there is a need to address this problem more directly. And I think the only way it's going to work is to put the pressure on the individual institutions to make the IRB more important than it has been, emphasize the education, and tie it to funding. And I don't think there's going to be a better way to do that. DR. LEDERER: But not by stipulating that greater citizen involvement be necessary for IRB operations? DR. GLATSTEIN: Well, that's another way of improving the problem but I don't think it's going to be enough by itself. And who's going to do that? I think you have to make the institutions do it themselves. And I think the only way that's going to fly is by tying it to funding. DR. RUSSELL: Many of these problems that are addressed here are not the kinds of things that citizens, lay citizens, can deal with. The risk/benefit issue is very professionally specific here. DR. GLATSTEIN: Most of them have one or two lay people on the board. Maybe they need to have more. CHAIRMAN FADEN: Well, it's also tied to training. This is all of a piece. If you can say that to the range of everybody out there, look, if you are being approached to being a research subject, here are the things you want to ask and here are the kinds of answers you should be receiving. You can provide that training to people who are not professional bio- medical investigators before they go on IRB's. There actually have been some studies that have shown that you can prep patients and effectively change the exchange between patient and doctor by a session in advance of going into the doctor's office that says, what do you want to find out; let's practice it; blah, blah. And you can bring people's abilities to become assertive in a specific context. You can't do that for every potential person who might be approached as a research subject, but you can certainly do it for lay members of IRB's. DR. GLATSTEIN: The IRB's need guidance, too, actually. that's the point. CHAIRMAN FADEN: Yes. DR. LEDERER: I know. But for me, one of the lessons of this Committee has been sort of the distrust in expertise and sort of strengthening the powers of experts. It doesn't strike me as something that's going to please American citizens on the whole. DR. GLATSTEIN: Maybe it will be that there needs to be broadening of membership of the IRB's to include more lay people. I don't have a particular problem with that, although I would hate to see more of them in majority. CHAIRMAN FADEN: I have my list and there's Ruth and Henry who have been waiting patiently. DR. MACKLIN: What this conversation, discussion, suggests is that these recommendations are not directed towards only one body or group and that we might want to give a little thought to whom they might be directed and name those individuals or agencies. As Anna and Ruth know, in the report that the IOM did on Women in Research, many gave a lot of thought to addressing recommendations to IRB's, investigators, IRG's, funding agents, et cetera. The IRG's being the study sections. Because some of them really have more impact if they're going to be implemented. Now, Jay's question will always remain, "Who's going to listen?" You know, if there's no teeth in it and who's going to listen, that may always be a problem. But people might listen better. I mean, as Dan pointed out, one sent to citizens. And maybe some of these recommendations might even have to be broken out in certain ways; citizens or prospective research subjects should be thinking of doing (a) or (b). And then Eli's point about the funding agency. So that they don't just get lost as recommendations made in the air but that they be targeted. And it's certainly possible that any one of these recommendations might be directed at different bodies or agencies who may have different tasks to do with respect to them. So I think we should try to give a little thought to to whom they might be addressed and to whom that might -- and how that might be effected. DR. GLATSTEIN: Well, if you try to get funding for animal work, you have to show that you live up to certain -- the institution has to show that it has an animal program and lives up to certain standards. I don't see why you can't do the same with the IRB's. DR. FADEN: I think what we're getting to is -- if we could move ahead. And I want to move ahead on Look Backwards. And there is, if you march through it, there's -- maybe what we could do is start right now for getting a sense of whether these are the right Committee views and tentative agreement that these are areas about which we want to make recommendations. And then we can refine it. So one is on the distinguishing of research and treatment. There was consensus that this was one. Just moving through. The next is on this articulating the medical benefit issue. Jay has given us some wonderfully compelling examples of the problem that remains with respect to the appearance of more benefit than perhaps or in fact is there. The area that's identified on page 29, Back to Basics, emphasizing why consent is being sought. A nothing, I think, that has emerged in the discussion that the consent forms are -- ones say too much and say too little, is what this is intended to capture. We've lost -- perhaps lost sight of what are the most essential elements that we are trying to communicate. In some cases, at the expense of veracity. The notion behind this is if you give somebody tons of details about the risks of the therapy and they don't understand that it's an investigational drug and this is a Phase 1 trial, who cares kind of thing. We drown them in detail about what could happen but they think it's the latest and best treatment. DR. GLATSTEIN: The Phase 1 program was largely supported by drug companies. CHAIRMAN FADEN: Which raises some points. DR. GLATSTEIN: Yes. DR. RUSSELL: There's no lever here. CHAIRMAN FADEN: You see, if you put the leverage on the university or the research institution that says, okay, you've got to meet these standards regardless of where the source of funding is, performance outcomes. So figure it out. But we should identify that. DR. GLATSTEIN: That's right. I think those kinds of things I think can be built in. And I think you'll find most of the academic programs will respond very quickly to that. DR. MACKLIN: But now, here's the problem. And I think -- I don't know if this -- CHAIRMAN FADEN: The problem or a problem? DR. MACKLIN: No, no. A big problem. It's not just the drug companies who supply consent forms. It's also, for example, as Eli would know better than I, the cooperative oncology groups. Researchers come to the IRB and they say, sorry, I've got to have this 15-page consent form because ECOG requires it. Sorry, I've got to have these lists and lists and lists of things because ECOG requires it. The researchers who are doing studies for drug companies say the drug company won't let me do the research or better, better -- and this is where the hook is -- the institution won't hold me harmless or the drug company won't hold the institution harmless if you change the consent form. In which case it's the company's lawyers and the lawyers for the institutions who are saying, don't change a word. Otherwise, if there's some adverse event then the researchers are going to be held liable. DR. GLATSTEIN: That's a very legitimate problem. CHAIRMAN FADEN: I think that's very helpful. We need to flesh that out. DR. GLATSTEIN: But I think that in terms of cooperative study groups, cooperative study groups get their funding predominantly from the NCI and I believe that you can get the NCI to make some suggestions on altering the consent form process. Not the consents, but how the consents get written. There's no reason why the individual institutions, the members of the individual institutions can't write the consent form themselves and make sure that it includes all the materials that the group as a whole requires and just simply change where the writing takes place. It could be peripheral and still centralized. DR. MACKLIN: But isn't that the problem, Eli? That now the current requirements for the cooperative groups are that they tell the researcher -- they give them a model form and then they say -- DR. GLATSTEIN: It's done by committee. And that's the problem. DR. MACKLIN: -- anything that's every come out that would go into a patient package insert should go into the consent form. And that is clearly a higher standard than anyone ever -- CHAIRMAN FADEN: I think we should march on. But I think the recognition is that Ruth's point is to something very, very powerful, which is whether it's a cooperative clinical trial, it's a ACOG or ECOG group of whatever, if the funding is federal, you could fix it at the basic level. I mean, there's a connection. And this Committee needs to be mindful of pointing out that you've got to have a large scale effort directed at getting the priorities straight, whether we want to call it back to basics or whatever. When the funding comes from drug companies, the complications with respect to implementation jump orders of magnitude. DR. KATZ: Could I ask Eli a question? CHAIRMAN FADEN: Okay. And we don't want to be naive and pretend that it's not an issue that you're involved in the counsel's office of a private industry that has a different set of considerations and are speaking to different kinds of incentive structures than those investigators whose research comes from the public sector, even if it's filtered through a cooperative clinical group like the ECOG and like organizations. So you're pointing us to -- in terms of again, to whom this is directed. It is very important. Jay and -- DR. KATZ: Eli, I want to ask you a question in terms of that. Would you support a proposal which the National Cancer Institute could also involve drug companies to, but generalizes it. That assuming that a research protocol has been approved for three years, a particular research study, that if in the second or third year the investigator will simply data that because he or she has followed the informed consent process, patient accrual has slowed down significantly, that automatically the research will be funded for an additional three years. DR. GLATSTEIN: No. DR. KATZ: That's the crux of the problem of the industrial research. But would you support it? DR. GLATSTEIN: I think I probably would. But I'm not sure that I'm in the majority of the investigators. I don't have a problem with that. DR. KATZ: Not the investigators. The investigators might even possibly like it, but -- DR. GLATSTEIN: I think they probably would. DR. KATZ: -- but what about NCI? CHAIRMAN FADEN: You know what? The very interesting question is you'll reduce the number of projects that can be funded as a consequence. DR. KATZ: You may. DR. GLATSTEIN: But the problem is money. Right. DR. KATZ: And inviolability of subjects of research. CHAIRMAN FADEN: That's the tradeoff. That's the tradeoff. If you believe that behind some of this is the pressure to get enough subjects into your -- DR. GLATSTEIN: But if in fact the laws were changed so that the insurance companies paid for clinical research that included the Phase 1 and Phase 1 drug studies, then I think you'd have a basis for payment right there. I don't think you'd have. I mean, a guy pays his money for 25 years for insurance and comes down with cancer. When he really needs it and he wants to go on a clinical study, he may get the same treatment, a standard treatment versus a standard treatment plus something new. If he goes on a randomized study, the insurance company won't pay even though it's standard treatment. And it's a little crazy. But if that were changed, I think that would cover the money. CHAIRMAN FADEN: Well, we're an inventive Committee. (Laughter.) And at least all of the stuff is getting -- Ann and I are taking notes and probably other people are, as well, as we're going to try to feed this back in some fashion. DR. ROYAL: Because money speaks, a number of people have suggested that one way to get people to behave better is to work through funding agencies. It's not clear to me that that is a good idea because I don't think that the funding agency -- the funding agency has a conflict of interest. The funding agency is in business to do research and there's a disincentive for them to do anything that would seriously impair their ability to do research. So I would be in favor of a more independent body. DR. GLATSTEIN: Well, in tying it to funding, all I meant to imply by that was the ability of the funding agency to spell out in some detail, for example, what sorts of methods they use to maintain IRB education on some of these points. Do they have or is there a regular program for making sure that each person that goes on the IRB has the background and so forth that we were talking about earlier. DR. ROYAL: But there is a disincentive. They're not going to do anything that's going to make their job, their primary mission, more difficult. DR. GLATSTEIN: Well, I don't think they really have to. All they have to do is point out that the individual institutions have to make the changes. They are simply establishing some guidelines. And those guidelines shouldn't be translated into a great deal of expenditure vis-a-vis the sorts of things taking place in Washington right now about mandates. CHAIRMAN FADEN: I think there's a different -- your proposal or your -- I don't think you want to call it proposal yet, but your position you're articulating with respect to the independent body is regarding the sort of overall oversight responsibility for -- DR. GLATSTEIN: I mean, when this cancer treatment evaluation program evaluates a protocol, that's about a four or five month process which goes back and forth to the investigators to make changes and so forth. And I don't understand why it wouldn't be possible to build in some of these other requirements during that process. CHAIRMAN FADEN: That's right. That's true. DR. ROYAL: I guess one of the earlier proposals in the Openness Section is the central registry concept. CHAIRMAN FADEN: Right. We'll go back to that. DR. ROYAL: And as a potential independent way, or more independent way than the funding agency, I think one of the reasons why the system doesn't work as well as it could is that there's just no feedback loop. And one way you could do an expedited review is to just have -- you're already sending the consent forms to the central agency for preservation, and theoretically you don't need a lot of expertise to read the consent form because that form is intended -- CHAIRMAN FADEN: For lay people. DR. ROYAL: -- for lay people. And, I mean, I really have been surprised at the variability of the quality of consent forms that we've seen with contemporary research and I would think that you could get quite a big bang for your buck just by having a group of people who are interested in the issue of how well you communicate risk and benefits to patients, and they could read the consent form and decide for themselves whether or not they would be able to make any sort of intelligent decision based on the information that's provided. You don't know how accurate that information is, but at least you can separate those studies out from which someone could make an intelligent decision. CHAIRMAN FADEN: So you're thinking about some sort of a mechanism whereby -- DR. ROYAL: Well, one of the other suggestions was already to send in consent form. CHAIRMAN FADEN: Right. Exactly. So off of that mechanism there's some periodic review that's pulled out? This is what I'm thinking about in terms of performance outcomes. Some way of looking at the output. The process that we have now all looks at the input, sort of sets up the regulatory side; you should do this, you should that, you should do the following thing. What this Committee has done, which is what we could attempt -- not that it's not been done before, but certainly not on this scale -- is looked at the output, what comes out from this regulatory thing through which everything is pushed. And we learned -- we're learning a lot. So what you're suggesting is some sort of regularizing of that. A look see. A kind of let's take a look at that from time to time. DR. ROYAL: And I actually think that having this feedback loop, if some outside agency says the consent form could be better, and means could be better in the true sense of communicating with the patient; not better to protect you from medical/legal consequences or whatever or to meet the federal registry's requirements that aren't necessarily communicating anything to the patient. I think that for the amount of effort that's put into it, that you're liable to get the most amount of benefit, and that would be a starting point. If that didn't work, then things like sanctions and stuff would be appropriate. But I wouldn't start this off as being -- setting up this agency that's going to sanction you. It's really setting up this agency that's going to help you write better consent forms. DR. GLATSTEIN: But the point I'm trying to get at is that there is an agency that exists now. These protocols and their consent forms have to go through the -- at least if they're funded by NCI money, they go through the NCI now and the protocol doesn't begin until the NCI signs off on that consent form. And they usually make a bunch of changes. Now, it's clear they're not making the right changes. CHAIRMAN FADEN: Right. DR. GLATSTEIN: It's clear that the orientation is not -- that they have, is not really aimed at patient rights and patient protection. I hadn't realized there was this big a problem but there obviously is. And that's where I think you could tie it. And I think it represents no additional bureaucracy because that bureaucracy is there and functioning at this moment. DR. RUSSELL: I want to clarify something in regard to that. The Defense Department has two levels of review with the committees, with community members on it and so forth for all of the high risk -- the normal risk protocols go through one level. If they're greater than minimal risk they go through two levels of review. And obviously at NCI the same parallel committee structure is in place. Is that a committee review or is it an administrative review? DR. GLATSTEIN: That's a committee review. DR. RUSSELL: There's a second level committee that -- DR. GLATSTEIN: Yes. DR. RUSSELL: -- does the same thing. Now, one of the questions I would have from the analysis is are there problematic protocols, the ones that seem to be the most problematic, have they undergone two levels of review or a single level? That's one question. CHAIRMAN FADEN: Well, we could go back and try to -- DR. GLATSTEIN: Take a quick look at that. CHAIRMAN FADEN: We could take a quick look. I also should emphasize we should remember that these studies that we're looking at, these research projects, come from -- how many different agencies? Four? Five? VOICE: Five. CHAIRMAN FADEN: Five. Okay. So when we think about mechanisms, we haven't yet gone back and tracked to see which ones are coming from which agencies. But we have to remember that while NCI may make a -- if it looks like they're all cancer, which we don't know yet, that are problematic, then of course NCI would loom large. but even NCI is not the only place that funds cancer research in the federal government. So we have to step back and realize that our research projects -- this is the other thing that's kind of unprecedented. We're looking across the federal government at humancentric research. We are not looking solely or exclusively at research funded by NIH, although obviously NIH is in there. We've got all the other people. And so we need to look better to see connections when we start thinking about mechanisms and to whom to direct this. As we look at it by who's funding these projects, it may emerge that the recommendations disproportionally go to one agency or it may not. It may be that -- you know -- DR. GLATSTEIN: Within the NCI it's called the Cancer Treatment Evaluation Program, CTEP. CHAIRMAN FADEN: Right. And we have to see how many fall within that. That's just by way of background so we can all remember that the projects we're looking at, we haven't broken them out yet by agency on this issue. They come from across the federal government. DR. GLATSTEIN: The other question I have was whether - - the issue is fundamentally a quality assurance, quality control issue with regard to the human volunteer system and how do you make a system like that work better. One is you keep your hand on the money and don't let the money out until all the arguments are satisfied, and the other is the accreditation systems within the medical treatment - - our medical treatment world. We have the JCAH. Are they focusing at all on the IRB and the process by which -- DR. RUSSELL: We have not seen any evidence of that. DR. GLATSTEIN: I don't think so. Do they -- CHAIRMAN FADEN: I don't know the answer to that. DR. GLATSTEIN: They do look at the existence thereof and they look at whether it's -- but I don't know that they -- DR. RUSSELL: They look to see that there is one. They don't look to see if it's doing a good job. DR. GLATSTEIN: Right. DR. MACKLIN: But that would only cover hospital based IRB's; right? DR. RUSSELL: Exactly. But there's also a parallel system being built in. But my point is that's another pressure point that you can put on the -- whatever system. I would venture to say that a very, very large number of our high risk protocols we're concerned about are going to fall under the purview of either that system or a similar system for the HMO's. DR. MACKLIN: Does that focus the question? Does JCAH at all have anything to do with the veterans system or -- DR. RUSSELL: All hospitals. DR. MACKLIN: Is it every hospitals? DR. RUSSELL: Military hospitals included. DR. GLATSTEIN: Every hospital that seeks accreditation. CHAIRMAN FADEN: They're pretty powerful. It reaches - - DR. RUSSELL: That seeks accreditation. Yes. That's true. I don't know what percentage of -- CHAIRMAN FADEN: Are unaccredited? DR. RUSSELL: There are some. DR. GLATSTEIN: There are some, but not very many. CHAIRMAN FADEN: This is all very important, but if we could just march through a little bit and get a feel for where else things are going. Can we assume that we want a subset of our recommendations to speak to the issue that's raised on page 29, line 16? This comes out of our historical experience, making sure that the range of purposes for which research may be conducted the range of sources for funding somehow has to emerge as an issue. This obviously comes out of our looking at some historical ones. Whether this is a problem today, I don't know. Pat? MS. KING: Is this intended to cover the end payor situation where the researcher also has a financial interest? CHAIRMAN FADEN: Yes, it was. I don't think it's been spelled out. MS. KING: Because it should be spelled out. And I think that it actually came out in the report, but I'm very much aware of how controversial such a recommendation is. So I just point that out. But I think that we need to clearly address it. We have to give some reasons for why we have come down on one side of the issue. CHAIRMAN FADEN: We may have to pull that off to the side and see. It may be inappropriate. And I spoke too quickly. This issue, abstracting the question of financial interests of the investigator, speaks out of our historical experience being the base for saying something about it. The particular question we haven't hit as a Committee in any of our other work. So I have to maybe go back as to whether we should be really pursuing it or not. And let me say as a general backdrop, I think obviously the strength of our Committee is to speak from what we have learned together as a Committee, so our recommendations -- and we have so much. We have contemporary data that we are amassing and we have historical analysis that we have conducted, so we have a very rich base from which to speak with some authority about our recommendations. So we should probably concentrate our energies on making recommendations that come most strongly from our collective learned experience. MS. KING: I think I agree with that. But I would note that in the future, the financial conflicts are the major issue in terms of language here about purposes for which the research is being conducted, just as the period of which we come out of it may have been the multi-purposes in terms of military purpose versus benefits, et cetera. CHAIRMAN FADEN: That's a good point. MS. KING: So you can argue both ways about whether -- we have something to say about it from our past experience that perhaps has implications for what happens to subjects when there are other purposes going on that they're not aware of. CHAIRMAN FADEN: That's a good point. We'll flag that and separate it. Perhaps provide background for Committee members who aren't familiar with that issue in there. If we could just march -- I don't know. If this is bad, tell me. If we don't -- I'm just trying to give a little help to staff the most. If we could march through this and get some sentiments. On page 39, "Avoiding -- line 8. "Avoiding Presumptions of Agreement." Several Committee members commented that they're irritated -- their irritation at continuing to see consent forms written in the first person. I will have this happen to me; I will have that happen to me. It's a tiny point. DR. MACKLIN: It's even more that "I understand that. I understand that. I understand that." CHAIRMAN FADEN: And it sets up a presumption that you already agreed and makes it really weird to say no. It makes it very awkward, so that it's -- I was surprised to see so many of these still remaining, like this one here. DR. LEDERER: Do we have any input from the subject interview survey about that? CHAIRMAN FADEN: Not yet. DR. LEDERER: But is that a question we could get? VOICE: I don't think it is. CHAIRMAN FADEN: I don't think we get anything that particular. Because again, as Nancy was -- and Jerry, you were pointing out, the whole thing was crafted to minimize asking questions where recall would be really a problem in getting an answer. So that's always an issue because you're asking people to recall things that happened to them in the past. The more detail-ish you get, obviously the more it could just be the forgetting curve problem and not a real problem. So we tried to concentrate on areas that were less vulnerable to disputed interpretation because of the passage of time. DR. LEDERER: So what's the evidentiary base for this? CHAIRMAN FADEN: The protocol review project. We're getting consent forms in the research projects that we're reviewing that are written in this form. DR. LEDERER: And we have evidence that people do feel more constraint? CHAIRMAN FADEN: No. That's the presumption on our part. DR. LEDERER: Okay. That's what I'm asking. CHAIRMAN FADEN: I'm sorry. DR. LEDERER: It's the presumption rather than actual empirical evidence. CHAIRMAN FADEN: We have evidence that these forms are still -- no. We have empirical evidence that people are writing forms in this way. And it is the judgment of some Committee members that that's offensive and/or inappropriate. But no empirical evidence. And that would be important to establish. DR. ROYAL: When you say it's a judgment of the Committee members, I'm just trying to better understand the issue because I know that in my own IRB at one time we were told to write in the first person and then another time we were told to write in the second person. And so I'm wondering if there are any sort of global recommendations about first or second person. That issue has not been explicitly addressed in any organized way. CHAIRMAN FADEN: I don't know. Maybe we can look again. I don't know if anybody's ever done an empirical study in which people have been given forms in the first persona and in the second person and measured their sense of -- DR. ROYAL: But has anyone ever made a recommendation that carried any weight in any of the federal agencies? Do they care? CHAIRMAN FADEN: I don't know. I don't know of any. DR. RUSSELL: Part of the form have to be in the first person. CHAIRMAN FADEN: I agree. DR. RUSSELL: It has to be there someplace. It may be one sentence, but part of it has to be in the first person. DR. KATZ: Unless there's some objectification observed in the research, what about putting it in the third person, calling them its. (Laughter.) DR. MACKLIN: Some consent forms mix up the persons. They say the purpose of the procedures, subjects will be asked to, et cetera, et cetera. Then they go to you and then they go to I. So I mean, that's really pretty confusing when they mix it up like that. But I think the uniformity is desirable, but after what Phil said before, I'm a little concerned that too much uniformity may drag us down. CHAIRMAN FADEN: No, no. I think we all have to think about that. It's an interesting challenge. Six is a placeholder. We have been asking chairs of radiation safety committees to provide us with any suggestions they might have on how their committees have approached the issue of communicating risk in relation to radiation and we have been very fortunate in every respect. People answer us when we send these letters out. They actually write back, which is terrific. I mean, when we write to chairs of IRB's and ask questions and they write back, and we write to chairs of radiation safety committees and we're getting answers back. People are sharing with us what their committees have thought about these issues. DR. KATZ: Well, you've gotten answers? CHAIRMAN FADEN: Yes. Oh, yes. DR. KATZ: Many of them? CHAIRMAN FADEN: Yes. And we're starting to look at what people have been trying to do. Obviously, we have colleagues sitting around the table who have struggled with this and we are now trying to augment your impressions with suggestions that are coming from chairs of radiation safety committees who say this is how we have worked it out for your committee's consideration. And I don't know that we'll come up with a uniform recommendation or even that we should try, but at least we can give some guidance as to how people are approaching this problem; how much of a problem they think it is; and -- DR. KATZ: Can we get copies of these things? CHAIRMAN FADEN: Yes. We'll send them around. They're just starting to come in. And also, some of the suggestions that are in here come from chairs of IRB's who wrote to us and said we could use some help of the following sort. Could you please -- if your Committee could say certain things, that would be very helpful to us. So that's available, too. Pat, and then Henry. MS. KING: This is just a comment, because I'll wait, as always, to see the justifications. But being a potential subject and not a member of an IRB, I can't see that it makes a lot of difference to me whether I'm addressed in the first person or the second person. And I don't know if I'm the only person who feels that way but that raises for me a question of de minimis recommendations. I mean, in terms of do we want to make a recommendation about everything. And so, I may be wrong about this one. There may be substantial reasons for going to discuss one person versus the other person. But it's a concern for me that arose when I -- CHAIRMAN FADEN: I think what you're saying is well taken. And my personal view is that we would be better off if we had, you know, 10 big deal recommendations than if we had 332 recommendations. And that some of the smaller ones could be in the commentary underneath some bigger one, so as not, you know, pulled out by itself and given equal weight. So if we could, thinking about how this report comes out, this Committee sees 10 important things and these 10 things were done, the world could be better, it would be a whole lot easier to communicate than if we have 2,226 specific recommendations that we would like to tinker with. So I'm in general -- I assume by the nods of heads around the table that the Committee overall would prefer a structure that took more of that character than some other. So that's a point well taken. Henry? DR. ROYAL: I wanted to bring a paper to the attention of some Committee members, if you're not aware of it. But there actually is a paper written by Frank Casternovo about communicating radiation risk. MS. MASTROIANNI: Yes. I think it was sent out early on. CHAIRMAN FADEN: But we thought we sent it out to everybody. DR. ROYAL: No. MS. MASTROIANNI: Early on? DR. ROYAL: What they did is they actually did a survey of IRB's. Asked them to send their preferred language and then the sent all the preferred language out to the radiation safety committees and they all voted on what they thought was the best language. So there actually is some information available from the literature. CHAIRMAN FADEN: We'll circulate that. MS. MASTROIANNI: I thought we had circulated that. CHAIRMAN FADEN: I did, too. I'm sorry. And so what we were getting from people would be augmenting that. We'll see where we're going. Actually, your point -- Phil's point about checking to see how many levels of review the more problematic studies have raised, to me that's obviously very important to draw the parallel to the isotope. What has the experience that evolved in the radiation research area where there is two levels of review and if we are in fact -- we have adduced that. If we can adduce any evidence that suggests that that second level of review actually has the effect of improving the ethics of research, that's worth noting. And that would be important to pull out and see if a specialty review really does pay off from the perspective of improving the ethics of research. Okay. On page 31, we begin recommendations specific to certification and training. And if we -- they are kind of a piece that begins with the notion, this notion of certification, which actually emerged as a recommendation that was sent to us by an IRB chair. MS. NORRIS: Was that only one? CHAIRMAN FADEN: Pardon? MS. NORRIS: That was only one, from one IRB chair? CHAIRMAN FADEN: One IRB chair. Other people suggested we need education but he was the only person who linked it to something formal like certification. But the idea here being that -- and many of us know that there is a question about the line that begins, "It is." We started out with just being shocked. Some people. Not everybody. That why wasn't the Nuremberg Code better known, so on and so forth. And the issue is how many people today know what the Belmont Report is and know the principles that lie behind research of human subjects today, including IRB members, since we don't have a whole lot of evidence that the research community is more knowledgeable today about the underlying principles of research involving human subjects than previously. Nor do we have evidence to the contrary, except anecdotal, from people telling us. This is intended to say, look, out of our experience, there's a gap in principles from today until tomorrow, and if the people who are supposed to actually live by them don't know about them, they couldn't possibly honor them. So the idea here -- at least they might honor them, just out of some other set of moral convictions, but they're much less likely to honor them if they don't know that they're supposed to live by them. So the idea is as simple as that. Whether certification is the right mechanism or not is a separate order of issue, but the notion is a simple one. That we've learned from the past that just because somebody says there's a code out there, doesn't mean that anybody knows about it. DR. KATZ: Are you serious about this proposal? VOICE: I hope not. DR. KATZ: I mean, it's -- I have to interject. Particularly, I want to get the deans, the presidents, the CEO's, IRB members. I mean, it is -- I wouldn't want to train them. CHAIRMAN FADEN: You're a university president. Tell us. Is this terrible and awful or what? How would you respond? DR. KATZ: Let me put teeth in it. DR. TUCKSON: Let me, before I get any more people yelling at me, seize the ground. First, now I'm nervous because -- well, I'm glad he's leaving. (Laughter.) Because I'm going to disagree with him. I want to take a larger perspective on this. I think that from -- it's hardly a juxtaposition between -- I read -- I went back and re-read all that -- a lot of that stuff between the AEC and the Department of Defense and Shipman versus Shields Warren and going back and forth and reading all that stuff. And then I read this part and it seems to me that I think one of the most important things that could come out of this is that the government changed its behavior and that the public is sure and is assured that this isn't just a rhetorical exercise, even if it was a remedy that had to do with money, and that's good. We could say, well, we sure got their attention. But that there was something in place that changed the culture of the way in which government behaves. I know that -- I'm a member of the IOM and I know that for some reason -- I never asked. I'm a fairly new member to the IOM but I'm always with you, so -- but some reason, when it's time for conflicts of interest, enormous energy is spent in meetings regarding discussions of conflict of interest. Something changed their corporate culture to the point that for an hour before discussions would occur, regularly you must sit there. And there is a lawyer. In fact, the Executive Director of the place sits right there with you and everybody must disclose who they are and who their grandmother got stock from and it's very serious. And as a new member of that culture, I am extremely aware that I am not supposed to screw up regarding conflicts of interest. (Laughter.) And it seems to me that it is such similar mechanisms that the government widely defined says we do know about something called the Belmont Code and we do know something about the Nuremberg Code and we are aware of the standards of the day. And one thing for sure. Within the agencies and with our relationships external, you cannot misread how doggone serious we are about protecting the lives of American people and being ethical about it. So, I would just first come down on the point that I know it is possible to do this and I know that it is important to do it. And I know that if there's any recommendation that we will make for the future, these are the most important recommendations that we will make for the future in my opinion. Now, at the level of technical detail about certification, I'm prepared to listen to other conversation. But I'm getting, to end my long-winded analysis on this, specifically I'm asking that the issue -- before we get to certification at the institutional level, I think there needs to be a government discussion around the way in which government culture will be dealt with and what are the issues in how the government handles these matters internally. And then, secondly, how does government then affect the behavior down the line with those external to it. So, I'd like to open up that bigger issue. CHAIRMAN FADEN: Thank you. Reed, I think you've captured -- corporate culture, it is an issue of culture. This recommendation is intended to address changing the culture, as it's written now, of the biomedical research community. I'm not sure about whether it's more important to change government versus the biomedical research community. I think you clearly need to be addressing both. But I think you can talk to the government from today until tomorrow. If the biomedical research community doesn't have the view that this is one of our primary obligations and just like you're an IOM member and you'd better get your conflict of interest stuff straight, if you do research on human subjects, you've got to get this stuff straight and you better be damn sure you don't screw up this end of it. DR. TUCKSON: But Ruth, I would just say this. I think we cannot accept that you can't change the culture of the government. CHAIRMAN FADEN: No. I'm not. I want to change that, too. DR. TUCKSON: I mean, -- I understand. Yes. Because I think that's both important. Because first of all, it is, -- again, I have no idea of what conversations are going on between the Department of Defense and somebody else. I don't know if there's another Shipman writing a letter to another Shields or whether some knucklehead in the Air Force is going to decide we're not going to flag down the planes because we don't -- in other words, I just think that there's something in the word we're about to enter so complex and the issues are so unknown that I think that it just -- maybe what you've said means we have to be even more Draconian. CHAIRMAN FADEN: Pat, then Henry. MS. KING: I don't disagree with changing the culture that Reed talked about, but I feel strongly that certification doesn't do anything but relegate something off to another expert who's in charge of the problem. And I'll try to speak to that. I was struck by a comment about the IOM. I, too, am a member. Probably between the two of you. And I've been struck with how perfunctory some of those conversations can be. I've also been struck that in a different -- I just came through one that was totally different from a perfunctory approach where we got beyond financial conflicts of interest and really got people to talk about what their biases were, what their predispositions were when coming into a new area. It was a wonderful conversation and went well beyond what I've also participated in, the very perfunctory ones. I own stock in this and, you know, I'm a consultant for that. But it doesn't really tell you a lot of meaty stuff in addition to that. I was struck by that because what we really want to happen in IRB, for me, is for people to have a conversation where they are not barriers but conversation about why it's important to everything that they do that they be aware of the fact that you get consent. You do a lot of things that we all take for granted. And I don't think that we have to talk about codes in order to do that. That was my point yesterday. You don't need to know the terms of the Nuremberg Code or the Belmont Report -- which I happen not to like a lot and I helped draft it, but I don't like it at all, so I want to be on record as being very happy to let people forget the document itself, but not some of the principles and the ideas that I think that we were trying to capture in the document. Probably do a better job today doing that. And I think of certification as another way to do credentialism, which is another way of being expertise in satisfying requirements and open up cottage industry. I would much prefer seeing requirements that required or suggested to IRB's that they retreat and go off and discuss problems or that they start every year by trying to duplicate the IOM message. Credentialism is a way to meet a requirement. You go off to class with X, Y and Z and you come back and somebody certifies that you went. I think what we want to do is think about suggestions. And I think of them sort of as suggestions for IRB operation to help accomplish a goal that we all think is important. And maybe IRB's will do it differently, but there has to be ways of working on the integration in IRB's so that the ethics person is not the ethics expert, because that's not what you want. CHAIRMAN FADEN: Pat, I think what you're doing is the opposite of what I want. You're not casting the net widely enough. You can educate IRB members for today and tomorrow. It's the whole rest of the community that's the problem. If I chair an IRB -- MS. KING: Oh, we're not disagreeing on that, Ruth. CHAIRMAN FADEN: That's what this area is directly towards. It's not explicitly or primarily even IRB members. It's the whole biomedical research community. I chair an IRB and even if I've got the most wonderful members and we are honest and we discuss, if the rest of the community thinks we're a pain in the butt committee, the sole purpose of which is to pass paper through, so that you can get a stupid stamp so you can send your -- I'm exaggerating for purposes of effect here, but that the end result is just so I can get the stupid form signed so I can get my grant application in on time. That's not going to accomplish what we want to accomplish. MS. KING: I'm not disagreeing with you, Ruth. CHAIRMAN FADEN: So that was what this was speaking to. MS. KING: I'd be perfectly happy with the wider net. But I think that when you talk about the wider net, that the credentialism is even more of a problem. Because what you really want people to do is not to have to jump through another hoop which they -- I don't want them to jump through a hoop because I teach some of those hoop courses that people come to, and you do to. And to get eight people to buy into why this is an issue is easier when we have the people who are there because they are motivated to come, than some of the encounter who say I need a continuing education credit. That is my experience. I think that the kind of things that we want to think about is getting people to see it as a part broadly of the biomedical enterprise that you have to do certain things. That takes us back to where people are educated. Not their credentialism. And credentialism, I think, doesn't help. It is often a serious handicap to what we're trying to achieve, which I think -- that's my view, anyway. But Reed says that what we're trying to do is change the culture. We want people to think more broadly, focus more broadly. So, I don't like this one. I'll talk about the next one when we get to it. CHAIRMAN FADEN: Right. You don't like the certification element or whatever we want to call it. The general goal seems to be one that people are agreeing to. I saw Henry and Jay and Sue. Henry? DR. ROYAL: I'm sort of surprised at the amount of debate that this has brought up. Maybe it's because we all have a different view of what we mean by credentialing. And maybe it's also -- it doesn't seem like such a big deal to me because when you write the material, I mean, you have to -- I mean, it's not a big deal. It means that you have to spend an hour reading something to -- and then we actually have a little exam that you take that takes 15 minutes to show that you read it and you have some idea of what you're doing. And if that's what we're talking about, making sure that people understand what the basic principles are of conducting research ethically and we're talking about a one or a two hour thing for a new investigator in some sort of annual recertification thing, that might just consist of passing out some written material that they sign it and they say, you know, I've read it. Then they can't go and say later on, well, you know -- CHAIRMAN FADEN: I never heard of it. DR. ROYAL: Yeah. CHAIRMAN FADEN: They didn't know about it. DR. ROYAL: It seems like a very simple thing to do. But maybe that's not what certification is meaning in this context. I don't know. CHAIRMAN FADEN: Well, there's two. I mean, I see your response here, but there are two issues here. One is linked to the issue that we have heard, is "I didn't know I was supposed to do this." And it gets very difficult to hold people accountable because you say, well, where was the breakdown. Did the administrator not effectively communicate this? Is it the person's fault? Is he or she culpable for not knowing that she was supposed to do this? So it's this narrow accountability problem. And then there's the broader one of changing the culture and whether sitting down for an hour and reading something and signing it changes the culture is doubtful. It may serve the other purpose, though. But let me ask you. Do you think people learn something from that? Do they learn how to handle radioactive materials as a benefit, able to do it, or do you feel like it's a Mickey Mouse kind of thing? DR. ROYAL: It depends on how well it's done. I think it can be very useful. As a matter of fact, there is a paper about using fluoroscopy where some hospital instituted a program of education for using fluoroscopy because in a hospital, fluoroscopy can be used by anyone, not just a radiologist. And the actually got comments back from physicians who were being required to do this about how useful of a program this was. So, I think if it's done right, it can be -- MS. KING: But people have a reason to buy into the program when they themselves have something that they can see is a clear benefit for themselves as well, which is -- DR. ROYAL: But the clear benefit here is that you've going to be allowed to do research. MS. KING: I don't think that's the way people approach thinking about ethics and ethical principles. But I'll keep quiet. CHAIRMAN FADEN: Well, don't keep quiet. We want to hear from everybody. But we've got Jay and Sue waiting, so I mean -- DR. KATZ: You know, there is something nice, Ruth, about the spirit that you're proposing. CHAIRMAN FADEN: I didn't propose. DR. KATZ: Well, -- CHAIRMAN FADEN: I'm not saying that I don't like parts of it. DR. KATZ: But I wonder about certification . And indeed we've become the most over-certified kind of body. I get asked to be certified in all kinds of things and I just say it's too late for that. (Laughter.) And to pick up on something that Henry said, there might be something nice. Forget about certification. There might be something nice, even if it's just to some extent even symbolic at this time to have a few hours a year of compulsory participation in some seminars. Maybe even with a little exam attached to it. Particularly if the requirement is that all the senior people, first of all, the senior investigators have to attend that seminar and learn something about the ethics of research. It might have a salutary impact on the younger people. Maybe it can be done in a double mirrored room where the presidents and junior investigators can sort of listen in to what's going on. And to do something that you think through. I'm really not trying to be funny, but serves the purpose behind it. To do something that can be both meaningful and symbolic and that there's at this point there's something to be learned here. The major problem I have is to go back to juvenile who asked who shall stand guard over the guardians. Who will be the teachers of these people? Surely, you very well can appreciate if I were the teacher it would be quite different message conveyed than some other people also impressing the same issues as I would be the teacher. But that's inevitable. But this is just, I think, -- however wonderful, it's just too much in its present form. CHAIRMAN FADEN: Sue and Reed. DR. LEDERER: Well, I guess I can't sit here any longer and say that if people knew the history that that would also change the culture. And I think that knowing the history is an earlier recommendation, I think, in the Looking Forward. But I also wanted to make the point that it seems as though -- CHAIRMAN FADEN: That's well taken. That's the notion behind introducing Nuremberg. Not because it's a code but because we've got to have people understand where we came from. DR. LEDERER: But I'd also like to make the point that it seems that aren't there already sort of accreditation for people who use animals in research? Don't they have to take some sort of course in the ethics of using animals? They have to account for the animals that they use. And that we could ask whether that has changed the culture of using animals in this country as research subjects and use that as a model. DR. GLATSTEIN: Actually, I don't think we have -- I'm not aware that that's true, but if it is true that in England it takes you much longer to treat animals than to treat patients. There's about a six month check-up that they put you though, whereas, all you've got to do to treat patients over there is register with the General Medical Council. DR. LEDERER: I understood that in this country that if people are going to use a particular animal species, for example, you had to take a course in -- CHAIRMAN FADEN: I don't think so. DR. GLATSTEIN: I think that's desirable but I don't think it's necessary. DR. RUSSELL: The Laboratory Animal Review Board system changed the culture. The veterinarians that monitor it and manage the care have made a tremendous impact on the medical side of the culture. But the sea change came when they put in the system of a review board for protocols. CHAIRMAN FADEN: Your phrase of sea change is kind of interesting. If you're arguing that a sea change occurred when the federal regulations came in in a big way, then maybe it's sort of time for looking for another sea change. Whether the answer is regulatory or certification or whatever, I mean, it's been 20 years and we now know things aren't perfect. There are still issues. And we're looking for -- what we're struggling for are the means issues. DR. GLATSTEIN: But the idea that I had originally for educating the IRB's is the same thing as here. You could leave out the certification process but still a required amount of time every year for each individual, including the people that remain there, to go through an informative process. CHAIRMAN FADEN: If a person is suggesting that the president of the university and the deans and the chairs of the departments were speaking to the thing that Jay was mentioning, that unless you get people in leadership -- DR. GLATSTEIN: Yes. CHAIRMAN FADEN: -- to give evidence that this is serious, important and high priority and they care about it and it's really part of being a professional in our institution, it's hard accomplish this sea change or whatever. Maybe sea change is too dramatic a metaphor. But I think that was the force of this person's wanting to sound to elevated and go all the way up to the president of the institution. That that was the issue. Whether certification is right or not, but it's sort of like whether that IOM stuff is too helpful or not, but Reed's mention that when the Executive Director comes down it clearly communicate that this is serious and we take this seriously. It's part of what this person I think who wanted to put this forward for our consideration wanted to communicate. That's the help he's seeking. How can I get my institution to overall support me as an IRB chair in taking all this stuff really, really seriously. Which is not to say that there aren't tons of people out there who already take their obligations seriously, but it's not in this person's very, anyway, diffused enough in the culture. I don't know how to do it. Reed and -- I'm sorry. Ruth and then Reed. DR. MACKLIN: I think both sides who've been arguing about this proposal are right. I mean, both sides are right. (Laughter.) The reason I think both sides are right is this. When Pat and Jay talk about certification. Once you have certification, the emphasis is on the piece of paper. And having the piece of paper and waving the piece of paper and then asking, do you have this credential, and it tends to elevate what you have far more than it deserves. So, for those reasons I think the certification -- you notice how quickly certification got picked up as credentialize, although it says certification. So a little certificate -- MS. KING: No. I mean, as some people here now, there's a big discussion now about whether bio-ethicists should be certified. And the people in the field are studying this. I mean, I think it's a revolting notion. (Laughter.) What it does is it erodes the idea that someone can get a certificate and then go out and charge money to be a bio- ethicist. And that really is the bottom line. I mean, I can charge for counseling patients. DR. MACKLIN: And charge to train them. MS. KING: Exactly. I mean, that's the revolting part. What's the good side? What's in between it? DR. MACKLIN: What Eli just said -- and maybe there is a kind of mechanism that fits in with the culture of medicine. Now, I mean, some may think this, too, is Mickey Mouse because you don't get any guarantee that people learn anything. But there are CME requirements and people -- many people take those seriously. I mean, if those are treated also and dismissed in a way -- I mean, I don't know what else to say. People don't want to continue to learn things. But putting it more under the heading of CME, where people do have to come and sign in because, you know, -- I mean, it doesn't prove that they learned anything. It proves that they sat that; right? And maybe they slept and maybe they were awake but they also can't say I didn't know or no one told me because they were there in that room. I've been surprised. My institution, my IRB has actually had an educational program running for several years now and we've had different levels of attendance at different times. The first time we had general education sessions very many people came. We learned a few things. One thing we learned is take the administrative aspects out and put that somewhere else because there are going to be a lot of IRB administrators who come and people want to know how many pieces of paper and when are they due and all of that stuff and how many copies have to be there, how long ahead. Set that stuff aside. Then there are people with very specific interests, such as pediatricians, people who do pediatric research, people who do AIDS research that have to meet certain other kinds of -- so, we've had some specialty sessions for people like that. The attendance has been reasonably good. And what has been gratifying is people are really interested in the ethical underpinning when they actually hear it. When they view it as more forms, more pieces of paper and more regulations, their eyes glaze over and they have more pieces of paper. But if someone mentions what the Nazis did and why do we care about research ethics and why do we have these things -- and I always begin with a little bit about Tuskegee and a little bit about Willowbrook and a little bit about Nazis, and people then see that this has to do with how doctors treat people and how researchers treat people. So, I think putting it into the educational mode without the certification and that stuff -- and people don't want to be educated. You can't drag them kicking and screaming. But it can accomplish both the end of saying I didn't know. And then if it's done well, people may actually be interested. CHAIRMAN FADEN: Reed's been waiting. DR. TUCKSON: A couple of comments. First, I think that Ruth is really right on when she says -- I know that as a function of participating on this Committee and by being made aware of the history I know that I have already removed the person that was running my IRB and we've got a whole new process, a whole 'nother level of intensity. I do know that I personally am communicating with my campus that says I, as the president of the university, am saying this is damn well important to me and it will be damn well important to you. And I've learned that that is important that the person on the top communicates that through. I think that I came to that conclusion not with sanction, not with certification, but just with information, just as a human being. And so I didn't have to have anybody to force me to do it, but I was aware of information, which is an educational role that I think has to be played. I think that one of the ways that perhaps this gets done then and would be in one of our recommendations, might be that we might recommend that through the appropriate mechanism, whether it's the National Academy of Sciences or whatever, that there be some convening of appropriate leadership of American universities for the purpose of discussing how to best accomplish a generally, I'm sure, mutually agreeable goal. So that maybe we should not have to think about trying to figure out all the mechanisms here in isolation but to write our recommendations in such a way that there could be no doubt that we are expecting clearcut guidelines, but maybe we do it in consultation with folk so we put this on the positive as opposed to the negative. However, I think the second issue we must be concerned about as we put forward our ideas -- and Ruth used an important word in the contemporary political landscape, this word regulation. Now, with the government and the Congress that will receive our report anti-regulation, and nobody's going to want to do anything that's going to add to government bureaucracy, I think that that's going to be very important in terms of whether or not our report will be received and acted on in an effective way within the agencies and within the Congress. And so I think that perhaps we may have to find ourselves moving more in that direction. The last thing I'll say is -- and it will be just counter to all that I just said -- is that I think back and as a university president, again, what gets my attention. I remember that the way we conduct our vivarium, the way that the Department of Agriculture review, when they will snatch my license in a minute if we don't meet some very clearcut issues, is an extremely important way of getting my attention. And it takes all the crap out of it. And those little rats will have their little cages cleaned, thank you very much, because those doggone Agriculture people come in there and review that stuff every -- whenever. And if there's not enough -- so, I'm just saying that that gets it done. CHAIRMAN FADEN: Well, that goes to the other recommendations. What you're suggesting is you can't throw that stuff out. DR. TUCKSON: Yes. CHAIRMAN FADEN: Let me just move in the other direction. Pat? MS. KING: I want to add a different -- I always see red when I see certification, so -- I have this -- and it now relates to the second point, now that we've talked about the biomedical community and a high awareness of ethics. I'm always reminded about how I got started in this field. I had no background in philosophy, ethics. I have a law degree and it made me more acceptable because I had a law degree. And when I teach people who want to know about ethics now, I don't start with principles of philosophy and all that kind of stuff. I start with trying to empower them. And I think that one of the things that's been lost in the IRB process is just not the broader biomedical community. Also what has been lost is that one has to have peculiar knowledge in order to be effective in a setting like that. And we have a requirement of public members on IRB's for a purpose. We have never ever really done anything with it. And that, to me, is a part of the culture change. I don't think that one has to have a J.D. degree to ask a common sensical question if one has lived in the world. And I take a lot of IRB review -- not the science review, but the consent process and people's perceptions of risk, et cetera, not to be a function of biomedical knowledge. And part of the culture change that we're talking about, I think, has to be in a culture change about understanding that at this aspect of the enterprise there are knowledges -- that's a terrible word -- that's valuable to bring to the enterprise and that people who we now ask to sit should be empowered in ways so that other people pay attention to them. The worst thing in the world -- and I've endured this, of course, as those of you who know me though, this has never stopped me. But to be the only person outside of a field when you're then asked to review something is a very difficult thing - - difficult position to be in when you risk being put down because you don't have certain kinds of knowledges. So part of the culture change is not that we're talking ethics. Part of it is that we're talking about human endeavor, a societal enterprise. A society in which biomedical enterprise is highly valued. And part of the value, its continued perception as being valued, is dependent upon the broader community's continued belief that this is valuable. What is being undermined -- that's why you have to have appreciation for some of that outside knowledge. What is being undermined with some of these conflict of interest rules -- I mean, the reason people have latched onto the conflict of interest rules is because they sort of sit as a glaring issue that creates problems of trust and distrust in the broader community. You don't get your biomedical funding because people have suspicions about your motivations, et cetera. And I don't know how to get that group, but I don't want to leave the cultural issue defined in terms of I'm expanding the culture of the biomedical community, because a lot of the tension is these are people from the outside who have no understanding of the biomedical enterprise imposing rules and regulations on the entire enterprise. Why don't they just go home. Thank you. Give me the money and go home and let me go do what I have to do. The culture question somehow has to deal with that, as well. CHAIRMAN FADEN: Yes. DR. TUCKSON: Can we at least at some point in one of our recommendations, if it's possible to cause the relevant -- a relevant set of material to be available to those who would like to do it right because they want to do it right. Somehow or another it seems to me the background stuff, the things -- the curriculum that people are teaching, the things that Pat is talking about, the things that Ruth would recommend, that you would recommend, Ruth. But at some point it's a small recommendation but I don't know if it's our job to compile such or to cause or direct or ask somebody else to do it. But that we would have something to say that it ought to include -- this is a small point but I think it's important. Again, if you want to get folks to do the right thing, make it easy for them to do it. CHAIRMAN FADEN: Right. That's not a small point. It's actually a large point. DR. TUCKSON: And what I find myself doing now is -- and actually, I've already -- I'm asking folk individually. I'm getting ready to ask Ruth. You know, it's like give me the stuff you think I need to teach our medical students. Give me the stuff that I need to give to my newly constructed IRB. What would you have them read as a minimum bibliography, and so forth and so on. And so if I'm asking it, others would probably want that. CHAIRMAN FADEN: Yes. There's no question about it. And I think that's very important. And I think all of this stuff is very important. And that's not here at all in any form, so we need to get that in there. In case people are getting hungry, we should probably break now. We're probably in need of food to keep on going. We're going to break, come back at 1:30. Let's come back at 1:25 so we can really start at 1:30. I mean, if we could really start at 1:30. And we're going to maybe take another half hour to sort of go at this stuff and then switch to situation 1, 2, 3, 4 from yesterday. (Whereupon, the luncheon recess was taken at 12:25 p.m.) AFTERNOON SESSION [1:45 P.M.] CHAIRMAN FADEN: It's now quarter of 2:00 and we have until 4:00. DR. RUSSELL: P.m. CHAIRMAN FADEN: P.m. Yes. We have until 4:00 p.m. Here's what we need to do, okay? Now, whether we can do it all, I don't know, so we'll have to prioritize it. It would be nice if we took a quick look, just a sense of the group reaction, at some of the other Forward Looking recommendations that are here. We also, however, have to return to situations 1, 2, 3 and 4, where we left them yesterday afternoon. DR. GLATSTEIN: Was it yesterday afternoon? CHAIRMAN FADEN: That was yesterday afternoon. Three we hadn't yet gotten to, which is the notification one. We have material on that and we really do need to have a collective discussion. The people that are working on the notification part of our charge, both Committee and staff, need guidance and we need to debate as a Committee what direction we want to take the notification steps. And that has to be clearly -- time must really be set aside for that. So, I'm thinking, since it's quarter of 2:00, do people object to our not having a formal break? People can get up; the coffee is there and food is there. But we're only talking about going for two hours. It seems like we can go for two hours and 15 minutes without having a break. So, having dispensed with break, it seems it should be doable. Maybe what we should do is take only a half hour, no more, to continue to leaf through and brainstorm about the future of oriented recommendations. At 2:15 we will stop and return to the discussion we had yesterday afternoon. If for some reason that discussion does not take up the rest of the afternoon, we can return to Forward Recommendations. Within the Forward Recommendations, Phil, I don't know whether you're reading to have us take a look at some of the ones that were directed at research involving soldiers or not. We could get that page xeroxed and circulated. DR. GLATSTEIN: It's being xeroxed now. CHAIRMAN FADEN: It's being xeroxed now? DR. RUSSELL: The one I gave you last night? CHAIRMAN FADEN: Yeah. DR. RUSSELL: That's fine. CHAIRMAN FADEN: Is that fine? So maybe -- the concern I have is that Phil is going to be in Australia at the next meeting. We all had a trip planned years and years and years ago. He'll have to miss the meeting next time. So if we're going to look at any recommendations that speak specifically to research involving soldiers it would be a good idea if Phil was present when we had that discussion. So let's spend 15 minutes perusing this through and then 15 minutes looking at the recommendations which we have not yet seen, but they're being xeroxed as draft ideas to discuss and see if this is worth pursuing for research involving soldiers. And then we're going to return to the Backward Looking stuff. We were involved I think in what was a terribly important discussion and I hope that our notes will do it justice. We had not gotten to two topics that are really important to get just a sense of the group for, one, still staying with human subject research. There are recommendations on pages 34 and 35 and 36 which gets into accountability, oversight and sanctions and I don't know whether we can do anything with them right now other than -- it would be nice to spark a little debate and discussion about whether the Committee wants to comment on these questions. DR. GLATSTEIN: I'd like to comment on periodic audits, IRB performances. I have no problem, but who's going to do it. Who's going to pay for it. And the problem is with what's happening in the Congress right now with reductions of budgets, I can't see that anyone's going to be able to afford new people to do this. CHAIRMAN FADEN: Well, I think there's sort of two issues. One is do we think this is an important function. If we think it's an important function and it ought to happen, then do we -- but do we make that recommendation, given the climate. Can we think of some other way or can we think of the most resource minimal way to accomplish the same objective given the current constraint. I'm not -- I understand what you're saying. I mean, I don't know how to factor in the political -- DR. GLATSTEIN: I mean, we're going in the opposite direction to what everything else is going if we make this recommendation. CHAIRMAN FADEN: Right. On the other hand, you heard Reed's statement that nothing galvanizes his approach as a top university administration more than the fact that they're going to -- when they come to inspect the vivarium, if the rats don't have their square feet, they don't get their permission to continue to get animal funding research. So, to throw that mechanism out altogether would be problematic. On the other hand, you're right. We're swimming -- maybe we're swimming against -- I don't know. MR. GUTTMAN: We're going upstream. CHAIRMAN FADEN: Thank you. I always look for Dan when I'm trying to think of metaphors. Okay. I see Phil, Pat, Henry. And I am going to be a little more -- and Lois. I'm going to be a little more like -- a few comments on this one; let's go to the next one. Just to get a sense of the group so the staff knows. Phil? DR. RUSSELL: In those instances where there are two levels of review in place, such as the Cancer Institute and military for high risk research or greater than minimal risk research, there's functionally already a way of evaluating the performance. And what's probably missing is a feedback to the IRB. The investigator sends it to his IRB and gets through; goes to the second level of review, doesn't get through; comes back to the investigator. And it isn't used to evaluate the performance. It may have to come back through the whole loop again. DR. OLEINICK: Well, it does go back if it's not approved. DR. RUSSELL: If it's not approved. DR. GLATSTEIN: It's typically approved with revisions, subject to revision, so that there isn't a complete circle. CHAIRMAN FADEN: And so one discussion is let's look at all the mechanisms that are in relation to that and see what we can add on. DR. RUSSELL: It's a possible mechanism for improving the feedback to the local IRB's. CHAIRMAN FADEN: Pat? MS. KING: I thought that HHS was initiating its own review of the IRB process and the review process. If I'm right about that, one way to deal with this would be to find out more about what they're doing and endorse it to answer, in part, a little bit of Eli's question. If I'm wrong about it, then you can scratch this. CHAIRMAN FADEN: I think I know what you're talking about, but let's not confuse issues. Let's find out more and make sure we're thinking about the same thing. Henry? DR. ROYAL: Item Number 4, cumulative tracking of radiation exposure. I think the benefits -- CHAIRMAN FADEN: Where are we? DR. ROYAL: Page 36. CHAIRMAN FADEN: Yeah. DR. ROYAL: I think the benefits to be accrued by that are questionable and with the resources that it would take. CHAIRMAN FADEN: I will look at where that came from. We'll start a dialogue with the originator. DR. THOMAS: Well, I'd like to be in on that dialogue. I don't know where it came from. I don't know who's developing it. But I actually think it has some potential if only for epidemiologic studies. CHAIRMAN FADEN: Okay. I will try to find, for at least two of you, will try to find where this came from, but we can think about it. I have no thoughts because I don't know anything about this area that would speak to whether -- I don't know enough certainly to know whether this is a useful or not useful suggestion. MS. MASTROIANNI: E-mail will start between Henry and Duncan and we'll try to coordinate that. CHAIRMAN FADEN: Lois? MS. NORRIS: I'll try to keep this short. I recognize that we have to be cognizant of political realities. But on the other hand, I think if there are recommendations which we feel are sufficiently important, that we should nonetheless go ahead and make those recommendations. To say that we don't think it's going to be done or we don't think that it's politically acceptable at this time is limiting and I don't think we should be limited entirely by that. The other thing is with respect to the on-site audits. It seems to me that if we have a system in this country which has on-site audits for the animal review boards, I think it's appropriate then that we should give equal consideration to human subjects. CHAIRMAN FADEN: We'll find out more about that. MS. KING: We don't have a human subjects lobby. (Laughter.) That's a facetious comment. CHAIRMAN FADEN: It's not irrelevant. Practically speaking, we function as that at the moment. MR. GUTTMAN: In fact, we asked this over at the Defense Department. They said they're now putting on Internet all of their animal experiments. Of course, we said what about human experiments. Nobody care about those. CHAIRMAN FADEN: Ruth? DR. MACKLIN: One thing I don't see -- it's not in here, and one thing that I don't know that has ever been done, although there is likely to be great resistance to it, is a monitoring of the actual consent process. The federal regulations as currently written permit IRB's to engage in monitoring activities. It doesn't specify it but they do say something like that. And yet everyone shudders at the thought that members of a committee -- we're not talking about whole committees trooping anywhere, but that a member or selected members of a committee might be authorized to observe the consent process. I'm also not only not suggesting, although I don't think anyone has suggested, that they go into doctors' private offices. But these are -- very many of these are hospitalized patients. The IRB is either a hospital IRB or a medical school IRB of which the physicians are on staff. It seems to me not unreasonable, especially in teaching institutions where many people troop to the bedsides and do things of much greater indignity to patients in the training mechanism, like doing pelvic exams on women, et cetera, et cetera, sometimes when they're unconscious and they're under anesthesia, seems to me not unreasonable to suggest a monitoring, a periodic monitoring. And this can be done openly with notification to investigators that from time to time someone from the IRB may show up and announce himself or herself and acknowledge or identify himself or herself as a member of the IRB to engage in a monitoring of the consent process. And that might include who gets the consent, do they send a resident in there, "Hey, consent this person." That's now a verb. "Consent this patient." (Laughter.) Whether it's a research fellow who is presumed to know something about the research; whether it's the physician, et cetera. So I think the time has come to suggest something like that. I mean, with a Committee like that could at least have the imprimatur of suggesting that monitoring is not an intrusion on the doctor-patient relationship. CHAIRMAN FADEN: Again, this is an interesting suggestion. Monitoring doesn't only -- we're not -- it's to whom the recommendation is directed and how it's executed. If it's done that way, it's different than if the federal government sends a team of people. DR. MACKLIN: Oh, but that's right. This -- well, talking about auditing of records is very different from giving - - from -- I mean, Ruth, are we asking for any of these to whom are they directed? And what I'm suggesting here is that this be directed to IRB's if we're going to direct anything to IRB's. And I think we are about consent. That this expand the -- not expand, actually, enable the IRB to do something that is within its current charge. We don't need anything different in the federal regulations, but that an explicit mention that it would be an appropriate thing for the IRB to do, to engage from time to time in a monitoring of the process for consent. DR. KATZ: But, Ruth, I think you appreciate as well as I do that in these situations it's not the dignity of the patient that's involved but the dignity of the investigator. I've talked with a number of heads of IRB's about that issue and all of them were opposed to it for one reason. They say that is an indication that we do not trust the investigator. And when I said, look, it's not a matter of trust, it's a matter that the issue of how to obtain -- how to make disclosures and obtain consent. It's very, very complex and we have to learn about what's going on so that we can improve the process. It had very little impact on them because they felt it's an insult to the moral integrity of the investigators. CHAIRMAN FADEN: That's the argument generally provided for any kind of monitoring of IRB functions or what investigators do. This is a system predicated on trust. DR. GLATSTEIN: Undoubtedly true. But if it's required by the funding institution, they'll put up with it. DR. ROYAL: I don't think that having someone stand there while consent -- which is much of an audit -- while consent is being obtained, because who knows what the consent -- how that changes the process. And it also would be inefficient. You'd have to sort of get everyone together at the same time. But I think going to talk to patients who have been enrolled in a research patient and say, "Did you understand that it was voluntary? Who got your consent?" And doing that kind of an audit would be a good thing. The other thing is if investigators were required to give you a list of the patients that they talk to to enroll into a study, that would give you some idea of what percent of patients agreed and did not agree to participate in research subjects. And I think that there are probably some investigators who have very high recruitment rates. And every time that they don't recruit a patient they sort of feel that they've failed in some way. If you actually are logging and keeping track of their failure rate, if a patient told them no, they might think that's a good thing because they know that the IRB is then not going to question them about them coercing patients. So, suddenly this thing which they've always regarded as being a bad thing and a failure, it's okay that an occasional patient -- CHAIRMAN FADEN: That's fascinating, actually, because you know the whole review process when you put in for competitive renewals is predicated on, not only because of the issue that Jay raised which is can you get your sample approved in the time frame that's necessary but also the bias issue. If you have a refusal rate, then immediately your research is suspect because you've got some sort of refusal bias. So the whole incentive structure, not only the money but the science side of the incentive structure works against your approaching this in such a way that you would feel okay about having somebody say no to you. If there's a little way you can make it feel okay wouldn't hurt, you know. DR. ROYAL: And it doesn't require much effort. We're just asking for a list of names of patients and whether -- CHAIRMAN FADEN: Maybe not the list of names because of the privacy issue but some sort of a -- I don't know. We can work on it. That's interesting, kind of interesting. It's a very interesting suggestion, as these all are. I want to draw your attention, only because we've got to march on, to the -- in fact, march backward with this. We're going to look at particularly notification which we have as yet left unexamined communally. The last recommendation that I want to do is some directed research involving soldiers that aren't in this package, because we will lose Phil next week. But I also want to spend like five minutes on the class of recommendations that don't bear on human subject research that's in here but that speak to openness, the other history of a rather big territory to which we lay claim in this Committee. The last one on sanctions -- and I don't know if you want to discuss this now, but we're going to take a look at it. Sanctions are -- it's presented here as the end of a loop. That basically you have to have a complete process. It speaks out of our history because, remember, we have addressed the question of whether we can reach judgment about culpability about individuals, let alone address questions of sanction. And we have said that for lots of reasons this is really difficult and inappropriate to do. And the line is but we've got to do this in the future. In the future we've got to make it clear that it's possible to draw such judgments and apply sanctions in an unambiguous straightforward seamless web of obligations, duties, sanctions, audits, violation sanctions. That's what this is intended to capture but it may do it poorly. I see Pat and Duncan. MS. KING: I think of this as being very hortatory -- is that the correct word? You know, involving good people. I think it would be a better approach to call attention to the sanctions that we would find acceptable, rather than short of like this general call for -- see, I think that people, if you violate some of these human subject rules, then you don't get funded again. That's where it hurts. DR. GLATSTEIN: That's right. MS. KING: And so we should be explicit about what we think is warranted. I don't mean give specifics, Ruth, but be willing to go on record as standing behind strong sanctions or egregious behaviors and listing the kind of sanctions that we are talking about because unless we're willing to do that, then whatever else we recommend doesn't really amount to a hill of beans. And quite frankly, we see a lot of problems out there now just because the likelihood of being caught and the likelihood of having something bad happen to you is so minuscule that people can run big risks. CHAIRMAN FADEN: Well, that's why the notion of some sort of oversight mechanism, whether auditing -- MS. KING: Well, then, the sanctions must be willing to say you lose your -- it's poor science, I have always thought, to conduct a research study in a way that jeopardizes the human subjects. And you ought to be sanctioned for it that way. DR. GLATSTEIN: Yes. If you'd refuse any application for at least a five year period, that hurts. CHAIRMAN FADEN: That's right. Duncan and Ruth. DR. THOMAS: Mine was in a similar vein. I support the notion of sanctions but I find the language too nebulous. It doesn't tell me what types of sanctions nor does it tell me who's being sanctioned. Types of sanctions could range anywhere from funding, an excellent suggestion. There are some publications which I believe you already have, but it's not probably uniform across journals. CHAIRMAN FADEN: We know from Wilhelmine's project that there are some sanctions already in place and we will be able to fit this against the sanctions that are there and how much is known about how frequently they are applied, imposed. And, of course, the big hole is if no one knows if a bad thing happens unless there's a crisis or a controversy and the connection breaks, that's where some sort of monitoring or oversight or something has got to be there. Otherwise, as you were saying, to surface someone to whom a sanction is appropriate. MS. KING: I haven't thought this before but there are two ways to get compliance. One is monitoring. And I'd have to think about this, but the federal government has gone to this. The other way is that you place incentives in place to get people to whistle blow. That you don't look for your -- in fact, they're having great success with whistleblowing now because they pay them money. I'm not suggesting that. But part of this is is there something to work on the other side in terms of getting those people who've been asked to participate in research, some way to get them to talk about and to surface their concerns. A lot of them are still quite cowed. MR. GUTTMAN: You mean get paid to be a subject and then you also get paid to blow the whistle? MS. KING: You can't pay subjects. Are you kidding? CHAIRMAN FADEN: Ruth? DR. THOMAS: Well, let me just finish. CHAIRMAN FADEN: Sorry, Duncan. DR. THOMAS: The other types -- I think there are a wide range of sanctions open to us. I agree that one of the things that we can do is make a catalogue of what's already out there. I can imagine various forms of professional stigmatization, whether it's just bad publicity or actually involving the professional organizations in stronger measures, right up to on the line to civil and criminal proceedings. And then I further want clarification as to whether -- as to which of these sanctions are appropriate for investigators, for institutions, for IRB's, for government agencies and so forth. CHAIRMAN FADEN: Okay. That's -- so, level of detail. I'm not sure how far we can go, but we'll try it, more detail. Clearly what we're hearing is the Committee wants to say something about sanctions with strong language and wants specifics. Ruth and Eli. DR. MACKLIN: In the last few years since the federal government has gotten interested in scientific misconduct, there's now a growing track record of sanctions, of denial of grants, pulling money away from people, saying you can't be a PI for the next X number of years in violation of one or another -- either regulation or accepted rule of scientific conduct. So the current activity and the flurry working through local institutions, whistleblower -- allegators is what they're called. The people who make the allegation. (Laughter.) The people who make the allegations that scientific misconduct have occurred -- don't pay them any money. But that's a process that has taken place. CHAIRMAN FADEN: Yes. The allegators. DR. MACKLIN: Now, one consequence of this which is in a way interesting is that there are now more sanctions and more - - there are more sanctions imposed and more whistleblowing, against people who violate scientific misconduct than those who might violate rules or jeopardize human subjects. They're not even jeopardizing the animals here. I mean, it's plagiarism. It's the government's money. It's falsification of data and all that stuff. There's a great deal of attention to that. So, I mean, this seems to be a perfect time to say, well, maybe we care about people, too. Now, one more thing. And that is, what should be the institutional mechanism to review this misconduct. Every institution now has to have some layer of committees in more or less compliance with the ORI or the OSI now, the Office of Scientific Integrity or the Office of Research Integrity. I forget which. It was one, then they changed it to the other. But some layer of review of allegations of misconduct. Now, some people have argued that if you've got some kind of violation of human subjects research that's not scientific misconduct. That's some other kind of misconduct. And therefore, -- I mean, maybe human subjects research misconduct or whatever, but it's not, narrowly speaking, scientific misconduct which raises the question whether those bodies that are already in place are the right ones to look at it. The question is are IRB's the right committees to look at it. That's not what they're structured to do. That's not what they have traditionally done. And I think I told this story. I will make it very, very brief. In the first year or two that I was on an IRB at Albert Einstein and some researcher at the institution was doing blatant -- no one questioned that he was doing things wrong. He was doing blatant violations of all kinds of things and people knew it. And the question came up should the IRB censure him. Not report him to anyone, but just censure him. And I brought up a little statement. I was asked to do it because I was new on the Committee and I was an editor. But I wrote this little statement that accused him -- in fact, that was ultimately what the IRB was going to sign -- that accused him of unethical behavior and unprofessional conduct. And they said, oh, you can accuse him of the unethical behavior but not the unprofessional conduct. That's a red flag. You accuse a doctor of unprofessional conduct and he's finished. And as it turned out, the IRB refused even to censure him for anything. I tell the anecdote because maybe the times have changed. Maybe they have not. But maybe the IRB is not the right mechanism. And since any place that gets research funds now has to have these other committees in place, that might be -- if we want to be a little more specific than what's here. CHAIRMAN FADEN: They're already there, basically? We're going to let Eli have the last word on this and then I'm just going to -- MS. KING: Can I follow up to Ruth? CHAIRMAN FADEN: Yeah. MS. KING: In the consent form discussion which I missed this morning, what we might consider doing is informing subjects, which we do at some places, that if they have problems with what has occurred to them, they can go someplace. But in addition, we should inform -- subjects should be informed of the possible sanctions that can be brought to bear to encourage them to think about this as being serious. Because I think that they will need that. Most subjects are not going to go do this. CHAIRMAN FADEN: Right. But if they're told that actually if you do this something will happen? MS. KING: Right. So we might want to think about that next time we take a look at the consent form issues. CHAIRMAN FADEN: Okay. Eli? DR. GLATSTEIN: Before we move back to the other subject, I want to address Items G and H on page 37. And this has to do with research with soldiers and oversight of intentional releases. It's hard to anticipate when we're going to have another resurgence of issues of national security, but I would certainly like to make it not impossible but damn difficult to see some of the things ever repeated that have been done. And I would like to see a restriction in there that deliberate exposures of soldiers to atomic weapons, atomic explosions, would require an authorization from the President of the United States, the highest elected official in the country. There may be some reason why he would permit it, but I think it requires an elected official to approve that. I don't want to see this left in the hands of admirals or generals. And by the same token, intentional releases, I don't want to see it left in the hands of someone who is running a nuclear power plant. There may be urgent situations where there's no time to do something, but if there's a planned release, I want to see some restrictions on there that that just can't be done at somebody's whim, no matter how well motivated that individual might be. CHAIRMAN FADEN: Well, the intentional release, that falls into a whatever right now. We'll need to work with that. We do have something on soldiers. Why don't we just go to soldiers right now and add Eli's concern, the discussion of what Eli has presented to us just now. We're all looking at you, Phil, so not to put you on the spot here, but the notion is -- the suggestion that's coming out, Eli, you're saying that there ought to be some clear recommendation that basically says in this kind of a context you can't -- DR. GLATSTEIN: Shouldn't be allowed unless there's a written authorization by, I think, the highest elected official in the country. DR. RUSSELL: At the present time, that kind of an authorization is delegated to the Secretary of the Army. CHAIRMAN FADEN: The issue is not whether there should be above ground nuclear testing. That obviously isn't. The issue is whether you -- DR. GLATSTEIN: That's not our business. This is about ordering people to go someplace on a non-emergent basis. CHAIRMAN FADEN: So it's not wartime. So you're talking about -- DR. GLATSTEIN: Not wartime. It's not when there's been a nuclear accident and somebody has to do it and it falls to the military to do it. That's not the issue. This is forcing people, ordering them to attend some atomic explosion -- exposure. DR. LEDERER: Is this only radiation related exposures, or would you include other things? DR. GLATSTEIN: That's all I have in mind. DR. ROYAL: I'm confused about what level of exposure we're talking about. Soldiers get ordered all the time to do things which have some risk to them. And whether or not you have in mind that the trigger should be the magnitude of risk that they're being exposed to or that you really mean that the trigger should be radiation, per se. DR. GLATSTEIN: I have in mind an atomic explosion, a non-trivial exposure. DR. ROYAL: Well, but as you get away from ground zero, you go from a point where there's a high exposure to the point where you get close to background radiation. DR. GLATSTEIN: I find the business of ordering people into ground zero or near ground zero, depending on how you want to define that. CHAIRMAN FADEN: Dan, did you want to come in on this? MR. GUTTMAN: Yeah. This is probably going to complexify it, but we've been thinking about this. And somebody has talked to Phil and some of the people. And just a couple of little points that may or may not be relevant. One is, I understand the tests, each test series, was in fact authorized by the President. It isn't clear the President knew or had before him that troops were going to be marched in. All of that was public. We actually found congressional correspondence with the Joint Committee on some of this. The second point, and this is the one that was a surprise to me. And General Russell will probably be able to tie in better. As it turns out today, surprise, we were talking about whether the risks, as we look at the atomic vet story, who was in charge of looking at that set of risks back then. And as we've been discussing at great length, you've got this peculiar situation where some of the folks were experimental and nine out of 10 were the similarly situated people who weren't experimental. And I guess the perspective we have and the story that's drafted is that the people who could have called the whistle -- blew the whistle on the risks were wearing multiple hats. They were both the doctors, not only the generals but the medical people. Today, -- and Phil, is this correct, what we were told? Is that if you were going to develop a weapon you'd have to do in effect a health assessment for the soldier who were going to use it. And we were talking about -- remember that discussion? This may seem like a quirk and an oddity but in fact in some ways since that period the system has now begun to look at it. And Phil, do you remember that one? DR. RUSSELL: Yeah. There is a very complex system in place which deals with the experimental development of equipment, weapons being one of them. Some of the problematic ones as far as soldier exposure are things like smokes and obscurants. That's a good example because the system or the weapon has to go through a st of human interface evaluations, which is done by the research people. The medical community only gets involved as a part of that safety evaluation. If there's a database available in which the safety can be evaluated, then that's done by the safety people. And it usually requires as part of the safety evaluation a clearance from the medical community. There's basically no research involved. If the information is available in which, for example, radiation, that standards are in place and if there's a source of radiation in the equipment or if it's a laser, for example, where there's a substantial danger to the user, physical data and the physiologic data are pretty much available. But if there isn't, then there has to be experimentation, some of which may involve human volunteers. But the fact is that there is an incredibly complex system in place to deal with the safety issue of the new equipment. CHAIRMAN FADEN: Can we go to the core question? The core issue is whether that mechanism answers Eli's concern. I mean, that's the issue. Would it not allow what happened then to happen again? MR. GUTTMAN: Can i just capsulize it? Because there are two steps here. One of the things I think looks like it happened back then, either because of the times. Everything was happening in a rush and everybody thought whatever, but there was no -- that the failsafe mechanisms, the risk review mechanisms, as Phil said, there were may places where things could have been checked and they didn't work. So one is do you today have a risk review mechanism that can at least find facts if somebody would say, well, gee, there may be a risk here. DR. RUSSELL: That's a very extensive question. MR. GUTTMAN: And then, too, Eli's question is in an area that is going to be as sensitive. And there are so many players and so many parts of the bureaucracy. What triggers at what point what kind of risk or what kind of -- you know, it is radiation or atomic bombs. Do you say that can still only be done with an approval that's non-delegable? I mean, from the highest level. So, there are two questions. One, you have to have a risk review mechanism, otherwise it doesn't really matter. CHAIRMAN FADEN: And then there's a way that they cannot say that the call has to be made higher than that? MR. GUTTMAN: Right, right. And is that the way to fully phrase the question. DR. RUSSELL: I really don't understand your last question because the issue of exposure to radiations is so dealt with in the radiation safety issues that I don't see the kind of problem that might be -- CHAIRMAN FADEN: Let me unpack this for the rest of us. Phil, is your response to Eli's concern about specific repeating of what happened in the '50s, it couldn't happen because -- DR. RUSSELL: The system is different. CHAIRMAN FADEN: -- the system is different. And it couldn't happen because now we have all these standards for radiation. DR. RUSSELL: For radiation. CHAIRMAN FADEN: For radiation exposure. You've got all these standards and marching to ground zero would clearly exceed those standards. And so the risk mechanisms of the Army wouldn't allow that to happen. DR. RUSSELL: Well, there's a little cultural change, too. CHAIRMAN FADEN: And cultural change. That's sort of what I hear you saying. And the issue is they exceeded the risk standards it looks like sometimes in the past, too. So what's are the issuances? MR. GUTTMAN: They were waivered. They're waivered. DR. GLATSTEIN: What's the assurance that there won't be a return to the previous system? CHAIRMAN FADEN: It might be that if you want something that speaks to this particular situation, although I don't know how likely it is that we're going to have that again. Maybe the more forward looking thing is to anticipate. DR. RUSSELL: The fact is we've got a different -- CHAIRMAN FADEN: I don't know. My mind doesn't -- to get to the waiver questions and to get waivers, you can't waiver radiation. Only the President could waive radiation -- DR. RUSSELL: We're no longer in the business of testing atomic weapons. CHAIRMAN FADEN: Right. We're not now. DR. RUSSELL: Not above ground or not ever, not anyplace right now. Hopefully, never again. CHAIRMAN FADEN: Right. DR. RUSSELL: So it's not a realistically addressable issue in my mind. Now, are there other kinds of -- CHAIRMAN FADEN: Hazards. DR. RUSSELL: -- hazards that are -- and I've mentioned a whole set of them that the military has come up against and they've been, I think, dealt with by a very complex bureaucratic system for evaluating and so forth. MR. GUTTMAN: Let me try -- can I try another way around it? DR. RUSSELL: Can you get by that? MR. GUTTMAN: Let me try some other approaches. CHAIRMAN FADEN: That's the key question. I mean, isn't it the issue that you can get by it? MR. GUTTMAN: Yes. Let me try a couple of other approaches here. CHAIRMAN FADEN: Why do we need to? Can't we just stick to that question? Can we find out if you can get by it? And if you can get by it, who has the authority to say you can get by it and is this Committee comfortable or maybe we don't have the expertise, but we can say, look, somebody's got to look at the rules by which you can get by it. MR. GUTTMAN: Let me give you an example. CHAIRMAN FADEN: Okay. An example. MR. GUTTMAN: This may be the real world. Part of what happened in the past is in some ways I think quite relevant to the present. And the basic institutional questions are laid out. And one of the things if you look back in the past is you had -- there were two levels of check going on at the bomb tests and there was the internal Defense Department where theoretically you had doctors who were radiation experts who were going to say, you know, you can't do this. Then you also had the AEC and its biomedical experts. And one of the things that happened -- this gets to the waiver and the check. The AEC standards were routinely waived for the troop maneuvers. And in fact, the interesting story is that in relation to the international standards with our partners the Canadians and the British, they didn't like what any standards were. So, in other words, the situation, to focus even more finely -- and maybe this is -- I don't want to use the word Persian Gulf or anything like that, but you may have a situation where there's another agency with expertise. That in these situations which are as important and as focused and as sensitive, you may have multiple standards set; right? And so the question is does the Defense Department become the arbiter of risk in the face of a countervailing alternative. What's that balance? Let's say the AEC is there tomorrow and says our standard is 3.9 but it's a military operation. What happens if the DOD makes a call or -- DR. GLATSTEIN: I don't want it to be the DOD. MR. GUTTMAN: Well, I don't want to talk about that. CHAIRMAN FADEN: But that's what Eli wants to talk about. MR. GUTTMAN: But I'm saying in the real world -- DR. GLATSTEIN: I want it to be an elected official. DR. RUSSELL: Let me ask you this. Who has the waiver authority? MR. GUTTMAN: These are the questions. DR. RUSSELL: No. Who was the waiver -- what's the historical record on who was the waiver authority? Who signed it? MR. GUTTMAN: Well, very interesting. It looks like it was a delicate dance of elephants. (Laughter.) The AEC saying, you know, in terms of -- well, gee, we really don't want to get into this. This is political. But, hell, these guys are going to do it. But on the other hand, we look like we're abdicating and we're going to get blamed if this is a mess. You know, it's really internal arguments enclosed -- this was all done in secrecy. So that's part of the system. DR. RUSSELL: You didn't answer the question. MR. GUTTMAN: Not the President. It was the AEC. DR. RUSSELL: The AEC had the waiver authority. MR. GUTTMAN: I don't know if they had the authority, but they did it. DR. RUSSELL: The AEC did it. MR. GUTTMAN: Yeah. Now, whether they legally did it - - CHAIRMAN FADEN: A civilian agency. MR. GUTTMAN: Huh? CHAIRMAN FADEN: A civilian agency. DR. RUSSELL: A civilian agency. I rest my case. CHAIRMAN FADEN: That's very telling, but it actually also speaks to Eli's question. DR. GLATSTEIN: The concern is what happens when we get another era of paranoia. The concern is what happens if we get into another Cold War and we're more concerned about these issues than we are at the moment. I want to put some real restrictions on that. CHAIRMAN FADEN: All right. What I think is we need to do some hard work here. We clearly don't even have the sort of backward story set up the right way to do the forward story on this narrow point. It's a terribly important point but you're making it very narrow. And that's as it should be. So, let's focus on -- we'll try to work on trying to get something that captures the spirit of what you say, Eli. We may not all agree about the President, but the idea is somebody - - DR. GLATSTEIN: I want to put -- and I see an analogy with respect to intentional releases -- CHAIRMAN FADEN: Okay. Right. DR. GLATSTEIN: -- that could come from nuclear power plants or something of that sort. And I want to make that difficult, too. CHAIRMAN FADEN: Now, the question of whether -- DR. RUSSELL: Let me make one point here. CHAIRMAN FADEN: All right. DR. RUSSELL: I think there's a generic issue that who is responsible within the military system for the health and welfare and well-being of the service members, and not on the battlefield but in a broader sense, and that generally is -- who's responsible for feeding them and clothing them and so forth. And that kind of authority and responsibility are invested in the service secretaries. And that's why you see the secretary of the service being the approval authority, final approval authority for all of the high risk kinds of volunteer issues. Because it's just part of the culture, part of the way the services work. Fundamentally, the civilian control over the military extends down that chain and I think Eli is a little bit extreme there because the delegation of this authority is virtually two steps from the Office of the President. And that's -- DR. GLATSTEIN: That's not close enough. DR. RUSSELL: Well, that depends on the frequency and the level of the issues. CHAIRMAN FADEN: Right. I think that's right. And we can't have this be like an every day event. DR. GLATSTEIN: I can't imagine that it would be. CHAIRMAN FADEN: Right. So the issue is, though, can you signal -- let me separate those. One issue is this issue of where to place the President in all this, and another is this sort of general issue of what's in place now, who has waiver authority, how does this work out, what are the protections. And we're speaking and thinking in the context of around nuclear testing but presumably there are other hazardous contexts. DR. ROYAL: Why don't you think about it in terms of waiving the usual occupational safety standards? CHAIRMAN FADEN: I was about to do just that. Right. I was about to do just that. That you have mechanisms and a civilian counterpart. And you could sit there -- and don't know, but I have a feeling that there's a whole world out there about which I know nothing, so I'm hesitating. All I'm suggesting is we want -- the Committee needs to deliberate recommendations on this topic. We don't have anything before us right now and that's in large part because we haven't done the work that needs to be done. MR. GUTTMAN: Well, actually, we are now because Phil has got this work refocused and we're collecting the standards and so forth. DR. RUSSELL: There's a huge system of bureaucracy out there that we don't know very much about. CHAIRMAN FADEN: Well, that's part of the problem. The point is we've got to figure out to do. We're going to forward. The IR stuff there is similar sort of scrutiny. We've tried to do that as well. I hate to push us on but I think discussions in ignorance are often useless. And since we have so little information, most of us -- I include myself in this, on this point right at the moment, I'd like to hold back and let us have a good discussion on this next time where we've had a background paper or document or something that can educate us. DR. OLEINICK: Okay. So we're going to be educated then not only about the issue of risk, which is one issue, but the other is the ability of the soldier to volunteer for an experiment. CHAIRMAN FADEN: Right. And let's look at these three recommendations. DR. GLATSTEIN: Where did these come from? CHAIRMAN FADEN: Well, Phil and I talked about them and I tried to capture, so I did the typing. Okay? (Laughter.) I told Phil I was the scribe. We had lunch. I told him -- we talked about it and I tried to capture his suggestions. And you looked at them, Phil, so I guess I haven't violated them too much. They're at a much different level than the discussion about -- take a quick look at it. And again, the language isn't at issue here. We're going to work on the language. But it's these kinds of recommendations. I'll just direct this to Phil -- and we can do this briefly. Could you speak to the middle one? Because this is something -- I thought that was very interesting, the one about the investigative officers. DR. RUSSELL: This speaks to the issue of the interface between training and human experimentation. We felt that the way to assure that the current regulations, which are very detailed, very comprehensive, and if followed were pretty good, are followed in the best possible manner to educate the people involved. Well, it turns out that there's a very large community out there outside of the medical community that gets involved in these issues. They have to be instilled in the officer education programs up through the system, so that's a recommendation that they embed concerns about human volunteer issues and experimental issues in the education of officers. Most officers go to school at least four times during their careers, a basic course. There's an advanced course, there's an Army staff college or equivalent and a senior service school, Army War College, Navy War College. So, you have that as part of the curriculum of all of those courses, some education in this with regard to these regulations. It would probably do a lot more than revising the regulations. DR. OLEINICK: It seems to me that if this kind of -- these regulations could be transferred into the civilian world, it solves our major problem. DR. RUSSELL: Well, we're always ahead, you know. DR. GLATSTEIN: With one proviso and that is if everyone could agree on what is research. Because my concern, that some of the issues of what you and I call research, would not necessarily be classified that way by a professional military man. Not every professional military man, but by some. And it's this confusion of roles, again, that makes me very concerned. DR. RUSSELL: Well, that goes to recommendation number one, which says to ask the secretaries to review their policies and procedures that speak to distinguishing between research and the usual business of the military. I don't know that if the subject is sufficient by complex that being more prescriptive and telling them to go back and look at the issue is very difficult. CHAIRMAN FADEN: I see Ruth. And I'm going to be real Draconian here. Ruth and Henry, and then -- DR. ROYAL: I don't want to talk. CHAIRMAN FADEN: Okay. Ruth? DR. MACKLIN: This is just a question and I apologize because I forgot the answer when we discussed this once before. And it goes to Eli's question. The last sentence in paragraph 1, medical interventions that are intended to protect the troops. What was the category? Wasn't that the category under which the Gulf War -- I can't even remember what the material was that the soldiers were given, the substance that they were given. Wasn't it under this category, medical interventions that are intended to protect the troops? And quite apart from the question of whether it was procedurally correct, would that count as research or would that count as medical intervention? DR. RUSSELL: Medical intervention to protect the troops. DR. THOMAS: Even though the intervention is still unproven? DR. RUSSELL: It was proven to the extent that it could be scientifically proven without challenging with nerve gas. CHAIRMAN FADEN: It isn't, again -- let's try to be straight. There really wasn't anything you could have done in that kind of time frame. I mean, I shouldn't say that with such authority, but it's something that I've looked at. I've become persuaded that this was a rock and a hard place issue rather than a clear example of something gone wrong. At best it's a mess and a muddle. DR. THOMAS: And if it can be followed up by an epidemiologic -- hypothetically, if it were to be followed up by an epidemiologic study to find out whether it was effective, that's still not research. DR. RUSSELL: There weren't enough casualties to count. CHAIRMAN FADEN: Let's go to Ruth's question. DR. MACKLIN: The question of whether anything else could have been done is a separate question from whether it should have been considered research. I mean, -- or whether it was an innovative -- CHAIRMAN FADEN: I understand what you're saying. DR. MACKLIN: Yes. I mean, -- and Eli asked who judges that or who determines that. DR. GLATSTEIN: Yes. DR. MACKLIN: Now, whatever the muddy -- I mean, to even to say there wasn't anything else that could have been done, that may be to justify it, but not to answer the question whether it was research or not. That is, one might justify a research maneuver on the grounds that we don't have anything else. This is research. Therefore, we're going to be doing it because it may be the only way to protect them. CHAIRMAN FADEN: I think the question is is it research when you use an unproven material, regardless, or whether you're trying to answer a scientific question. That gets into what's research, too. DR. KATZ: You can't call it research. DR. OLEINICK: This was not research. CHAIRMAN FADEN: It's not research. DR. KATZ: It was not research. I've reviewed many of the documents. CHAIRMAN FADEN: It did use an unlicensed product for that use. That's true. So the question is if you count it as research -- DR. MACKLIN: Did anybody have any interest in whether it worked or not? DR. RUSSELL: It was not addressable under those circumstances. DR. KATZ: That was really the big question that remained moot. In this kind of a situation, should or should not data have been collected after the event. It never became an issue. CHAIRMAN FADEN: I think what we should do there is we need to look at this. We need to provide documentation that these recommendations are generally in line with the sorts of things the Committee would like to consider. I think we can provide to those of us who are not. And I certainly don't know what the authority or language or meaning of the term "medical interventions that are intended to protect the troops" are -- is. What does that mean? I think it's like language that means something in the world of the military. And so for the rest of us, we need to understand better what that means. And that I think goes more to your question than using the example of the Gulf War, because then we go off on a red herring. So let's try to find out what that term means for those of us who are not familiar. DR. RUSSELL: Let me address one more question that I think is very important. There's a civilian counterpart to the comments that were made by Duncan and Dr. Katz, and that was if you gather data after the use of a medication or a medical intervention, is that therefore defined as research and therefore you have to use -- and I put to you that we have a legal requirement in the United States for post-licensure surveillance of all drugs and vaccines. Now, -- so you cannot use the data gathering -- CHAIRMAN FADEN: After the fact. DR. RUSSELL: -- after the fact, as defining a research. It isn't. DR. KATZ: Ruth will cut our heads off, so let's talk about it afterwards. CHAIRMAN FADEN: The reason I'm trying to avoid it is because I know the kinds of issue it will raise. DR. KATZ: Well, let's make it research. CHAIRMAN FADEN: Look. I'm going to do -- (Laughter.) DR. RUSSELL: We will all agree on that. CHAIRMAN FADEN: I'm getting more Draconian by the minute, so here's what we're going to do. Okay? If you don't like it, you can leave. (Laughter.) Here's what we're going to do. DR. GLATSTEIN: Tough lady. CHAIRMAN FADEN: We are not going to talk about this any more. (Laughter.) Until next time. DR. RUSSELL: Come on, Ruth. I'm just getting warmed up. CHAIRMAN FADEN: No. What we have to do, even though - - we got consensus that we got so much else to do and we've got to get -- what I'm trying to do is just give staff enough of a feeling so they can take this further so we can go beyond it. We have not looked at all, and we need to, at the recommendations on openness. They'd be on page 21. And we'll spend a short period of time going through those and then we're going to move to notification, which we didn't touch at all last time and we have to do something with before the next meeting. If we don't exhaust the notification issue before 4:00 o'clock, we will return to situation 2, which was left in distress. But we haven't talked at all about situation 3. But before we do that, can we look at the preliminary recommendations with respect to openness very quickly, and just so the staff can get the same kind of sense of the group about what looks promising and what doesn't look promising, as we did for the research involving human subjects. So on the openness business, the first one is the recommendation that Henry alluded to before lunch, the notion that a registry be created in which information is routinely preserved on funded -- approved and funded research, for a series of purposes, not the least of which is so that if there's ever, God forbid, a committee like ours again, they don't have to go through boxes. And hopefully, technology should make this a lot easier. DR. OLEINICK: I am certainly not against this recommendation. I would like to know whether there is any thought to going beyond the studies, just those funded by the federal government, and asking particularly those funded by pharmaceutical houses. And there's a lot of human subject research funded that way. MR. GUTTMAN: The answer is that's what they had in the '50s, believe or not, and it got abandoned. CHAIRMAN FADEN: Oh, really? MR. GUTTMAN: The Navy pulled some of its. The National Academy of Sciences sponsored something that included, for example, the Damon Runyon Cancer Fund and all that kind of stuff. DR. OLEINICK: Yeah. All those foundations. MR. GUTTMAN: All that foundation stuff. Yeah. CHAIRMAN FADEN: No problem. We can recommend whatever. DR. OLEINICK: We can recommend it and somebody along the line can decide not to. CHAIRMAN FADEN: And yet they probably could say you've got to drop this stuff off if you want your drug approved. Before you get approved, you've got to drop this stuff into the registry. I would imagine there are mechanisms. MS. KING: Well, actually, other than a federal handbill, you need legislation. So your recommendation has to be for legislation. CHAIRMAN FADEN: Good point. DR. LEDERER: Does this registry include the names of research subjects? CHAIRMAN FADEN: Research subjects? DR. LEDERER: Yes. CHAIRMAN FADEN: I don't know. We have to think about that. MR. GUTTMAN: I'll tell you where that goes under, technically. The question -- the big -- is in all the studies not done by direct government workers. All the data is kept by the private institutions. And it turns out there's just no rhyme or reason as to whether it's kept or whether the government has access or whether through the government the citizen has access. That's separate. It doesn't cover the drug companies but it covers the other government funded people, contractors. CHAIRMAN FADEN: Sue's question is whether you want the names of research subjects in such a registry. And if you don't, what are the implications. MR. GUTTMAN: I know. But what I'm saying is going through the loop or the chain, if you knew that that set of data was kept somewhere; right? That's the first question. You know, then you could say this is at Johns Hopkins. Go to Johns Hopkins on these subjects. Right now there's no requirement that Johns Hopkins keep -- CHAIRMAN FADEN: Ruth? DR. MACKLIN: I just wanted to -- maybe Dan just said it and I missed it, but if as Nancy is recommending this is something that includes all research since I mean, a lot of the drugs are going to be FDA approved and therefore come under some federal purview, is this the kind of information or material that drug companies are likely to view as proprietary after the fact and, therefore, make a big stink about? MR. GUTTMAN: It depends on the level of detail. DR. OLEINICK: Yeah. I would think that would be the amount of detail. I mean, -- DR. MACKLIN: It may not depend on that at all. What I mean is it's not only the trade secret business, but if there are lots of charges floating around that drug companies conducted research that had different results or iffy results there in some of them, raw data or some of the earlier data that eventually got reported or reported out. So the question here is whether or not they're going to claim, on whatever grounds, that the whole matter, the whole ball of wax is proprietary and therefore resistant. In which case the Supreme Court of the United States is going to uphold it. MR. GUTTMAN: There's whole set of questions having to do with the non-directly related. CHAIRMAN FADEN: Yes. We will look. DR. OLEINICK: I think that needs to be looked at. We might want to actually interview somebody from a drug house, or - - CHAIRMAN FADEN: We can get staff moving on that and try to figure out where we stand on that issue. There obviously are also redaction options for proprietary information and I don't know what relief might be found in that kind of a mechanism. But okay. Those are both important points. This is the sort of thing we need to hear. People are generally thinking this is a good idea. What are your concerns; what are your reservations; what are the worries. Lois? MS. NORRIS: Are you going to look at a response to Sue's question as to whether it's appropriate to list individuals? I think that would require very careful study. CHAIRMAN FADEN: It does. Because on the one hand, if you think about our experience, people can't find out. If you can't look by people it's problematic. MS. NORRIS: Well, you've got confidentiality problems. CHAIRMAN FADEN: So either way it's problematic and probably there is a creative solution, but I'm not sure that we'll come up with it. It's a very important issue to flag. Very important issue. Other things that come up generally, it looks like people think this is not a bad idea but it needs development, refinement, stuff like that. Is that right? MS. KING: I actually would like to hear somebody talk about -- like from HHS, which has the largest bulk of -- storage of protocols, what are some of the problems here. Because, you know, a lot of ideas, which I'm sure we're the first people to think of this idea. And I'm really curious about what have been some of the obstacles other than funding. CHAIRMAN FADEN: For? MS. KING: For doing it. For establishing some kind of central repository. MR. GUTTMAN: Well, we can check. Actually, some of this is now being automated on line, which is happening in some of these places sort of spontaneously. MS. KING: We don't have to make the recommendation. Make the recommendation that what has started go forward. That's a different kind of recommendation. DR. ROYAL: But it would be a good idea to talk to people who have experience with a central registry and find out what sort of problems they've been having. CHAIRMAN FADEN: And there are lots of central registries for lots of other sorts of things, so it's both for people who haven't tried it what do they think are the obstacles, and for people who have central registries for one thing or another, what works and what doesn't work. So, you know, both would be -- it's not like the world has never had a central registry for any information. There's also kinds of central registries, just not for this kind of stuff yet. Those are good points. The next one, the next recommendation calls for the preservation of our collection of all the information and material that the Advisory Committee staff have sort of painstakingly accumulated accessioned is the term. Accessioned into our system. So this is a recommendation that calls for the importance of keeping the entire collection of this Advisory Committee intact for the historical record. Is there any discussion of this, other than the obvious -- my obvious view that this is terribly important? Does anybody -- DR. GLATSTEIN: That is be kept as a separate collection? CHAIRMAN FADEN: Yes. That's it. As a distinct, separate historical -- for obvious historical reasons we already experience that hopefully other people will want to look at as an experience. Sue, did you want to -- DR. LEDERER: I guess I understood that that was part of the FACA regulations. Is that not so? MR. GUTTMAN: We're talking about something very practical and when the collection gets broken apart and, you know, dissipated or whether there'd be a distinct -- nothing is clear in today's budgetary world and all these other kinds of worlds. DR. LEDERER: No. I mean, I have no objection to it. It's a good idea. CHAIRMAN FADEN: So that is a recommendation we currently have. I don't think it's a trivial one, by the way. It is not obvious what happens to our stuff, so there's a great concern. This next one is for an ombudsman for citizen access to historical archives. MR. GUTTMAN: Let me just take two seconds on this. This is in a world where we all know more regulations and all that are not something anybody wants. The basic thrust of this is that the Committee staff and Committee, I guess, -- clearly there was a disconnect. The federal records system was broken. There was no connection between the vast amounts of material in the warehouses and what you have in the front counter. Anybody who went through the Freedom of Information Act was just going to get somebody who turns around, looks at the warehouse and says, "I don't see a box that's got that label on it." Now you're beginning to get roadmaps, as the DOE says, and we are now aware there are terrific efficiencies. So, for example, you've got lots of classified indexes of documents that you could declassify. You've got a lot of records that aren't in the National Archives system, which is relatively well organized or in record centers, other places that are totally inaccessible to the public. The question here is what's the best way to use the public energy that's been identified for the people out there and the way in which we now can see how things can be locatable without spending more money but just continue to get things out in the public. And sort of what's the mechanism. I don't think it's an interagency -- when you go through the Freedom of Information Act, there's stuff at one agency, so there's no kind of central person saying, "Well, bits of that is over here and bits of that is over there." So the notion of this is that there's an opportunity, hopefully at low cost, to bring the public into kind of cleaning out the records. It's just tell the public here is this vault. We'll get rid of the two classified documents in it and you guys can go through it. And so that's the notion. It's a way of sort of sorting through all the ick. Having some mechanism. We use the word ombudsman because we're not trying to think of a committee or commission, just a very practical solution. DR. LEDERER: Is there a precedent for this kind of significant discussion? MR. GUTTMAN: Well, the closest thing to a precedent that I know of is this law with the State Department. You talk with the person -- there's a committee of historians that helps the State Department try to get out its basic historical documents. The CIA, actually, has prevented the publication basically of a recent volume. But that's the closest, the closest thing we've got to independent -- that's not the word I want to use -- search of documents. The full record has yet to be made public. Basically, the notion is taking all the energy of all these people out there who would like to get into these documents but all we can do is file a Freedom of Information request and wait a decade. And we're saying it's not necessary. CHAIRMAN FADEN: Wait a decade? MR. GUTTMAN: Yeah. We're saying it's not necessary. The warehouses can be opened up. CHAIRMAN FADEN: Pat, did you want to respond? MS. KING: I don't have -- I mean, anybody who has any experience with FOIA knows the inadequacies of FOIA. So the justification makes a lot of sense to me. What I have a problem with -- and so I can't render judgment. Unless we've got something concrete to propose, we're whistling in the wind. MR. GUTTMAN: I know. MS. KING: I mean, this kind of stuff has been around for a long time. Now there are two ways we could proceed. One, there are groups and organizations -- and I'm sure Dan knows them better than I do, who have some experience with trying to get information out of the government through FOIA requests who might be able to give us some ideas for some very specific things to do. I would not be in favor of just a general open-ended thing unless we got some specific say, even though I absolutely agree with you. I want to make this part clear. I absolutely agree with you that our stress on openness and accountability in the government seems to me to carry with it a parallel obligation to be able to get the information you need. But I'm so serious about that, unless we can say something specific, we ought not say anything. MR. GUTTMAN: We've got two things here. One is we can say quite clearly -- and a little bit is here -- that there is no reason in the world why Oak Ridge's classified vault should still be classified. Either the documents that are really legitimately classified should be removed and the public should be let in, or they should let the public into the whole thing. And there are places like that, because of this experience with the agencies, we will have the ability to identify. CHAIRMAN FADEN: That's a different thing. That's very different. MR. GUTTMAN: I understand. That's different. But what I'm saying but then the point is how do you build on that. As we go forward, we can identify more and more so that there'll be less need for this government information bureaucracy. MS. KING: But we're saying something else. If you like specify the collective collections that we know about, that is still backward looking, although we have an interest in the task. What we also want to be able to do is say that, thinking forward -- CHAIRMAN FADEN: Exactly. MS. KING: -- that we will take care of some of the same problems. And so it's got to be specific. You know, the likelihood that this will gather dust, all this will gather dust, is larger than I'd like to think about sometimes. But on the other hand, that one little bit says somebody may listen to you. So if they look at it, you've got to tell them something specific. MR. GUTTMAN: You're right. The answers is we've been talking and the problem is all these people with these interests. There's nobody that's got a particular easy idea. They say it's a good, good point. Sounds like a nice -- what can I say. CHAIRMAN FADEN: Was there other comment on this? MR. GUTTMAN: We'll have to think about it. CHAIRMAN FADEN: Because if not, we've got -- this is an issue that there's very specific particular collections that we know about. That's one thing. But the forward looking one, if we could sharpen it up, there's a general sense that sure, we can speak to this because we have had this experience. So we can say, look -- you know, this is not an easy thing to do and there has to be some way to make this better. MR. GUTTMAN: So just think of a way to put it in some terms that actually somebody can either say yes or no to. CHAIRMAN FADEN: Right. That if somebody wanted to do it, they could do it. MS. KING: That they could do it. That is the guide. CHAIRMAN FADEN: The point is we've got two levels of problems. One is will anybody listen to us. And the if they listen to us, is it something they could actually do. And those are like the two tests that have to be -- the first one we have just to hope somebody -- that the force of our recommendations are powerful enough that people who are well-intentioned with some authority will pay attention to them. And then the other is are the recommendations something somebody who wanted to, had a will, could actually seek guidance from and implement. Okay. The register of offices of records and other federal entities. This gets into some smaller -- MR. GUTTMAN: Yes. These are more along the lines of what I was saying to Pat. These are the particulars. CHAIRMAN FADEN: I think we can move out of this because these are the particulars. And we also have a general sense, I think from the group, that we would prefer, as we said, 10 big recommendations than smaller things. MR. GUTTMAN: We can put all these particulars under one big recommendation. CHAIRMAN FADEN: Exactly. Exactly. DR. LEDERER: Which is maximizing public access to all of this historical information as it's generated. MR. GUTTMAN: And we'll give 10 examples. CHAIRMAN FADEN: So that's what we're looking for is a report that words it that way. All right. Now, with that, if we could switch -- okay. Did you want to say something, Duncan, before we switch or are we ready to switch? DR. THOMAS: You're going backward now? CHAIRMAN FADEN: I was going to notification. DR. THOMAS: I just want to put two other thoughts on the table before we leave this group. I don't see anything here expressly, unless that's what's implied under recommendation 3, on subject of future -- any future restrictions we might wish to suggest to the use of secrecy. CHAIRMAN FADEN: There's an openness requirement -- DR. THOMAS: Things on declassification. Maybe it's here and I missed it. I don't see it. CHAIRMAN FADEN: Yes. And there's also a whole section on classified research. DR. THOMAS: It seems to me there are other points we might want to make under that broad heading of number 3. The other thing is I don't see anything in here in the spirit of situation 4, retrospectively, guaranteeing prospectively the citizen's right to access to the government's on records on himself or his next of kin in the event that he's dead. CHAIRMAN FADEN: Good. Also, I was grumbling. There were recommendations on classified research we need to talk about which, the special subset of issues dealing with what we have learned about, to the extent to which we've researched, what human subjects today can still be classified and the oversight of those and what we want to say about that. So that will come back to the Committee, as well. I'm sorry to be so directed, but the notification issues is plaguing us and we really need to air it in full in the full Committee. So, just to refresh everyone's memory, yesterday when we left off we had -- we were into the world of human radiation experiments, the biomedical experiments in particular. And we had -- the draft, as its currently constructed, identifies four particular situations, two of which we have discussed extensively, situation 1 and situation 2, not reaching resolution but discuss it extensively. Then on page 7 there is italicized situation 3. And this language, to remind everyone, comes directly from the charter. We begin on page 8. There's essentially a very long -- not long, long-ish memo. It goes from page 8 through -- let's see. Where does it end? DR. GLATSTEIN: 20. CHAIRMAN FADEN: 20. On this issue of notification. The origin is in the Executive Order in the charter. The language is on page 8. We were specifically asked in our charter to comment on whether there should be notification of particular subjects of an experiment or their descendants, of any potential risk or the need for medical follow-up. And the context is to protect the health of individuals. So the language, just because this issue has already come up multiple times, there may be other reasons the Committee may want to consider notifying people, but the Committee charge speaks specifically to FERC and we must answer that charge. We must address that. Whether we choose to address other justifications for notification is up to the Committee, but we have to say something about this. So, looking at this question of protecting the health of individuals, we started thinking -- and this was a long time ago, so we may not all remember -- well, how might -- who would be -- we can't look at every experiment. We can't pursue every one. So who might stand to be at -- most likely to be in this category of still being able to benefit by some protection of their health if they were notified today. And obviously, the first response was subjects who were young. Even when we're talking about studies that went on a long time ago, many of the people who were older persons at the time, older, adults, will no longer be living or will be of an age where they, if they had an ill effect, it has already materialized and done its damage in most cases. Which is not to say you still couldn't have a person who was 30 then be around and essentially benefit, but when it comes to an allocation of resources question, we decided to focus on research projects done in our historical period, '44 to '74, where there's the greatest likelihood that his protection of health benefit might be extended. So, we identified research involving children and started a project trying to look at research involving children. We identified research involving -- in which fetuses were exposed to ionizing radiation generally because of some research project in which their mothers, while pregnant, were exposed. And so while we were looking at the issues for the children born who were fetuses when exposed, we also looked at the pregnant women themselves to see whether there was any issue there. We also -- so those were the two groups, or rather three groups; children, pregnant women and people who were exposed while they were still fetuses. And then we had the issue of prisoners, the prison studies. Because these were young men and because we knew something about the kind of exposure they had had. This is the testicular irradiation studies. And we got people starting to work and think, both staff members and Committee members, on this question of how to understand the charge with respect to protecting the health of people and to see if any recommendations could be brought to the full Committee. And I don't know how to do this. Whether we should have little reports from the different people involved, or how to proceed. DR. THOMAS: Just to complete that, the fourth group was the genetic studies. CHAIRMAN FADEN: Yes. And then there was yet another - - well, we haven't looked at studies for that. We asked Duncan to do some thinking about that part of the charge that speaks to -- or their descendants. So the issue is if there are any second generation issues that would raise protection. But there we didn't look at studies as such, but asked Duncan to give us some thinking about what we would have to consider and what might likely -- might be a reasonable recommendation. So, I don't know exactly quite how to start. I don't know how many have had a chance to read this material. You have here little short reports on each area, each of the four subject groups, and the future generations question. The first one, the first specific one that appears is children. We're going to inject back in here -- we should just start. Henry? DR. ROYAL: One of the things that I was surprised at when I saw this document was the one in 1,000 figure shows up again. Because I had thought that at the last meeting that we had discussed that. And I had thought that we had come to the conclusion that that was not a particularly defensible criteria. So I guess I need to be brought up to speed about whether or not that's something we have or have not decided. CHAIRMAN FADEN: The question was raised -- I have no idea. I think we need to discuss it as a group. I did ask -- I guess through Gary to ask Jeff Botkin his reasoning. Please give us his reasoning for the one in 1,000. And I think the first thing Jeff said is he was only thinking thyroid kids. So, he's not suggesting this is sort of for everybody. And his reasoning, I think, is expressed now, although it may not be adequate, on page 11, lines 13 to 18. DR. ROYAL: Of the 25 to 37 percent probability -- CHAIRMAN FADEN: That seems to him to be -- to get a value judgment in there wouldn't be transferable to anything else. DR. ROYAL: The fair thing to do would probably be for me to write some reason why I don't think that this is a very wise thing to do and to circulate it among the Committee. The wise thing to do that I'm referring to is the one in 1,000. I would like to make up a table of the possible harms and benefits that would occur if you started screening people for thyroid cancer who had a one in 1,000 chance of thyroid cancer. CHAIRMAN FADEN: You mean in excess, an excess case of risk. DR. MACKLIN: What are the harms? DR. ROYAL: In the older -- in older populations, somewhere between 20 or 30 percent of people have thyroid abnormalities detectable by ultrasound. So to find your one case in 1,000 that's going to be your excess thyroid cancer, you're going to have somewhere between 200 and 300 people who have other abnormalities of their thyroid. So you're going to identify maybe 300 people who have abnormalities of their thyroid. Then in order to determine whether this is a benign abnormality or a malignant abnormality, you're going to have to do some invasive study, potentially do a surgical procedure to biopsy the nodule. So you have to realize it would confuse some of the -- DR. MACKLIN: No. I'm not confused. I just want to -- CHAIRMAN FADEN: Yes. Go ahead. DR. MACKLIN: -- pursue this. CHAIRMAN FADEN: And I also hope people will want to look at Jeff's text on page 12. The actual memo is in there. DR. MACKLIN: I just want to address the question of harms and benefits. The question of notification in order to protect health has to be distinguished from harms and benefits or harm/benefit ratio in doing procedures. Now, notification is one thing. What you do about it and whether people are prepared to go ahead and undergo biopsies or whatever else is a second thing. So, the question whether people might be harmed by a biopsy or any other diagnostic procedure is once again a question of informed consent if it's put properly, of course, that people then have to decide, do I want to undergo this procedure for this. But the notification doesn't mandate undergoing the procedure. DR. THOMAS: I disagree. This is one point that Henry and I are in clear agreement on and it's one which we have discussed before. And I think Henry cogently the last time made the case why the one in 1,000 figure is, although it has its own justification which has now been written down for us in this section on page -- line 13 to 18, it's a justification for the wrong thing. And it isn't really relevant to the real issues at hand. And Henry has touched on it. We discussed it in brief at -- I think it was the January -- maybe it was the February meeting. I'm losing track. I ripped it out of an old copy, which I happened to bring along. We had three paragraphs that might be worth circulating again, under the heading of Medical Monitoring, back in the days when we were discussing that. And the issues are the same for medical monitoring as they are for notification. CHAIRMAN FADEN: Sure. DR. THOMAS: So, if anybody wants to refresh their memory with what the issues are, they're here. Now, to address -- CHAIRMAN FADEN: Well, let me just step back one second. Medical monitoring was not the same as notification. DR. THOMAS: No. They're not the same. That's what I'm going to say. Ruth makes a good point that to notify somebody is not necessarily to proceed on to all of these other steps which have their other concerns. But there is nevertheless, I think, some potential hazards, just in the pure act of notification. DR. MACKLIN: Meaning psychological? DR. THOMAS: Yes. DR. MACKLIN: But that's paternalistic. We don't know whether people might, if they find out say -- who are you to decide what kind of emotional harm I might have. If I was exposed to something, you could at least do me the courtesy of letting me know and not decide I'm going to get emotional anxieties. DR. THOMAS: Well, I just feel like we're in a somewhat different ethical position. If somebody approaches us and says, I want to know, then of course there's no excuse for not telling them. But if -- MS. KING: But nobody's going to approach us because the whole point is they don't know enough to approach us. DR. THOMAS: I'm getting to it. But then if you out and you tell somebody who says I would rather not have known, now I'm not yet persuaded that that's a compelling reason not to go out and tell anybody, but I am concerned that there will be at least a few people who won't turn around to us later and say maybe the vast majority say thank you for telling me, but even if there's a few people to whom we cause severe psychological harm as a result of telling that, I don't want that on my conscience. MS. KING: Before you go to the next step, let me say this. This is not the only arena in which this occurs. And this is not the only time we get this issue. The issue is one that can be handled by processes that have been used in other areas. There's a risk in not notifying. Ethics. People want to know. they don't want to be patronized. There's a risk in not notifying and there's a risk in notifying. Even if you got closer connection to the disease because of the reasons that you're talking about. In the genetic area, as well, what they do is they start to make provision for how you approach people about trying to inquire whether they would be interested in knowing or not. And that is what I think that we need to be talking about as opposed to coming down firmly on the side of notification or non notification. DR. THOMAS: Bingo. Exactly. What I'm trying to communicate is not that we should be simply saying we should notify, we should not notify, but that we have to do it consciously so that we have the right mechanism in process. And I think the genetic model is exactly what I had in mind. Now, you ask somebody first do you want to know. And then you have the proper support services in place in the event that they accept. I mean, these are the kinds of things I think we need to think about. DR. RUSSELL: We can't do that in this situation, can you? CHAIRMAN FADEN: Let me just interrupt. We have two orders of problems here. I mean, I don't know whether we want to go to the theoretical question or the practical issues before us. If you take the children one -- and Gary tried to draw this. Gary Stern has had the unfortunate task of having to pull this together in an area that is totally outside of his expertise and he's done a really masterful job. And it's been an case of the blind leading the blind here, again, and I am sort of backing off trying to figure out how to proceed here. So I personally wanted this discussion with everybody all together because I think we need to have it. So, let me just lay out. One issue is if you want to have some sort of threshold for deciding whether we should even be in the business of having this debate about whether to notify people or not notify people. DR. ROYAL: Isn't establishing a threshold paternalistic? I mean, -- CHAIRMAN FADEN: Well, that's what I was about to say, Henry. Let me just complete this. You either say you notify the whole world, even if there's a one in a zillion chance that they might be at excess risk for something or you say that as a matter of human resources and public policy we cannot notify everybody; it doesn't make sense. And of course, so you get into an issue of a threshold question. We've got to decide at what point do we even think it's worth debating whether we should be notifying people or approaching them as to whether they want to know. Because there are costs attached to this that go to the public purse, quite apart from the sort of human issues that we're talking about here. So then there's the question whether that should be one in 1,000; whether you could have a general one in the excess risk case; whether you have to look at a disease condition by the disease condition and so on. Then you hit the threshold for even debating this. And then you have to say, okay, well now we get into this; what about the harms, the follow-up procedures and Ruth's point versus Duncan's point versus Pat's point. There is also the issue here in this particular case -- and this is very important and we haven't yet gotten to, which is all of a piece because it can make it moot. That if you look at Jeff's analysis all the way through and his colleague, Greg Moskun, what Jeff and Greg do is they go through this exercise. If you look on page 12, lines 7 to 16, and they say, look, let's assume, Henry, let's just grant it for a moment that one in 1,000 makes sense. Maybe it should be one in 10,000; maybe it should be one in 100,000; maybe it should be one in 100; maybe it should be one in 50. But let's for his argument's sake say let's say it should be one in 1,000. He then looks at the numbers and says it looks like we have 570 people who if they are still alive were exposed to I-131 as children in research projects. That would meet that criterion. But guess what? And this is where the next issue comes out. Depending on your view about lifetime risk versus how the risk curve goes, if people have gotten -- those people that would have gotten thyroid cancer as a consequence or thyroid disease, odds are already have it. That doesn't mean that somebody still out there couldn't still have it, but if you read that to say there's this next issue about the question of the latency period between radiation exposure and expression of an illness. And if you look at the fact that for the people we are more like 40 to 50 years out, the actual likelihood that somebody doesn't know that they have thyroid cancer is way lower, or that they have it and it's asymptomatic is way lower. So, after all of this -- and this is very contentious and we need to discuss it -- Jeff's conclusion is on protection of health grounds -- there may be other grounds -- it doesn't make sense to notify people. That doesn't mean there may not be other reasons to notify them, but his reasoning, which we need to address. So if this reasoning is persuasive in this case at least, we don't have to look at the one in 1,000 issue. We don't have to think about how to notify people. Because he is basically concluding don't notify anybody for a reason that's totally different, namely, that most of these people are already ill and have become symptomatic and should have received treatment if anybody got ill. MS. KING: Does health include reproductive health? CHAIRMAN FADEN: I would think so. Except in this case -- MS. KING: I think that -- well, I think that part we need to check out. Because what concerns me is the unknowns. We know -- we think we have all the answers now. We think we know what all the links are. But everything continues to move and we're going to acquire different information -- medicine will in the future. And the only repository where we're likely to know that I was exposed at one time to SUS and I have to worry about it in a reproductive context in the individual. And that's why I think that the other big issue is reproductiveness. CHAIRMAN FADEN: I would like to -- MS. KING: So if we could just out what he meant, it would help. CHAIRMAN FADEN: No. He was speaking only about thyroid cancer. He took the view that with I-131, exposure at the doses that these children were exposed to, the only consideration that really loomed as worth addressing was diseases of the thyroid. Now, it's a separate issue whether -- I have no technical expertise. So if somebody would tell me that there's a reason to think that I-131 exposure might be related to reproductive cancers -- DR. ROYAL: There are studies of much larger doses of I-131, treatment doses of I-131 and then subsequent studies about pregnancy and outcome that have been unable to show any adverse outcome in several hundreds. CHAIRMAN FADEN: So we can pursue that. But let's for a moment table that and let's just look at the issue that we've got here. And I want to get some sense of the group about where we are. And I don't need to say that we shouldn't be taking the larger questions on. But frankly the pace that we're in, if it's out for this other reason, let's go on to the next one and look at the fetus one. DR. ROYAL: The only thing is I would wish that the logic not necessarily be what the logic is. CHAIRMAN FADEN: Okay. But I'm not sure that the conclusion -- that everybody -- DR. ROYAL: The conclusion is fine. CHAIRMAN FADEN: But I'm not sure that everybody buys this reasoning for the conclusion. So, if everybody doesn't then we have to go back to your argument, for your reason for the same conclusion. Do you see what I'm saying, Henry? DR. ROYAL: I see. CHAIRMAN FADEN: I want to see if this reason for the conclusion is persuasive. Then we don't have to fight these other battles. If it is not, then the Committee has to address these other battles. Duncan? DR. THOMAS: Yeah. I'm not yet completely persuaded that the reasoning is sound on the grounds that -- and I'd like the opportunity to go back and review the data recently, but it's my impression that at least the risk for thyroid cancer is continuing to rise in atomic bomb survivors, even now, 45 years after -- sorry, 50 years. The data is 45 years old -- after the exposure. If that's the case, it may not be true that given that an individual has not yet contracted thyroid cancer he is therefore unlikely to in the future, almost certainly the probability that he will in the future is continuing to decline as time goes on, but I'm not yet comfortable saying that it has reached zero. For that reason, I think we have to deal with Henry's point, which is that this rationale that's provided here does not address Criterion D. It labels it. I mean, it points out what are the criteria. Well, -- and he gives some details on A, B, C. But then he never actually comes back and revisits D, which is the crucial question, in my view. CHAIRMAN FADEN: Would somebody here who knows more than I do tell me whether it helps to know if you've got thyroid cancer early or hypothyroidism early? Does it help? Eli? Are you better off knowing? DR. GLATSTEIN: Oh, hypothyroidism isn't -- DR. ROYAL: The way thyroid disease has been traditionally detected in the past is someone gets a lump in their neck and then the diagnosis is made and certainly if the thyroid cancer has not spread at that point, that's much better than if it had spread. But the issues, and it's an issue with many cancers, not just thyroid cancer, is that now that we have more sophisticated diagnostic tests, we're able to detect cancers when they're at a microscopic stage. And it turns out that many, many people -- and I do mean many, many people. For example, if you look at men aged 70, maybe 50 percent of them have microscopic prostate cancer. The whole issue comes out if you start looking for it, you're going to end up starting treating people for their microscopic prostate cancer and it never would have harmed them in their entire life or their remaining life. But they're going to now have to undergo surgery and have all the associated morbidity of being treated. DR. MACKLIN: Can I just ask why? I mean, where's the logic in that? If as you're now saying as a knowledgeable person there's more morbidity -- no, no. The treatment is unnecessary if it's at a late stage. It's a slow growing cancer. It's a microscopic level. So why isn't the standard of care leave it alone? DR. ROYAL: Because there's going to be some dividing line between -- you know, there's a continuum between microscopic and macroscopic. And where to draw that dividing line is a constant debate. DR. MACKLIN: Right. It's always hard to draw lines. CHAIRMAN FADEN: I'm kind of confused about this question on the -- if we have this problem, if there is this -- let me step back so I can articulate it now. It is acknowledged that the risk doesn't disappear. And you're saying there's a suggestion that it's lifetime, although the risk reduces as the time lengthens past this 10 to 30 year or whatever period is. So maybe the first issue is, whatever the number should be, shouldn't the analysis be what's the likelihood of there being an excess cancer 40 to -- 30 to 40 years out. Because these studies are at least all 30 years ago. So how many excess cancers would be left to be picked up? And they turned out to be very small. Quite apart from your point, Henry. I mean, the prostate issue is one which everybody is analyzing like frantically in the outcomes world because it's so fascinating. And yet I do my own little private survey whenever I'm at a dinner party with outcomes researchers. I ask them whether they have their PSA levels checked and they all do. (Laughter.) Now, I always have -- and that's probably an exaggeration because my sample is very small. But the point is that there's that human desire that even if on a macro level it may turn out that it doesn't cost out to do this, on an individual human level if there's a teeny, teeny cancer -- DR. ROYAL: I'm not even talking about cost. CHAIRMAN FADEN: I know. But if there's a teeny, teeny cancer, people somehow want to do something about it. Now, they may be wrong or misguided. Maybe that's a wrong value. But we don't have enough information yet that we can hammer people over the head and say, if you've got a microscopic thing we shouldn't do anything about it. DR. ROYAL: But one of the arguments that Jeff makes for having notification is that it represents 37 percent of all of the cancers. But if you start adding in the 15 percent of people who have microscopic cancer, then it's a very small fraction. So then the justification you have to make is if 200 people out of 1,000 have cancer including the microscopic cancer because they've been exposed to radiation, it's going to be 201 out of 1,000. Do you really want to subject that patient population that has 201 out of 1,000 to some kind of different medical follow-up than the ones that have 200 out of 1,000. CHAIRMAN FADEN: I want to call on Pat. But what I'm trying to get out of this Committee now is what does the Committee want to know in order to make this decision. And it's not clear to me that we've got it yet. Pat? MS. KING: Well, the first thing I want to know, and maybe we can ask this here because I can tell you the rest of it. And that is what is it in this range of people that we might not possibly notify do we think it is that they don't know. Is it that they were in a research protocol? Is it that we want to tell them they were in a research protocol where they were exposed to radiation -- that involved research and they were exposed to radiation? I mean, I need to start at the beginning. What is it that we think these children don't know? Do we think that they don't know they were in a research protocol? CHAIRMAN FADEN: We have no idea if they know or not. MS. KING: Well, I think that Ruth is right and we ought to keep the question of notification separate from what is coming behind it. Because my way of thinking about this is today we make assumptions that people know that they are involved in research protocols. That's what the consent process is supposed to be about. We make assumptions -- you notice I'm careful. I'm not saying they know. I just say we make assumptions that they have been told about the risk of participating in the research and they have some awareness of the risks. So, today, we proceed on these assumptions that people have this knowledge. So if anything comes up in the future they will have to make certain kinds of these crazy decisions or sane decision or whatever that we're now discussing. My first question is why can't I put the people that I can detect or find on the same footing as somebody who would participate in research today? This leaves aside all this information about what the risks of the disease are, what the this, what the that and all this kind of stuff. That goes to the question of money you're going to spend, to me. Whether you're going to spend any money on medical monitoring or medical follow- up. And so I can't escape the theory. If I had been in a research protocol as a child and I had been exposed to radiation, I quite frankly am not interested in you all's one in 1,000. I would like to know that I had been in such a protocol and that I had been exposed. Now, if you want to tell me that the exposure is not dangerous in your view, dah da, dah da, dah da, I'm willing to listen to all that, too. But I would want to know. There are people out there who would not want to know. I think that that's right, too. Now, I want to know why -- what are the objections to telling them without getting into medical monitoring, what anybody who participates in research would have a right to know today. DR. THOMAS: The difference is that you've already done it to them. Remember, I'm not saying that you shouldn't tell them. But knowing that there possibly are a very small percentage of people out there to whom these things have been done that don't want to know about it, then I still have a problem trying to figure some way of telling the 99 percent of people who do want to know without harming the one percent that don't want to know. If I could figure a solution to that problem, I would be all for it. DR. MACKLIN: But wouldn't the ones who do want to know be equally harmed if they knew that there was information out there and that you were not telling them? DR. THOMAS: On a net benefit basis there's clearly ways to tell everybody. CHAIRMAN FADEN: All right. Let him explain what the problem is. There is a problem and it's a human problem and it's a practical problem and it's a economic problem. In most of these studies we don't know the names of these people. We don't know who they are. It's going to take a lot of work to find out who they are. It's going to take a lot of effort to find out who they are. So if we have -- and we want to do this, but I just want to lay out what's at issue. In principle, Pat, I think you're right. The problem as a practical matter is that -- MS. KING: It's not a practical problem. And you've answered in part, as far as I'm concerned, your question. And that is, if you have to make a cost/benefit judgments, which is what you're talking about, the starting point is, for me anyway, those people for whom we have -- when we have come across names. If we have information about them in the course of our work where people were exposed and we feel that they may not be aware of it, then my own view is that they should be notified. The incremental cost effort it would take to search for people to notify -- and that's a different thing, so we ought to specify what notification means. Sometimes notification means you tell them or have tried to find them. Some means you have to go find them, you have to go find the names and then go find them to tell them. And that may require some highest stage of effort to protect. So you want a showing that says we have a stronger reason for expending this amount of money to go out and now look for -- That is the approach I would take. I mean, because part of what we're deliberating here is how to think about this. CHAIRMAN FADEN: Right. And we were starting at the opposite end. And maybe that was my mistake. I was starting with the charter, where the charter gives you what would be arguably the strongest justification for expending money to find out who these people are and locate them. And that is, if you could still offer the benefit of some kind of protection of their health, either preventing cancer, which is unlikely, or an illness or more likely getting early treatment, improving quality of life, whatever. So that was the strongest justification. And going the other way, your reasoning from the opposite direction. MS. KING: I'm reasoning from the other end because as always you know I think that we need to know why we're doing things. And part of it is to reaffirm what lies behind even thinking about notification from the very beginning. And it's always -- it is not always to prevent a disease because using that as a basis puts it into an arbitrary time frame in the sense that the judgment that you make is based upon current knowledge, the best you can do at the time. But we all know that that is exactly what that is and there may be other reasons for notifying. There may be reasons for not notifying. So I always start with the case and then let it drop off as these other considerations come into existence. And it may be that if we started that way, we really wouldn't have very much left. CHAIRMAN FADEN: Which way? MS. KING: If we started moving down -- how many people's names have we come across in the records. And have we moved -- have we identified any possible diseases or connections where people might still be alive? CHAIRMAN FADEN: Well, that's -- I mean -- MS. KING: But it would answer these disturbing issues going around the room in the background when we're talking about we're at cross-purposes in our discussion. CHAIRMAN FADEN: There's a way to put the discussion together, which is to say, look -- and I see Reed and Henry. One way is to say, look, we have this morass on this protected health business; the numbers, the crossovers, whatever. If you went to a pure autonomy basis, kind of an argument, the one that you're floating, and you try to combine it with the public health whosy-whatsy, there is a happy coming together, which is it happens to be that people who are most likely to be still alive are the people we're talking about in the first place anyway. And you simply say, let's bag this whole thing. Let's notify the 800 people that all totalled fall into this category of people who were children and fetuses at the time they were exposed. They're most likely to still be alive. We can't do everybody, even if it's a reasonable slice into it as possible. The justifications are both that we would like to honor everybody by letting everybody know that it's an overwhelming task and we can't do it, we have another agenda, which is these are people who can still use the information. Maybe the best use of that information is to ignore it. But put it together and say, okay, this is -- that's a strategy that puts the two together. We are not talking about thousands of people in any event. There are -- in the children, the case of the children study, 607 of them, in the case of potential children. Oh, no. It would be more than that. I'm sorry. You're right. These -- it would be all the children, but it would be all the people who were children. MR. GUTTMAN: But basically, just to get to the practical, though, there are a couple of populations like Vanderbilt, obviously, which a large -- where at one time there were lists of names. Maybe there are still. That's a question. In most of the cases, it's from journal articles, so that at the best you would be doing is going back to the university or the researcher -- CHAIRMAN FADEN: And say, "Do you have the names?" MR. GUTTMAN: Presumably -- the situation we have in this whole loop situation is presumably most of these cases there are patient files in hospitals but they're not linked to whether or not anybody was in an experiment. And if there is a patient file, if there's no consent or if there's no notification that somebody's in an experiment in the first place, then it might be separating at birth in terms of the connection. MS. KING: I understand. And I understand what Ruth's was, too, but on the court it looks different and has a different tone and it doesn't sound as though you only notify when there's health interests, which I think is the critical difference. We were also saying where there's something out there that we haven't uncovered yet and there is data or there are names, unlikely, that the desire is to notify or at least inquire whether they would like notification. That's a different kind of -- that's the only reason I did it the other way, Ruth. And I'll shut up now. CHAIRMAN FADEN: Reed and Henry. DR. TUCKSON: Let me just ask actually Henry or Duncan if it matters. If it was possible to send a notice to a person who's name we knew for sure was studied and be able to say to them, we have information that suggests you might have been, if you would like to know more about that, you can do the following. In other words, if there's a way that we could fashion it such that the individual would have some opportunity to decide to want to know about it, if you say it to them in a way that doesn't give it a certainty that you have been, it's just a likelihood that you might have been. Leave it open. And then give that person the choice about whether they decide to know or not know. Putting them in the same category, say, of somebody who's -- you know, again, with a disease they would get -- Parkinson -- they'll get something when they're 80. And whether or not they have gene, you can decide whether you want or not know whether you have this gene or not. DR. THOMAS: I think I would be quite comfortable with that situation. What I don't want to have happen -- that's why I keep making these points, is I don't want a letter to arrive at my desk saying your dear mom did something really foolish to you when you were a kid. She enrolled you in this stupid study. And as a result of this, you may be at increased risk of some disease for which there's no cure. We can check you out and tell you whether you have it now and make you dread it for the next 50 years, but as a result of the fact that you're going to get this disease, you know, your insurance coverage has been dropped and all these other horrible things are going to happen to you. I mean, that's what I'm -- I'm making a separate case. DR. TUCKSON: Okay. But do it the other way. DR. THOMAS: But if you did the way you propose, you would give the person the option. DR. TUCKSON: Right. DR. THOMAS: I actually posed this question to Cooper Brown yesterday or the day before because he had raised it in his public testimony. And he said, well, we actually took a survey of our membership. Now, admittedly, his membership is not representative. These are the people who already know that they are members. So it's not quite the kind of data we need to resolve this question, but at least it's some data. He says, our membership wrote back to me. The vast majority of them would like to know. They were glad to have been informed. So that makes me feel a little bit better. But I still continue to worry about that small minority of people. DR. TUCKSON: So the answer, -- I mean, I'm just trying to make sure I understand. And maybe Henry can. If you write it to them such that it is not given with the degree of certainty, it is given that we have information that suggests you may have been exposed to such. We don't know for sure. We will do nothing unless you come to us and ask for more information and track this down. You may be very comfortable in never knowing. There's no obligation for you to ever do another thing. We won't do anything unless we hear from you. DR. THOMAS: What you've essentially done is describe the paradigm that's used in genetic notification. CHAIRMAN FADEN: Let me point out -- let me just ask Dan. How many people's names do we have, roughly, names of subjects, before we get into too -- MR. GUTTMAN: In the children area, I don't think many other than the ones that are in the Vanderbilt case and are known to people. CHAIRMAN FADEN: In general. This is across the board? MR. GUTTMAN: Sporadic. I mean, we have lists of dozens of TBI patients from the 1940's. It's random. We've got assorted random lists. CHAIRMAN FADEN: I've very sympathetic. I just want us all to understand what we're doing here in terms of -- we might have the names. We have no idea where these people are now in many cases. And there's an effort that -- I don't know how many names. We have 100 names? MR. GUTTMAN: No. We have many more than 100 names. CHAIRMAN FADEN: Do we have 1,000 names? MR. GUTTMAN: Probably more. CHAIRMAN FADEN: It's important. We're trying to figure out what we're dealing with here. MR. GUTTMAN: I understand. CHAIRMAN FADEN: Not children, just overall. MR. GUTTMAN: We have more than 1,000 names. CHAIRMAN FADEN: I'm just trying to get a sense of what's happening. MR. GUTTMAN: Let me try the other problem, though. The other problem is that if you wanted to do it, let's just focus on children. You know where these things took place. At the least you could go back to those institutions or the investigators. Some further effort with some further success. DR. TUCKSON: But what I'm hoping -- and I understand. I think I understand what you're doing and I think that I'm influenced by Pat's point, if I understand some of the implications of her point. And that is, we have already raised the ugly monkey. Now, whether or not practicality will permit you and how you deal with the practicality of the cost benefit issues, the one thing for sure is that in the record of our deliberations is we raised the question. And the question then becomes how do we resolve it intellectually, first. Then, secondly, gets to practicality. We may decide that -- let's say we may decide first that it's important philosophically, ethically to notify, given the following caveats. Secondly, we decided the cost benefit of doing so is impractical, therefore, we decided not to do it. But while I appreciate the practical point, I don't think we can evade. Once having raised it, we've got to deal with it. CHAIRMAN FADEN: That's what I'm trying to do. DR. TUCKSON: Well, I thought you were trying to basically say -- CHAIRMAN FADEN: No. What I'm trying to do is figure out -- see, I think there's several levels of practical. One is, okay, if we took the strategy that -- we had the general principle that people should know that they were subjects of research. We don't know whether anybody was or wasn't but it seems reasonable at the very outset to presume that people who were children and fetuses are less likely told at the time that they were research subjects, just as in today are less likely to know that than someone who was 30 or 40, although they may not have known either. So that's -- yes. You start to build up the arguments for why you're zeroing in. This is the multiple arguments for landing on the same people as the people where you might want to say we can't. There is limited resources so on whom would we want to concentrate if we were going to do this. And there are sort of multiple arguments coming together. Henry, and then Eli. DR. ROYAL: I just want to make certain that my position has been stated clearly. The statement that's on the piece of paper here regarding notification in order to protect the subject's health, and that was the issue that I was addressing. I personally would be in favor of notifying people whose names we have and that we can notify. I think that we would have an obligation if we notified those people to let them know something more than just that they were in a radiation experiment. That we would have to make some recommendation to them or give them some information that would allow them to know whether or not they should have anything special done because of the fact that they were involved in a radiation experiment. So I think that we're going to have to be prepared to do that. I mean, just to -- I would be very much against notifying people and then having them go to their family doctor and perpetually get misinformation. So I think the notification is tied in with an obligation to notify them about the circumstances of the experiment. CHAIRMAN FADEN: If we know them. DR. ROYAL: Well, we know -- DR. MACKLIN: Well, you know something. CHAIRMAN FADEN: Whatever we know. DR. ROYAL: I can tell you that we know a lot more than family doctors are likely to know. CHAIRMAN FADEN: Yeah. Okay. DR. GLATSTEIN: There's precedent for this. I mean, realistically there's the experience of Michael Reese Hospital, which is not necessarily an experiment but a planned form of treatment that they used to give kiddies with radiation to reduce the size of thymus gland at the time of birth. And once they recognized -- it came 20 years later -- that there was a finite risk of malignant disease associated with that, the institution that delivered the treatment tried to chase down as many of the survivors as they could, get them to come in for follow-up or urged them to see a physician if they had moved away. But the onus was on the place that delivered the treatment. And I think that that's the only way that it can really be done effectively. There should be a list in those institutions. I don't think it's our obligation to chase down every list of people who have ever received radiation. The onus should be on he institution to do this and check that out. I mean, that's the way it's been done and I don't see anything wrong with it. DR. ROYAL: But I think the issue that the Committee has to answer is if we have a name, how are we going to notify it. DR. TUCKSON: Or do we push and encourage in very strong language and say that as an ethical matter it is our conclusion that every institution that conducted such research has an ethical responsibility to go through their Rolls. DR. GLATSTEIN: Yes. I would say that. DR. TUCKSON: And will find those folks. If that's what we believe. DR. GLATSTEIN: Do as much as they can. CHAIRMAN FADEN: Do we believe this, given the radiation research project that was conducted from 1944 to 1974? DR. TUCKSON: The institution has the moral right -- responsibility, to go back and do that work. That starts to get at mechanism. It shouldn't be a government apparatus, perhaps, to do it. DR. GLATSTEIN: Yes. DR. TUCKSON: That's an interesting way to solve the problem but it still -- but we still haven't decided whether you should opt to do it. I'll just tell you this. Pat, I don't know. I'd be interested, Pat, in your view on this. I know -- Duncan's point I really do appreciate. I appreciate what Henry is saying. I mean, I'm an African-American. Surprise. (Laughter.) I'm going to be really doggone honest with you. Our experience in this country -- and I don't think, by the way, there's any homogeneity among the African-American community on this either, so I want to be real clear about that. But black folks, most of the folks I know would be pretty damn mad if the United States Government did some stuff with their kin and then somebody made a decision that said, well, it was too much -- for a whole lot of other reasons, you don't even have the opportunity to know because of a whole lot of other complicated -- look, I'm tired of that. And I'm going to tell you. It will be real hard for me to go see my momma and my folk if I sat around this table and said, well, it was too complicated for them to know. And people who have been poor, prisoners -- I mean, it's just rough to try to get past that one. DR. MACKLIN: This whole discussion has been cast in terms of risks and benefits, possible harms and wanting or not wanting to know some of the harms that could come from the people who don't want to know. The other analysis, and I don't think Pat used the word, but it's what she and I have in mind here is whether people have a right to know. And when people have rights, sometimes the exercise of rights actually results in some harm. There's not a perfect fit between having rights and having benefits that accrue to those rights. So we haven't yet discussed whether or not -- but I think Pat was going very strongly in that direction in making the analogy with present research subjects. If we could agree -- I don't know if we can in two seconds, but if we could agree, it might be worth just a straw vote, on whether or not people have a right to know whether they were subjects of experiments in the past, then we don't totally dismiss the question of whether there might be harms, but we have a very different take on it. We don't sit around weighing. Because in order to override a right you need some very strong evidence of likely and probable harm that would overcome the right. So, if anyone wants to put forward -- and I'll be glad to do it. (Laughter.) People do have a right to know if they were in experiments. That doesn't answer the question of whether some people might be harmed by being informed but it puts a very different cast on the discussion. MS. KING: And it also doesn't answer -- it does not carry the necessary implication with what others must provide and give in order to be able to exercise your right. In fact, that's one of the big issues in this country and that is lots of us have lots of rights and very little wherewithal to carry them out. That is a fact of life. But I quite agree with Ruth and I am not advocating spending a lot of money trying to locate people. I do think, though, that it's an important principle to have out on the table. And I think if we would be like philosophers -- and I'm a lawyer, remember, so this isn't perfect. When people think about rights they often think about corollary duties. So, Henry -- I mean, not Henry, Reed's idea about having institutions think about having moral obligations, which may resonate with some institutions more than other institutions is worth saying, even if we don't say somebody should pay us, a law to make you do it, because some of those institutions will in fact take their obligations seriously, but some institutions it won't be as onerous as it will for others. And some will try to do the best they can do. And I would want to facilitate that or foster that. And I think that's important. Now, when it comes to -- when you told people what is theirs and you get to the point of what can we do for you after we've told you something was yours, I think where we started is a real appropriate set of considerations, which is the hard question for the Committee. Are there any people in any risk of disease that we can think of, based on the work that we have done? And thyroid seems to be the only candidate that we've come up with so far where we would be willing to do something more than that. Where we might be willing to offer either a greater search -- that's one way of looking at it -- or to offer a greater benefit, some kind of follow-up or health examination, if that's what we'd like to recommend. But I like it like that. Then we can quarrel about the -- CHAIRMAN FADEN: I'm just trying to lay this out so we can tell where it's going and understand where the discussion is going. And I understand that. So if we're arguing that we want to acknowledge that former subjects of research -- and for what it's worth, I want to get clear. Are we now thinking exclusively of human radiation research? Because that's all we're talking about. Okay. This is another one of these things that will reverberate potentially. People have a right to know whether they were research subjects or not. And we don't know whether these people do or not. We don't know if they know or not, for all the same reasons that we've been talking in situation 2 about a presumption favoring government culpability. The guess is that some of them probably didn't know. And certainly the children, the people who were exposed as fetuses don't know. So we say there's a right to know. But you're also, though, not saying yet what the Committee would recommend by way of who and with what level of effort people are now obligated or have a duty to assist people in the exercise of that right. MS. KING: I'm saying that. CHAIRMAN FADEN: Okay. That's what Pat's saying. So Pat's saying we can have a position that says people have a right to know without necessarily saying that there's a strong duty on the part of somebody to make sure they find out. MS. KING: I think we do that all the time. CHAIRMAN FADEN: Okay. I just want -- then it becomes -- because the reason I'm saying that is because eventually we're going to get back to where we started, with some nice additions like tell the institutions insofar as possibly they can, try to find the people. But they're going to seek guidance. They're going to say, well, you know, just anybody? Any research project? Or -- we have limited resources and can't track down everybody. Can you give us some guidance as to where it would be most appropriate for us to put our resources to try to locate people. I mean, you can see this sort of dynamic operating if you just endorse the principle but then have no strict, firm views about how far people need to go to assist other people in respect to that right. DR. MACKLIN: This is all kind of -- it's like the New Yorker's view of the world. It's all institutional centered. Part of, I think, what's implicit in what Pat is saying is that sometimes people know darn well what they want to know, but they're told by the institution you don't have a right to get this information. It's their patient files with the detailed history they're legally entitled to. That's one thing. But suppose it's Dr. So-and-so who has notes. So that there's a lot of this which is self-enforcement. And that's the gap. MS. KING: Thank you. That's exactly what I feel. I mean, it sort of like goes back to the discussion about animals. You know, this Committee and the federal government can't do everything. Sometimes you have to make it possible for other people do to things and the animals versus humans was a good analogy for me because it shows you what the power from the outside has done. DR. GLATSTEIN: Well, maybe a lot of those institutions faced with a potential lawsuit would be very willing to do a simple diagnostic procedure. CHAIRMAN FADEN: Can I relate this to the -- can we try in the last five minutes we have left to try to connect this discussion to the responsibility under the charter, which was to indicate whether anybody should be notified? Which is different than saying that somebody is supposed to take some assertive steps to find them. Okay. Because I don't think it answers that problem. All we're saying is people have a right to know and reasonable efforts should be made to try to -- no roadblocks should be put in the way, first of all, of someone trying to find out if they were research subjects and they should get assistance from institutions. Secondly, reasonable effort should be made in institutions who have been notified that they have to conduct -- or human radiation research has been conducted, that they should try to find people. There's still the issue is there anybody out there and by what criteria, where an active effort has to be made, ought to be made, to find them or not. Are we just going to just drop that and say we're going to take this other approach? MS. KING: I would not drop it. CHAIRMAN FADEN: Okay. So we're back to -- we still have the issue we started with. MS. KING: And I think that the provision of a health benefit which is why it's in the charter and why the charter doesn't have this other stuff, is a reason for requiring more, given the whole -- where we're going. And the issue I can't resolve, because it's where I need Duncan. When I say I couldn't resolve it, I can resolve it and get some more information. It's where I started to need to hear again Duncan and Henry talk about how to make connections between what has happened to people and what kind of likelihood of them having an increased risk. And I actually think that's complicated, but if I heard them, I'd have some guidelines. Because then you would be able to assess what it means, I think, to have declining likelihood that you're going to have cancer. And my other question that I need an answer to is -- and Henry answered it, I think, but I just want to make sure it's true for other diseases. And the other thing that's worrying me is reproductive health, if we've got cases where there's something other than the he mentioned. But I'm willing to take a crack at that. Make a decision about that. CHAIRMAN FADEN: Duncan has -- we're at 4:00 o'clock and we obviously have advanced the discussion of notification but not in the direction that perhaps was originally envisioned. DR. THOMAS: Well, no. We've advanced it a lot. I mean, we've gotten consensus that there is a right to know whether you're a participant in a research project, and agreement that that right should be -- does not necessarily carry an obligation to tell. And that any program to inform a person that they're a research subject should be done in such a way as to respect the rights of those who would prefer not to. know. And we had a very practical suggestion. CHAIRMAN FADEN: I would just change the middle of your summary, Duncan. Which is not that there's not an obligation to tell. There's an obligation to tell someone. There may be limits that are practically put on how far, how much effort, or how far someone has to go to seek out. Certainly if you are asked as an institution, "Was I a research subject?" you would have the duty to answer that question. DR. THOMAS: I'm not sure. But you said it very well when you said no roadblocks. CHAIRMAN FADEN: Right. Ruth, could you clarify on that one subject? DR. MACKLIN: What? CHAIRMAN FADEN: Did you want to clarify? DR. MACKLIN: All I wanted to say here is that to say there's a right to know is not to specify the steps that have to be taken in order to satisfy the right. But it's at least to say if a person asks and someone has the answer, they're obligated to tell. But it's in between the questions of what steps you have to take, how much effort you have to make, and how you get around the problem as with the genetic circumstances so that you don't do what's called imposing unwanted information or truth-dumping on people. DR. THOMAS: With respect to whether or not there ought to be an active program of notification for the purpose of protecting a person's health, that turns on the questions of first of all, is there any increased risk in the first place and secondly, whether or not if a person is at increased risk, whether we can do them any good. And those are the questions that are not well known to us. I think we've explored them pretty thoroughly. We don't have a clear answer to that. DR. GLATSTEIN: You can't answer the second question until you know the answer to the first one. DR. THOMAS: No. I think they're two separate unrelated questions, Eli. MS. KING: One of the things we have resolved, Ruth, is with that kind of contact, I think it has implications for which way you lean. CHAIRMAN FADEN: Exactly. That's where I was trying to go. I some ways, though, if you say, okay, there is a background right to know which we would all like to respect. Instead of obsessing very narrowly about whether the protection is this or that or the other thing, you can say look, let's just find a category of people where there's even a slight possibility where there's a health protection. And since we think they have a right to know anyway, we can make an effort to find them, still with that proviso that says you may be ineligible. That kind of thing. DR. THOMAS: I don't see the point of an active program of notification, just to tell people that they were participants in a research subject even. But it's not going to do them any good to know this other than -- CHAIRMAN FADEN: It's saying that you can relax your sensitivity range or something with the air you breathe, because you can say that's not the only reason why you might want to give this information -- give them access to the information. If you had endless money, you'd find everybody. I mean, if you take the principle of the right-to-know right, if this could be done in a heartbeat because everybody's name and address was in some computer filing and we could just E- mail them, we'd do it tomorrow. So the issue is ideally, if notification was real easy to do, we'd find everybody. But we can't find -- if you follow the logic of this, if we could find everybody in a keystroke, we would write a letter to everybody saying you may be in a research project. You might want to know this. The point is we can't find everybody by a keystroke, so you get into that gray area of trying to figure out, well, can we identify any groups of people. It's justifiable to expend extra effort to find them rather than just seek -- help them, should they seek assistance. I don't know. It's 4:00 o'clock. DR. THOMAS: Before everybody drifts off, I just have one last comment. CHAIRMAN FADEN: Why don't you have the last word. The last comment and then -- DR. THOMAS: All I want to do is invite people, please, to look carefully at the section on genetic risks, page 16 to 20. This is something that I drafted in a hotel room without any access to literature. I feel very insecure about what I've written here. I'm particularly insecure about the final conclusion, which I'll let you read for yourself. But this is something that we should begin to think carefully about. CHAIRMAN FADEN: Okay. Well, thank you for that. Reed, can you officially -- sorry to close on such a whatever note, but we have accomplished a lot at this meeting. DR. TUCKSON: Ruth, for the record, you continue to do a marvelous job. I hope you feel good about it, Ms. Chairman. CHAIRMAN FADEN: Thank you. That's very nice of you to say. (Whereupon, the proceedings were concluded at 4:10 p.m.)