ADVISORY COMMITTEE ON HUMAN RADIATION EXPERIMENTS TUESDAY MAY 9, 1995 The Advisory Committee met in the Terrace Ballroom of the Doubletree Hotel, 1515 Rhode Island Avenue, N.W., Washington, D.C., at 9:00 a.m., Ruth Faden, Chair, presiding. COMMITTEE MEMBERS: RUTH FADEN, Ph.D., M.P.H., Chair KENNETH FEINBERG, J.D. 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. MARY ANN STEVENSON, M.D., Ph.D. DUNCAN C. THOMAS, Ph.D. STAFF: GAIL GELLER DAN GUTTMAN, L.L.B. VALERIE HURT NANCY KASS LANNY KELLER ANNA MASTROIANNI, J.D. JONATHAN MORENO, Ph.D. SHOBITA PARTHASARATHY MONICA SCHOCH-SPANA JEREMY SUGARMAN, M.D., M.P.H, M.A. A-G-E-N-D-A PAGE NO. Opening Remarks by Chairperson Ruth R. Faden 3 Committee Discussion of Biodistribution, Radioisotopes and Children and Pregnant Women. 8 Presentation by Dr. Jonathan Moreno and Ms. Valerie Hurt 144 (Lunch Break) Committee Discussion on Rules for Consent by Government Agencies. 151 Committee Discussion with Dr. Jeremy Sugarman, Dr. Nancy Kass, Ms. Monica Schoch-Spana, and Ms. Pat King. 211 Committee Discussion on Research Proposal Review Project with Dr. Gail Geller and Ms. Shobifa Parthasakathy 256 P-R-O-C-E-E-D-I-N-G-S 9:09 a.m. CHAIRPERSON FADEN: Good morning. Here is where we are. Valerie and Jonathan, who disappeared already, and we should give them our special thanks, who worked late last night putting together a summary and collecting the documents in chapter 2 in one place so that we could revisit the issue of whether the government had articulated standards, policies, whatever we choose to call them, contemporaneously such that we can make judgments about contemporaneous standards. What they're doing right now is coming up with summary interpretative statements of what the documents taken together in their opinion justify with respect to claims about the extent to which the various branches of government had articulated standards on each of the points at issue. There is three bullets that we added in for our's yesterday, consent with healthy subjects, consent with patients put at unusual risk, or hazardous experiments, and consent for patients with research generally. What I'm going to propose is that we wait and have that discussion after lunch. I had hoped that we could have the document sort of together and that it would be short enough that we could take a few minutes, read it, and then go right into that discussion. But it isn't ready and it isn't ready in the form that probably would advance our discussion the most. So rather than ask Jonathan and Val to kill themselves to cover some business item for a half hour and then get to it, I didn't want to press them that hard. We've given them until just before lunch and then they'll come back with the document. You all have reading time at lunch built into the schedule, so that hopefully you have already looked at the two contemporary chapters which will remain on the agenda for this afternoon, and then we'll do both. We'll do the revisiting of the question of how to look at the government standards for judging the government's conduct as well as shifting to the contemporaneous world after the break, the modern world or current period after the break, our two contemporary projects. I'd like to propose that we move right into some of the case studies. That may help us actually think through what we want to say with respect to government standards because as some of discussed yesterday after the meeting, and I think as all of us recognize, this is very much an iterative process. One's views are formed by kind of thinking abstractly and then thinking concretely and then going from your intuitions about the concrete case to the more general positions you might want to defend with respect to something like judging the government or judging physicians or what have you. So I'd like to propose that we go to the cases in the case studies in the order in which they were on the agenda. Which would mean that we begin by biodistribution, radioisotopes and get as far as we can this morning. Is that all right with everybody? We'll try, okay. No, I don't, I want to start with these two first. The comment I got is that we should do our best to get to children sometime today while Dr. Webster is with us, so we will do our best to try to get through three chapters this morning. If we could get through biodistribution, radioisotopes and children and pregnant women this morning, okay, then break for lunch, and then resume with the general topic of how we ought to judge the standards for judging the conduct of the government during the period from '44 to '74. And then after the break the question of how we are viewing the data we have obtained with respect to this current status of research and -- so that's the general approach for the day. Is that acceptable to everyone? It looks like it is, okay. That means that we have roughly three hours to get through three chapters including time for a short break. So I'm going to try to keep clock and say that we're going to spend an hour per chapter, and that should get us through the three chapters. I thought it was very helpful if what Pat suggested yesterday, basically going around the room and getting a sense of where people were, and perhaps it might be useful to do that at the beginning of the discussion of the biodistribution chapter, basically where people are on this new version of the chapter, if you have a position on it. Again to emphasize, the purpose of our collective debates of these chapters is not initially to discuss issues of style or presentation. We had a general discussion yesterday morning in which many of us expressed our concern about the overall tone and style. I would urge us initially to address the conclusions drawn and the judgments drawn in that chapter, in the plutonium chapter, and see if we agree about how to view those experiments. Including how we want to view the conduct of the experimenters who conducted those experiments and how we might want to view the government's role in sponsoring those experiments and distributing the isotopes for them, or the plutonium in this case for them. And if we have time, if we discover we're all in agreement about what conclusion the committee wants to draw, the committee's finding about these experiments, then we can go into a discussion for the rest of the hour on page 8, I didn't like your tone here in page 22, I didn't like your tone there. But let's go to the hard issue first. Is that agreeable with everyone? What is the committee's findings on the plutonium experiments, what's the conclusion, right, what's the conclusion that the committee wants to draw that then translates into the finding that's bullated at the end that is then shared in a succinct way with the public, the press and so on, the bottom line on the chapter? Is it okay if we just go around the room and see how people find the conclusion as it's drawn in the chapter? If you don't have a comment yet and you want to wait to hear more of the discussion, of course that's fine. Does anyone want to start and then we'll pick up from there around the table? Duncan, thank you? MEMBER THOMAS: Before turning to the conclusions, I want to turn to the promises. There is a promise made at the bottom of page 10 which says or where it's outlining what this chapter is about. And it says at line 18 "Where it can the committee renders judgments about the moral responsibility of those who conducted and oversaw these experiments and what remedies may be due to the families of the subjects." This promise seems to me to be unfulfilled in this chapter. There is a strong moral judgement about the ways in which the experiments were conducted. And by and large I'm pretty comfortable with the conclusions as they read at the moment. I'm persuaded by the evidence that's offered that inadequate consent was obtained. And that comes in for strong condemnation at the end of the chapter. So I don't have any fault with what's there, but the promise is larger than what's offered here. At no point do we issue sort of moral censure either of the investigators themselves or of the people that oversaw the experiment that I could find. CHAIRPERSON FADEN: Can I just probe you for a minute as we go around. Do you think we ought to? MEMBER THOMAS: Well, I thought about that a little bit and in my written comments I invoked Allen Buchanan's text on the subject of why we ought to drop moral judgment about individuals. And I didn't take a stand on that. I think I'd still like to hear the views of the committee a little bit before committing myself. By and large I've been an advocate for doing that. In this situation it isn't clear to me yet whether we have the evidence to justify that. And I'd be curious to hear what other people say about it. If we are convinced that we have that evidence, then I would have no problem doing that and would advocate pushing the committee in that direction. CHAIRPERSON FADEN: Okay. I'm going to get to you in just one second. Duncan, if I could press you further, you see the chapter as concluding that the evidence can be interpreted, although it's incomplete, as supporting the view that adequate consent or consent was not obtained in the plutonium experiments? MEMBER THOMAS: That's my view. CHAIRPERSON FADEN: Okay. And that is your personal view, that's what I'm trying to get at? MEMBER THOMAS: Yes. CHAIRPERSON FADEN: And you also see the chapter as concluding that that was wrong? MEMBER THOMAS: Yes. CHAIRPERSON FADEN: And you agree with that? MEMBER THOMAS: I agree. CHAIRPERSON FADEN: Okay. That's what I'm trying to get everybody to do to go as far as we can with that. MEMBER ROYAL: Can I ask a clarifying question? CHAIRPERSON FADEN: And Ruth had a comment too in the way of a clarifying question as well. Ruth and Henry. MEMBER MACKLIN: Yes. CHAIRPERSON FADEN: I think we should do this, we should be pressing each other's views insofar as we can. MEMBER ROYAL: The question that I have is we've now used -- CHAIRPERSON FADEN: Everybody -- excuse me, speak into the mic. We had problems yesterday. MEMBER ROYAL: The modified era of the word "consent" is now adequate consent. Yesterday we talked about simple consent and informed consent. I don't know what adequate consent is. CHAIRPERSON FADEN: Well, why don't we go back. MEMBER THOMAS: Very good. CHAIRPERSON FADEN: All right, let's go back and ask Duncan, is it your view that consent was not obtained or that adequate consent was not obtained based on the evidence? Or do you want to separate it by institution that the evidence is stronger in one case for one institution than the other? MEMBER THOMAS: I'm not enough in touch with the details of how it varies from one institution to another to do that. As we tried to tease apart this concept of consent in the earlier draft of chapter 5, it seemed to have three elements. You know, simple consent, the subject's understanding, and non-coercion. CHAIRPERSON FADEN: Right. MEMBER THOMAS: The only element of coercion I see here is that these are patients who are in a doctor-patient relationship with someone and that relationship may have been abused. I can't point to specific evidence for that. So I would say of the three elements, that's the weakest. Information conveyed I think was inadequate, and I'm not relying just on the fact that they weren't told that the element was plutonium that they were being injected with, to me that's not particularly important, what doesn't seem to me adequately communicated is the idea that there may have been risks associated with that. So I guess when I used that word "adequate," which I'd now like to withdraw because it's not a well defined concept, I was relying on the quality of the information that was communicated in order to get their consent. I'm not even convinced that simple consent was ever obtained. MEMBER ROYAL: Are you convinced that it was not obtained? What's the evidence if you are convinced it was not obtained? MEMBER KING: Can I pitch in here? I think this is a tougher issue in terms of what we mean by consent because when one talks about injecting somebody, and this carries us back to the then practices, and I speak a lot from how we have framed this issue and law, when a person stands there and raises their arm you have a consent issue when they see a needle coming. I want to be clear about that because somehow we've got to take account of the fact that you can make an argument that there is consent. The consent of what becomes a big issue. But there is consent in the sense that a person is certainly consenting to the injection. There is a famous legal case on this question, if one wants to know the truth. If you take it a step further and ask is it important, must they have known what was in the needle? That's a question. Must they have known not only what was in the needle, but what the risk and the benefits to them were from the substance in the needle? You keep taking it that kind of step. But understand that the issue of raising your arm implies consent as well. So in terms of how we think about consent, that may be the discussion. CHAIRPERSON FADEN: Ruth, you've been waiting, so? MEMBER MACKLIN: Well, let me go on this, I mean I had some questions for Duncan about what the conclusions, how the promise went farther than the conclusion. I mean here there are two things that haven't been mentioned about this consent in what Pat just said and in this discussion of whether it's simple or adequate. One is that the people who were patients were being used as research subjects. I mean that's an element. They can raise their arm for an injection, but if they believe that the doctor is going to give them an injection in the doctor- patient relationship that's going to help then, then the fact that they're raising their arm and are consenting is less relevant than the knowledge or than the understanding of their consenting for a research maneuver. And the second part of that is that the maneuver was not designed to benefit them. So the consent, and I don't, Pat, about the case, the famous case, whether it's in a therapeutic setting -- MEMBER KING: It's not in a setting. It's the woman who was being vaccinated. And the issue is not the way -- I don't want to make too -- I talked too much yesterday. I don't want to make too much a point of this, but this consent question is more complicated. You say what is more relevant is what is in the mind of the patient when they receive the injection. There is an argument that what is also at least equally relevant is what the person providing the injection can reasonably rely. And so you can't ever break through this stuff. I mean I think what you have to do is lay out those things when you discuss the discussion. Now, today we would clearly say some different things I think, but in discussing what was long ago, this is an issue. I would say, because Ruth wasn't here yesterday, I actually find this the strongest example of even beginning to try to make a retrospective judgment. But I'm not sure I can find in here the chapters I read because of some other factors, but I do think that the consent issue is not as simple, so I'm agreeing with Duncan, the consent issue is not as simple as we were putting it out here. And I don't disagree with what Ruth said. I just think that that's to take one side of it, is just to take the full picture of it. MEMBER KATZ: Ruth, can I follow up on something Pat said? CHAIRPERSON FADEN: Why don't we just make sure that Ruth got her points in and then you can. MEMBER KATZ: Sure. MEMBER MACKLIN: Well, I mean I agree with Henry and others who nodded asset that the word "adequate" consent is vague. That is unless it's spelled out. Nevertheless, we may be able to provide necessary conditions, maybe not necessary and sufficient, but necessary conditions failing which consent is not adequate. And I would suggest that one of those necessary conditions is the knowledge on the part of the subject, the patient, that the patient is being used as a research subject. That I would say is a necessary condition for adequate consent. And secondly, that the maneuver, even though the patient is lifting his or her arm, the maneuver is not designed to benefit the patient. (A) it's research, and (B), it's research that is non therapeutic. That, I mean whatever else we want to say about adequate consent, it seems to me those are two necessary conditions. MEMBER THOMAS: And third, there ought to be some disclosure of potential risks and benefits. MEMBER MACKLIN: Right. But that's what everyone's been -- yes, I agree. CHAIRPERSON FADEN: But you know what, Duncan, in many ways that's icing on the cake in the sense that if the person doesn't know it's a research maneuver and doesn't know it can't benefit -- MEMBER THOMAS: Of course. CHAIRPERSON FADEN: -- I mean -- MEMBER THOMAS: Well, the first two are prerequisite. CHAIRPERSON FADEN: Right. I mean it's true that they also ought to know if there are any risks involved, but it's almost gratuitous if they -- MEMBER THOMAS: Sure. CHAIRPERSON FADEN: -- the language isn't very felicitous that I'm using, but there's a way in which by the time, if you've established the first two, you've already got such a big problem that the third one starts to pale. It's, you know, more often the case that, if they know it's a research project, they may or may not know it benefits them, and what's at issue is how much of the risk do they understand. And that gets -- MEMBER KING: This is not a discussion about the facts I want to be clear about because the facts say that there as no disclosure, they were not told, all of those kinds of things. This is a discussion of in light of the facts as we know them that there was no consent in the way that Ruth specified. What, if anything, do you say about it? Because of this, I'm not arguing that consent, something called consent, took place or did not take place. I accept the description here. I thought it was very good. Certain things did not happen in the interactions. The question is, that's not the issue. We have documents, I assume, to show that. CHAIRPERSON FADEN: Well, I just want to make sure first of all that everybody is in agreement about that interpretation. And that's not clear yet, Pat. MEMBER KING: Okay -- CHAIRPERSON FADEN: So we have -- MEMBER KING: -- -- which is a separate discussion. CHAIRPERSON FADEN: -- I think this dialogue is very useful. We've had Ruth provide us with a stipulative definition, if you like, of adequate consent for this purpose where it involves the persons being told that this is being done for research purposes, and that this is not being done to benefit you medically, okay. MEMBER KING: But, Ruth, doesn't the stipulation go to the second question, not the first? When you go through and you describe what happened, when you start to ask was there an adequate consent you are into my second stage. And what I said before was describing what happened from the documents is one step, how you characterize what we get from the documents is a second step. CHAIRPERSON FADEN: I think we're all agreeing to that, Pat. The question is, are all agreeing with the initial description that those two conditions were not satisfied in this case. You agree, Duncan agrees -- MEMBER KING: Oh, okay. CHAIRPERSON FADEN: -- I'm not sure that everybody else agrees. So I want to get that out first to see if everybody agrees that indeed the evidence points to the conclusion that patients were not told that this was a research maneuver and that patients were not told that it was not for their benefit that the injection was being done. If everybody agrees that those two descriptions, that the weight of the evidence supports those two descriptions, we can then go on to your second step. I just want to make sure that everybody is there first, that's everybody's interpretation of the evidence. Jay, you wanted to comment? MEMBER KATZ: Yes, I just wanted a brief comment, and I think it's important that Pat might correct, but I am going to say next, and it goes to what Duncan said. We've got to appreciate that in terms of informed consent, that informed consent in law is a type of concept. And that informed goes to the disclosure obligations of physicians and professionals. And consent goes to something else. And the Supreme Court in the Danforth case in an interesting footnote when it discussed informed consent issues, they said we don't really know what consent means and they're just going to bypass this, but it did discuss the disclosure obligations. So when we begin to talk about meaningful consent, simple consent, we're inventing something new I think, and if we can define it, it's fine, but so many people believe that informed really means that inform defines consent or namely it has to be an informed consent. That is not what it means, it means full disclosure. And as far as I see in this chapter or another I am willing to make a judgment who knows what the consent was, but not sufficient disclosures were made to these people to my mind, but of course one can differ. The consent is to a considerable extent spurious. Would you go along with that, Pat, or not? Not with that conclusion, but with the problematics of informed consent. MEMBER KING: I think that you're talking about the second question and Ruth is trying to get some agreement on the first. So if you can wait, then we can have a discussion of the second question. Is that correct, Ruth? CHAIRPERSON FADEN: Yes, I think that's right. If we could just first get clear -- in fact maybe the easiest thing rather than go all around the room is clarify where people are on this first point, which is an interpretation of the evidence, okay. If you like, there is a proposal before the committee, think of it in that fashion, that the committee concluded that the evidence is sufficiently strong to reach the conclusion, and the language is very bad here, that, first, the patients were not told that this was a research injection, and that they were not told that this was for their benefit. Is there anyone who wants to say that they don't feel comfortable with that. Henry? And I'm taking names and what the reasons are. MEMBER ROYAL: I thought the chapter itself was somewhat ambiguous about the consent issue. And I think the evidence is somewhat ambiguous about the consent issue. In terms of whether or not the patients were participating in a research protocol, it's my understanding that at the University of Rochester that they were moved to a two bed metabolic ward that's separate from the normal hospital beds. Some of the quotes in the chapter say that there was no consent, but then there is a quote, which I've now lost, which says that it's unlikely that consent was not obtained. This was from the 1947 memo. If you want me to -- CHAIRPERSON FADEN: Yes, I know the memo, but maybe everybody else doesn't. I think it's page 37 of the Warren discussion. MEMBER ROYAL: So the thing that's confusing to me about consent is the patients were moved to a separate facility. There really are three issues. They were moved to a separate facility. Having an unusual number of urine and stool collections, and by an unusual number I mean all of their excreta are collected for literally months at a time. The third reason that I don't understand why people wouldn't have explained what was happening, is I don't understand the motivation why they would not have told them. Duncan was saying that they would need to tell them about the risk, and I agree with that. Although risk communication is very interesting because one can honestly communicate risk in so many different ways, and depending on how you frame it, make it sound either safe or dangerous. The people at the University of Rochester were injected with an amount of plutonium which was similar to the maximum permissible body burden, in that neighborhood. And in the document that Barbara Berney just brought to my attention, they talk about how the maximum permissable body burden was set for radium. And in that document it says that Robley Evans sat around the table with a bunch of fellow scientists and they said to those fellow scientists how much radium would you allow your wife or your daughter to be exposed to, if she were a radium dial painter, how much would you think would be safe? And that's how they arrived at the maximum permissible body burden of radium. Now, the reason that I bring that up is because a researcher in explaining the risk of the plutonium injections could, based on how the maximum permissable body burden was picked for radium, say to a potential subject, this is an amount of a radionucleide which I believe is safe. It's an amount that I would allow my wife or daughter to be exposed to. So the reason that I don't understand why -- I just don't understand why, if asked, they would have hidden any information. I don't understand what the motivation was. Now, if they didn't get consent, it would have been because that's the way things were done in those days. It wouldn't have anything to do with this particular experiment. But I think the evidence is ambiguous. And because they had so prolonged contact with these people it's just hard for me to imagine that they didn't ask questions and, if they asked questions, it's hard to imagine that they weren't given answers. So that's I think it's ambiguous about consent. Yes, I completely agree that if consent was not obtained that that was a wrong thing to do. CHAIRPERSON FADEN: Okay. Who else wants to raise questions? Again, Henry is using the word "consent," and we were using the language that the patients weren't told this or that this proceeded without -- we go back and forth between -- MEMBER KING: But Henry has a point, and I think that this is -- I don't like to harp on this, but I think it runs throughout the entire report. You cannot leap from a document to a conclusion without making some interim steps. And mostly this is a problem of evidence as lawyers call it, or weight of evidence, but there are terms and other disciplines as well. When I went back to the raised arm, you can't get around my problem by talking about stipulations. Henry just said he cannot imagine the patients who were there for a long time not asking questions and not having their questions answered. In a day where nobody understood all the requirements to be written consent, then the question does in fact arise whether the patients were -- and how we handle this, whether the patients were comfortable at the time with the exchanges that were going on with the physician, and whether the physicians were comfortable at the time with the exchanges that were going on. This is facts. This has got nothing about our moral conclusions. Whether the physicians were comfortable at the time with those interactions so that all parties were satisfied. Now, I know whether we call that consent or not, but in those days, and this is why we can't escape this issue of those days, in those days it does not surprise me that patients didn't ask questions, they don't ask them today. What we have done over time is change the obligations of what we expect physicians to do. We are clear about that. I'm not sure it has changed a lot in terms of what patients themselves are willing to accept. I go to law not to talk about the difference between law and ethics, but to go back to a field that I am comfortable with. I don't know what we call, how to describe, and I prefer to just describe, I don't know what we do with this interaction between patients and doctor. CHAIRPERSON FADEN: We don't know what the interactions -- these are no more facts, these are speculations. I don't understand the claim here. We don't know, okay, what happened between the doctors and the patients. What we have -- MEMBER ROYAL: That's what I don't understand, how we can talk about -- CHAIRPERSON FADEN: -- right, that's clear. What we have are a series of different sources of evidence, documents, recollections of 1974, IG report, the conclusions that they drew based on the interviews they took. We have testimony from people taken at the time who said that their impression was the following, okay. We will never have either way, we know that. So the challenge before us is, given the evidence available is it strong enough to reach that conclusion? We know we're not there. The point is, if you hold the position that unless we had a tape recording or a wayback machine and could watch what happened there, we can't draw a conclusion, then fine, that's a position. The other, the question before the committee now is the other evidence available to us, is it sufficient to conclude that it is likely that this did not happen? That's all we can do. We cannot go back and say what were the interactions or what kind of interactions did doctors and patients have that we don't know, okay. But we do have certain pieces of evidence. Some of those are documents of the sort that we call "documents." Some of those are interviews with people in the early '70s. Also we have the evidence that points to what was said after the fact in the follow-up studies where there's every indication that they were hiding stuff from these patients. Well, if they knew from the beginning, why was there all this accusation after the fact? It's circumstantial and it builds a case. Now, I'll allow my view. It builds the case to my satisfaction, particularly with respect to Rochester, even though it was at Rochester where they were moved to the metabolic wards. And also to the other two cases. But that's what's at issue here. It's not like we can know for certain. The point is raised inferences that cause him to question where the -- have to reach those conclusions. And each of us has to sort of lay those out and see which way it goes. I mean that's all we can do here. But we can't sit there and bemoan the fact that we don't have a wayback machine, we don't have it, okay. I mean that's sort of the given. Jay? MEMBER KATZ: Look, I very strongly want to support Ruth Faden's position, and I think that's almost the first issue before us right now and we have to come to a conclusion. If we want to apply the law of evidence, if we want to be in Los Angeles and be at the O.J. Simpson trial and really find out exactly X, Y and Z, then we cannot come to any conclusions just because of the issues raised, namely we weren't there when the investigators interacted with these patient subjects. But I think from everything that we've collected, also from the interviews with researchers in the '70s, with the researchers that we interviewed in the project, and what we know about the way physicians and researchers talked with patient subjects, and also from these documents, to my mind, yes we might have to say that we can't dot every I and cross every T. The evidence is there to make a judgment the disclosures were utterly inadequate and that a consent was spurious by and large. I'm willing to do that on the basis of the evidence. But, Pat, if I understand her correctly has in important point, and -- MEMBER KING: I don't disagree with Ruth. MEMBER KATZ: Pardon? MEMBER KING: What I'm saying is that I don't disagree with Ruth. I said at the outset that I had reached my conclusion on Ruth's question. What is the problem is, that this is the way the language seems to me to have to go. That based on what evidence we have, all of the evidence, it is likely that there was no disclosure. Based on all the evidence that we have, it is likely that subjects did not understand themselves to be research subjects. Based, and this is Henry's point now, based on all the evidence that we have, people being in a place for a long period of time, something that keeps happening to them that's unusual, that we also have some evidence that may make it more difficult to reach a conclusion about what is a conclusionary phrase, which is consent. What we have to do is break down what we understand the component parts to be. But one of the issues is was there simple agreement? Did the patients mind being there and having themselves stuck with a needle and having those tests, follow-up tests? Well, I would say based on the same look at the same record, it is likely that they did not object to that because there is an aspect of what we mean about agreement or consent that takes account of all of those aspects. And one of them is when you put your arm up and you let the needle go in, that says something too, and you have to draw an implication from that as well. That is all I -- so I'm agreeing with Ruth. I'm also saying that when you write it you don't say it is likely there was no consent. You say that it is likely there was no disclosure. You have to say that it is likely they did not know they were research subjects -- CHAIRPERSON FADEN: Or you can say based on what he said -- MEMBER KATZ: And Mr. Kate had to flee from the hospital -- CHAIRPERSON FADEN: -- it is likely -- MEMBER KATZ: -- Mr. Kate had to flee from the hospital. Remember that -- CHAIRPERSON FADEN: Yes, I'm sorry, yes. MEMBER KATZ: -- and they had to escape. CHAIRPERSON FADEN: Yes, which would make you think it was for your medical care. I mean at the very least it would seem to me from what you have said, Pat, that you could say that it is likely there was no consent to being a research subject. MEMBER KING: I'm willing to say that. CHAIRPERSON FADEN: And so we just have to step back and -- MEMBER KING: And break it apart. CHAIRPERSON FADEN: -- okay, and break it apart. Which is what Ruth is saying is the operative concern. That they consented to having their bowel movements collected is fine, okay, if we're seeing that, that's fine, but the really troubling thing is whether they consented to being a research subject. All right, I've got Phil and Mary Ann waiting and Ruth again, and Nancy, and everybody wants to weigh in, and Susan and that's great. Phil, Mary Ann, Ruth, Nancy and Susan. MEMBER RUSSELL: Without entering into this discussion, which I don't think I can contribute to, it occurs to me that our uncertainty about the level of consent and so forth is not as important as the fact that the way the whole set of issues were handled by the government officials did an immense amount of social damage because of the perception that no consent or inadequate consent was obtained. And that plus the way it was shrouded in secrecy, which I object to as a term in the document by the way, did an immense amount of social damage. So whether we have varying degrees of certainty about whether there was simple consent or on the level of informed consent, that's not as important as the fact that the perception is out there and that they're was where the immense social damage was done. CHAIRPERSON FADEN: I want to return to that. That's important. Phil, to put you on the spot here, is it your interpretation at the moment, are you willing to endorse the interpretation that the evidence supports the conclusion that the subjects were likely not told that they were research subjects? MEMBER RUSSELL: Yes, with the term "likely" in there, I'm sure. CHAIRPERSON FADEN: Yes. You're comfortable with that, okay, and then we can move on. Mary Ann? MEMBER STEVENSON: I guess I weigh in a bit with Henry. It's no so clear to me that the patient's weren't perhaps aware that they were research subjects. In fact Warren's narrative or recollections on page 37 describing his remembrance of what Hamilton had said, you know, says that the patients would receive an injection of a new substance. It was too new to say what it might do, but had some properties like other substances, and Warren admits this was hardly informed consent. But I think what's really troubling to me is that the purpose of this experiment was not in the least bit medical, it was military, and that's what really makes a difference from other experiments that we're going to analyze in biodistribution that may have the same problems in terms of whether or not the patients knew they were research subjects. Research for what? I mean I think these patients or some of them may have been aware that they were research subjects, but they thought it was for medical purposes - - CHAIRPERSON FADEN: Or to benefit them. MEMBER STEVENSON: -- themselves. Exactly. But even in the broader sense for medical purposes, you know, maybe it would help cure cancer, maybe it wouldn't, but they were really being used for an entirely different purpose and I think that's what makes this experiment unique. It was really a military purpose. MEMBER RUSSELL: Is occupational health a military purpose? This is occupational health issue. MEMBER STEVENSON: That occupation was directly related to the military. MEMBER RUSSELL: Making bombs -- MEMBER STEVENSON: Making bombs is not a civilian activity. MEMBER RUSSELL: But it's a health issue, it's the health of the workers that was the big concern, the health of civilian workers. So it wasn't in a -- CHAIRPERSON FADEN: See, I think there's a value judgment suppressed that Mary Ann is operating with which I think a lot of people have, and I'm not sure, if we want to deal with it directly, which is somehow it's better if research advances a cure a cancer than if it was used for some other whatever. I'm not sure that that's true, but if that's true, that somehow the value of curing cancer is more important than the value of increasing crop production or whatever the deal might be, or producing bombs, the response to that would be but look, this is really to promote health too. It's to promote the health of the worker -- MEMBER STEVENSON: But I think it's different. MEMBER ROYAL: I would think that preventing cancer would be better than curing cancer. CHAIRPERSON FADEN: Right, preventing cancer. All right, so preventing cancer, and this is an intent to prevent cancer, it's an intent to prevent cancer in workers as opposed to prevent cancer in -- MEMBER STEVENSON: But I don't think they were that long sighted. Well, perhaps they were. I guess they have the radium dial painters to think about -- CHAIRPERSON FADEN: That's presumably what they were worried about. I mean that's why I -- it wasn't to benefit them. And this is where this parsing is relevant. What I'm hearing is some people are uncertain about the extent to which case by case the evidence says that these subjects -- the evidence can be interpreted as saying that it's likely these people didn't know they were research subjects. If you move it to the next statement, I mean some of us have said already we're comfortable with that interpretation. I hear Henry and Mary Ann pulling back. The next statement is that they knew that this was not going to benefit them. And there you're comfortable saying they did not know. MEMBER STEVENSON: Did not know, and I think it's -- CHAIRPERSON FADEN: And the evidence suggests that they did not know that. MEMBER STEVENSON: They did not know what the real purpose of the experiment was. CHAIRPERSON FADEN: The real purpose, okay. MEMBER ROYAL: I don't know what that evidence is. Again, what is the evidence that they didn't know - - MEMBER STEVENSON: I'm basing this on -- CHAIRPERSON FADEN: If you take just that sentence, the sentence suggests that even if you say that that's what -- read it again, I'm sorry, Mary Ann? MEMBER STEVENSON: It's on page 37 and it's the transcript of Warren's interview in 1974 "They would receive an injection of a new substance that was to new to say what it might do, but it had some properties like other substances that had been used to control growth processes in patients or something of that general sort." And then he went on to say "You could not call it informed consent." But, I mean nowhere in the document do I see any evidence that the patients -- that anybody came even close to telling the patients what the true purpose of the experiment was. MEMBER ROYAL: Again, the reason that I don't understand is, if I were trying to do a study, I can't think of a better position to be in than to be, number one, a physician, to be able to say that I was going to inject an amount of a substance that I did not think was going to cause any harm, and during this war time and immediate post war era be able to say, and this has something to do with important national security issues and, you know, you appeal to the person's patriotism. So I'm actually not saying that -- CHAIRPERSON FADEN: If they had said that, would they then be motivated to hide the experiments and keep them secret? If these people had all been patriotic volunteers - - MEMBER ROYAL: Well, but the people that were interested in hiding the experiments were not the investigators? CHAIRPERSON FADEN: But if they had the assurance from the investigators, these people know what's going on, they know it's to help the war effort and protect the poor war workers from danger, we told them it was likely not to cause any problems, and they said fine. I can see the AEC public relations people then going, you know, full out with the public relations campaign in line with the sort of things Susan has been showing us. You know, I was a human guinea pig to advance science kinds of testimonials. I mean they could have turned it around and it would have been a public relations bonanza for the AEC instead of cries of great concern about potential legal liability and embarrassment. Again, we're working with inference, but you're entirely relying on your sense of gee, it doesn't make any sense. And I'm saying that the evidence we have suggests that if they had followed that, and it doesn't square with the evidence we have with respect to the way in which the people responsible behaved after the fact. If it had all been this above-board, rah, rah, rah, patriotic, you know, protect the worker stuff, why would they have gone to such lengths to edit out the initials of the patients in the report so that the -- MEMBER ROYAL: One of the things that I had asked for, which I haven't received, is there were some newspaper articles about these injections in San Francisco. And so it's not like this was hidden from the very beginning, it was only when the -- CHAIRPERSON FADEN: It's about the child, it's about the dramatic story of flying the child from Australia. MEMBER ROYAL: Correct. CHAIRPERSON FADEN: It's not about helping the war effort or being -- it's the story of this -- MEMBER ROYAL: But you were saying that if it was such an upright thing to have done, why didn't they publicize it. And what I'm saying is that there was some publicity about patients having been injected. CHAIRPERSON FADEN: That a patient having been brought from Australia who was a child, the Red Cross bringing this heroic mission. It didn't say that, you know, it was a totally -- MEMBER ROYAL: Totally misleading. CHAIRPERSON FADEN: -- it was not the whole story or even close to it. It was in the context of this child being transported. Again, this isn't an argument in persuading one another, but I'm worried that if we can't reach agreement on this point, we're never going to go to the next point. So if we could hear from -- I've got -- where is my list? I've just lost my list. Oh, Ruth Macklin, Nancy and Susan. MEMBER MACKLIN: Maybe the conclusions would be more closely tied to the evidence if we broke it down by cite rather than make the global statement and the conclusion and that this discussion is having about these patients. NOw, it seems to me from trying to look through this in the last few minutes, once again, that it's here in these pages. So Henry says, and quite correctly, well there's some evidence that some patients were informed, but then there is other evidence that other patients were not informed and how can we draw some conclusions from that. Now, because we have the quotations, and I'm going to say right now just what they are, it seems to me if we test the conclusions in terms of Rochester, UCSF, and Chicago, we can tie into what Pat is asking for, which is tying documents to evidence and drawing conclusions. And so we see on page 21 that Hempelman says he believed the patients injected with plutonium were deliberately not informed about the contents of the injections. And then we have a second quote, Durbin quoting Waterhouse who was the resident at the time, believed that all three persons would be agreeable, etcetera, most important that they did not know that they received any radioactive material. And this is all Rochester. And then later, going to Henry's point about what the doctors might have told them, and this is now the decision not to declassify, on page 35 when the guy from Rochester, Dowdy is his name, who was the, whoever he was there, is writing to Los Alamos, he refers to -- he makes the suggestion not to do this without our foreknowledge, etcetera, and makes the suggestion because of possible unfavorable public relations and in an attempt to protect Dr. Samuel Bassett from any possible legal entanglements. Well, why protect, why does Bassett need protection? Presumably because Bassett did some things to patients that patients or their families didn't know about. And I'm now picking out the kinds of things that might be cited as the evidence that these subjects weren't told. So let me move very quickly to UCSF. There we have a different line set of evidence, and that begins on page 29 where the quotation from the letter from Chapman says these doctors state that the injections would probably be made without the knowledge of the patient, okay. And there may be more on that, I don't have that. So I mean we can pull together what we have about UCSF. And then the last, Chicago, is the place where there are these comments about consent. It probably was not done without their consent. That's the letter quoted on page 33. It is unlikely that these tests were made without the consent of the subjects. And then again on 34 one of the doctors at Billings Hospital said that some form of oral consent for the injections had been obtained. So what we can say about Chicago is very much -- there the evidence is unclear, but it looks like maybe some sort of oral consent was obtained for something. But I wanted to go back for one second, sorry, about UCSF. The quotation that Mary Ann gave just a moment ago, that was half the quotation. You couldn't call it an informed consent because they didn't know what it was but they knew it was new and unknown substance. The rest of that quotation says "If Durbin is correct, Hamilton's remark fell far short of aiming at informed consent. It could even be regarded as disinformed consent since the statement might logically lead the patient to believe that he or she would be receiving a substance with some hope of curing his or her cancer." Which goes to the question of what was the purpose? Did these patients give consent, say yes and give consent to something? Did they know that what was being injected into them was for their benefit or not? Well, according to this, no, and in fact it was misleading. MEMBER KING: Is that last part a quote? CHAIRPERSON FADEN: Well, that's not a quote. That's the committee. MEMBER KING: Which I think is a bad interpretation from the -- CHAIRPERSON FADEN: I think -- MEMBER KING: -- I think no. That's one of the places I've marked for style changes -- CHAIRPERSON FADEN: -- I think it's only over -- with respect to cure. They treat, I think it's right. I think when you -- I mean I think the language is -- MEMBER KING: Yes -- CHAIRPERSON FADEN: -- but I think if you say that you're saying someone didn't like something that has been used to, what is it shrink tumors or? MEMBER STEVENSON: Control growth. CHAIRPERSON FADEN: Control growth of a tumor to somebody who is a cancer patient, that sure sounds to me like this might help me when in fact there was no reason to think that plutonium was going to shrink their tumors, or it wasn't even being investigated to shrink tumors. MEMBER KING: That's part of the argument that we're having, Ruth. What one can draw from this -- what reasonable inferences one can make from the statement. CHAIRPERSON FADEN: That is what the next sentence has. This is the inference that the author feels -- MEMBER KING: Right, and what I said -- CHAIRPERSON FADEN: -- can be reasonably drawn -- MEMBER KING: -- and what I said is I was uncomfortable with that inference. CHAIRPERSON FADEN: Right, so there is a disagreement. MEMBER MACKLIN: Let me just separate that from the rest of my remarks. The point of which was simply to suggest that one way around this debate that we're now having is to break down the conclusions that we draw with regard to each of these cites where the plutonium injections were made, and acknowledge the uncertainty but say, as we have been saying all along, it is likely based on these documents and these statements and these letters that consent was not obtained at Rochester. It is likely based on these documents and these statements and these things, that consent was not obtained at UCSF. And it may well be that consent was obtained at Chicago based on these documents. MEMBER KATZ: Ruth, can I -- you have an interesting suggestion, but in doing it this way aren't we then almost, because the documents are inadequate, arriving at a weight scale for each institute because one will, in terms of what we have, will get an A, will get a B, and a C, not explicitly but implicitly. And people might have all kinds of reaction for having gotten on those -- MEMBER MACKLIN: That would be an unfortunate -- MEMBER KATZ: -- examination mode -- MEMBER MACKLIN: -- that would be an unfortunate inference to make from this exercise. The point is not to rate the institutions, but to draw some general conclusions about the nature, existence and quality of consent -- MEMBER KATZ: You wouldn't be concerned about that? MEMBER MACKLIN: -- on this set of research. MEMBER KATZ: You wouldn't be concerned? MEMBER KING: I think you could dispel the problem of trying to rate them if you don't make the leap that Ruth just made. This is a careful construction. Her leap was, there was consent here, there was not consent here. That's not the leap. The leap is, at this institution, by institution I agree with her, the evidence indicates subjects were not told, subjects did not know they were subjects. You've got to break it down. You cannot say, when you say "there was no consent," you have added a judgment. Wait a minute -- MEMBER MACKLIN: That's right. MEMBER KING: -- and there are judgments and judgments. Because part of what you were talking about is, see I know where I'm going on this because when you say there was no consent, then you can say what they did was morally unacceptable, and that is because you have eliminated saying anything about what were simple consent practices of the day, what were practices of the day, and I'm not willing to make that leap. So it is important to be careful in how you state what you conclude. Stating there was no disclosure is a different statement than saying there was no consent. CHAIRPERSON FADEN: I rephrased it as there was no consent to being a research subject. MEMBER KING: Ruth didn't say that and I didn't talk to you -- I talked to your Ruth, but Ruth concluded by -- CHAIRPERSON FADEN: -- we can clarify -- MEMBER KING: -- different formulation -- CHAIRPERSON FADEN: -- it however you like. MEMBER MACKLIN: I'm using the language that now appears on page 45 following the bullets. If we want to change that language, then we change that language. The language now is in the form of adequate consent. And if we stipulate some meaning of adequate consent of the sort that we discussed a few months ago, we might be able to draw this conclusion. If you want to make it a little different, what Pat is saying we can more clearly draw from the evidence is that there was not adequate disclosure so that whatever subjects were consenting to, it was -- CHAIRPERSON FADEN: It was not to be -- MEMBER MACKLIN: -- I mean you can insert the disclosure part and then say if there was not adequate disclosure then, although patients may well have consented to something, they were not consenting to a research maneuver that would not benefit them. MEMBER KING: Well, then the way to put the question so that people don't lose sight, this is a building process. My comments to the committee on the chapter, and as of what time are you talking about this being adequate or inadequate consent, because the end point is in the conclusion talks about moral acceptability. CHAIRPERSON FADEN: Right, we are stepping back -- MEMBER KING: And that is at what time? CHAIRPERSON FADEN: -- get rid of the language of adequate consent and just take the description. They were not, whatever they consented to, the evidence points to varying degrees, with Rochester being the clearest and Chicago the least clear or the weakest, that they were not consenting to being a research subject in a study which could not possibly benefit them. Now, not everybody is comfortable with that formulation, but at least we've gotten some place. And still waiting, and Nancy and Susan have been patient, so Nancy and Susan, do you want to come in? MEMBER OLEINICK: Well, let's some of what I had to say has been said. But in a way I liked Ruth's suggestion to break down the discussion into the cites, but although we don't have statements about what each of the 18 patients was told or not told, it somehow seems to me that these were 18 individuals and that it seems inconceivable that every case would have been handled absolutely identical to every other one. It is very hard to believe that there wasn't one individual who asked a question and who was told something. So I'm uncomfortable about lumping everything together into a package of inadequate -- well, inadequate disclosure was probably the case because at least we know they weren't told it was plutonium. I mean that's for sure. But in terms of all the rest of the kinds of information that could have been given it just seems to me unlikely that there wouldn't have been some information. So however it comes out being worded, we need to have that escape clause I think. Because of the absence of evidence I would not want to come down and say there was never complete non disclosure. So that's one thing I wanted to say about it. And then the second is the comment came up some few minutes ago about wanting to keep all this information under wraps. We do have some documents that suggest, at least the one where Hymer Freidell wanted to declassify information. Now, it's also inconceivable if he thought it was going to damage himself or his colleagues that he would want to declassify that information. And it was some classification officer who nixed it because that went up several levels. If I remember seeing that document, it was Hymer Freidell signed off and then a whole other, several levels, of people signed off and it was a declassification officer who probably wouldn't know much about what actually went on in the design or the implementation of the experiment who said no don't do this because of legal liability and so forth. So I can't imagine that they felt that this was anything that was going to damn them if they said sure let it out MEMBER MACKLIN: That example, I mean the discussion is on page 32 and 33, and that happens to be one of the cases in which the statement is made it's unlikely that these tests were made without the consent of the subjects. So that may not have damaged him, if in fact it wasn't made without the consent of the subject, and this is an example of his wanting declassification quite clearly so he gets a benefit out of it, right, he's not interested in open disclosure. He's interested in his publication and, you know, advancing his scientific career. But this would be less damaging than all the other ones where there's evidence that there was no disclosure. CHAIRPERSON FADEN: Susan? DR. LEDERER: I guess I think we're going to have to resolve, as difficult as it is, you know, what we mean by simple consent and what they meant by consent. Because I know in the '30s and '40s sometimes physicians would in their publications say the patient offered no objections, and that would be synonymous with their understanding of consenting the patient. But I wanted to ask a question about how the committee resolves the evidence having to do with CAL 3, Elmer Allen, which the claim is made that the experimental, procedure of experimental nature was explained to the patient. The patient was fully oriented. It's documented in the record, and then in the text it's followed by the public testimony that we've heard and then there is no discussion about how, you know, what is our take on that particular consent issue. Are we saying that consent seems -- I mean we have documentation of consent, but we assume or we infer that it was inadequate disclosure. I mean I would like to know how people -- MEMBER KING: My comment to that was either take it out, it didn't fit -- CHAIRPERSON FADEN: Take which out, Pat? MEMBER KING: The quote that she's talking to which is on page -- CHAIRPERSON FADEN: You mean the Elmer -- DR. LEDERER: I have it on page 38. Well, I'm looking, let's say I'm reading from the April 20th version. MEMBER KING: Well, anyway it's that same quotation. It's the same quotation and my comment was that the quotation didn't fit as put it. It wasn't an evidentiary issue, it is an opinion statement or a belief statement and if we wanted to include it then it had to be identified as such, that somewhere you interrupted the flow and you say that there is some opinion or belief that this was not the case as stated or something like that. DR. LEDERER: At the very least it deserves some comment, but as it is it's just sort of placed in there. But I assume that in the conclusion though we're saying that it was inadequate consent including that one. MEMBER STEVENSON: Well, I think the point was probably they never even mentioned the word plutonium. I mean they may have gone to some effort to explain they were injecting a radioactive substance, they probably didn't say why, and they probably didn't mention plutonium, so in fact if you -- DR. LEDERER: I guess I come back to what I understood Duncan's point to be earlier. The disclosure that it was plutonium may be sort of less important than the fact that it was a research and that it was non therapeutic. MEMBER STEVENSON: I agree, but I think what the family members is reacting to is the word "plutonium," if you read the quote. DR. LEDERER: Well, but I mean I think that that needs to be commented upon in the text. Or the fact that it appears there seems to suggest that we're taking a side on this particular issue. CHAIRPERSON FADEN: The second paragraph is less relevant. I mean Mrs. Bell's claim is that her father never gave consent, and that's got to be signaled in the report because it's contrary to the evidentiary record. It's what it is. It's her claim that her father never gave consent. To her mother's recollection she was not consulted either. It needs to be acknowledged. DR. LEDERER: To plutonium? CHAIRPERSON FADEN: Pardon? DR. LEDERER: To plutonium? I mean that's why I get back -- CHAIRPERSON FADEN: And if you say conducted, allowed in the first paragraph it makes it clear that she's saying they didn't get consent without -- her sense is that the scientists are conducting experiments without getting the patient's consent. We could go back and clarify it, and this just happens to be what she said, and I don't think we should hold it to these exact words and over read it. She's giving testimony and I don't think she's -- if we had turned around and asked her the question, Ms. Bell, do you think that your father gave consent to be a research subject. We could go back and ask her, but my guess is it's her family's contention that the answer would be no, okay, despite the evidence or record to the contrary. So that's what this part of the text is intending to signal, that you've got documents that suggest (A) and a family member is speaking on the part of family says not (A), okay. DR. LEDERER: And what does the committee say about this, that's my question? CHAIRPERSON FADEN: Now, what does the committee say. I believe that this is, you know, very difficult because like any other context in which you've got this -- MEMBER KING: I think in evidentiary terms it is not difficult. It may be difficult in terms of what kind of respect you want to afford people who testified before the Commission, but in evidentiary terms what you're having is a question of somebody looking back and being a part of a family with a series of facts and a family who forms an opinion or a belief, which I am not attacking in any way at all, but that has nothing to do with when you're talking about what documents existed at the time. That's a different statement than if it had been from the patient at the time, or even a different statement maybe if she said this is what my father, this is what my parent told me. But in evidentiary terms I don't think it's hard. I just think that we can say that this view is challenged by the beliefs of others -- CHAIRPERSON FADEN: We can phrase it that way -- MEMBER KING: -- committee is saying it's not a part of the evidentiary -- CHAIRPERSON FADEN: -- I think to get to the core question of what we can say about the situation, the evidence that points, and I don't know if you count this as evidence, Pat, but in 1973, if you look on page 43, there is the discussion of the follow-up of Elmer Allen where, and this is what comes out in the IG's, the report that's done closer in time than we are, okay, they're 20 years away as -- less than 20 years as opposed to us who are 50 years away, and there it's Elmer Allen's physician had been told that the purpose of bringing Mr. Allen to Argonne, blah, blah, blah, blah, was interest in the "treatment he received at the University of California." That is the stipulation that Ms. Allen has said as well, that they thought they were going for follow-up on the treatment that he received, okay. Which suggests that however it was explained to the patient at the time, again this inference that it was treatment for them rather than a plutonium injection that -- MEMBER STEVENSON: That's exactly my point. I mean the word "plutonium" is emotionally charged. I mean people react to that in a different way than they do iodine 131. Even among isotopes plutonium evokes an emotional reaction. CHAIRPERSON FADEN: And so? MEMBER STEVENSON: And so I think -- CHAIRPERSON FADEN: The assertion here is that the inference was that it was treatment, not whether it was plutonium or it was iron or it was anything else. The issue is that somehow there is an impression given that this was given to you because you had a medical problem, this was experimental, and it might treat you, whatever that -- MEMBER STEVENSON: Right, I mean which goes back to my original point. CHAIRPERSON FADEN: Exactly. MEMBER STEVENSON: So there was some kind of consent, but it was not full disclosure for the purpose -- CHAIRPERSON FADEN: -- parsing it and parsing it, but the evidence is I think mixed. You know, there is evidence in the record that he consented to something and the physicians told him something. There's also evidence that comes in the follow-up study that suggests that what he was at least told in the follow-up study, but perhaps also at the time, was misleading, right, and that's all we can say. Does that seem reasonable? MEMBER STEVENSON: I mean it's clear none of these patients were informed about the true purposes of the experiments until the AEC mandated it in 1974. I mean they wouldn't do that if the patients had ever been told the true purpose. I think that ultimately says exactly what was or wasn't told. CHAIRPERSON FADEN: Now, how are we going to get off the dime here to the next issue, folks? This has taken us an hour to get to an agreement about a description of what happened, and I'm not even sure we have an agreement. We'll have to rework the chapter and see. The next issue is now what do we do with this description that some of us at least are comfortable making. Let me summarize the description. It sounds as if there is agreement among most, if not all, the member of the committee that at the very least the evidence suggests that the evidence varies from, the degree of the evidence varies from, institution to institution, with Chicago being the least clear or perhaps pointing in the other direction, that the subjects were not told that the purpose of whatever it was that was done to them was research not intended to benefit them. That seems to be as close as we've gotten. Henry? MEMBER ROYAL: Let me just point out one other thing that came to mind. I think it was Cal 1 was actually offered money to have urine and stool collections done several months after the plutonium injections were done. It would seem unusual for doctors to pay you money to do routine medical tests. That's part of the record that they were going to pay him money. CHAIRPERSON FADEN: So your interpretation is that they actually -- MEMBER ROYAL: Actually it's another piece of evidence that people, at least some individuals, had to know that they were participating in a research project. MEMBER MACKLIN: Well, if he were, we don't know really, but I mean if he were told that these things were being collected and he was paid, it may not be clear that it would be, the distinction would be made for general research purposes or for something that may indicate something about his condition, namely particularly if he has to inconvenience himself or stay longer than he would stay or go to a place that he wouldn't otherwise go to. I mean the distinction between paying people for tests done on themselves, paying people for general research purposes just may not have been clear. I mean you're now questioning what he inferred, which is a fairly sophisticated inference, based on namely doctors do research, they only pay people when they do research that's not designed to benefit the individual patient. I mean we'd have to build all those premises into this -- MEMBER ROYAL: I don't think that's a big inference. If you were going to a hospital and they had been collecting your urine and stool for a while and you said this is inconvenient for me, and the guy said well, we'll pay you to do this, you'd think that that's a big inference to think that it's not for your own benefit, that it's for the hospital's benefit. CHAIRPERSON FADEN: I'll tell you what, guys, I mean let's do this. I don't think -- we cannot hammer this down to the wire here. We have to many other things to do. We will try to come up and point out -- I mean maybe the fairest thing is to state the general conclusion, point out where the evidence suggests otherwise, okay, and why either all the committee or some of the committee on balance still things that the general conclusion is correct, okay, and then see if that fits. Pat? MEMBER KING: I'll risk making a prediction, but based on experience that's always a risk, but I don't actually think we're that far apart. I think that this is in large part a writing problem and this is the way I think that the writing should happen. We're not that far apart because an inference was after all an inference, and reasonable people can make different reasonable inferences. Our issue is weight, what I call weight, and that is I think that what I hear from some people is a plea that the writing give all the inferences that we consider are reasonable that we can draw from the evidence first. And then, if we take a look at that, some people, and it's very hard to do this without seeing the writing for some people right now unless you're following this discussion real closely, then to see how many people once you see it all laid out, everything, your concerns, that the inferences could cut in several different ways, that the weight of what you see would support a statement like it is more likely than not, or it is likely that (X), (X) being that with the conduct of these experiments, that it is likely that -- I'll take one where it has a clear agreement, there's no disclosure that the substance was plutonium. The reason I say that is because I think that what I heard some people say was they didn't like the statement of the inferences all going in one direction. And that was to a statement and not to a weight. So we may not have as much disagreement as you think about weight. CHAIRPERSON FADEN: I actually don't think we have much disagreement either. I'm worried about the process of getting through to the other 16,000 judgments that need to be made about this chapter, so I'm concerned about going forward. But I think you're right, Pat, that the caution that the writing would benefit considerably by being more step by step. The evidence is clear that they weren't told about, the evidence clearly is that they weren't told about plutonium. Maybe that doesn't matter much, but the evidence is clear. Next step, were they told they were research subjects? Here is the evidence that suggests that they weren't, here is the evidence that suggests that they might have been situation by situation, and overall the committee's view is that it's likely that, and we'll see if we can agree to it. Next thing, were they told that? We can write it that way, and that probably will be -- MEMBER KING: But the reason I make -- CHAIRPERSON FADEN: -- to accept. MEMBER KING: -- the point is that this is not a problem peculiar to this chapter. CHAIRPERSON FADEN: No, it's going to be all the way through. MEMBER KING: And so one of the things is, if we could understand as a group now that part of the discussion would be facilitated where we have to draw inferences so that we place inferences that we don't like, that another writer doesn't like or would not draw, but an effort to allow all the inferences. When we get to those chapters in a discussion today, I would like to be able to refer back and say treat this one like we agreed to treat biodistribution and maybe that will facilitate some of the discussion -- CHAIRPERSON FADEN: Is that agreeable to everybody? If we can use that as code for this way of laying out the evidence and the inferences and the conclusion that the committee draws about where the weight of the evidence falls with respect to which of the inferences seems most plausible, okay, and the strength with which the committee believes that it's plausible? Okay, here we have a dilemma, that's helpful. It's now 10:20 and we're supposed to get in two more chapters and we haven't gotten to any of the other issues that are raised in this chapter, namely the one Phil raised with respect to how we're to view the government officials' conduct with respect to keeping this secret. Jay, did you want to comment? MEMBER KATZ: Just a very brief comment because I think it's, to my mind, basic in the light of Pat's comment. I don't know whether we are far apart. I don't know about the "we." I am far apart from some of the statements that I've heard in the last hour and a half. CHAIRPERSON FADEN: Could you tell us how, that would be helpful? MEMBER KATZ: Well, because that's one of the problems with the conclusion is to me, I thought that there are some problems and I gave you a list of problems, but on the whole I thought that the chapter was very well written. But the conclusion was in a sort of sense completely inadequate, that it was to some extent the roaring of the lion in the rest of the chapter and then it became the squeak of Mickey Mouse. And as I said in my comments, which some of you may have read, you know, it requires to some extent going from the irony of Balzac and the anger of Zola to write this conclusion. And I'm not sure from what I've heard -- CHAIRPERSON FADEN: Jay, why don't we move to that. What conclusion have you drawn? MEMBER KATZ: Huh? CHAIRPERSON FADEN: What conclusion have you drawn? MEMBER KATZ: That I think that on the basis of the evidence presented in the chapter and what we know about the history of practices from other sources that even the committee has assembled, that the disclosure process we find out was completely inadequate. That when patients go into a hospital they become, and I'm just responding now to Henry whose points were very well taken, but they become completely overwhelmed by the authority of the physician and what looks to us like reasonable questions that we would ask, they wouldn't ask questions when they are asked to collect urine ten times a day, they are agreed to have these urines collected and they'll comply to the maximal possible extent because they expect, and this comes out in the subject interview study of today, they expect that everything of course is going to be done in their own best interest. I would, in light of the evidence of the chapter, I would make a strong condemnation about disclosure practices, about the spuriousness of the consent issue in relation to most of the things that we're discussing in this chapter. And I don't get the impression that -- I do not know how many members of this committee would join me in this. CHAIRPERSON FADEN: Henry? MEMBER ROYAL: Jay and I really disagree. So I won't disagree with him here. I think certainly an important issue is whether or not the plutonium injections were somehow different than the other injections like the uranium injections or any of the other, and were somehow different than how medical research was done at the time. When Jay spoke, Jay said that part of the evidence that he was using was not about the plutonium injections, but was about how medicine was practiced at that time. If we're going to use that evidence, that is how medicine was practiced at the time -- CHAIRPERSON FADEN: Or how medical research was practiced. MEMBER ROYAL: -- how medical research was practiced at the time, I think that that's strong evidence that the kind of consent that we would like to have done was not done at the time. But to me that's a very different statement than saying, than singling out the plutonium injections as somehow being what the problem is. And I think it's a very important distinction because what is it that this committee wants whoever reads this report to focus on. Do we want them to focus on the uniqueness of the plutonium injections, or do we want them to focus on the fact that the plutonium injections are really a reflection of what medical research was at the time. And I think those are two very very different things. CHAIRPERSON FADEN: I'm seeing people shake their heads. Can I infer that there is consensus that the context has to be provided? MEMBER ROYAL: And I'm very much against singling out the plutonium injections as somehow being an aberration compared to how medical research was done at the time. MEMBER KING: I couldn't agree more because yesterday's comment on the case studies is that the case studies need to start with the reason for why the case study is here. And what Henry is suggesting is a reason for why the case study is here, specify as terms of agreement. What I also am in agreement with and Henry is, we need to face up at some point more clearly to what we want to do, where we are putting the marbles in the basket. And I like my marbles being used to illustrate what I didn't like particularly in the past and I hope will never again occur in the future. And I'm not interested in finding it morally unacceptable or language to that effect. I'm interested in saying this is why this case doesn't -- this is why these are the kinds of practices -- CHAIRPERSON FADEN: Pat, what I don't understand about your language is you say you don't like it. Why don't you like it? MEMBER KING: Because if you start telling me, when I'm talking historically about why something is morally unacceptable, I want you to specify what you mean by morally unacceptable. CHAIRPERSON FADEN: What you want to say is you don't like it because what, when you say you don't like it, what is it about it that you don't like? MEMBER KING: Because I think that when I say it is morally unacceptable, I'm saying something about the people at that time. CHAIRPERSON FADEN: All right, so what -- MEMBER KING: And I am not prepared to -- CHAIRPERSON FADEN: -- to you want to say? MEMBER KING: -- say anything about the people at that time. I am prepared to describe what they did. I am prepared to describe that those are not consistent with our current standards. I am prepared to say that they illustrate. I'm prepared to do a lot of things. I am not prepared to go back and say you, you researcher, it was wrong. CHAIRPERSON FADEN: So you're not prepared to say the injection of plutonium into, let's say the case in which it's clearest, that they did, where the evidence is the strongest, let's make it one person at Rochester, you're not prepared to say that was a wrong thing? MEMBER KING: Ruth, I'm not prepared to say it. And I would put the question in a different way and that is, why is it important to say it? Now, I know that there are answers to that because I read the first part of the chapter, but my point is I think it's more important to say some other things. CHAIRPERSON FADEN: That's not at issue. I don't think anyone would disagree that it may be more important to say something else. But the question is whether -- this gets to the point -- MEMBER KING: We don't want to get back into the essays discussion. CHAIRPERSON FADEN: -- no, I know, but I'm trying to figure out -- MEMBER KATZ: That's yesterday's discussion. CHAIRPERSON FADEN: -- it is yesterday's discussion, and it is also today's discussion, and it's the rest of the report's discussion because we have to decide what kinds of statements the committee wants to make and what kinds of statements the committee is not prepared to make. Now, I don't know exactly, can we visit this from period to period. We've heard Pat's position on this question, and I don't know if anybody else wants bring in about whether they are prepared or willing to say that this was wrong as opposed to saying -- I mean to say that you don't like it is to say something. I'm not sure what kind of judgement it is, if it's not a more -- you just describe it and say and we don't want this to happen again. MEMBER KING: I'm prepared to say that we would like to see and would condemn in the future, if these practices were carried on. I'm prepared to be future oriented. It is the problem of being past oriented that is, I find, profoundly troubling. And I've got a long list of reasons there, but I don't think we'll be -- I'll be happy to sit down, Ruth, and explain it, but I don't think I should waste the committee's time. MEMBER KATZ: You just don't like to indict Aristotle and Plato, that's your problem. MEMBER KING: I think that that's right. I mean I'm having a lot of trouble with that. And besides I don't need to indict them to accomplish what I want to accomplish. CHAIRPERSON FADEN: All right, Ruth, why don't you comment and then I think we need to go to the second part of this chapter for five minutes which is the issue that Phil raised which doesn't speak to the general question of the practices of the day with respect to human experimentation, but the issue of the secrecy, the -- and the government's stuff afterwards and see where the committee sits on that one. Ruth, do you want to comment? MEMBER MACKLIN: No, I'll save it for the next time this issue comes up because I'm sure it will. CHAIRPERSON FADEN: Okay, yes, I have a feeling it's going to come up again too. Can we take a few minutes on the second part. What does the committee want to say, okay, not about the question of what was or was not said to the subject based on which they were used in this research, the discussion we just had. I heard agreement that we need to put our condemnation, as it were, in a context that says that look, this is what was going on at the time. Plutonium is not unique in this respect. We've identified in our other chapters, we've laid this out and this is very bad that this happened, whatever language we're going to come up with, we don't want it to happen again. What about the government side of issues, the keeping it quiet, the not saying. Phil, do you want to explore that? MEMBER RUSSELL: The last paragraph starts out -- CHAIRPERSON FADEN: On what page, Phil? MEMBER RUSSELL: On the last page. CHAIRPERSON FADEN: On the very last page. MEMBER RUSSELL: The last paragraph. CHAIRPERSON FADEN: Last paragraph. MEMBER RUSSELL: Starts out implying that the public relations and legal liabilities issues were somehow not linked to national security. In other words, challenging the motives of the managers. And I see no reason to do that because I see a very logical, clear logic, in this that the leaders of those agencies felt that anything that inhibited the ability of the agency to conduct its activities was a national security issue, and therefore that the public relations and legal liability were clearly linked to the effectiveness of the agency and therefore to national security. I don't see any reason to challenge that. What I would rather see is that their actions that were based on public relations and liability issues in retrospect showed very bad judgment because the outcome was a loss of public trust and a set of scandals revolving around how the agency did business. And I would rather challenge them on judgment rather than on motivation. CHAIRPERSON FADEN: Okay. So what you're saying is they may have been motivated by national security concerns, we don't know, but in any event they judged wrong? MEMBER RUSSELL: In any event the outcome was very bad, therefore the judgement was wrong. MEMBER KATZ: That opening sentence doesn't make any sense in the last paragraph. It's impossible to determine -- the preoccupation of AEC -- MEMBER RUSSELL: Well, it implies that they had some other motive other national security. I don't see any reason to doubt -- CHAIRPERSON FADEN: I mean in other words what you want to challenge is they may have judged wrong in keeping -- MEMBER RUSSELL: If this other motiva. MEMBER KATZ: Motivation, yes. MEMBER THOMAS: Their motivation I can't challenge, their judgement I can. MR. GUTTMAN: I just want to make a technical point. In the interim since this was written we've discovered what is now in the secrecy --are new evidence that seems to be that at the time there was a clear distinction in what they saw as a legal tradition between things that could be kept secret for national security reasons and things that while not endangering national security would nonetheless, the word they used was "cause administrative embarrassment to the AEC," so this doesn't go to the motivation. I think the question here in terms of the evidence, for whatever weight one wants to give the evidence, is that at that time they recognized that there was national security. And then there were things that would not by the terms of their own rules in the interim -- MEMBER RUSSELL: In the record. MR. GUTTMAN: -- right. What Phil may be saying is that it all was a ball of wax that was indistinguishable, that's a separate point, we're just saying that there is a body of evidence that shows they actually had that distinction in mind. Whether or not it was a real operative distinction, it was there, you know. MEMBER KING: But is that a distinction, are you trying to draw a distinction between you can classify for purpose of national security, you can classify for other purposes as well? CHAIRPERSON FADEN: At least then you could. MEMBER KING: So that's what -- MR. GUTTMAN: Well, it looks like it you could try to puzzle it out. In fact what may have happened is Hymer Freidell said well I got the national security regs here. This passes muster. Let's get it out here. And someone else says yes but there is another check box, public relations and embarrassment even though it may not be national security. Now, if someone wants to day it's all the same because it endangers the agency, that's another level of -- CHAIRPERSON FADEN: And the agency is essentially a national security agency -- MR. GUTTMAN: Right. MEMBER KING: But what you just said goes to support as I understand what you're saying, Phil's point, that there is no reason for us to get into motivation -- CHAIRPERSON FADEN: But what I'm hearing is the main conclusion that Phil is proposing the committee draw is look, this had a bad outcome, it was a bad judgement, and what the lesson is, is you don't lightly keep secrets like this because odds are it's going to result in bad news, right. There's this notion that we can manage and kind of hide and steer from the public what we're doing and get away with it and be better off for it is naive and misleading and we should really discourage this kind of thinking within government officials, is that right? MEMBER ROYAL: And the point really should be that this is what we should learn from this as opposed to they should have known this at the time. CHAIRPERSON FADEN: Right. MEMBER KING: But this is a structural point for the report. The committee has to debate that last point. What I would do with this chapter is I think Phil's point is so critical that it is not merely a chapter conclusion. It is a report that -- CHAIRPERSON FADEN: No, it's a finding for the whole report. MEMBER KING: -- so what I would do with this chapter is not use the broad language, but what I would do with this chapter is now go get the child of the patient who did not believe her father gave consent, and I would use with reference to this set of experiments those kinds of outcomes that lead us to Phil's conclusion -- CHAIRPERSON FADEN: That's very nice. So basically say look, here's an example. You've got a whole national scandal that resulted from the fact that these people showed bad judgment and thought that, you know, let's not take a little risk and some bad press, look at all the bad press it ultimately reaped over -- MEMBER KING: And look at how citizens feel about their government, I mean in the context of the plutonium experiment, is the way I would use some of that language at the very end of this chapter where when we're drawing -- CHAIRPERSON FADEN: That's a very helpful way to do it. And by the way what Pat just did would be very useful. If we at any point, if we want things, there's a big enough finding that it should be flagged as a finding -- okay, that may be supported throughout the document. That would be helpful to hear -- our candidates. Henry, and then I saw Phil wanting to come back. MEMBER ROYAL: I like very much Phil and Pat's suggestion. The only thing that I would caution is that again in retrospect it's very clear that this is a bad judgment. It's just not -- it's not -- I don't know that if it's fair to say that at the time they should have been smart enough to know that it was going to have all these bad -- when you say that it was bad judgment, we have to distinguish whether or not that's a statement which we think should be applied prospectively -- CHAIRPERSON FADEN: But the core point being is from now on government officials -- MEMBER ROYAL: Absolutely. CHAIRPERSON FADEN: -- should know this history and should from this history realize that it's not -- there are other things to put into the calculus rather than in the short time we might get an article in the local newspaper and have some trouble with some local communities, if this gets out here. So let's sit on it for 20 years and then let's go ahead and lie to family members about why we're doing the follow-up study and a bunch of other stuff that seems that the AEC itself in 1974 says it's going to tell these people the truth about why we're wanting their family members remains and so on, okay. This is difficult and not entirely satisfying, but definitely progress. So if we take a break, a quick break, we're going to try to get two chapters in before lunch. That's not going to be easy because these are not any less difficult chapters. We'll take a very short break, ten minutes. (Whereupon, at 10:44 a.m., off the record until 11:17 a.m) CHAIRPERSON FADEN: We keep getting repeated requests to speak into the mic. Excuse me, we're about to start. We're getting repeated requests to speak into the mic. Obviously it's a courtesy to the people in the audience so they can hear us. Moreover, the transcripts turn out to be very important particularly to the staff as when they do the redraft they look at the transcripts to get, in addition to their own notes, a fuller -- remind themselves of where the committee's debate was going. So it's really very frustrating later when you look at a transcript and there's a gap. So as irritating as it is, maybe we can, all together, move our microphones closer to us at one leap and leave them there. And avoid coughing into them, if possible. All right, we've had a request that we skip or go out of order, given how long it took us to get through the first one, skip radioisotopes temporarily and go the children's chapter which is the next one on the agenda because Dr. Webster can only be with us today, and he's been of such great assistance in helping us figure out some of the risk questions here. If we don't do the children's chapter now, we're likely not going to get to tie because the afternoon is pretty over-determined and also fixed by the availability of certain people's presentations. So if that's agreeable with everybody, we'll do children now and then go back to radioisotopes either this afternoon -- I mean either later this morning, which I think is unlikely, or tomorrow which is more likely. Is that okay with everybody? Jay, what was that term you said the papers had used "I don't object" or "I don't approve" when they reviewed it? MEMBER KATZ: Nihilo upstat. CHAIRPERSON FADEN: Yes, what does that mean? MEMBER KATZ: Nothing stands in the way. CHAIRPERSON FADEN: Nothing stands in the way of our doing the children's chapter next, all right. Hearing no objections, we'll go on to the children's chapter. I'm not even sure how to sort of frame the importance of this discussion. This is the most primitive in some respects of the chapters that we have before us, earliest in its formulation and indeed the first time, and this is also true for that matter for the radioisotope. We had a full committee discussion of the children's chapter. I know that Duncan and Mary Ann in particular, others as well, have some comments they already want to make. Do you want to just start us off either one of you? MEMBER THOMAS: I've had a lot of difficulty with the risk estimates that are offered here. I made a request in an earlier draft that there would be some explicit treatment of what the basis of the risk estimates are and that's now identified as this sort of total detriment model from ICRP report 60, which I've had the opportunity to look at just for the first time during the break, and I confess it leaves me somewhat puzzled. I don't think I want to belabor the point at this point, maybe other committee members want to contribute, except that it seems to me we need some more expertise to look at the appropriateness of this choice of model and perhaps visit some alternatives. The fundamental difficulty for me seems to be that ICRP 60 is aimed at external gamma radiation and is an attempt to come up with some sort of sensible average risk totaling a whole lot of different end points. Whereas what we are faced with, with the isotopes that are -- what this chapter is primarily about is very much organ-specific risk. So it doesn't seem to me that that model is appropriate. Let me just raise one other concern lest it get forgotten, and perhaps not a major one, but it's one that I would like to see prepared by this committee so that the staff gets some direction. There is no language in this draft, that I don't recall seeing before, and it appears near the end of the chapter about the appropriateness of excluding women who are at the risk of pregnancy from studies involving radiation. And it appears to conflict with conclusions that were offered earlier in the chapter. I myself haven't made up my mind as to what I think the right thing to do in the circumstances. This came up in reviewing one of our clinical trials, one of the research protocols in the RPRP, and I think Sue was on that particular one that we had some discussion about. And I was objecting to the use of pregnant women, or I guess I was not objecting to it, the investigators had excluded women on the grounds that they may get pregnant and they may be at increased risk. And as I recall Sue was saying but wait a second, isn't there now an NIH directive saying that we were interested in supporting research on women and we shouldn't just exclude them because they might get pregnant, aren't there pregnancy tests around and so on. So there is several pages near the end of this draft which addresses this one. And it isn't really clear to me the relevance of that in judging the past when that was not one of the objectives of NIH. So I just put that on the table as one other issue for discussion. CHAIRPERSON FADEN: We, and we can certainly talk about, and I agree with you that it's important and we've got to get clear in the report overall because it does come up in the contemporary project significantly as an issue. I'm violating my own rule, Anna is reminding me, which is to use the mic. If you'll forgive me, Duncan, I want to spend -- I want to focus on the risk one first. MEMBER THOMAS: I understand. CHAIRPERSON FADEN: And, Mary Ann, could you do me a favor and capsulized what we were saying at the break about why, what role the risk stuff in this chapter plays, you think, for the report overall, why it's important that we get it straight. MEMBER STEVENSON: Yes. Again we've jumped ahead and not look at the radioisotopes chapter. But in the present version there is no data, no case study, there are no data or case studies included in the isotopes chapter. So that in essence the case studies that appear in the children's chapter are carrying the day in terms of the committee's opinion as to the relative risk that we perceive to be associated with these myriads of isotope experiments that we can't possibly analyze. And so what we've done is gone to the worst case, gone to the children or fetuses where we know biologically the risk could be highest, try to determine what that risk might have been, the physical harm might have been, and address those cases as the worst case. So that's why, again echoing Duncan's concern, it's absolutely critical that we get some kind of consensus and comfort with the risk analysis being used. And I too have great problems with using the ICRP analysis. And sent a memo around to that effect in April. I don't know if it was distributed. Again, concern about that analysis being based on whole body exposure with a number of assumptions somewhat arbitrary in many cases being made, and I just don't think you can do that particularly when a number or actually the bulk of these studies that we're looking at in the children's chapter involve iodine 131 in particular. Which is unique in that when you look at mortality and morbidity in many cancers they sort of go one and one, if you're willing to wait the time which has not for very long. In thyroid cancer, secondary to radiation exposure that's not the case. In fact mortality is about a tenth of incidents. So it's a very different picture and it has to be treated as such. CHAIRPERSON FADEN: I would just elaborate about the significance here. It's not that we're in the business of doing risk assessments, in general we're not, but the issue and what Mary Ann has said is right, we are making a presumption that the evidence suggests that indeed most of the time these isotope studies that were done seem to have included exposed people to defensible levels, or whatever the right language is, I don't want to struggle with that now. And that the likelihood that anyone was harmed as a consequence is low. We need then to provide an evidentiary base for that, and we have several ways of building that case. But one of the critical ones is to look at the children's study for using the rationale that Mary Ann has just suggested since if the dose levels were the same in the adults who would be less biologically susceptible, and I'm saying this as a non scientist, to the potential harmful affects of radiation. And the kids fared a certain way, we can infer that the adults fared better. MEMBER STEVENSON: Right. CHAIRPERSON FADEN: Okay. MEMBER STEVENSON: I mean the other thing too, it obviously has great implications in terms of remedies, notification. CHAIRPERSON FADEN: Well, then I wanted to underscore the other thing. We are really really being asked, it was in the chapter from the beginning and we will return to it tomorrow, to make a comment about whether we want to recommend to the administration whether anyone should be notified in order to protect their health. This comes back every time and we keep struggling with a mechanism for doing that. But we have to answer it. If the answer is no, we need to say so. But we need to say something. And again the children and the people who were exposed while they were still fetuses are the most likely candidates for an answer of yes. So if we have to look at this population again carefully for that reason, so if our answer is to the administration nobody needs to be followed up to protect their health, here's our reasoning, or yes the following people do and here is our reasoning, go find them. But we really ought not to punt on this. We've been asked to provide advice and that's one of the reasons why we were constituted. With that, Nancy and Duncan, the question is what do we do now? MEMBER OLEINICK: Well, the first thing I would like just some information. We came back from the break and there were the results of two studies on our chairs. Now, obviously I haven't digested these completely, but basically they are two risk analyses of the Vanderbilt studies. I think these come from --where did they come from? MR. GUTTMAN: Basically it's very simple, the Oak Ridge people had submitted a study, and the reps, that is the Vanderbilt -- CHAIRPERSON FADEN: Yes, I think we will look at it, but it's not -- MEMBER OLEINICK: Oh, okay. I just thought somebody had perhaps gone through this and could come down with -- MEMBER STEVENSON: And we haven't made any conclusion about those studies. MEMBER OLEINICK: Okay. CHAIRPERSON FADEN: It's not staff work. You know, we gave information and analysis from lots of sources, all of which has to be digested in terms of claims -- and everybody else -- MEMBER OLEINICK: I just wanted to know where they were coming from. CHAIRPERSON FADEN: -- that's my understanding of where they're coming from. MEMBER THOMAS: It was. CHAIRPERSON FADEN: And it's all looked at? MEMBER STEVENSON: Yes, ma'am. CHAIRPERSON FADEN: Then we figure out our own view. Okay, Duncan? MEMBER THOMAS: Well, I was puzzled by your characterization at the conclusion of this chapter as saying that most of these studies were at acceptable levels of risk. CHAIRPERSON FADEN: I wasn't characterizing this study. I was talking about the general radioisotopes one, not the adult one, not this one. MEMBER THOMAS: Not this chapter? CHAIRPERSON FADEN: No, not the children's chapter. MEMBER THOMAS: Okay. Because I take quite a different conclusion from the text as it's written here. CHAIRPERSON FADEN: No, I'm sorry -- MEMBER THOMAS: That substantial numbers of these experiments exposed the subjects to quite high risks. And that's why the importance of getting our risk estimates correct is really crucial, if we're going to reach that conclusion. CHAIRPERSON FADEN: You know, here I think I'm speaking as one person here. I really feel at the mercy of those of you who have the relevant expertise. Tell us what to do and we'll do it. But I don't know what to do, okay. Pat? MEMBER KING: I just want to make a suggestion that -- MEMBER THOMAS: Use the microphone. MEMBER KING: -- oh, sorry. I was going to make a suggestion that those who have expertise in risk analysis with respect to radiation form an ad hoc committee for the purpose of straightening out the analysis to their satisfaction. Because there are lot of other problems -- CHAIRPERSON FADEN: With the chapter. MEMBER KING: -- with this chapter that needs the thought of the entire committee. And we can't contribute anything to that risk analysis that these people can't undertake, that I can think of anyway. CHAIRPERSON FADEN: I think that's -- and also just to make it clear, we will have a discussion later about outside reviewers whatever. This is not that kind of problem. If we need to hire consultants to do work, we hire consultants to do work. I mean this is not an issue of let's get outside reviewers and how we can do that and what's the view of personal, not personal, official, unofficial. This is different. This is, if we need technical assistance, we will buy technical assistance. If we need -- the question is can we find quick, quick technical assistance. But if we need technical assistance, should we just see who would like to be -- is that solution satisfactory to the three or four of you who are interested, work it out? MEMBER THOMAS: Yes. I'm looking at Mary Ann, Henry, Duncan, Eli, do you want to join that? Nancy, do you want to join that? We're obviously tagging the people with the expertise. Go figure this out and we will give you staff support. Can you get something to us quickly. If people need to be hired. If you need to ask Dr. Webster to do more work. Whatever you need to do, okay, do it, but quickly. MEMBER KING: So that we have some analysis that the committee members are comfortable with as an analysis that they're willing to say to the rest of us, this is an analysis, this is where we come out after we do this analysis. CHAIRPERSON FADEN: And there really are two steps. One is first everybody agree about the risk assessment analysis -- MEMBER KING: Right. CHAIRPERSON FADEN: -- and then somebody who looks at the notification questions and analyzes for us the tradeoffs involved in notifying people and not notifying people, maybe two kinds of experts, two classes of experts. Anna had a very good suggestion, if the five of you could sit at lunch today, we could maybe have a staff person sit with you, and decide on a plan of action. To do that would be very helpful, so we could leave today with some sense of who is going to do what next. Take advantage of the lunch break on that issue. Eli, did you want to comment? MEMBER GLATSTEIN: Could we just hear from Henry, I think he wanted to say something on this point. You were raising your hand there. CHAIRPERSON FADEN: Thank you. MEMBER ROYAL: Well, I basically agree with Duncan and Mary Ann that there are some problems with the risk assessment both with using the ICRP model. And the approach of taking the worst case is always peculiar approach if you want to accurately portray the risk, because knowing that one individual got (X) dose really doesn't tell you what the risk was from that experiment because you don't know whether or not that individual's dose was representative of the group that was exposed or not. And I have no idea how many people were in each of these groups, and so there is a lot of fact finding we still need to do in order to make any sense of the risk analysis. CHAIRPERSON FADEN: The only thing that I was just commenting is it's sort of scary that we're still here at this point with this problem. There's nothing to do about it except do it. So that's fine. Is everybody agreeable? So the five of you know who you are, meet at lunch, and then we're just going to move. If Dr. Webster could -- that would be great, that would be wonderful. And then we'll just see where we are. And this is just to get clear on --no, it would be really good at the end if you could say this week we're going to do this and next week we're going to do that, and so on, and we'll move on. So should we then go to other issues about the chapter that are in addition to the problem that the committee is unsatisfied with the basis or the technical work that underlies any description or interpretation of risk and harm. Okay, now it's open. I see Pat and Duncan and Ruth. All right, Pat, Duncan, Ruth in that order. MEMBER KING: I think it's important to get clear on the purposes of the chapter in addition to its link to radioisotopes and its link to notification. Because it deals with pregnant women and children we really have three classes of subjects here. That is pregnant women, fetuses, and children. And I think that there is a purpose in going here to say something about these three classes of subjects. The most important of which is that we've got, in my view -- well, I won't say that because I care a lot about the stuff that happened to pregnant women, but one of the areas that it's very clear, that leaps out, and that is there are no existing rules to my knowledge on institutionalized children because the recommendations, if I recall, of the national commission were never adopted. They were adopted, Michael? MR YESLEY: They were not. MEMBER KING: They were not, thank you. This chapter involves institutionalized children. And the purpose and one of things that I would like to explore is what we can learn from the facts of the research conducted with children in these institutions. Because I can see emerging from this, not a recommendation that the -- on behalf of the commission be adopted, but that it is unacceptable in light of all this history that we still do not have rules today that govern how you can -- with respect to institutionalized children. So I feel strongest about that lack. And I think I won't explore the purposes of pregnant women. I think one of the reasons that I think the chapter is important is, it is important to know about the health of pregnant women, not because of what happens to their fetuses, but because pregnant women need to know about their health. And part of this tells us about a history with respect to pregnant women that's very important and it does in fact tie into the IOM report even if we are not willing to endorse the conclusions of that report or disagree with it. It is a problem and so we ought to have that here. And it goes without saying that research on fetuses is a problem because it still exists, even though we have rules and regulations. So I think that it is an important purpose of the chapter is to get additional information about fetuses and to build that into lessons for the future too. CHAIRPERSON FADEN: That's very helpful, thank you. Duncan? MEMBER THOMAS: In comparison my point really seems like a small point, and I raise it only because there seems to be an objection to it, and if there is an objection to it, then I'd like to see it discussed in that case. If people are already persuaded by this point, well then hopefully we can move on. I noted in my comments that there are repeated references, I counted four in the previous draft, I haven't carefully studied this draft to see whether all four are still there, but repeated references to the extent that it's scientifically inappropriate to use institutionalized children as controls. Scientifically, not ethically inappropriate. And I offered a whole series of reasons why under various circumstances it might be quite scientifically desirable to use them as controls. Not ethically, but scientifically. So if anybody really has objections to that point, then I'd like to hear them. If they're accepted, then I would like to see it incorporated in the draft. MEMBER KING: Duncan might be interested to know that the national commission found them both scientifically necessary sometimes and ethically acceptable to involve institutionalized children, even institutionalized children who were mentally retarded institutionalized children in some research under careful conditions. MEMBER THOMAS: Thank you. MEMBER KING: It wasn't adopted because people didn't like it, but that's what we found. MEMBER THOMAS: Okay. CHAIRPERSON FADEN: Henry, is this on Duncan's point? MEMBER ROYAL: No. CHAIRPERSON FADEN: No. Then I'm adding you to the list, if that's all right. Ruth? MEMBER MACKLIN: In Duncan's initial comment I thought he was going to come back to that just now, which he didn't, and I wanted to comment on the women in research. Could I just ask Duncan to state again what his concern was there because I wanted to address it, but maybe I forgot his concern in the interim? MEMBER THOMAS: Well, I'm puzzled and left at a loss as to know what to believe myself as to whether faced with a national initiative that women's health needs are understudied and ought to be given national priority for funding. Whether if some of that research to accomplish this national aim involves risks to women or their offspring. Whether it is appropriate to make an across the board exclusion of women who may have unrecognized pregnancies and therefore at additional risks that we should be concerned about. And, you know, I thought that that was really quite an appropriate exclusion to make until I was educated by Susan on this point, who I think feels quite differently from me. And I for one haven't made up my mind on this issue and we, I won't say came to blows over this particular protocol, but that we had a rather spirited discussion on the point. MEMBER MACKLIN: If you haven't yet done it, in your leisure during your sabbatical, I recommend that you read the IOM study that Anna and Ruth were two of the three editors, and I was on the committee. And not to, you know, what was said there, the concerns about women as subjects, as you've stated it, one of the conclusions was women should not be viewed as "vulnerable" and pregnant women should not be viewed as "vulnerable" subjects. So quite apart from the need to get information about women and pregnant women that would be health related information, there is also the question of who is the "vulnerable" subject. So the exclusion somehow, and the language of the regulations, the federal regulations, includes pregnant women among vulnerable subjects when it's really concern for the fetus or the future child. So that part I think needs to be made abundantly clear. The fact that women may get pregnant or are in a permanent state of pre-pregnancy, as people have put it, is not to acknowledge or recognize that there were very many people who successfully avoid pregnancy, who take steps to avoid pregnancy. So that it was overly protectionist and overly paternalistic for regulations and drug companies to lump together, as traditionally it has been done, women of child-bearing potential. Which usually means pre menopausal and not surgically sterilized. Now, having said all that, what the chapter I think need to do is to distinguish between the risks that existed back then and what we would hope or to try to take steps do not exist now because of the emphasis on informed consent. What the IOM report concluded was the enrollment or participation of women of child-bearing potential or women actually pregnant women should be the woman's decision but subject to a great deal of scrutiny and circumspection with regard to informed consent. That is a great deal more attention to the consent process. I don't mean the disclosure, but the consent process. Now, I think what we probably could do more strongly than exists in this chapter, is to point out that what was inappropriate then in the inclusion of pregnant woman was inappropriate precisely because of the very poor consent process that existed then. And even though we may have some qualms or questions about the consent process today, the conclusions in the IOM report which are prospective are that care should be taken and the process should be improved. So we need to say that there is no inconsistency in condemning the inclusion of pregnant women in the past given the fact that informed consent was either non existent or minimal at best. No inconsistency between condemning experiments, radiation experiments that may have harmed the fetus in the past, and at the same time endorsing the inclusion of women including pregnant women today. MEMBER THOMAS: I like all that language. I mean it makes eminent sense to me. And it's what I find lacking in the present draft. It's just not that clear. There is also an element which Mary Ann explained to me better than I could now over the break, that there is an element of retrospective judgement here that she senses at least. And we're applying a national priority today for inclusion of women and minorities in research to judge the selection of subjects in the past. Have I captured your thought adequately or am I misrepresenting it? MEMBER STEVENSON: No, I guess what my concern was is the chapter built itself up to sort of condemn the research, and then at the very end folded back on itself and says well actually all these regulations were drawn up, protection was afforded these people, but now we think that's a bad idea. I mean it can be at least interpreted that way. I think it has to be carefully worded otherwise it sort of ends up nowhere at the end of the day. MEMBER MACKLIN: See, I mean I agree with that, and we have to fix the wording, but the protection, I mean Pat's comment here is very important. You've got two different subjects, two individuals who stand to be affected. I'm going to be very careful with my words, okay. You've got the pregnant women and then you've got the fetus or the child to be. The protections were all protections geared at the fetus or the child to be. MEMBER STEVENSON: Right. MEMBER MACKLIN: The regulations or the change today and the rethinking to seek to insure that research is done that will yield results that can be beneficial to women. MEMBER STEVENSON: Right. MEMBER MACKLIN: So it's the complication of having these two individuals potentially affected embodied in the same biological entity. MEMBER STEVENSON: It might be the regulations were really geared toward protecting the fetus, but meanwhile potentially deprived the pregnant women. MEMBER MACKLIN: That's correct. MEMBER STEVENSON: And I think that's the benefits -- MEMBER MACKLIN: Potentially deprived women, that's right. MEMBER STEVENSON: -- of the research. MEMBER MACKLIN: That's right. Women generally or pregnant women who have different metabolism and other kinds of problems that occurred during pregnancy. CHAIRPERSON FADEN: I think it would be important to point out that insofar as some of the studies with pregnant women were really intended to advance an understanding of what could go wrong in pregnancy that could harm the pregnant woman. That was good, you know. I mean it was not that we want to say it was bad, that people wanted to do research to eliminate better how an obstetrician should manage the medical care of pregnant women. We don't want to say that was a bad motivation. We want to say, just as we want to understand better how to care for someone with cancer, we want to make sure that people know well, physicians know well how to care for the complications of pregnancy when they occur. So that part we don't want to step back from, and that's why it has to be sort of carefully, like everything else here, it has to be laid out in a more refined fashion. I've got Henry and Pat. Pat is your point on the women? No. All right, then we'll proceed with Henry and then Pat. MEMBER ROYAL: I also noted the apparent contradiction between all of the urgings to be careful about doing research on pregnant women and children and at the end when then says well we shouldn't discriminate against them. I think it can be written in a way that makes sense, but it's not currently written in a way that makes sense. The chapter, particularly the beginning part of it is very risk aversive. It talks a lot about doing research when you're uncertain about things. And it really makes this very strong argument about not taking a risk when you don't know what the uncertainties might be. What's not considered is what I call the risk of risk aversion, and that is if you're too risk aversive in medical research, yes you're going to have those populations avoid the risk that they might have to bear if they participate in medical research, but they are obviously also going to be denied the benefits. So the more you trump up the risk aversion, the more you're going to change the risk benefit ratio and less research you're going to do. So I found that to be a troubling thought. The other thing is that there are statements in here that just are overtly untrue. Let me tell you about two of them. CHAIRPERSON FADEN: That would be helpful. MEMBER ROYAL: One is that current standards -- CHAIRPERSON FADEN: Where are you? MEMBER ROYAL: Oh, I'm sorry. Page 3, line 23 and 24, and this is the April 27th edition. It says "Current federal standards require heightened scrutiny for research and showed it effectively banned its use in women." That is not true. There are -- CHAIRPERSON FADEN: In pregnant women? MEMBER ROYAL: -- in pregnant women. There are different mechanisms by which you can use radionucleides in people. And I think it's 20 C.F.R. that is what the FDA's rules are for drugs that have proven to be safe and effective. And it's true that under those rules, 20 C.F.R. you cannot use radionucleides in pregnant women. But there are other mechanisms by which you can use. So under those rules you can't, but there are other mechanisms that you can go through. And then the other statement that's just hard to believe is there's a statement in here that there's a 34 percent risk of hypothyroidism. The hypothyroidism is very different than cancer induction, what's called a deterministic effect, that is it has a threshold. You need to get above a certain dose before you start seeing hypothyroidism. And the dose that you have to get above is a few thousand rads or rems, and to my knowledge none of these studies come anywhere close to that kind of dose to get over the threshold. And I have no idea where this number came from, but it's really untrue. CHAIRPERSON FADEN: I'm sure you wanted to make sure that was publicly stated because the draft floated around somewhere. But we know the risk stuffs. For what it's worth the risk stuff in here is going to be redone. So the whole world can know that. However it ends up, it ends up, but the risk stuff in here -- I'm sorry, however it ends up, it ends up, but the risk stuff in here is going to be redone, the estimates to risk to the women and their offspring and the children will be redone. However, whatever the new conclusions will be interpretations will be able to have to say. Okay, Pat, yes, you're been waiting, thank you. MEMBER KING: This is a total different point. CHAIRPERSON FADEN: Fine. MEMBER KING: Okay. I've already mentioned this with respect to the chapter that we discussed previously, but I want to raise in here too. All these chapters speak most to the question of consent. They speak less well to the question of who was selected to be the patient or the subject. And in the Vanderbilt study which is included in this chapter, I was looking for and I actually, to tell you the truth, don't remember what the data is, but I was looking for information about who these roughly 2,000 women were. What is here is that they were outpatients, it looks like, or maybe have been clinical patients. This is a university hospital. and so what I would like to have at least factually, and I'm prepared to make some conclusions from what I see from the facts, some information that even within the category of women and children, women as well as children, we need to have some discussion of why these children were selected. Now, I start off with children were selected -- CHAIRPERSON FADEN: There is one thing -- MEMBER KING: -- institutionalized kids. Why these women, pregnant women, were selected -- CHAIRPERSON FADEN: -- actually on page 46 there is discussion. Look at page 46. I know there is one paragraph. We should look at it and you should say, Pat, how it needs to be augmented. MEMBER KING: That's not it exactly, page 46. CHAIRPERSON FADEN: It's at the bottom of 46 and it's at the top of 47. It is beginning of the factual information that we have -- that is the factual information I assume that we have about Vanderbilt. It's line 15 on 46 and it continues to the top of 47. MEMBER KING: Right. It says they were young clinical patients, respected physicians -- CHAIRPERSON FADEN: And they were poor. MEMBER KING: -- and they were poor. And I think that the lessons that we have to draw with respect to the pregnant women and the lessons that we have to draw with respect to children have to explicitly address the question of why these women, why this cite. CHAIRPERSON FADEN: We know they were poor white women is basically what we know. MEMBER KING: That makes it wonderful. CHAIRPERSON FADEN: Right, that's what we know. MEMBER KING: Because I don't want to have people reminded of what Barbara told me during the break and what Ruth just said, I don't want people to think they're vulnerable because you're black all the time, or because you're Navajo. You're vulnerable because you live in the country and you're disadvantaged, and people ought to understand that. And this is a good place to make those points. And if we know most of them were white women, I would want to state it because I want white women to know they're vulnerable too. CHAIRPERSON FADEN: Yes. With what we know, it's in the footnote, they were exclusively white women. There was a study decision made -- MEMBER KING: It's even better than I thought it was going to be. CHAIRPERSON FADEN: -- they were poor white clinic patients. And I'll swear there is somewhere in here and I don't know where it is, maybe Kathy can tell us, I know it's in here somewhere, there is three lines or four lines that says we don't know very much about the characteristics of many of the children in the other studies, women in the other studies. I mean here we know, and a couple of other places like obviously Fernald and Wrentham, we know something about who these -- the backgrounds of these male adults and children. In a lot of these we don't know if they were clinic patients or private patients or poor people or not poor people or what their ethnic background was -- MEMBER KING: Well, what I'd like to do -- CHAIRPERSON FADEN: -- but where we know it we can comment on it. MEMBER KING: -- it's in the footnote on that page. That's where the statement is made, 115. CHAIRPERSON FADEN: Yes, there's a line that says we don't know, we don't know much about who they were. MEMBER KING: But what we want to do is someplace at the end of this chapter, at least I'm interested in doing what we did -- what I'm interested in doing a little bit what they started to do in the preceding chapter, and that is when you had a summary statement at the end, there was a bullet about selection of subjects which I would revise by the way with respect to the prior chapter, but at least there was a bullet that entered the conclusions about selection of subjects. And I think that then we might explore what we might recommend in the future or how we might look at this in future research with respect to these issues. CHAIRPERSON FADEN: I would like to make a comment about the first part of what you said with respect to this chapter talks mostly about risk. I actually think this -- MEMBER KING: -- consent -- CHAIRPERSON FADEN: -- I actually think this chapter talks mostly about risk. MEMBER KING: -- risk. CHAIRPERSON FADEN: And the consent stuff is overlooked also. And I very much liked what you said, Pat, in the beginning, there's three reasons, modern reasons, why we would be interested, regulatory voids or where there are controversies currently, the fetuses, institutionalized children, and clinical research on pregnant women. But it also is evident that this is a chapter largely, if you put it in therapeutic research which is under-developed and maybe should even be dropped, my proposal is we drop it, that this is largely a study about research on children and pregnant women where they do not stand to benefit, okay. So this is that very tough issue which we struggle with generally. Thank you, we've got an interesting answer on that comment. That we struggle with generally which is particularly with respect to children. MEMBER KING: Risk. CHAIRPERSON FADEN: Under what conditions can you do non therapeutic research on children. There is a regulatory solution, but it's contested and people argue over it. So this remains a very contemporary question. People struggle with who has the authority to allow people who can't consent for themselves to be research subjects when they don't stand to benefit medically, when it's not an alternative for their medical care. And that's what Wrentham is about and that's what Vanderbilt, no, not Vanderbilt, excuse me, but the Fernald school is about, and indeed all the children studies that are reviewed here. So in this category we know there is a contemporary debate about whether it is minimal risk, or can be considered minimal risk, to expose healthy children to radiation for non therapeutic research purposes. So this is, you know, an important project. Now, the issue that Sue and I were briefly discussing before, the risk thing is very relevant because in principle there is a problem with doing research on people who can't consent for themselves when they don't stand to benefit. It is more a problem the riskier the risk becomes in at least some people's analysis. So there is a connection conversely when you do research of this sort. The burden is very very great, and this is what Ruth was saying, to make sure that the risks are very very low because the people can't make the decision themselves whether they want to make the tradeoff. In the case of the pregnant women they weren't given the chance because those were the practices of the day. But the children never can, never can decide gee, I'm willing to be altruistic and take on this level of risk. So the burden is very great on the medical community to make sure that the risks are very very acceptable for you, whatever acceptable is. So I think that's an important way to cast the study overall. And I would like to put a proposal out and see how the whole Committee feels. That we forget about the therapeutic research and concentrate on the non therapeutic, the tracer studies, since the other part is under-developed, we're short on time, and all the interesting questions that we've surfaced so far fall in this area. Is that all right with everybody? That would be good guidance to staff and would make staff's life a lot easier, to let go of that -- MEMBER STEVENSON: So are we talking about dropping therapeutic in both children and pregnant women, okay. I meant the only thing I would raise is, I mean I agree because I'm having problems with it, but within that therapeutic category, the nasopharyngeal appeared once again and we've been dancing around that topic for about three meetings now, so are we going to address it or are we not going to address it? CHAIRPERSON FADEN: That's a big problem. I hadn't thought about that one. MEMBER KING: First of all, your basic point is still good. There may be a reason to have to address this issue that would mean we have a section devoted to it, but would limit what we have to say to what we decide we want to say -- CHAIRPERSON FADEN: To that -- MEMBER KING: -- but the rest of the chapter could concentrate on -- CHAIRPERSON FADEN: -- yes, work with pregnant women and kids. What I was envisioning is you have it in the introduction say there was research done that was therapeutic and certain benefits -- study the committee didn't look at it and blah, blah, blah, blah, blah, and then focus on this. Yes, I don't know -- MEMBER KING: It could still be done. CHAIRPERSON FADEN: Just a box and the committee say, you know, one of the studies that has come to the public attention is, it was a therapeutic study and here is the committee's take on it. Handle it that way because I think we cannot ignore it now that it has been brought so often in letters and so on to the attention of the committee. There's no text on that here yet. MEMBER KING: Yes there is. MEMBER STEVENSON: Page 26, 27 and 28, actually going into 29. CHAIRPERSON FADEN: That's right, that's right, there is, okay. So is that proposal with that modification agreeable, that we don't have a full scale examination of therapeutic research in this area, but that we do pull up in this nasopharyngeal area because of the attention that's been given to it publicly? MEMBER THOMAS: I like that suggestion. The only difficulty I'm having with the nasopharyngeal is it's placement in this chapter means that we can't address the parallel nasopharyngeal studies in submariners. And I hate to see that one ignored, but I don't know where to put it. In the structure of this report I keep coming back to it and I don't know what to do with it. CHAIRPERSON FADEN: And they're also very different kinds of studies too. MEMBER THOMAS: They're different kinds of studies, but both of them could be used to address what I see as one of the gaps here of the sort of standard clinical trials of therapeutic irradiation. CHAIRPERSON FADEN: Okay, let's look at the table of contents. Does anybody have a suggestion or shall we just work away at it? MEMBER OLEINICK: Well, it's certainly not total body irradiation, but it is therapeutic irradiation, and it could go as a section in that chapter if the chapter were somewhat renamed to include total body and other therapeutic irradiation, but that would be the only example there of that. CHAIRPERSON FADEN: Well, I mean that's all right. Okay, so that's another alternative. We can write the box and see where it fits best. I mean that's another alternative, right? MEMBER THOMAS: I think that's a good idea. Let's try to find a place for it, yes. Let's see what we have to say about it and then figure out the best place to put it. CHAIRPERSON FADEN: Okay. All right, so we'll do that. So now that the floor is open again for comments -- MEMBER THOMAS: I meant here must be many, many, many other examples of therapeutic irradiation other than the TBI. And including this period that we're looking at. I mean certainly today there's oodles of such studies I would think, so -- MEMBER OLEINICK: There are, I mean I imagine there are, but I think we elected not to go through the whole universe of therapeutic irradiation. MEMBER THOMAS: But I mean it turns on this question of the benefits of radiation research, right, which is presently addressed in chapter, part one, chapter one now, and that's essentially the only place where it's told. And it's told only in a few, you know, two or three pages there, that's it. So I think we could still -- MEMBER KING: -- radioisotopes MEMBER THOMAS: -- yes, you're right, radioisotopes. But there of course it's just isotopes. So nowhere else do we talk about radiotherapy. CHAIRPERSON FADEN: I think -- MEMBER THOMAS: It's not just the benefits I'm trying to get across, it's -- CHAIRPERSON FADEN: -- it's a very large world of research -- MEMBER THOMAS: -- yes, what it's like to be in a trial. CHAIRPERSON FADEN: Right. Mary Ann, did you want to comment? MEMBER STEVENSON: No, not really. I'm trying to think of where to put it. CHAIRPERSON FADEN: Let's be realistic. We cannot now, we've revisited and dropped and revisited and dropped the issue of whether we wanted a separate chapter on whatever we're going to call it, therapeutic research with chapter on radiotherapy research, whatever the right technical term is. Most of the time we thought about radiation oncology was the most obviously example with the nasopharyngeal. You've got other medical problems that were clearly addressed, attempted to be addressed by radiation therapy and where research, clinical investigation was conducted. We decided not to do it and we can't do it now, okay, we can't add a new chapter now. So the issue how to handle both the nasopharyngeal thing in particular where we have two kinds of studies and they are quite different, they just are using the same intervention, they're different, and a general question which we keep revisiting of whether the benefits, the products, the usefulness from the perspective of medical care that has emerged from radiation research is adequately enough handled in the draft, and what we need to do more or better. And I know that their comments have been coming in. My own view is this is better than the last time, but we still have to do more and better. Ruth? MEMBER MACKLIN: Yes. We're discussing where to put the nasopharyngeal, and Mary Ann points out that it's been brought to our attention several times, and it was oh yes, of course. I would like to be reminded why that is important and why it's been brought to our attention and why it's an exception that deserves to be addressed in the report even though we've decided we're not going to do all the others, and we agree we're not going to do all the others, why does this deserve to be an exception to the conclusion that we've made. And that might help us decide where to put it. CHAIRPERSON FADEN: Fair enough. That's right. Dan? MR. GUTTMAN: This is probably not -- but it seems this fits into the discussion that's resumed this afternoon, is there is some sense when you look at all the things that look like whatever -- of reasons, right, they're questionable. There are instances where people may have been, you know, taking advantage of reasons that are arguably non therapeutic, and the question is why is there, you know, an argument, and that's a separate set of questions. But when you look at the part two case studies -- CHAIRPERSON FADEN: This is therapeutic though. MR. GUTTMAN: Yes -- MEMBER OLEINICK: -- why do we have to deal with it -- MR. GUTTMAN: Right. MEMBER KING: Let's be crass about it, people are upset about there, there are newspaper articles about it, people have written us letters about it. Is that a reason enough for us to comment on it at this stage? That's Ruth's challenge, okay. CHAIRPERSON FADEN: It is a concern to several groups of people. And what concerns the public we have taken very seriously. So that's part of the argument, where people have brought problems to us from the public, we have made efforts to respond to those concerns, that's part of the function of an advisory committee. This is in the category of issues that have been brought to our attention by concerned members of the public that does fit in our charge. And there is not a charge issue here because this is human radiation research that's of concern to some members of the public. That's the backdrop. Nancy and Duncan, I'm sorry, Nancy and Duncan? MEMBER OLEINICK: I think one of the arguments for including this, if it's possible at this stage, if it's not possible I guess, then it doesn't get done, but one of the arguments for doing it is that this is a population of individuals who may need to be notified. May, I don't know, we haven't really drawn that conclusion yet. But because of the doses involved and the potential for dilatory for cancer, brain cancer, that it is a population that may come within that frame work of notification, I think. MEMBER THOMAS: I was going to say essentially the same thing. The reason for including this is that it is of all the experiments that we've looked at, this may be the only one, at least on the medical side, or at least one of the few for which there is a potential for a demonstrable level of risk. Arguably fairly substantial, although I don't want to get into a quibble with committee members about what I mean by the magnitude of substantial -- CHAIRPERSON FADEN: You can do that to your satisfaction in your subcommittee at lunch. You can have indigestion together over that one. MEMBER THOMAS: What we are hearing from the public as well as from some scientists that maybe, you know, a substantial number of people were indeed harmed by this experiment. Again, not to get into the question of net benefit which Henry keeps raising, and it's a very valid point. So I think that it will help animate our discussion about notification and the merits of, you know, neurologic follow-up studies that we will get to the concluding chapter. CHAIRPERSON FADEN: May I make a proposal to add to the work of this subcommittee. Could you include the nasopharyngeal studies in -- MEMBER THOMAS: Our discussion. CHAIRPERSON FADEN: -- your discussion -- you send stuff out for another round of expert evaluation, would you think about whether that needs to be done as well. And could you also think about the prisoners. We're thinking ahead towards the notification and any recommendation we might make about follow-up studies that where any recommendations turn in part, not in whole, but in part on estimates about risk. Phil, do you want to join the subcommittee? It's up to you. You can decide at lunch. By where you sit, you'll go with your feet. Anybody who wants to deal with this problem is welcome to sit at the table where the other people are sitting. Get a table that's big. Is that all - - MEMBER THOMAS: That's an eminently suitable approach to that problem. I just want to point out that the concluding chapter is not the place to introduce the nasopharyngeal. We've got to get the facts out beforehand. And if we're going to rely upon it as the case study with which we're going to talk about the notification, then the facts have to be introduced somewhere in part 2. CHAIRPERSON FADEN: So the answer to Ruth, see if this is satisfactory, is there are two arguments. One is that we have made an effort throughout the life of the committee to respond to concerns from the public where they fit in our charge and this is a concern to us raised by members of the public and it's in our charge. And the other is we have this responsibility to make a comment on notification. And while there may be other studies out there that also involve radiotherapeutics that we don't know about where notification might also be appropriate, this one has come to our attention. At least some members think it is a candidate for notification or medical follow-up. And therefore we need to -- MEMBER MACKLIN: And it's a candidate presumably because of the level of risk -- CHAIRPERSON FADEN: -- correct. MEMBER MACKLIN: So there I think maybe that element should be included. CHAIRPERSON FADEN: And it may pan out that it's not after they've looked at it, but it is a candidate for consideration. MEMBER MACKLIN: Right. DR. LEDERER: But the rationale for its appearance in this chapter, I mean needs to appear. It needs to be made explicit that we are responding to public concerns and that there -- MEMBER MACKLIN: Otherwise why are we -- DR. LEDERER: -- because it's somewhat mysterious, a light appears here, and what point a reader should draw from it. MEMBER MACKLIN: -- well, no I think it's the other point here actually, the notification point, because it's children. That is, the likelihood that there will be long term consequences and the need for notification when there are long term consequences is going to arise mostly with children. So that part is in here and it's in the children's chapter for that reason primarily I would think. DR. LEDERER: I mean I don't disagree with you, but I think this could be much more explicit. CHAIRPERSON FADEN: We have discussed several times needing to provide a rationale for why a case study was selected. What's missing is the introduction to the section. There's supposed to be an introduction to each section including an introduction to part 2 which lays out why these case studies were selected. So that before the reader gets to them, presumably we've already oriented, explained ourselves to the reader, why we picked the case studies we picked. And that's a very important brief section, but very important, had not yet been written. The committee has to look at it. And we could also --we need to lay out the reason why every single one of these is here, and if there's a special case for a section within one, we can also lay it out in that preface. This has been a very good discussion on children. I think our position both for the rewriting to continue on the non risk contingent parts of the paper at the same time that some of us will solve the technical problems, and the whole committee will make determinations obviously about what the risk means, but you will come to us with a technical assessment that all of you are comfortable with. And if you end up with disagreements, bring us to rival technical assessments, whatever you need to do. May I suggest that we break for lunch. Before we break for lunch we have very much homework, which is that Jonathan and Valerie have given over a last item this morning to producing something for us. Do we have it to distribute, Anna, Jonathan, Val? Jonathan or Val, do you want to make any comment about this before we go read it or should we just go read it and it's self-explanatory? DR. MORENO: I need to have my lab teacher, Mr. Katz, help me out, but -- CHAIRPERSON FADEN: Excuse me, could we just have your attention for one more minute and then we can break for lunch. DR. MORENO: The documents that you're getting are two kinds, well three really. One of those there is a general attempt to, as Pat asked us to do, to lay out the case on behalf of the judgment that in a particular agency at a time there were, and now I'm worried about the language I'm going to use, there were statements that looked an awful lot like policy, and the basis for those judgments. And the second document is a revision of the three bullets we talked about yesterday in line with the request that they be tied to specific agencies or departments in the federal government. And the third is a denser version of the documents that were interpreted at length in chapter 2. CHAIRPERSON FADEN: So they're basically-- DR. MORENO: The bullated piece item is the memorandum that's attached to the top of the second set. There are two sets, but three different items in the two sets. One is the argument, two is the memorandum that says this is the revision of the three bullets. It's four numbers, four numbered paragraphs. And the third is the condensed citations from key documents. CHAIRPERSON FADEN: And the third is labeled "Appendix," okay. The third page says appendix, is that right? MEMBER KATZ: Which order do you want us to read them in? MEMBER MACKLIN: Does it matter how many documents -- that's the confusing part. That's the only thing -- DR. MORENO: I think that the -- don't worry about the appendices unless you're obsessive, which is probably the case. Start with the italicized, the pages that have the italicized paragraphs on them. That's I think the key argument. CHAIRPERSON FADEN: Okay. So, yes, I'm sorry? DR. LEDERER: Is there a section about articulated standards for consent from patient subjects not involved in high risk research or just for patient subjects in general? DR. MORENO: We think that we can make it -- we can say some things about that. We can't say very much about that. The argument of chapter 2, if your call is that, in this current draft, is that these statements in that period of time, the mid '40s to the mid '50s, late '50s were mainly couched concerning patients in terms of risk. So higher risk research for patients is the key focus of most of these policies. MR. GUTTMAN: Jonathan, answer Susan's question with the same evidence that Susan is interested in, Wilson -- DR. MORENO: Some, but not all of the same evidence. Some of the evidence pertains to patients in high risk research may be construed as also pertaining to patients in low risk research. We had this -- DR. LEDERER: But isn't that -- DR. MORENO: -- for the last year and we-- DR. LEDERER: -- the basis of the conclusions of chapter 5, namely that they would have known? DR. MORENO: They should have known by analogy. CHAIRPERSON FADEN: Okay, and not because they had articulated standards. DR. LEDERER: Okay, I just wanted to make sure of that distinction. CHAIRPERSON FADEN: Only because they had sort of half baked articulation. In other words what you can do is read the two AEC letters, the Wilson letters, and draw your own conclusion about -- they're in there, they're in the fat one. And also in chapter 2 which we all have, about how far you want to go with respect to research on patients in general. DR. LEDERER: Okay. CHAIRPERSON FADEN: Is that the kind of conclusion where we are Jonathan, that the case is strongest, most clear with respect to research involving patients where it's considered to be unusual or novel or something risk. DR. LEDERER: Right. CHAIRPERSON FADEN: And beyond that it's a weaker case and the only evidence comes from the AEC. But since the AEC is so pivotal, since it's the hub of the radiation staff, it's important. And it's only the AEC that kind of diminishes it because the AEC was at the core of the enterprise of interest to this committee. Ruth? MEMBER MACKLIN: But if we broaden both the language and the concept from policy to articulated standards, then the fact as we've discussed them is well documented, but a lot of these people are sitting on the same committees even though the AEC had one trajectory that led to a policy, that DOD had another trajectory, these people talked to each other, spent time with each other, and served on joint committees where discussions took place. So if we're talking about policy, we've got to stick to the agency's. If we're talking about articulated standards, the should have goes to the question of whether these people talked to each other and discussed standards for the use of human subjects in research. So somehow I think that little link can be made to show that even though something happened in one agency, it wasn't unknown. DR. MORENO: It's the culture of medical research that cuts across the bureaucratic divisions. CHAIRPERSON FADEN: Culture of government sponsored research. MEMBER KING: If you call it in the culture, you send a different message than you do with articulated standard because culture gets you partly around the problems of agency, and I mean agency as an institution, but agency as who can act on behalf of others. CHAIRPERSON FADEN: All right, I'll tell you what, it's going to clearly be a difficult -- as it were after lunch. So don't -- DR. MORENO: Thank you, Nancy. CHAIRPERSON FADEN: -- we are going to resume at -- you know, it's closer to 1:45, I guess do we need that for the reading time? DR. MORENO: Yes. CHAIRPERSON FADEN: 1:45. (Whereupon, at 12:21 p.m., the proceedings in the above-entitled matter were adjourned to reconvene this same day at 1:57 p.m.) A-F-T-E-R-N-O-O-N S-E-S-S-I-O-N 1:57 p.m. CHAIRPERSON FADEN: I would like it if we could do this reasonably efficiently. But it would seem to me that we have spent on it -- let's reconstruct, yesterday we had an exhausting and exhaustive debate about what we could and could not say in chapter 2 about what standard to hold the government, not investigators, not the medical profession to in this period. The first thing that happened is that we edited those summary statements, and they have been revised in the fatter document, the top sheet, which we all had a chance to look at. The key issue, the --issue, that we were left hanging with was what can we make of the evidence for a claim about how formal or informal the standards or policies, whatever language we want to use here, were on the points at issue. So we've got three points, but only two are really covered here. And Jonathan and Val, you didn't do the risk one because that's pretty -- that was uncontroversial and the case was very good that the AEC at least had policies, effected the policies, and it's not a contested one. We're not too worried about that one, that one looks like it's in really good shape all the way around. So what was contested were the consent policies or the extent to which they were articulated standards agency by agency with respect to -- requirements for research funding are conducted, and we have three categories, healthy subjects, patients who were involved in, what's the language you used here, higher risk research, more problematic research or more whatever the word is, and then research with patients generally. Can we take the category first of consent from healthy subjects. You've all read this. Could you look at it again and see if you can accept the characterization in the italicized text or your proposed, Val and Jonathan's, proposed statements about how to characterize the documentary evidence with respect to -- can somebody -- I would like to hear if anybody objects or wants to change or challenge the italicized statements. These pages aren't numbers, but on the first and second page with respect to healthy subjects. Pat? MEMBER KING: This is a question of clarification. What do we mean when we say consent standard? DR. MORENO: I take it said to be a place holder for some notion of un-coerced participation. MEMBER ROYAL: And informed. DR. MORENO: I don't know what exactly to make of level of information. I got into a conversation with Captain George, and I don't know if he's still here, but pointed out that for example there is a tradition in the uniformed services that asking for volunteers for medical experiments, phase one. Phase two was now that you have volunteered here is what we propose to do. And this is one I think plausible interpretation. So that there is a two-step process and there was an implicit, I suppose, opportunity to decline at the second stage as well as the first stage, but the levels of information were different at each stage. So that's the kind of procedure that we're trying to capture an open space for. Lots of things went on that were construed as not coerced participation at the time. CHAIRPERSON FADEN: You either used the word "consent" or say that you had to have volunteers? DR. MORENO: The word "consent" was used also at the time. MEMBER KATZ: Jonathan, when you talk about healthy subjects, are you talking, are you including also healthy patients, are you also including in a certain sense healthy patients used in the total body of radiation experiments where in a certain sense they were in some respects healthy, but also used then for non therapeutic experimentation? DR. MORENO: I puzzled about that a little bit in the case of something like Fernald or Willowbrook -- MEMBER KATZ: Willowbrook, but even Cincinnati -- DR. MORENO: -- but what we're going for here is people who do not have active medical problems because that's -- MEMBER KATZ: Who don't have active medical problems? DR. MORENO: -- no active medical problems. MEMBER KATZ: Then I'm beginning to have problems because by the way that's not defined here what we mean about healthy, because I always thought about healthy patients as the astronauts, what is the -- DR. MORENO: It's clear from the -- these statements were made, the vast majority and correct me if I'm wrong, Valerie, with respect to the problem of recruiting people who did not have active medical problems. MS. HURT: Who were not in medical care. DR. MORENO: Who were not in medical care at the time, prisoners, soldiers in particular. MEMBER KATZ: And all these other things. Well, then I can only say about this, it reminds me either Goethe or Schiller who said (speaks German) "I hear the message but I don't believe it." DR. MORENO: Well, I'm not suggesting that these statements might not have been used, extended to other kinds of people, but it's clear from the origins of the statements that primarily the people who were involved in these projects, participating in these projects, were people who were not under medical care at the time. Frankly I think for the most part, Jay, they didn't want those kinds of people, they didn't want to have to worry about them. CHAIRPERSON FADEN: I'd like to just emphasize, we're not saying anything about whether these articulated standards, these standards were implemented or anything, it's just that they were there, okay. So when you say, Jay, that you don't believe it, we're not saying whether they did anything about it, all we're saying here is were there pieces of paper, yes, and how do we want to interpret the pieces of paper, as articulated standards or not articulated standards. People violate standards all the time or they don't implement then or they don't anything. All we're trying to do is establish whether, how strong a case can be made for whatever it is, now formal was the discussion or the position of the agencies on these rules for human subjects research. Pat? MEMBER KING: Then I think it would be not more accurate, but I would say less misleading, to say there is a strong case that there was a requirement of uncoerced participation (consent or a consent) what we mean as uncoerced participation for the use of healthy subjects (not in active medical care). I'll come to articulated in a minute. What I'm trying to say is that if you -- we ought to say what we conclude from there, and that was why I pushed Jonathan that he thought most of the time that where he saw consent that it was really talking about uncoerced participation. And that doesn't capture it completely either. CHAIRPERSON FADEN: I think it you want to go your route, Pat, why don't we just use the words that they had. And the two words they used were whether they should be volunteers or that they should give consent. Those were usually -- isn't that how it went back and forth, either the policy said -- DR. MORENO: Or sometimes informed volunteers. CHAIRPERSON FADEN: -- were informed volunteers -- DR. MORENO: The word "volunteer" is pretty ubiquitous in the armed services anyway. CHAIRPERSON FADEN: Right. There was a strong case that there be a requirement that healthy subjects in research be "informed volunteers" give their consent. You get the idea. MEMBER KING: Yes. CHAIRPERSON FADEN: Sometimes there is consent, sometimes you use informed volunteers. DR. MORENO: You all raised the question about the VA and the answer is we don't know. MEMBER GLATSTEIN: Did the VA actually carry out research on healthy subjects? DR. MORENO: I don't know -- MEMBER GLATSTEIN: Because I think it's kind of Catch 22, they had to have a diagnosis to be in the VA. DR. MORENO: -- I don't know that we have any evidence one way or the other. They could have --well, they might have been sick at one time on the books of the VA -- MEMBER GLATSTEIN: Yes, but the VA -- DR. MORENO: -- and they might have gone to them to recruit them later. MEMBER GLATSTEIN: -- yes, but technically the VA is only going to take service-connected diseases. DR. MORENO: Right. One could imagine somebody who was discharged from the VA hospital, and they call them up a year later, two years later and say would you like to do this. I don't know. I'm completely -- MS. HURT: Contract research. DR. MORENO: -- contract research? CHAIRPERSON FADEN: You have to be on the mic or we can't, it won't work, Val. MS. HURT: The 1958 general counsel's opinion is with respect to contract research. I don't know anything else about that, the research that was proposed, but I know it was proposed to be conducted by contractors. Whether it was in the VA hospital -- CHAIRPERSON FADEN: We'll pursue the VA, okay. We'll have to pursue the VA. DR. MORENO: Well, we tried to do that. There really isn't much to pursue. CHAIRPERSON FADEN: So all we can say is what's there. DR. MORENO: We can say that. CHAIRPERSON FADEN: The VA not, all right. Which is why earlier we're saying that where we have the most to go to the table with here are the other three agencies, AEC, the Defense Department and NIH. DR. MORENO: NIH, right. CHAIRPERSON FADEN: And NIH are the three where we have documents to deal with. So is the characterization with the modifications that's just been put in there acceptable, the first italicized one? We're going to use the terms that are there, and there was a requirement. And whether we call it a standard or what is it, there was requirement, and to me that's a standard. It was a requirement, okay. MEMBER KING: Well, I think that the idea is that the reason we're doing this is we have to have some understanding of how we make do, make a step about measuring, and so I don't care if it's requirement or standard or anything like that, so I'm comfortable with that. I just think that we should specify, if we don't use "consent standard" anymore, my problem about standard, part of consent standard, is taken care of. CHAIRPERSON FADEN: We use there terms, so we use the terms. This goes all the way through on the healthy subjects. Are people comfortable, are the committee members comfortable with the characterization for the AEC and for the NIH? MEMBER KATZ: As long as there really is a definition in here with emphasis on something. What to begin with, I haven't through it through yet, but I think we should include here what we mean by healthy subjects because healthy subjects I wonder about though I wasn't sure. As I said the astronauts and other kind of people recruited of the -- who are healthy and who -- CHAIRPERSON FADEN: Every -- MEMBER KATZ: -- that's really not what is meant and so we're in an entirely different ball park. DR. MORENO: No it isn't -- MEMBER KATZ: Okay, I'll modify -- DR. MORENO: It's a good thing the strike is over otherwise we wouldn't have an analogy. MEMBER KATZ: What? DR. MORENO: It's a good thing the strike is over or we wouldn't have a metaphor. CHAIRPERSON FADEN: Isn't it correct though that the contrast between -- usually the term that was used, which we avoided, was not "healthy subject," but "normal volunteer?" MEMBER KATZ: No no, that's not a good word either. CHAIRPERSON FADEN: I know, that's -- DR. MORENO: That's the way they talked then. CHAIRPERSON FADEN: -- how they talked about it. And it was often in contrast to patients. So your sense is correct, Jay. I mean what was intended to happen as best as we can figure out by this stuff was what they used to call the normal volunteer. DR. MORENO: The gray part, the gray area is this population of institutionalized people who are convenient and available as a study group. Under which circle in the then diagram do they fall. And that is an interesting philosophical problem and it is one that got them into trouble because the AFEB itself in the case of Willowbrook raised the question whether these kids were truly volunteers or not, and the answer they got was yes because they're wards of the state and the state volunteered them. So that is a matter of record. CHAIRPERSON FADEN: I was just about to raise the same example, Jonathan, because that can be put in to explicate Jay's concern. DR. MORENO: Right. CHAIRPERSON FADEN: That at the time there was a -- knew that it did apply to that, okay, that the institutionalized kids, but they then had wriggle their way around to see how they got it. DR. MORENO: Right. CHAIRPERSON FADEN: But they didn't say they don't count, their institutionalized persons and therefore they're not covered by this. They said gee, it should apply to them, have we satisfied it, and here's how we satisfied it. We may not like how they went about thinking that they satisfied it, but there was a view that they had to think about their requirement when they were supporting the work at Willowbrook. It wasn't like they said, oh these are patients, so they're outside of the orbit of our concern. So it's a little muddy. We're talking now about how they viewed the world, as best as we can construct it, not what we think they should have done or what they actually did about it when they implemented it. MEMBER KING: I assume that when we write this that we're not going to have the breakdown that Jonathan did for us, so part of the italicized which is the relevant part should carry throughout what you've got in part here. And that is that it ought to specify AEC and Department of Defense, and it ought to have a sentence about VA that is drawn from the data below. That's not in there. CHAIRPERSON FADEN: Now, we get to the -- are we all right with this then? I mean this going through to the NIH which is pretty straight forward. The NIH document also used the term "normal volunteers," didn't they? Isn't that kind of the term -- there they used the word "consent," right, and we'll get it. Okay, so now we're into Roman Numeral II, "Articulated candidates for consent from patient subjects involved in a high risk research." I don't know if high risk is the right term. DR. MORENO: Well, there were different terms that were used by the entities themselves. "Unusually hazardous" for example, "Higher doses for investigative purposes in the AEC." But it's rather clear in context that they're talking about risk related assessments of whether they could in conscious expose somebody to this material. CHAIRPERSON FADEN: Oh, good, Pat, we're up to that one. Is that summary paragraph right under the Roman Numeral II acceptable? MEMBER KING: Well, this statement really doesn't say. What is says is that the argument for asserting that there is a standard is weaker. That's an accurate statement for what I think that Jonathan just concluded, not that the case for consent. The statement should read that -- CHAIRPERSON FADEN: Yes, that it's the evidence that there was a requirement is weaker. MEMBER KING: Right, because we did the fact of what went on yesterday. CHAIRPERSON FADEN: I guess -- DR. MORENO: I guess the point of this statement, Pat, is that there's evidence of a cross cutting standard from one government entity to another than there is in the case of healthy subjects. Because certain of the agencies were interested in higher risk issues and others weren't. MEMBER KING: I'm sorry, Jonathan, truly it must be late afternoon and I didn't drink wine today deliberately, so it must be the lateness of the afternoon, but I honestly didn't understand what you meant by cross cutting. DR. MORENO: I'm sorry. What I meant to say is there does need to be something that embraces roughly the same time, say the late '40s, early '50s, the AEC, the NIH and the DOD. We have statements about this in the AEC and the NIH, we don't have something about this at the time from the DOD -- CHAIRPERSON FADEN: Why don't we just -- DR. MORENO: -- however, there's a however, in the case of the DOD, and we can even debate it elsewhere, there is lots of discussion about how much you can expose somebody to and lots of worry about maximally permissable exposures and so forth. I don't know what to draw from that. It's probably not enough. CHAIRPERSON FADEN: How about if we got rid of the first sentence in the italicized thing and got rid of the "while" and just start with "There is substantial evidence that the AEC and the NIH articulated a requirement for consent from patient subjects in higher uncertain risk research. There is no evidence from the DOD. DOD indicated -- from patient subjects," in this period we're talking about. MEMBER LEDERER: Is that only in the context of radiation or -- CHAIRPERSON FADEN: No, it's everything. For the AEC it's really isotopes in particular. We can say that for the AEC and all research at the NIH clinical center. It was the clinical center. MEMBER STEVENSON: It's intermural. MEMBER KING: Well, let me ask a question, I always have trouble with what substantial means now after we've made a strong statement that went before. Is Jonathan saying that with respect to narrow down the radioisotopes in AEC -- DR. MORENO: Yes? MEMBER KING: -- that the evidence is as strong, if not stronger, about a requirement for consent with, and I don't know what to do with "higher uncertain risk research" yet, than it was with healthy subjects? DR. MORENO: It's as strong I would say. MEMBER KING: But that's what we should say. I think I understand why you took out "weaker," but I think we need a comparative statement -- CHAIRPERSON FADEN: Why don't we just say it's strong. I mean there's good evidence. DR. MORENO: At least a strong, Pat, I would say. MEMBER KING: I think we should say that. DR. MORENO: But -- CHAIRPERSON FADEN: Okay, say strong, fine. MEMBER KING: So people understand what our reasoning was. CHAIRPERSON FADEN: Okay, yes. And then we can back it up with the documents there. And again we can use their language, the AEC called it, I forget what, and the NIH clinical center called it "hazardous experiments" or whatever. DR. MORENO: Unusual hazards. CHAIRPERSON FADEN: Unusual hazards. So they stipulated, it didn't matter whether it was radiation research or it was anything, it was unusual hazard and you had to get the patient's consent. And the AEC said if it's a higher dose you got to get the patient's consent. So we can say that. Is that all right then with those -- DOD says nothing, and the VA basically has that vague statement. That's all we've got, that's all we have. The question is where we go from this. We must make sure that we're all together on -- MEMBER KING: Well, the reason we come to those experiments that involve these issues, we have something by which to make the conclusions in those chapters I think. CHAIRPERSON FADEN: Now, what we haven't done, and Sue asked for this, what about the evidence for any kind of then existing requirements with respect to patients who were not in hazardous or higher risk studies? DR. MORENO: Well, you have the AEC letters that talk in 1947 that talk about consent and even informed consent, and even in one of the letters written, witnessed informed consent from patients and "human beings" is the other phrase that's used. MEMBER KING: Was that with respect to all AEC research? We don't know. I mean what do we know, is it unclear about what it applied to? MEMBER MACKLIN: There's nothing that indicates any constraints of qualification on the kinds of subjects, the kinds of work to which it would apply. MR. GUTTMAN: Actually we do. We have a document that we just got in two days ago, an interim. The context again was very clear. In January of '47 Stafford Warren gets together with universities who are going to be the basic core of the contract research program. And they decide they want to go ahead with this so-called clinical testing and that to do it they've got to have a "financial and legal opinion." And then they go meet with the lawyers, then the lawyers meet with Stafford Warren and then they come out with this Wilson letter. Now, a document we found the other day in Argonne, University of Chicago, includes an encrypted part of a letter from Stafford Warren which was an intermediary letter which says that the committee had approved the human research for Rochester and California right, Jonathan? California was where, you know, Stone was and Rochester was where Warren of course came from Rochester, so it was a very small community. And then in Warren's letter there was something, if you have it there, about this is a policy that will apply to approved programs for research for, what's the word "affiliated" with the AEC, Jonathan, we were looking at that last night? The question that was raised in this letter was, if someone at the Chicago, Billing hospitals is doing a human experiment but isn't getting AEC money, do they have to follow these rules. And the letter made clear that they were looking at legal -- it wasn't an absolute grand moral principle, but it was if these guys are intimately connected with the AEC, these guys should follow these rules. That was clearly a financial and legal definition of who would be covered. Jonathan, do you want to -- DR. MORENO: Yes, again although there is no indication in that material of any restriction on the kind of research on this particular point that's involved. CHAIRPERSON FADEN: If we're trying to get at what's going on, let's work backwards, okay. The DOD has nothing that speaks to research on patients and consent before the '60s, okay. The VA, we have this vague something or other, right. The NIH, as best as we can figure out, has nothing for patients in general except for this hazardous clause, okay. And the statement, the requirement is for the clinical center. There doesn't seem to be an extension to -- research again until the '60s, all right. DR. MORENO: Ruth, there's one qualification. CHAIRPERSON FADEN: What's that? DR. MORENO: The NIH does require consent from everybody, but they don't require written consent from everybody in '53. CHAIRPERSON FADEN: The requirement -- the document -- DR. MORENO: They're supposed to get consent from -- CHAIRPERSON FADEN: What's the document -- DR. MORENO: -- people in the clinical center. Well, this is to say, and I can hear Jay whispering in my ear, this is pretty weak, but what it means is you can't tie people down and do procedures on them. CHAIRPERSON FADEN: But what's the document that you're relying on for that, so we can see better? Is it the one that says -- MS. HURT: Group consideration. DR. MORENO: It's the group consideration from '53. CHAIRPERSON FADEN: Okay, so let's make sure that we have that because that's important. MS. HURT: And on page 3 -- CHAIRPERSON FADEN: Is it appended to this? DR. MORENO: Yes. MS. HURT: It totally described -- CHAIRPERSON FADEN: Why don't you read us the operative line? MS. HURT: And the document says "Information for patient, the patient or subject of clinical study shall be considered a member of the research team," blah, blah, blah, "each patient, each perspective patient will be given an oral explanation in terms suited to his comprehension supplemented by general written information or other appropriate means of his role as a patient in the clinical center. The nature of the proposed investigation and particularly any potential danger to him. After admission the patient shall receive information in keeping with the development of a sound physician-patient relationship." And then it goes on to say "With respect to patient understanding and agreement" -- MEMBER KATZ: What did it say about, could you read it again, before "physician-patient relationship?" MS. HURT: I'm sorry? MEMBER KATZ: Just the end? MS. HURT: Oh, it says that "After admission the patient shall receive information in keeping with the development of a sound physician-patient relationship" -- MEMBER KATZ: Well, that's quite a statement. Say nothing. MS. HURT: Well, then it goes on to say "Standard consent or agreement shall be used for surgery, anesthesia, other procedures ordinarily" with respect to what they ordinarily needed written consent for. And then it says "Voluntary agreement based on informed understanding shall be obtained from the patient and when appropriate from responsible next of kin when the approved investigation includes procedures which deviates from accepted medical practice. In all cases a notation shall be made on the patient's chart when in the opinion of the responsible physicians or of the advisory groups noted above a procedure involves an unusual hazard. The proposed procedure shall not be undertaken until the patient has voluntarily signed the statement." CHAIRPERSON FADEN: NOw, that's a little bit richer. MEMBER KATZ: It's what? CHAIRPERSON FADEN: It's a little bit richer. Even though I grant you, Jay, that you can -- MEMBER KING: It's not today. CHAIRPERSON FADEN: -- it's not today, Jay. MEMBER KATZ: Yes, it's always qualified physician-patient relationship, and that's quite a qualifier. CHAIRPERSON FADEN: But the point is that goes a little bit further than saying there's no policy on consent for patients. And somehow that didn't make it in the force that I think it should have into the chapter. Because that's, I think, a richer description and that can be taken as a policy statement for the NIH who says you don't need written consent, you're supposed to get something like consent -- allow for it. DR. MORENO: This isn't discussed in chapter 2 and it's also -- one, an excerpt from it on page 4 in appendix 2. CHAIRPERSON FADEN: So if we work backwards, the DOD is silent, we got that right. NIH we have just heard what they have with respect to research. We're talking about research with patients -- or whatever that special -- okay. So now we've heard what the NIH has to say. What we can say about the NIH is that they had this requirement and it's in their pamphlet for the opening of the clinic center, the group consideration document that is supposed to bound conduct for people admitting patients to the clinical center. For the AEC we have these two documents, okay. We have been stumbling over for some time as to what they're supposed to mean, the letters back and forth with respect to patients in general. It doesn't say anything in those documents that says only for high risk patients, it just says whatever. The confusion is, if we just get it out on the table, that at more or less the same time, and correct me if it's right, the three of you who know the documents better than the rest of us, at the same time the radioisotopes folks in the human use committee are not requiring consent except for this hazardous stuff. DR. MORENO: Right. CHAIRPERSON FADEN: Right. And they set up all these requirements. They're giving out the radioisotopes, and they don't have anything in their policy statements or requirements or whatever to give out the isotopes that says anything about consent except for healthy subjects or high doses, right? DR. MORENO: Right. CHAIRPERSON FADEN: At the same time that the AEC's two '47 letters say you have to have consent and in one case uses the term "informed consent" and in the other case uses the written documentation stuff. So what do we want to make out of that. Susan, how would you set it up, how would you characterize it? MR. GUTTMAN: Could I just add one thing? There is a third element which Ruth discussed, that's also the way in which the AEC treats the non therapeutic question because the '47 materials literally some of it says you can't do therapeutic experiments. CHAIRPERSON FADEN: That's correct. MR. GUTTMAN: And we also are giving out, we found in '53 when people -- MEMBER KING: You can't do therapy? CHAIRPERSON FADEN: Yes. MR. GUTTMAN: Not therapeutic therapy, right -- MEMBER KING: I'm sorry, I was -- CHAIRPERSON FADEN: And one plausible -- DR. MORENO: -- right. CHAIRPERSON FADEN: -- we kicked this around a little bit, and it almost looks like we're talking at cross purposes. On the one hand you have the two letters from the AEC that say you can't do research with patients, you can't do this clinical testing on patients unless there is a possibility of therapeutic -- remember this is in response to the plutonium war time experiments, and unless there's some sort of documented consent, okay. On the other hand we have these letters written to the AEC at about this time where the answers are coming back we don't do human experimentation. It's a little bit late in the '50s, we don't do human experimentation. Whatever the AEC is doing it's not doing human experimentation. And then we have the isotope division giving out isotopes, okay, to researchers all over the country saying the only time you've got to get consent as far as we are concerned is if you use a healthy subject or if you give somebody a high dose. MR. GUTTMAN: One way of reading the evidence is that there was something non therapeutic, and it could be a combination of what you and Henry and others have been talking about, something -- or what Mary Ann was talking about, there was some kind of constellation of things that was in non therapeutic research that somehow struck people as something that was a problem. And so from time to time they would say we don't do that, even though the right hand simultaneously, at some low level of risk, doing that as quite a routine process. MEMBER KING: It's not bizarre because if you worked in the government to not have the right hand know what the left is doing -- MR. GUTTMAN: Okay, well that's the answer. MEMBER KING: -- and the fact that they are contradictory things is not bizarre except in retrospect. It happens all the time. CHAIRPERSON FADEN: So then do you say that -- what do you say about whether they had any requirements for consent from patients in lower and non high risk studies, do you say they did? MEMBER LEDERER: Only at the NIH clinical center. CHAIRPERSON FADEN: No, but what do you say about the two AEC letters? MEMBER LEDERER: To me, I don't know how to reconcile the contradictions in the two letters. MEMBER KING: That's what you say. CHAIRPERSON FADEN: All right, so we simply say -- MEMBER LEDERER: I mean that's what I would say. CHAIRPERSON FADEN: -- AEC had confused -- MEMBER KING: Or you can again do what we did yesterday and try to give reasonable inferences about the existence of a requirement based on those data, on those statements. CHAIRPERSON FADEN: So we can do that. MR. GUTTMAN: There is a reconcile, but if you want to be a minimalist you could say that the '47 letters apply to the people that they were sent to, contractors. It's not the isotope licensees. That's there may have been some rationale that those millions of universities out there, as long as they didn't have legal responsibility and weren't going to be connected, they didn't want to impose themselves. There's still a great mystery as to why they didn't send them to more of the contractors. But you can find ways of breaking, you know. But then this goes to Ruth's question, are we looking at a policy or just a principle. What was articulated? If it's a principle, the principle was articulated. MEMBER LEDERER: Well, Could I just ask one question -- CHAIRPERSON FADEN: Yes. MEMBER LEDERER: -- Dan, about what to do with the letter that was sent out to contractors from the surgeon general to people like Enders? DR. MORENO: Right. MEMBER LEDERER: I mean isn't that - CHAIRPERSON FADEN: That's a DOD -- DR. MORENO: Right, but the way -- CHAIRPERSON FADEN: -- healthy subjects -- DR. MORENO: -- that's right, right. CHAIRPERSON FADEN: That's pretty clear under the surgeon general's Army thing that that's -- MEMBER LEDERER: That's just for healthy, okay. DR. MORENO: Yes. CHAIRPERSON FADEN: As best as we can figure it out, right. Because they don't weigh in. This is when Phil educated us bout the difference between the '70s series and the '40s series and Army regulations. I now know all kinds of things I never knew before. Okay, Pat? MEMBER KING: I'm struck by the fact that, and we should do part of this, of this need to be able to make sense out of everything. WHat I said yesterday about one of my problems in the report was, some things are not going to be made sense of, I mean because we don't have a complete record. We know that we've got incomplete data. We don't always know how to characterize it. That's okay to say, I think. Or it's okay to say these are the reasonable inferences and how the committee picked the one it likes best in terms of what it is willing to draw. CHAIRPERSON FADEN: Well, I think we've reached something like as far as we can go in characterizing what it looks like in the document requirement, and they vary from agency to agency. And what we can say is we can't quite figure out what the agency was requiring or not requiring with respect to was there -- patients and consent. It's clear what they required for the isotopes in terms of risk review. It's clear what they required with respect to consent from healthy subjects and from patients given very high doses. And we don't know what they required. Whether they did it or not is the next issue, but -- MEMBER KATZ: Ruth, this is an assumption we are making that we have incomplete data. Maybe we have complete data, maybe that's all the data that exists. CHAIRPERSON FADEN: We don't know that. MEMBER KATZ: No, no, I'm just saying the assumption of incomplete data has to be also carefully examined or known about. Because my hunch is that we also may have to -- it's a hunch, we may have the complete data. CHAIRPERSON FADEN: This may be all the AEC had. MEMBER KATZ: And it's very incomplete, but it's the complete data. CHAIRPERSON FADEN: That's a good point. It may be that the -- there are two rival hypothesis for the AEC, and could be three. One is the left hand didn't know what the right hand was doing. Two is Dan's point, that they were only -- this business about requiring consent that was in the two 1947 letters applied only to contractors, not to people you gave the isotopes to -- MR. GUTTMAN: Both are probably true. CHAIRPERSON FADEN: -- but just to people that were on contract research. The third is that they were somehow making a distinction between, and this is something we kicked around a little bit, radiation effects research versus isotope, other kinds of research involving radioisotopes. And that they were more worried about stuff that they thought when they said we don't do human experimentation. Maybe that's what they meant, we don't expose people to radiation to see how sick they get, okay. We don't do that anymore, but we do do this other kind of medical research. Then there's a document that says we don't do any kind of medical research at all. So it's not like oh, you've got the answer, now it's clear, and then you find another document where they write back a letter that says no we don't do any kind of medical research at the AEC. In 1953 they write this letter and -- MR. GUTTMAN: Jay may be right actually. We have also another document that Debbie Holland just found in the archives. It's a 1951 Chicago Argonne. Again it's discussing human experimentation. In their minutes they say, somebody says "Well, we tried to get the advisory committee in biology medicine to get a policy on human experimentation, but they never got to getting it done." Now, we don't know what they meant by policy, but again it's sort of something like Pat is saying well, you know, there are lots of people with lots of statements and whoever listened to them listened to them, right. CHAIRPERSON FADEN: Now, we have to go to the contemporary world. Before we do that can we now say what do we think morally all of this means, which is the next step. Ruth? MEMBER MACKLIN: Pat was asking for some connection, right, I mean some argument to link up everything we've been talking about with a conclusion about retrospective moral judgement. MEMBER KING: No, I actually did not because you can judge people by what was the standard of the time, which is a different kind of retrospective judgment. And what I asked for yesterday was what was the evidence of what were, I didn't even say "government principles," what were standards of the time that people operated by. MEMBER MACKLIN: What they operated by, let me, I just wrote something very briefly, so can I just read it now? CHAIRPERSON FADEN: Yes. MEMBER MACKLIN: I mean I don't know if this does the job. I thought Pat was looking for something else that was missing in the chapter that made the -- CHAIRPERSON FADEN: Well, maybe the confusion is the discussion, Ruth, that you missed. There's a claim in chapter 5 that says the government should have had. MEMBER MACKLIN: Right, should have, yes. CHAIRPERSON FADEN: So you were asking for evidence for the position that the government should have had a system to protect the rights and interests of human subjects -- MEMBER MACKLIN: Or that individuals should have done something. But I'm going to try to try answer the question you just asked now. CHAIRPERSON FADEN: You didn't ask that, I could have sworn you asked that, no? MEMBER MACKLIN: I did ask that at some point in the discussion but not in reference to this. CHAIRPERSON FADEN: Pat can ask what she wants to ask and I won't refer to anything that she might have asked or thought she asked or whatever. I want to try to answer your question of what this all means, okay, but just -- DR. MORENO: What's the evidence that she asked anything? CHAIRPERSON FADEN: Hearsay, hearsay. "When high officials of a governmental agency articulate ethical standards they believe should govern human experimentation, they thereby place themselves under an obligation to disseminate and implement those standards. Recognition or awareness of articulated ethical standards obligates those who conduct or sponsor human experiments to abide by their provisions. Researchers need not be bound legally or officially by an ethical policy or guideline in order to be held morally accountable for failing to adhere to articulated standards of which they are aware. These considerations provide a basis for retrospective moral judgments. Individuals who fail to adhere to articulated standards in government human experimentation can be held morally culpable for failing to disseminate, implement or abide by articulated ethical standards for the conduct of such experimentation." I mean it needs polishing. But I mean that would I think make the link or try to justify the ability to make those retrospective judgments for any or all of the people who may have been involved where they were going to call them policies, letters, guidelines, statements, or whatever, because all those different words appear in these various documents we've been looking at. MEMBER LEDERER: Could I ask a question about what you just said, Ruth? If I heard your correctly, you said articulated standards of which they were aware? CHAIRPERSON FADEN: yes. MEMBER LEDERER: So awareness is a requirement to evaluate conduct as culpable? MEMBER MACKLIN: Yes, awareness is required if what we're using here is standards of the day, okay. MEMBER LEDERER: Okay. MEMBER MACKLIN: I mean we might make another should have, you know, for people who were sophisticated or for doctors, we might make a different judgment about doctors. Doctors took an oath. The doctor's oath is to do no harm or whatever. Doctors who conducted experiments that were not beneficial, that were not beneficial, a non therapeutic experiment -- MEMBER LEDERER: Well, that's something different than what we were talking about yesterday about -- MEMBER MACKLIN: That's right. MEMBER LEDERER: -- consent -- CHAIRPERSON FADEN: Let's hold, we're going to get all hung again. Let's go into the document -- MEMBER MACKLIN: I specifically was included here awareness of -- MEMBER LEDERER: Okay, that's what I wanted to -- MEMBER MACKLIN: -- in order not to get into other kinds of should haves, they should have thought of this, they should have drawn on their moral resources, etcetera. Where, you know, awareness -- CHAIRPERSON FADEN: -- lots of people -- MEMBER MACKLIN: -- but where the awareness is certainly, awareness of articulated standards is a much weaker criterion than they're bound by a policy that they signed something that said I hereby, you know, submit to this policy. MEMBER LEDERER: Okay. CHAIRPERSON FADEN: It's of course difficult because we don't have the text in front of us, but are there reactions to what Ruth has proposed or do you want to read it again? DR. MORENO: Could she read it again. CHAIRPERSON FADEN: I think it would be helpful if you could read it again. MEMBER MACKLIN: It's a -- policy -- CHAIRPERSON FADEN: No, it's okay, everyone appreciates that. MEMBER MACKLIN: -- I mean I just scrolled this out. "When high officials," and I start with high officials, if you want to talk about low officials, we can go to low officials. "When high officials of a governmental agency articulate ethical standards they believe should govern human experimentation, they thereby place themselves under an obligation to disseminate and implement those standards. Recognition or awareness of articulated ethical standards obligates those who conduct or sponsor human experiments to abide by their provisions. Researchers need not be bound legally or officially by an ethical policy or guideline in order to be held morally accountable for failing to adhere to articulated standards of which they are aware. These considerations provide a basis for retrospective moral judgments. Individuals who fail to adhere to articulated standards government human experimentation can be held morally culpable for failure to disseminate, implement or abide by articulated ethical standards for the conduct of such experiments." So the whole thing turns on awareness. Standards are out there and they are aware of them. So if they didn't implement them, of if they didn't abide by them. See, what I think, what I hope this does is at least if our question as we've been asking it is, can we go to individuals -- individual's roles, okay, I mean there may be individuals who we can point to, but perhaps roles, people had certain roles, all one would have to say is they could not help but have known about these things. Certainly the people who write the letters, certainly the people who received the Wilson memorandum, certainly the two Wilsons. I mean anybody who did any of these things, stated them, received them, wrote letters. Stone got the letter from Wilson, etcetera. I mean it enables us to say, at least to be able to say these people could not have been unaware. Now, maybe some people don't read their mail but, you know. It at least -- and awareness is a very weak thing. I mean they read a letter, so they can't then say I never heard of this. And if they say well nobody does this, that's a different thing. CHAIRPERSON FADEN: Let me press you on one point because I think this may take us a long way, although I'm sure everybody wants to sit and ponder this, but given the evidentiary basis that we've just discussed and the conclusion that the weakest evidence that there were articulated standards is for research with patients that was not hazardous, whatever, or higher risk. How would interpret that statement for the absence of standards or roles requiring consent from patients in less than hazardous research, as a violation of an articulated standard or if there was an articulated standard? MEMBER MACKLIN: It may not apply, it may not apply. CHAIRPERSON FADEN: It may be that there was no articulated standard, so you're not culpable for that one. MEMBER KATZ: Ruth, are you willing to add an if Secretary Wilson and the higher officials were still alive that we might recommend that they be called forward to answer for their failure? MEMBER MACKLIN: Well, that's not part of this. MEMBER KATZ: No, no, I'm just saying are you willing to considering adding that to your -- MEMBER MACKLIN: Sure. MEMBER KATZ: -- you are? MEMBER MACKLIN: Yes. But I mean adding it, it's not added to this because this is a statement of a basis for making judgments. Then the -- MEMBER KATZ: No, no, but as an implication of this. MEMBER MACKLIN: -- yes, then the question of finding the individuals to whom it applies becomes a separate exercise. So if you're asking if we could find individuals by name or by role to whom this might apply, and if the evidence showed that they were, that they fit this description then it would be a next step, but it would be whatever that step is for holding people morally accountable for failing to adhere to what they should adhere to. CHAIRPERSON FADEN: And then presumably you go through that exercise and there may be mitigating circumstances that that individual -- MEMBER MACKLIN: Sure. Then all the other things that the chapter says about mitigating circumstances and a variety of other things, this was only an attempt to make a link to say what would be the basis for making a retrospective moral judgment where there was something less than a law, an official policy, or a regulation. MEMBER KING: I don't know how quite to say this, but at one point in yesterday's discussion I said that there were two ways for which I would be willing to make judgments and that is with people who put standards on paper then act inconsistently with them, that you could hold them accountable. The critical difference is you're holding them accountable by the standard of that time. So I don't have any problem with what I understand to be the thrust of Ruth's statement. I also don't understand that to have been the point of my problem yesterday. CHAIRPERSON FADEN: That's why I was pushing to the regular patient situation for which there does not appear to be much evidence in the times that anybody articulated standard of consent for research with patients, a requirement of consent for research with patients in other than the unusual or hazardous situation. That's why I was going to -- MEMBER MACKLIN: And none of these pages and excerpts and everything that we have speaks to the question of non therapeutic -- CHAIRPERSON FADEN: Two, three things do, okay, which we've already articulated, the NIH thing which we've just been educated about -- MEMBER MACKLIN: Right, but that was later, right? CHAIRPERSON FADEN: -- '53. MEMBER MACKLIN: '53, okay. CHAIRPERSON FADEN: Which says no written consent, the thing that Valerie read to us. And the two AEC ambiguous letters which make no qualification about how risky the research has to be with the patients, just clinical testing with patients needs to be with documented consent. So the question is how you interpret that evidence for claiming that there's a sufficient articulated standard to invoke the apparatus that Ruth has just provided. MEMBER MACKLIN: What would help me to see how then to go back and not necessarily re-craft this, but add an addendum is for someone quickly to tell me so don't have to think it through, to which experiments in our report his applies. In other words, we've now got this that may not apply to the research on patients. Of all the things that we have here in our case studies, which are the examples to which this would not apply? CHAIRPERSON FADEN: Well, you would have all of the, and mind you none of this makes a distinction between therapeutic and non therapeutic -- MEMBER MACKLIN: Right. CHAIRPERSON FADEN: -- presumably all of the research with women, all the tracer studies are research with patients, okay. So it's all of the tracer studies. MEMBER KING: Which question are you asking about Ruth's statement -- CHAIRPERSON FADEN: The issue of whether we have an -- requirement for consent from patients in lower risk research or not high risk research, however you want to phrase it. Which is where our evidentiary base is the weakest, okay. MEMBER KING: Okay. CHAIRPERSON FADEN: So Ruth is asking what falls under that. MEMBER KING: Oh, okay. CHAIRPERSON FADEN: And I will point out that I would take it that all of the tracer research would fall into that category. And in particular the way we've set it up, the tracer research with women, pregnant women, that whole chapter arguably TBI would fall into that category, or did somebody say it goes into the hazardous risk, but in any event TBI would fall into that. It's the patients, it's in one category or the other. MEMBER MACKLIN: But isn't that higher risk? CHAIRPERSON FADEN: Well, that's what would have to be debated, okay. But the point is depending on how you cast it there is a larger issue which is, you know, the view that the TBI wasn't in the research part, but we can back up on that. MEMBER MACKLIN: Look it's entirely -- CHAIRPERSON FADEN: Just take the pregnant women category -- MEMBER MACKLIN: Okay. CHAIRPERSON FADEN: -- and what applied to that category. MEMBER MACKLIN: So it's entirely possible as we've already acknowledged that in our look back we're not going to find everybody morally culpable, but there are other reasons for -- CHAIRPERSON FADEN: No. MEMBER MACKLIN: -- or I mean I'm asking the question because I think the hardest thing, and the judgement that is the most difficult the committee has been grappling with, is looking back and making retrospective moral judgments finding individuals, be they individual doctors and researchers or people in the government culpable. CHAIRPERSON FADEN: Remember too this is the standard for judging the government's conduct. Should the government have had a policy. MEMBER MACKLIN: Right. CHAIRPERSON FADEN: It's a separate analysis whether you want to say doctor so and so did a wrong thing or should have acted differently, or it was -- MEMBER MACKLIN: I did forget that because I incorporated this into -- I mean I made this broad enough to cover researchers as well. CHAIRPERSON FADEN: I will take that out. And we'll start with this one first and then go to the other one. It can either be identical or it might be different depending on how its -- MEMBER MACKLIN: It's stronger if it's identical in a way because if the scope is larger. CHAIRPERSON FADEN: It is, but the point is it varies in the way chapter 5 is set up. Now, it's approached separately and, if you reach the same conclusion, you read the same conclusion. I saw Jay's hand. MEMBER KATZ: Well, just very briefly, and it goes back to discussions we've had in the past. I do want to -- DR. MORENO: Use the microphone. MEMBER KATZ: -- I don't want to over generalize this point, but I do have problems with retrospective judgments altogether. And I have trouble with retrospective judgments in the area in which we are working in. To define it a bit, it's because it raises all kinds of problems and it surely will raise some problems when we get to the evaluation of the kind of research projects to which we will soon turn is even if we are only less concerned about what's going on now than I am, but I'm sure the data suggests that we have to be concerned, is when we're willing to make these kinds of retrospective judgments on the basis along the lines that Ruth Macklin suggests, what kind of retrospective judgments are we going to apply to what has transpired in 1993, 1994, etcetera? CHAIRPERSON FADEN: We're about to get to that. MEMBER KATZ: I'm just trying to flag a problem and then leave it. But I just want to say that I'm much more interested in -- I'm less interested in making retrospective moral judgments to evaluate the situation and to then concentrate on what we can learn from the past in order to make prospective judgments. And then create some teeth, you know, so that in the future there is less of a likelihood for things to happen as they happened in the past. But if we get into the morass of retrospective judgments, as we'll soon learn, and will learn to at least to a considerable extent, we'll be getting ourselves into trouble. At this point I only want to flag this problem. We may have to return to this formulation after we've taken a look at the current situation. CHAIRPERSON FADEN: I'm a little confused. I think we've probably gone as far with this as we can, and we need to go on to the contemporary situation. But Ruth -- sorry, Susan? MEMBER LEDERER: I just want to ask Jay one question. Are you unwilling to evaluate the conduct of researchers in the past by their own articulated standards, is that the problem you have with retrospective moral judgement? MEMBER KATZ: Well, there are two things here. I don't really know -- I really have a great deal of trouble to evaluate the so-called articulated standards to begin with. MEMBER LEDERER: Okay. MEMBER KATZ: Because I think that they were speaking now as -- well, I think they didn't really know what they were articulating. That's an assumption, but that's my assumption. I would like to make judgments, even committee judgments, about the way they conducted themselves. And to make judgments about it, but to get into the complex area of culpability and the accountability. That's why I raised the question with Ruth Macklin. Taking them, you know, hauling them before a court of law, which is implied in what she said. All this I have problems with. MEMBER MACKLIN: It need not be, excuse me, it just need not be implied if we're talking about moral judgments. A court of law is, if someone has violated some law or regulations. MEMBER KATZ: Okay. MEMBER MACKLIN: So what we want to do about finding someone morally culpable for what had been done in the past becomes a separate question. It's not all a matter -- MEMBER KATZ: But law and morality are intertwined, that's another problem then. CHAIRPERSON FADEN: That's fine, but let me try one of these just because I'm worried about the language. Jay, when you object to retrospective moral judgment, you mean judgments about culpability and blame -- MEMBER KATZ: Yes. CHAIRPERSON FADEN: -- not judgments about whether something happened in the past? MEMBER KATZ: Right, exactly. CHAIRPERSON FADEN: So I would take the first one as also a retrospective moral judgement, but we can call it whatever we want. You're comfortable deciding you can say something, this was wrong what was done in the past? MEMBER KATZ: Yes. CHAIRPERSON FADEN: But you had difficulty saying and so and so should be blamed for it? MEMBER KATZ: Yes. CHAIRPERSON FADEN: That's a harder judgment to make. The first one is easier. The only reason I distinguish that is if you look at the list of retrospective moral judgments, the first one, such and such was wrong in the past, is in the list of retrospective moral judgments. We should stop calling it retrospective moral judgement and let's just say what judgments are people comfortable making and what judgments are people not comfortable making, all right. MEMBER KATZ: Yes. CHAIRPERSON FADEN: And that's kind of the process that we're working towards. And we have made real progress, although again it seems elusive and scary given how much we have to do, this business of agreeing sort of, I think, about what to make of the documentary evidence about the articulated rules for consent by government agencies at the time. We're not talking about standards in the profession. That was a separate discussion that we had yesterday, okay. We have Ruth's formulation for what those articulated rules by government should be taken to mean morally in terms of, if there was a rule at the AEC and they didn't implement it, what does that mean. And Pat's concurrence that, if you're doing it by the standards of the day, that that has more of a resonance for her, and I presume for other people. It's an easier kind of judgement to make, okay, than judgments in the absence of evidence about what the rules were at the time or the standards at the time. We're going to have to stop now on this one. I guarantee you it will come back tomorrow. It may even come back this afternoon depending on how long the discussion today takes. But certainly when we go tomorrow either to the chapters or to the discussion of backward looking recommendations, the situations analysis, we're going to have to confront these issues again, so it's not going to go away. In the meantime we can have the statement typed up and distributed so that people, if you want to edit it a little bit, so that people can look at it tomorrow because we will want to look at the words and maybe it will help us with some of the discussion that we'll have tomorrow. Again, I want to thank Valerie and Jonathan for this, you know, beyond the call of duty scrambling last night and this morning to facilitate the committee's discussion. All right, it's 3:00 o'clock. We have to do two contemporary, both of the contemporary projects. And the question is, do we need a break now or should we go right ahead and then have a break between the two? Right now or keep going? All right, it's too close to lunch, fine. I just want to make sure because we're switching gears. Now, what we have now are both, most of the data but not all of the data, as Jeremy will point out, and I will point out with respect to the other project -- two contemporary projects are in, okay. Not all of it is in, but most of it is in. And I'm going to ask Jeremy who here with you, Nancy, Pat, Steve, Monica -- no Steve, if you could give us -- if we do that one first, if you could give us a very quick update. Because what I really thing we need is a discussion about what we think -- okay. And we may want to wait until we hear about both, discuss both projects, hear a little bit about both projects, and then discuss together. We're back to the question of the committee's voice, what is the committee going to want to say collectively based on what we've learned about the protections of human subjects today. Hi Nancy, hi Pat, hi Jeremy. Okay, this is a little bit -- we don't have the chapter draft to it. DR. SUGARMAN: I'm not going to reiterate the findings that we discussed last time and those that are found in your chapter. Is this one? CHAIRPERSON FADEN: It's on. We have a wandering sound guy. DR. SUGARMAN: How about now? CHAIRPERSON FADEN: We'll try and get someone. DR. SUGARMAN: How about now? Okay, I'm not going to reiterate the findings of the subject interview study to date that are found in your chapter, and those that we described briefly at the last meeting of the advisory committee. I can tell you the pieces of data that are missing from this analysis and from the chapter so that you'll have an idea about what's to come. The first piece is that there are missing hospital records data from 103 subjects in our study. Those data we should be able to gather most of that material over the course of the next week to ten days because most of those were missing from one geographic site due to the time we closed down data collection. We will be missing records probably in the order of around 50 or so because medical records are unavailable on some institutions because people are allowed to carry their medical and research records with them, but it's going to be a small proportion of the overall respondents to the study. The second area where we have not completed analysis on is on discordant responses. And, if you remember there were two types of discordant responses. The fist kind of discordance were those people where we found some type of record that they were a participant in research but they didn't know it. And the second kind of discordance was the type that people reported that they were research participants but we couldn't find evidence of that participation. We have been hitting the field rather hard since the last meeting. Pat has been doing a lot of this work, I've done some of this work. For the first kind of discordance, the kind where we found some evidence of research participation, but the respondent didn't indicate that they thought they were participants. We've actually gotten a lot smarter, and we've been able to clarify some of those issues. Let me just give you an idea of how some of those are settling out. In one case we identified a woman who was interviewed for the subject interview study and later that day enrolled in a research project. So in fact four or five days later when, you know, the abstraction was done, was she a research subject, yes. So that's not -- we resolved that discordance. Several other folks, it seems that they had some type of confusion over randomization. For instance another person was randomized to a vaccine trial for melanoma and randomized not to receive the vaccine and therefore thought she wasn't getting research treatment. And a few others were people who were treated in the past, you know, four or five years and were coming for a routine follow-up under a study, so officially I guess they are a research participant and continue to be. And those are the kinds of things. We did find some people who were being followed more approximate to that time. We haven't identified anyone who was sort of undergoing a therapy and didn't know it to date. We have notified when we've uncovered a discordance of this type, we've notified our local principal investigator and they've assured us that they will contact the individual investigators of those trials or whatever and talk with that research participant. So we don't know the absolute numbers. We don't know how all of it's going to fall out. Do you have anything to add on that kind of discordance? Okay, on the second kind of discordance -- CHAIRPERSON FADEN: Wait a moment. DR. SUGARMAN: Yes. CHAIRPERSON FADEN: Before you go any further to summarize your and Pat's intuition about how this is going to end up, what I think I'm hearing you say is it's unlikely that we are going to end up with any sizeable number of people who are currently research subjects and don't know it, is that right? I mean I realize you haven't looked at every single case yet, but it sounds like that's where you're going. DR. SUGARMAN: We are -- the question, I guess a more nuanced, I think that's close, the more nuancing is that under some paradigm the people may be coming back as research participants because they're being followed up say until death. CHAIRPERSON FADEN: But they're not longer in the intervention part of the study? DR. SUGARMAN: They're no longer in the intervention phase. Or there was some confusion over what they were doing -- CHAIRPERSON FADEN: But the question that I have about that one is, the item says were you ever a research subject -- DR. SUGARMAN: Right. CHAIRPERSON FADEN: -- and they said no. So the justification or the explanation is they forgot, is that the hidden presumption? There we don't know. DR. SUGARMAN: We don't know. CHAIRPERSON FADEN: I mean the point is they say they never were. We now discover that they were enrolled in a trial five years ago. That's what you're finding out. The intervention phase is over and now they're in routine follow-up. And so the reconciliation, if it's to be reconciled, is that they've forgotten that they were in a study. But we don't know that. So either they never knew or they forgot, okay. I just want to make sure that we understand. DR. SUGARMAN: And I guess it's one of the things -- CHAIRPERSON FADEN: -- that you have evidence -- DR. SUGARMAN: -- there are going to be several unanswerable questions with the way the study was designed, and I don't think we're going to be able to get a lot smarter about that. MEMBER KATZ: Yes, but to follow up on Ruth's question, will you let us know what all the complexities are of these kinds of data just for our own information, however we want to use them because there could be a problem, I'm not suggesting that it is, of trying to over reconcile. But it would be nice to know what remains ambiguous in all these figures. DR. SUGARMAN: Yes. Well, we're going to give it to you in a digestible format. And I think that we -- MEMBER KATZ: I have the format, digestible, yes, yes. DR. SUGARMAN: We will give it in sort of a very, where it is possible to categorize or lump in a fair way, we intend to do that and to describe this sort of finding in enough detail that meaningful explanations can be drawn from it and we're not going to over step the conclusions, make any conclusions for that, if that's what you're asking. Now, that was the easier kind of sort out. The more difficult area where people who believed that they were research participants, but we could not locate any documentation initially that they were in fact research participants. And this is a difficult thing to sort out for a variety of reasons. Sometimes people are on research projects which are conducted in another institution. It could have been conducted a long time ago. It could have been that they did not understand correctly what the care they were getting was compared to research. All that said, using the open-ended responses to the brief survey, we were able to track down the areas of concern that patients had or a misunderstanding in some cases. We are also preparing fairly detailed explanations in cases where we can find sufficient information to prepare that sort of thing. For instance there is one woman who believed or reported that she believed she was on a research project investigating different diagnostic methods for diagnosing breast cancer. And she reported that she underwent -- her mammogram missed her diagnosis and she was getting an MRI and a CT to see if this was a better method of diagnosing breast cancer. These are the kinds of responses she gave us. Well, when we reviewed her records it turned out that her mammogram did not miss her diagnosing. That's in fact how the diagnosis was made. In fact these were the tests being done for staging. And when discussions with the staff in the only location she had this testing done in the hospital at the time, she confused what was being done because she equated any sort of treatment or evaluation for cancer as research. So, you know, we have a fairly good explanation of where that confusion was, but we're not going to be able to provide that detail in every instance. So we have looked through records of both sorts at all but three institutions and those institutions will be completed at the end of next week. So the next aspect -- then there are obvious implications of these findings. Once we have categorized these kind of discordants and resolved what we can, we will then be able to provide additional analysis in the brief survey putting in this discordance information and concordance into models looking at those variables. MEMBER NORRIS: May I ask a question? DR. SUGARMAN: Yes. MEMBER NORRIS: Do you get a feel that any of these people who think they are on research but are not on research think that because the institution where they're being treated is commonly known as a research institution and therefore I must be in research? DR. SUGARMAN: I think those are the kinds of things which we're going to look for. And the implications that I'm just getting then are then we'll now have these in depth interviews. The implications for the in depth surveys are quite important. Right now we know that a substantial portion of the in depth respondents were, we had verified research participation. In the interest of being as rigorous as possible, the report of the in depth interview will include quotations and understandings for sure from people who we can verify research participation. We will also look very carefully at those we can't verify research participation, realizing that that's a little bit more of a leak. But we'll look at those data to see if those confusions are related to the institution or what they understand research to be. And fortunately we'll have this information from the in depth interview to get at further detail about that. Okay, the next part is the research projects in which respondents were enrolled in terms of getting them characterized. We had a meeting back on the 23rd where we got experts who in each of the areas of interest, empowered the expert with a generalist or someone without content area expertise, but is a physician, to weigh each of the research proposals. The group met to agree on how they would look at these and how they would characterize this research. And we had initially proposed that they use a minimal risk, more than minimal risk classification. In a discussion that was actually very interesting the group assembled felt that that would be an unfair task and too simple an explanation for what they wanted to do. So they wanted to make their job a little bit harder, and so they agreed to come up with something which was now terms "The population disease burden," and that would be what the average individual with the particular disease or those people were being recruited to be in that research project would have, and that would just be low, medium or high. So a low population disease burden would be something like a normal volunteer. Someone with a cholesterol of 207 or something that was being asked to, you know, do something, medium and high. And they were actually happy then to use a research incremental risk, and that was minimal or greater than minimal incremental risk. So what was it about being on this project that added to whatever the state was where you started, and they felt that that was a more dynamic and clinically significant way of approaching the subject. And then also they were fine about dividing them up the same way that the respondents had, which was fortunate, into therapeutic, diagnostic or other. We have receive something like 70 percent of all of the consent forms for the projects that people were on. We have reviewed 65 percent of those -- CHAIRPERSON FADEN: Let me just stop you here, Jeremy. So this review is on the consent form only or the abstract? DR. SUGARMAN: In a few instances we were provided the abstracts, but we only had received permission to seek the consent form, so we were using the consent form to make these judgments. And there's actually a lot of information in those consent forms. I don't know how a lot of people can read them, but there is a lot of information. CHAIRPERSON FADEN: That's the subject of the next time topic of the afternoon. We'll get to that. DR. SUGARMAN: And we will get the next batch and all the participants in this session were willing to look at them again and to make judgments independently and re- send them back and they were all happy to do that. So that information will follow in the next analysis. So with that, having told you what we don't have to give you right now, that's the direction we're headed and we would like to hear your comments on the chapter draft to date, recognizing those limitations. MEMBER KATZ: Do you have any preliminary information on the consent forms or nothing as yet? DR. SUGARMAN: Sure. Realize that this is 65 percent of the total we anticipate getting. And in terms of, let's see, of the ones that were treatment projects 62 percent of them were greater than minimal incremental risk. For diagnostic projects 22 percent of them were greater than minimal risk. And for the other projects 28 percent of them were greater than minimal risk. If you want to know the numbers, 126 of 171 were treatment projects, 18 of them were diagnostic projects, and 25 of them were other. CHAIRPERSON FADEN: That's fine. MEMBER KATZ: You don't have any value of this data yet, preliminary ones of comprehensibility and -- CHAIRPERSON FADEN: We're not doing that on these -- DR. SUGARMAN: We're not doing that with this project. MEMBER KATZ: Oh, you're not -- CHAIRPERSON FADEN: I mean we could, but we don't have the time. They're there and if somebody wants to do it, that's fine, but we're not doing it. Okay, I feel I need to be a little directive here. We've got Monica and Nancy and Jeremy and Pat here, and we have really two tasks. One I think is to ask questions of them or give them feedback that's large scale feedback, not tiny editing things that will help them do a better draft, final draft for us next time. That's important. And also make sure that we have questions, that if we have questions we would like this data set to answer to establish if this data set can answer them, and that's important. And then we also have the other task as a committee interpreting what this means. I mean what does this tell us about what we now know that we didn't know previously about human subject research. We may want to do that in conjunction with our interpretation of the research project review data as well. But while we have the four here it would be good if we have questions that are specific to them, either can help us better understand what this means or can help them write a better final draft for us. Sue? I'm going to look for hands. MEMBER LEDERER: I had a question about, on page 15 from the in depth survey, in which you discussed how doctor's recommendations carried a huge amount of weight with the subjects. And I was wondering if you could break down sort of that doctors, does that mean the recruiting doctor or was the recruiting physician into the study their personal physician, or can you tell us a little bit more about that? Well, similarly, I mean in the discussion on consent you talk about how the respondents to the in depth interview recounted that staff explained research projects. And I would be interested to know which staff, I mean is it the PI, it is a study nurse, does that make a difference in how happy subjects are, respondents are with their status as a research participant? DR. KASS: Yes, that's -- is this on? I don't know. Yes, okay. It's a very good question and I think that generally we can't answer it. There are times when the interviewer probed specifically. I think generally we heard from people "my doctor" which I think I read to mean their personal doctor. And often it was things like my doctor recommended that I do this, and I wouldn't question what my doctor said. And so I read that to mean their personal doctor. Is that your sense also? Okay. CHAIRPERSON FADEN: Jay, did you want to follow up? MEMBER KATZ: Yes. I want to just make two brief comments and introduce them by saying that when this project was started I had all kinds of personal reservations. I thought that you've come up with some information and data that many of us will think about for a long long time to come. And this is very important contribution. I only want to make two comments at this point. I have many more jotted down and I may make them available to you at a later date. One is that you didn't seem to suggest something that I'd always suspected, but now we have some data, that there is a much more widespread sense of altruism in this world that needs to be tapped and that is not being tapped by the medical profession because they are so leery of in a forthcoming fashion inviting them to participate in research and saying to them, look we need your help also and if you can, but also you are to carefully consider it, and are you willing to do X, Y and V for X, Y and C reason. There is more of it around than we are aware of. The second point is your discussion on trust. And of course what occurred to me in relation to the trust issue, that of course trust is always a dubious kind of entity, but in this setting it is also made more problematic because it is trust in the physician and trust in the researcher. And so much of the trust that patient subjects bring to this enterprise is really trust in the physician that he will do right by them and will only do things that is in their best interest, and they rely on this. And I think in the light of your findings, it is physician investigator's obligation to challenge that trust in the sense of saying this is --look I know you trust us, but I am not really before you as a physician alone, I am also here as an investigator. And in asking you to participate in this study, you also have to know that to some extent some of your interest have to yield to the dictates of the research protocol, etcetera. That when patients say I trust you, doc, do what you want to do, it is that trust should not be accepted without further inquiry into that further challenge. There are some other things that I learned from this already, which document, but I'll communicate this to you -- but these are two important issues. CHAIRPERSON FADEN: Sue, I don't know if you had another comment? MEMBER LEDERER: Well, I guess the questions that I had about who was recruiting the subjects into the study goes to the discussion about policy implications and trust, which Jay just alluded to. And one of the things in the text is about investigators must be careful not to inadvertently take advantage of this trust in recruiting participants for research. And that struck me as a somewhat weak statement and I wondered if there were ways that we could strengthen that based upon the data that you've collected to insure that that trust was not abused. Or to strengthen that. DR. KASS: Well, I don't know if this is an answer to that. I hope it is partly. We heard not only trust in specific persons where there may have been -- where we might not have been able to discern whether they were talking about their doctor or the investigator. But we also clearly heard some generalized trust, which was sometimes in research generally, and sort of generally they couldn't be asking me to do something that might harm me. So I think that speaks more broadly to a sense that research always must have some kind of protections in it such that perhaps -- you know, sometimes that was such that I don't have to read the form carefully, such that I don't need to ask a lot of questions, that kind of thing. CHAIRPERSON FADEN: Duncan? MEMBER THOMAS: Two very small points. One on style. Has there been a discussion amongst the staff, and I'd like to hear the committee's view, as to the use of just raw unedited text from the in depth interview? Often it's so incoherent it makes the subjects look stupid, and I don't think we want to give that impression that all participants in this medical research are stupid to be saying things like this when just a little bit of tidying up of the text might make them look a lot more coherent than they appear. CHAIRPERSON FADEN: You mean -- MEMBER THOMAS: I certainly want text from the transcripts of this meeting, some of my own remarks, reproduced as -- MEMBER GLATSTEIN: They're available. CHAIRPERSON FADEN: I don't how this is handled generally. The issue came up with respect to how we would use the testimony that was provided --other places you go back to the person and say would you like to clean up your text before we put it in here so your grammatical errors and your ums and ahs and stuff go out. We can't go back to these people. We're not in a position to go back to them and say here's what it looks like, would you like to take out the dozen ahs and ums even though, you know. So the issue becomes, what happens, do you normally do that, do you clean it up a little bit? You do clean it up? MEMBER THOMAS: Did our consent form say give us permission to reproduce their comments? DR. KASS: I think they're anonymous. CHAIRPERSON FADEN: I think at long as they aren't identifiable. MEMBER THOMAS: Okay. CHAIRPERSON FADEN: Monica, is the answer that you normally do clean up stuff like that? MS. SCHOCH-SPANA: Yes, there are conventions to indicate what is directly quoted text and what's been cleaned up. So I think we can use those conventions more heavy-handedly in the final draft and maintain meaning, but also include -- convey also coherence. CHAIRPERSON FADEN: Sue, did you want to comment? MEMBER LEDERER: That's the convention that's also used in oral history descriptions. CHAIRPERSON FADEN: Yes, so we'll follow that. Thank you. Did you have another point? MEMBER THOMAS: The other was a substantive but still minor point. On the distinction between research and medical care, page 13 lines 4 and 5, there's an implication when trust explicitly as to whether the researcher or the clinician had said that the research would with certainty make them better, respondents typically said no. The implication being that treatments would with certainty make you better, and research there's some uncertainty about whether it will make you better or not. I don't know of too many treatments that with certainty will make you better. Maybe I missed the point of what was being said here. Yes, we can. Well taken. CHAIRPERSON FADEN: The question is was it put to them that way, did they tell you for sure it would make you better? Because I think your point is, Duncan, that no physician could make that assurance for any treatment. DR. KASS: No, we didn't ask them. That's now how it was asked. I think it was in response to people saying, if I go into this research maybe it will cure my cancer. To essentially say well is that what they told you, or is that, you know. But we didn't say well what did they tell you the prospects for standard treatment were. CHAIRPERSON FADEN: I see Jay and then Mary Ann. MEMBER KATZ: Just one more brief question. I was struck by the fact that you discussed terminology on page 25 at the very end. To me the whole terminology is so important and so crucial, and crucial to even what preceded it that I would put it much earlier. And in thinking about consent I would want also to think about what the person said about the impact of the terminology on them. But who knows whether what should come first or come last, or what should come last should come first. But I wondered by you put it at the end. DR. SUGARMAN: So you could tell us to move it forward. MEMBER KATZ: What? DR. SUGARMAN: So you could tell us to move it forward. MEMBER KATZ: Right. DR. SUGARMAN: No, we're not committed to the ordering, and there was no decision. It really either has to come before the whole decision process. We tried to make it be the process of research, and it could either be at the very beginning or at the end, and really we're indifferent to that and there is no reason other than it sounded good, we thought. CHAIRPERSON FADEN: Mary Ann? MEMBER STEVENSON: On page 16 there is some fairly lengthy discussion about the doctor's recommendations carrying a hugh amount of weight as to whether or not patients undergo protocols. And I was wondering if you had any information or made any attempt or could make any attempt to quantify that because I find that problematic. I mean we all do as individuals and physicians have our bias about treatments whether they're established or protocol, but the fact of the matter is a protocol is a protocol because you don't know the right answer. And if a patient to some degree is not being given the information in an unbiased atmosphere, in other words with the physician to some degree not giving their opinion, is that really a free choice because of the issues of physician- patient trust and that kind of thing. DR. SUGARMAN: I think the latter part of your statement is getting at what's intended rather than trying to make quantitative claims from the in depth data. It would be hazardous to make any kind of numerical statement based on that or any frequent disclaim. Just as an overriding theme that in someone's decision making process one of the facts that contributes quite importantly are the physician's recommendations. MEMBER STEVENSON: I guess maybe I should be more direct. I feel that maybe that's something that we should comment on in a fairly substantial way. DR. SUGARMAN: Okay. MEMBER STEVENSON: Whether we think that's appropriate or inappropriate. DR. SUGARMAN: Okay. And using that, if you used it in the trust area, that, you know, it's probably related or tied to trust or decisions to participate. And, you know, we can't go back and find out more about that and maybe we can reread transcripts and look that sort of thing, but if there are areas that you would want explored specifically, that would be very helpful. CHAIRPERSON FADEN: Again, there is this problem of clarification for general order of magnitude. The impression you get is that most patients were most strongly influenced by what their doctors recommended. Is that an accurate characterization -- was that the most important factor that people -- some way of -- it's close to that, so how can we say it, or some way that can give an impression as opposed to some other factors that might have influenced them. The impression I'm coming away with is that the dominant force -- DR. SUGARMAN: Even staying away, remembering where this comes from or from the in depth interviews that a dominant force or an important factor, or is a more fair use use of those data. CHAIRPERSON FADEN: Well, what's unclear about that was, was it an important factor for five people or important because 50 people said it. DR. SUGARMAN: Right. CHAIRPERSON FADEN: I don't want the number, I just want to be clear on which it was. DR. KASS: The magnitude of the problem. CHAIRPERSON FADEN: Right. Which way does it go -- DR. KASS: Or the observations. CHAIRPERSON FADEN: -- it's terribly important for a few people or did you label it important because lots of people mentioned it, or was it both. And the impression that I got is that it was both. DR. KASS: Both. CHAIRPERSON FADEN: A lot of -- DR. KASS: My sense -- CHAIRPERSON FADEN: -- people and a lot of people gave it a high weight. But just to be clear on why you gave it the emphasis, I think we'll go to Mary Ann? Sorry Nancy. DR. KASS: Yes, Ruth, I think your summation was absolutely right, which was both. It was very important to people, but it was important to many people. MEMBER STEVENSON: Okay. DR. KASS: The one caveat that I would like to offer with that is that my reading, and again, Monica, jump in, was that that was particularly true for people who had serious medical conditions. MEMBER STEVENSON: That would be helpful to talk to and to introduce and it would make sense. DR. SUGARMAN: But, Mary Ann, I guess it would be helpful to push if there were other aspects of that, what you were talking about, you know, that you would expect people to follow their doctor's recommendations, the fairness of how that's presented, and how, you know, if there are those types of features which you would like the group reading these to pay attention to, then that would be helpful in making recommendations, then we could certainly look for them. MEMBER STEVENSON: I mean clearly there is background here and all through medical history that patients are very influenced by their doctor's opinions. DR. SUGARMAN: Right. MEMBER STEVENSON: And so when it comes to a protocol where in fact whether it's good, bad or indifferent, treatment is not known, that's why you're doing the protocol, you know, is the patient making a free and voluntary decision, they are receiving that kind of input from a physician in that position. CHAIRPERSON FADEN: Can I get a sense of the committee so that our drafters here have direction. I'm not hearing much criticism. Can I take it from that that the committee members are fairly pleased with the way in which this chapter is developing? We need to hear good news too. I mean it's nice, it's nice to hear some nice things. So we can take it that the chapter is going in the right direction and doing for us what we would hope that it would do. Jay already mentioned that he was pleasantly surprised as how useful the information is, the presentation, the comments. I mean now is the time because this is it, folks. If you have real objections to anything or really thing there are hugh gaps or holes, we want to hear it now. MEMBER STEVENSON: I guess I have to honestly say I have not spent as much time on this chapter as I could have, so some of this is naive with not enough reading. But when we started this we didn't know what to expect. I mean to some degree there wasn't a list of expectations, you know, and checking right or wrong. But it seems to me it would help from organization if we had some predetermined standard or something that we were looking for. I mean we were looking for this to how close it came to our ideal of what should happen in the research setting. And whatever that is, how close did it come to that? I mean we're trying to measure if contemporary research is close, far from what we would consider ideal in terms of consent issues, volunteerism, etcetera, etcetera. I mean I think it would be helpful in almost a bullet form at some point at the beginning to introduce why, I mean what's the purpose here. DR. SUGARMAN: I think providing a bullet or synopsis and what we're finding is a great idea. I looked at the endeavor as a way of describing probably for the first time in over 20 years systematically what the lived experienced of research participants are today and what patients receiving care believe research to be about. In that way to base your discussions and deliberations about making policy recommendations on an empirical database, not just on each one of your own experience with research, but in a systematic understanding of what research is rather than what it's supposed to be or towards what. MEMBER STEVENSON: But I guess we're making a lot of judgments at research wasn't in these past decades. And so is it better? I mean the things that we're finding deficient in the past, can we hold up and see if those deficiencies have been addressed and made clear. DR. SUGARMAN: And that's a part that's probably beyond the scope of what this chapter and what we can give you. We can tell you what it is today, which provides you to use either. if you're going to use it to say, do we want to compare it to what we've learned about the past. We also now know, you know, the federal government responded several times with some kind of regulations about -- MEMBER STEVENSON: Exactly -- DR. SUGARMAN: -- about what research -- MEMBER STEVENSON: -- but has it done any good? DR. SUGARMAN: -- is, so that we're not saying things based on documents that are 50 years old. CHAIRPERSON FADEN: Ruth first and then Nancy. MEMBER MACKLIN: I'm sorry, this last exchange was very puzzling to me because I don't see, I didn't understand that to be the purpose of this at all. And I think what perhaps needs to be done is instead of devote four lines on page one, maybe devote a paragraph on page one for the purpose. What you say here and it seems right, but elliptical, is the committee sought to obtain data regarding what it means to be a research subject today. Now, what it means to be a research subject is not whether it's being done well, it's not whether or not it's meeting the ideal. And you just said, Jeremy, I don't think that you can get at those questions with this. DR. SUGARMAN: Right. MEMBER MACKLIN: And certainly cannot compare it with the past because we don't have any comparable data or any comparable surveys. I thought the whole point here was to talk to people and find out what do they believe about research, what are their attitudes towards it, do they believe they're in it or not in it, what's their motivation for being in it, and what's their experience in it. DR. SUGARMAN: Right. MEMBER MACKLIN: Now, all of that doesn't answer questions about ideal. DR. SUGARMAN: Right. MEMBER MACKLIN: There weren't any questions that really address that in any systematic way. DR. SUGARMAN: Correct. MEMBER MACKLIN: So I think what's needed in part in order not to mislead or in order to make clearer what this chapter is about is from the subject's point of view, or from the point of view of patients in oncology and in radiation - - DR. SUGARMAN: And cardiology. MEMBER MACKLIN: -- what are their perceptions, their attitudes, and their beliefs about research today. DR. SUGARMAN: Correct. MEMBER MACKLIN: I mean it seems to me that's what the study is. And to spell it out a little bit longer in the first paragraph -- CHAIRPERSON FADEN: And those findings will help us comment together with the research proposal review findings. DR. SUGARMAN: Right. CHAIRPERSON FADEN: Whatever we want to say, which we're about to -- DR. SUGARMAN: Exactly. CHAIRPERSON FADEN: -- but we're going to emphasize too that this is a perception, a slice of the perception of subjects who are patients, okay, not healthy subjects and also patients who are competent. This doesn't tell us anything about the experiences in research and people who are children who are incapacitated in some fashion or whatever. So it's clinical research or whatever the term is. MEMBER MACKLIN: Right, and that has to be said. So I think the explanation of that -- CHAIRPERSON FADEN: Yes -- MEMBER MACKLIN: -- Can I just ask one very brief little factual question while I'm here? CHAIRPERSON FADEN: Yes of course you may ask. MEMBER MACKLIN: I'm sorry, one thing just that had puzzled me is a tiny tiny little point on page 14, so tiny there's only two words. This is on lines 11 to 12 and it says "Controlling for multiple factors patients reporting they had little choice tended to categorize their project as treatment project," etcetera, "tended to report that the projects involved radiation were Latino, did not feel they had enough information," etcetera. Those two words kind of leaped out at me. What does that mean there "were Latino?" I mean the others describe -- what was there about the fact that they had little choice describing that as the fact that they were Latino have to do with their having little choice? DR. SUGARMAN: These are all elements that turned out to be significant in a multi-variable regression, this thing that Steve enlightened us about last time, and now -- (Whereupon, equipment malfunctioned for approximately one minute.) CHAIRPERSON FADEN: What happened? I thought it was all settled. I think I'm working from the wrong draft. I hope I'm the only one working from the wrong draft. Wasn't that also the case for African Americans or did that drop out? DR. SUGARMAN: That's a different model. That's the fourth model. If you look to the notes, this model is described on probability changes. It's note number 2 on your last page. CHAIRPERSON FADEN: I don't have it. DR. SUGARMAN: Okay. CHAIRPERSON FADEN: Okay, never mind. But the point is, if it's there, then you would say this suggests that people who are minorities may feel, if it was building up to that, maybe more likely than people who are not to feel like they had no choice. Now, maybe that says something. It's only suggestive that maybe they feel they have less options than medical care. Who knows? You start to build a guess, but that's all it is. MEMBER MACKLIN: I don't like things like that -- CHAIRPERSON FADEN: No. MEMBER MACKLIN: -- reports. I don't like them at all. It's not it wasn't Latin American -- it wasn't -- minorities. CHAIRPERSON FADEN: Well, I thought it was in my model, what I had -- MEMBER MACKLIN: -- Latinos -- CHAIRPERSON FADEN: -- wrong data -- MEMBER MACKLIN: -- so if one has to say well how do you explain something like that or does it mean that there was a language problem because the Latino might mean being Spanish speaking. Does it mean that people who are Latino tend to be so much more differential to doctors that they'll do anything doctors say. CHAIRPERSON FADEN: Who knows -- DR. SUGARMAN: We can't examine those questions, but it raises areas that might warrant future examination. CHAIRPERSON FADEN: Ruth is going to the larger question of whether you put ethnic variables into -- DR. SUGARMAN: Okay, well the question -- CHAIRPERSON FADEN: -- big issue right now. DR. SUGARMAN: -- Steve, when Steve was talking about these models, he made a conscious choice and we discussed this. We've had several conversations, and we can remove ethnic variables from the models as well. It's completely legitimate, if you don't have an idea that there may be distinct differences in ethnicity that might contribute to understanding research, you don't put them in your models. We didn't put shoe size in. We didn't get shoe size, but we didn't put things in the model that didn't make sense although they might somehow pop in a model and be significant. The reason why Steve was persuaded was in looking at the subjects, I believe and I would have to pull out the two by two tables which we hurt you with last time, that pound of stuff, but I believe 11 of 15 of the Latinos participants in the subject interview said they responded in that way. And although there are only 15 subjects, and that's noted there, felt that is something that might warrant some better understanding. And that's all we can with that model in this study. Now, if the committee wants us to not do that because of the hazards of presenting it and not wanting to spend four or five paragraphs explaining all the reasons why it might be the case, we can certainly do that as well. CHAIRPERSON FADEN: I think we can look at this a little bit further, but we can't do it collectively. Maybe Ruth could talk, and I think Duncan wants to wade in, and whoever wants to wade in. Here's my concern, Nancy and Jay have been waiting. I'd like them to make their comments, ask their questions and then we really have to stop, take a break and go to the other project. So if that's agreeable, or even if it isn't agreeable, Nancy and Jay, and then we're done with expressed appreciation to all of you and to Steve for all the hard work that you're doing. Nancy? MEMBER OLEINICK: My comment merely is the following. This is a kind of path-breaking study, as I understand it. I'm certainly out of my area of expertise. But as I understand it, this kind of study has not been done before. And I think it would be a service to the community at large, not only to report what's in here, but also have a short section in which you lay out some of the questions that we were unable to address, but which maybe ought to be addressed in future studies. Or maybe something to the extent of the question of ethnicity. This arose, but we don't really know how to interpret, and it's something for future work. I don't think I would do this in every chapter, but I think because this is model and it may open a field of investigation -- DR. SUGARMAN: I think there are a myriad of unanswered questions as a result of the study, but -- MEMBER OLEINICK: Well, you might say there are myriads, for example here are three. DR. SUGARMAN: -- and the question we were -- these are the ones we like. We can do that in either place. We can do that in the final report or we can do this in the companion volume that accompanies the report. You know, we seek your guidance especially after you've heard about the research proposal review project about what goes where and, you know, we can certainly do that. We have lots of questions and it would be easy to put them down. CHAIRPERSON FADEN: Okay. Jay, and then we'll take a break? MEMBER KATZ: Well, I'll be very brief. As I said already this is a very rich study and it's a study from a certain perspective. It doesn't answer all the questions, but it really highlights a number of things that you discussed and the policy implications at the end. And that section really deserves to be enlarged considerably. For example you ought to talk about the terminology issue in here because it's so crucial for what is to come in the next chapter, namely whether you call something treatment, research study, etcetera. And the findings are very very important. I already alluded to the trust issue that ought to be expanded and some of the problems ought to be discussed. And on line 17 I probably would add be careful not to inadvertently or perhaps advertently to take advantage of the trust. And you also ought to say something about the altruism issue as I alluded to before because the issue, the data is incomplete, but it's important that these people are willing to say look we're also doing this in order to advance knowledge and for all kinds of reasons, and more attention ought to be paid to that. And I'm not sure -- oh, you did say, you did say something about terminology on page 29. I thought it ended on page 28 because I have this -- so I'm not sure whether something more needs to be said about it or not. My hunch is yes. But it is an important study and we might as well milk it also in terms of implications for what it can tell us. DR. SUGARMAN: And again I think you know it will be easy enough to elaborate on these issues, and we would again seek your guidance after you have discussed the research review project about whether you want us to draw independent sort of recommendations from each of the contemporary projects independently or whether you want to look at a sort of more general look at the end about what the implications are of these companion projects viewed together, and what is going to be most meaningful and what you would like in the final report and what would you like in the companion volume, and we can do all of that. CHAIRPERSON FADEN: Okay. Thank you all very much. We're going to take a ten minute break, no more. Come back at 4:00 and we're going to do the research proposal review project. (Whereupon, at 3:47 p.m., off the record until 4:03 p.m.) CHAIRPERSON FADEN: Sara, as I mentioned can't join us because she's had a death in her family, so she's not with us. All right, we're on to the RPRP or whatever. The research proposal review project that we have all been laboring under, and I think we're to the point now where two things, we're going to have to give again as with the SIS -- this is terrible, you create a federal agency, even a temporary one, and it cannot exist without creating more initials and acronyms and stuff like that. So as with the SIS we need to give Gail and Shobita guidance like, you know, what's wrong with this way of setting it up, what's missing, what do we need more, and so on. We also need as a committee to begin to the hard work of figuring out what we think this all means and what kinds of statements we want to make about this committee's interpretation of the contemporary world, which means drawing on both studies. I want to clarify one thing that Mary Ann and I were talking about at the break, which is the bearing of the SIS on our assessment of its temporary situation, and it follows on something that Ruth said. One of the motivations, which was quite simple, as I recall it, for doing the SIS was since we inferred that, and continue to infer, that it's possible that subjects, and we'll hash out our language later, that people did not know, did not often know, that they were subjects of research in the period of our historical investigation. That we were now going to see whether we could get any evidence that bears on the frequency with which subjects today don't know that they're subjects of research. So insofar as the data from the SIS suggests after Pat and Jeremy have finished reconciling all of the, whatever they're calling them, the ones that don't match -- MEMBER KING: Discordant ones. CHAIRPERSON FADEN: -- discordants ones, thank you, we will be presumably able to say that on that question the evidence, we now have evidence that suggests at least in a clinical population that that does not seem likely any more. Now, we all suspected that that was going to be the outcome, but again remembering that there is a difference between our guessing that that was the outcome and out having data on the outcome so that we can have a basis for saying to the American public that seems to be the case other than our impressions as experienced in our own other lives. So there is that kind of connection that is important that we should remember. And we're looking for those kinds of connections here as well. Now, before we get going and just sort of launch into it, I'd like to spend a part of the time on let's give Gail and Shobita feedback and let's ask questions and then a part of the time on, okay where are each of us in our interpretation of what this all means, so we can get a sense of where we're going with that. Let me just start off the questions to Shobita real quickly. This is reporting on a -- DR. GELLER: Can I just say that I think this study, if I understand it, gets at what you were asking for before, Mary Ann, that there are standards today and are we doing better or worse or than the same as we ought to be? MEMBER STEVENSON: Well, actually my question went beyond that because, are the standards working -- DR. GELLER: Right. MEMBER STEVENSON: -- we have standards that SIS was, are people getting anywhere with the standards. CHAIRPERSON FADEN: We would hopefully draw our conclusions about that complex of questions from both studies. This is based on 113 reviews. MS. PARTHASARATHY: Yes. CHAIRPERSON FADEN: How many do we still have, just real quickly, how many do we have left to do or are outstanding should be -- MS. PARTHASARATHY: Less than five. CHAIRPERSON FADEN: That's it? MS. PARTHASARATHY: Yes. CHAIRPERSON FADEN: That's it, okay. MS. PARTHASARATHY: So basically we're almost ready to go. We distributed our last round of reviews so it's wrapping up, yes. CHAIRPERSON FADEN: So it's extremely unlikely that the distributions that you see, the ratings, all that sort of stuff is going -- we've got five left, so not much - - it's unlikely that much will change, so that's important. So while this is not the final set, it's close enough to the final that it's worth having a real discussion about what this means. Okay, it's open for questions, comments, interpretation. Nancy? MEMBER OLEINICK: I have a lot of small stuff. There are just a few larger issues I'd like to know about. One of them is an issue that I keep harping on, and that is the question of scientific merit. And we decided that, what, 25 percent of the individuals could not say anything about scientific merit, so if you can't say anything, you can't say anything. But in the 75 percent where the individuals that reviewers felt they could say something, what would we say about that? That's not in here. I mean is there anything that we can say? MS. PARTHASARATHY: There is only one study which the reviewers felt that it should not have been done in terms of scientific merit. When we went back and looked at that study it was really just an --study health survey. That was more like it shouldn't have been -- MEMBER OLEINICK: The important thing is that whatever we can say we should say. MS. PARTHASARATHY: Okay. MEMBER OLEINICK: And I'd like to see it in here because I think, at least, you know, my view -- CHAIRPERSON FADEN: We should include that. MEMBER OLEINICK: -- the first question one asks when you're going to review a research protocol is, is there a scientific basis for doing the research. And then you get to the issues of all the evidence. But question number one is, is there a scientific basis. I mean I would like us to say, if it is true, that of the proposals that we reviewed where a statement can be made. Really there weren't any terrible studies. We weren't injecting plutonium, large amounts of plutonium, into people for reasons which were not clear or whatever. CHAIRPERSON FADEN: Well, the scientific merit ones, it could be that it's a good scientific question, but it was a terrible ethics thing. I mean this is just going to -- MEMBER OLEINICK: Oh, yes, no question about it. I'm just saying merely in terms of the -- CHAIRPERSON FADEN: Sure, we can say it. MEMBER OLEINICK: -- we should say it. CHAIRPERSON FADEN: Fine. MEMBER OLEINICK: I think it ought to be in here. CHAIRPERSON FADEN: Okay. MEMBER OLEINICK: That doesn't get to any of the other ethical issues. CHAIRPERSON FADEN: Right. MEMBER OLEINICK: Okay. The second point that I would like to ask about is Jay has done a mammoth job of reviewing 100 and some protocols, and they're mentioned briefly. There's some mention here that some of the percentages are similar in terms of the rating to percentages the group found, and I don't remember which figure that was. But anyway I would like to know a little more about that. I gather that the overlap of the protocols between his review and our review is not complete. But there is a set of protocols that Jay reviewed and that we collectively reviewed, and for that set I would like to know if we agreed particularly with the fours and fives, fours and fives, did we agree or is there some discordance in what we're saying. So I would like to know that, and I think that kind of information ought to be in here. I mean it's there, the information is there. CHAIRPERSON FADEN: We can do that. MEMBER OLEINICK: Okay. CHAIRPERSON FADEN: And I'm not sure in fact if it hasn't even been done. MEMBER OLEINICK: Well, it's not -- MS. PARTHASARATHY: We have looked at those studies that Jay got fours and fives. First of all let me say as a disclaimer that of the 100 proposals that Jay reviewed, some of them after being previewed by us were taken out of the sample altogether. So there isn't a complete concordance between the two samples. But -- MEMBER OLEINICK: So we're only looking at those where there is concordance? MS. PARTHASARATHY: Right. MEMBER OLEINICK: We're going to eliminate the others that are out of that data set, okay, and we're only going to look at those where there was an overlap. And then of the ones that either we or he said were a four or five did the other -- MS. PARTHASARATHY: All but one were -- MEMBER OLEINICK: -- agreement -- MS. PARTHASARATHY: -- they were concorded. The other one, yes, so -- MEMBER OLEINICK: -- then we should say that. DR. SUGARMAN: Yes. MS. PARTHASARATHY: Okay. CHAIRPERSON FADEN: Let me just, as we lead to that, and Jay will certainly -- we can comment on it as we circulate the new table. There's an issue about whether -- Jay's categories were not exactly the same. There was sort of highly problematic, ethically acceptable minor problems, and the issue was whether the "threes," but the whole committee gave a three to were what Jay would have put in the highly problematic category are not. So there's two ways of looking at, a concordance or lack thereof, and we're going to work on figuring that out. So it's a little more complicated than all of that because obviously different kinds should say it, and I don't know if this is evident. We looked at all the ones, twos, threes, fours, and fives, and I feel very comfortable that it makes sense to put the fours and fives together and separate the ones from the twos and the threes if you look at them. And there's a little cryptic description to that extent. We can describe it in more detail. But for the committee whole sample there was a real effort made, the kind of eyeballing thing you do when you're collapsing categories to see if there were differences across the categories and did it work. And the fours and fives kind of collapse. The threes look distinct from the twos and the twos look distinct from the ones when you look at it item by item, rating by rating. It was very heartening in fact to see that. But there remains the question of Jay's, you know, because these are so subjective. Jay, your cutoff versus the total committee's cutoff and sort of where do the threes fit. And if you lump the threes with the fours and fives, as we'll see in a minute, then the committees overall assessment and Jay's overall assessment is essentially identical. If you separate the threes and -- MS. PARTHASARATHY: Then it's just-- CHAIRPERSON FADEN: Yes. MS. PARTHASARATHY: That's a much stronger statement. CHAIRPERSON FADEN: Because we're working towards it, it's all evolving. Well, let's me just circulate it, let's go right to it. Is that okay, Jay, if we just go right to it? If you look on -- what this is, Shobita was kind enough to do this in a sort of quick -- yes, thank you. There are two things, thank you, that make it different, the committee-wide approach different from Jay's approach. One thing that makes it different is that when we had a middle category with respect to risk. We had minimal risk, more than minimal risk, and then maybe more than minimal risk, but the reviewers weren't sure. The tables in the text, the figures in the text, excuse me, lumped the maybes with the more than minimal risk. DR. GELLER: So Figure 3 in the chapter -- CHAIRPERSON FADEN: Figure 3 concretely, Figure 4 -- Figure 3 concretely has an end of 51 and reflects both the maybe -- had a 71 and reflects both the maybe more than minimal risk and the more than minimal risk. The figure that's just been circulated took out the 20 maybes, okay, and only looked at the ones that were evaluated clearly as more than minimal risk by the reviewers. And the gap between Jay's analysis and our analysis overall narrows a little bit. And if you put the threes with the fours and fives, if you make that maneuver, then for the clearly more than minimal risk we gave a three, four or five, that is we the committee overall, to whatever it was-- MEMBER OLEINICK: 47. CHAIRPERSON FADEN: -- 47 percent of the protocols. And Jay gave his ethically problematic rating to 50 percent. Now, if you take the threes out, okay, then you have a different picture. You have a view of the clearly more than minimal risk, it's now 30 percent roughly that got threes and fours. So depending on how you construct it. It's a little confusing and we just have to explain all that so people can see. And then we are going to take another look at the ones that we gave threes to and compare them with Jay's and see what the committee overall rated a three, Jay tended to put in the ethically problematic category. So that's -- MEMBER OLEINICK: Whatever it is -- CHAIRPERSON FADEN: I know, it has to be out there. MEMBER OLEINICK: -- yes. DR. GELLER: Can I just ask, are you interested in where there is discordance between the ones and the threes because there may be more than just one where the committee and Jay disagreed. I can think of a couple off the top of my head where Jay gave them a one and the committee gave them a three or vice versa. Are you interested in -- MEMBER OLEINICK: Probably less so -- DR. GELLER: -- of that discordance -- MEMBER OLEINICK: -- I don't know. I mean unless there was some reason that really stands out. CHAIRPERSON FADEN: We're looking for a picture. MEMBER OLEINICK: We're looking for a picture. I don't think one discordant one, I don't think I'd be terrible interested in. I would be interested in the reasons that either Jay assigned these proposals to his ethically problematic category and we assigned them a three, four or a five, was there some outstanding reason and do we agree on those reasons. Now, I'm not sure how much you can do, but if there's a pattern that stands out that -- CHAIRPERSON FADEN: Okay, we can do that. MEMBER OLEINICK: -- there were people in our review who found a category that we were calling ethically problematic or whatever, three, four, five, and Jay didn't or vice versa. CHAIRPERSON FADEN: Right, so we'll look for that. You're looking for pictures and patterns. So far I think there's more concordance than -- MEMBER OLEINICK: Well, then that's fine. CHAIRPERSON FADEN: -- yes, but we need to pull that out. Nancy, you had another question, and I know Duncan -- MEMBER OLEINICK: I just had one more and then I will retire and let somebody else talk. In calling out all this inclusion and exclusion criterion, the conclusion part - - CHAIRPERSON FADEN: Use the mic. MEMBER OLEINICK: -- sorry, here I go again. In the conclusions I see there is information on the inclusion/exclusion criteria -- CHAIRPERSON FADEN: What page are you on? MEMBER OLEINICK: I'm on the very last page 43. I see nothing about children. We did have protocols where children were research subjects, and I wondered how -- MS. PARTHASARATHY: It's page 39 on mine. I don't know if that's the same on your's. It's in the second section as opposed to the third. We haven't yet gone into this issue further. However, in one of the questions -- CHAIRPERSON FADEN: Page 40 for us in both text. I mean the fact that we had 15 studies that had children - - MEMBER OLEINICK: Oh, yes, yes, okay, to be developed. I'm sorry. But I guess what I was looking for is can we say anything specifically about those? MEMBER KATZ: The kids. MEMBER OLEINICK: Yes, about the kid's proposals. CHAIRPERSON FADEN: The only thing that we know so far is that seven of the 15 did not include assent forms which we now have to go back and look to see the ages of the children in the seven that didn't have assent forms, and assuming they're not all infants and toddlers then that's a missing document. But there's a lot more to do here than that, you know. The children one, that's a big hole. There are 15, so it's not a small number of studies in which children are the subjects. Duncan? MEMBER THOMAS: This concluding section has a number of references to categories which a high percentage of protocols were judged inadequate by one standard or another. And I wonder if it perhaps doesn't paint a somewhat bleaker picture than it really warrants given the subtleties of the way we had to answer this question from time to time. CHAIRPERSON FADEN: Where are you, Duncan? MEMBER THOMAS: I'm looking at the last page, last page 41 to the end. CHAIRPERSON FADEN: Page 41 through the end. MEMBER THOMAS: I'm thinking for example about the paragraph at the bottom of page 41, we note that a high percentage of proposals may have adequately talked about risks, they may have adequately talked about benefits, but then not address the balance between risk and benefits. And I can recall many many proposals that I read where I would be very hard pressed as an investigator to try to address the question of benefits, the balance between risks and benefits because there was just no sensible way to do so. Nowhere on the form did we really have the opportunity to say there's nothing relevant that we can say here in addition to what's already been said separately about risks and benefits. Now, I realize that there is a mandate that we're supposed to do this, but perhaps by simply indicating that the majority of proposals didn't adequately do that, but it doesn't quite convey the message that perhaps this is a waste of time. MS. PARTHASARATHY: The distinction I think that we were drawing was between inadequate as a response and not applicable as a response. Perhaps for a question, for example, where was risk benefit analysis addressed, if it wasn't applicable or it couldn't have been -- CHAIRPERSON FADEN: Yes, I think that Duncan's point though is well taken in the sense that for each one of these there has to be essentially a judgment rendered with regard to how big a deal is this. MEMBER THOMAS: Right. CHAIRPERSON FADEN: Okay. Some of these are bigger deals than others of them. And that's I think what you're calling for. MEMBER THOMAS: That's really what I'm trying to get at. CHAIRPERSON FADEN: There's no discussion section yet. There's no conclusion interpretation discussion where presumably that would be fleshed out. These are what we found. It's like, you know, here are the results, now what does this mean. This is a result, but what does it mean. MEMBER THOMAS: Okay, well I found it's placement in what appeared to be a concluding section. CHAIRPERSON FADEN: No, no, no. MEMBER THOMAS: The issue is that universal -- CHAIRPERSON FADEN: There are no -- this is the result section. If you want to think about it like a journal article, there is no discussion section yet. And what I was sort of hoping is that we would start to hear from the committee the committee's views about what does this mean, you know, has the world come to the end or are these minor problems and everything in between. I mean does these data indict the world, we should stop human subject research, it's a mess, or there's no problems, everything is fine, we think it's wonderful. I mean somewhere in between those two poles is the committee's position, correct? So what is the committee's position, how far can we go with these data, what interpretations do we want to lay I hoped was some of the discussion we would have. So if we could give a few more minutes that specific, you know, very specific narrow kinds of questions, and then go to the larger what does this mean discussion, that would be great. MEMBER THOMAS: I feel the same way about some of the other issues in the same section, things like recruitment process was pretty universally, very little information provided in the protocol, and yet by and large you could figure it out. CHAIRPERSON FADEN: Yes. MEMBER THOMAS: And so it got a box checked inadequate, and yet in my opinion in almost every case where I checked inadequate was it was no big deal. The same for many of the subject selection boxes. It wasn't immediately obvious whether, you know, students were included or not included, so it got a could not figure it out box. CHAIRPERSON FADEN: Which is not -- MEMBER THOMAS: But who cares. CHAIRPERSON FADEN: -- right. Ruth? MEMBER MACKLIN: But now, I really want to ask Duncan what the problem is here. Is it that these are trivial or unimportant questions or they have little to do with the ethics and therefore the fact that it's inadequate shouldn't really matter much? MEMBER THOMAS: Well, I guess the distinction that I kept falling back upon is many of the proposals I saw I thought were ethically acceptable but not well described. MEMBER MACKLIN: But ethically acceptable, I mean it's a very different thing to say they tell you the risk, they tell you the benefits, they don't address the balance of risks and benefits, nevertheless anybody who knows those things can figure it out and say something about it. That's different from not saying whether students are involved since the whole point of asking that question is whether or not people are somehow being unduly influenced or coerced into being participants. So the questions get at different things. I mean when you say it's one thing to say who care about the answer -- MEMBER THOMAS: Well, let me give you an example -- MEMBER MACKLIN: -- to this, it's another thing to say anybody can figure out the answer. MEMBER THOMAS: -- if it's a general population study in which anybody is eligible to participate and the proposal doesn't say one way or another whether students are eligible to participate, then I would have to check don't know. CHAIRPERSON FADEN: Let me -- MEMBER THOMAS: That to me is, there's no element of caution invoked and it makes it look like it's a bad proposal. CHAIRPERSON FADEN: -- let me interject just for the record in general. Having looked at this in detail, no projects were rated as problematic on the problematic end of the scale because there was a failure to indicate whether students were enrolled or not or the risk benefit. I mean so that in a sense our reviews reflected the sort of judgment that you're making, Duncan. MEMBER THOMAS: Yes. CHAIRPERSON FADEN: That is to say when people rated things down it wasn't for reasons like that, it was for other reasons. So in a sense the overall assessment, already the pie chart, okay, already it in a sense reflects just the distinctions you're trying to make. Now the language has to too. That when we do the interpretation we make it clear that these sorts of issues where they were a concern, you know. Sometimes the absence of knowing became important, and then it mattered, okay. Sometimes it didn't. So for example there was a population where people of questionable competence, and sometimes that was - - like stroke patients and there was no discussion. And then that did become -- MEMBER THOMAS: Sure. CHAIRPERSON FADEN: -- other times it didn't matter. So that reviewers combined their sense of what was significant in the context of that study in making, in deciding what t do with that checked box, or with that checked inadequate box, but the discussion has to break it out. I see Phil and Henry. MEMBER RUSSELL: I guess what I'm most interested in is the follow-on that you were just discussing, the what were the dominant reasons for putting them in the category four, five. Because as you go through this each individual determined is analyzed separately, but you don't get a sense of why they flunked. And I think this goes to Duncan's question, which of the various aspects, various parameters were deemed to be most important and which downgraded the ones, and I think that we need to -- CHAIRPERSON FADEN: The draft was set up to try to do that, so if it's not there yet, that's a problem, okay. I'm sorry, but do you see that -- MEMBER THOMAS: Yes, I had the same sense. Early on, the section that has all of these graphs, which breaks down the ones, twos, threes and fours in various ways by type, study, by agency and so on. And then there is the section which is a very important section "Issues contributing to the overall rating." CHAIRPERSON FADEN: That is the section, okay. MEMBER THOMAS: And that's a very qualitative section. And I mean I applaud you for doing this way. It's your attempt to synthesize the data rather that present us with a lot of numbers. CHAIRPERSON FADEN: Right, exactly. MEMBER THOMAS: Nevertheless, as a statistician, I find myself just yearning to do a regression analysis and try to see whether there are other messages that would come forth. And most importantly the extent to which some factors would explain apparent things that other factors, like for example in the early descriptive stuff, we are given data about whether, you know, the extent to which a study was minimal risk or not accounted for the ratings. And then another section which says well different agencies have differences. And then I'd sort of like to know whether or not well are the differences between agencies explainable by differences in level of risk of those types of studies they do, that sort of thing. CHAIRPERSON FADEN: Yes. DR. GELLER: We actually did a lot of that, Duncan. I think you're right though that it's buried. For example, there is a graph on -- actually it may be Figure 8. One of my questions was whether there was a difference in percentage of protocols that were greater than minimal risk by funding agency, extramural, intermural. It was my hypothesis that perhaps more intermural studies were greater than minimal risk than extramural. It turns out that that wasn't the case. We sort of did a lot of that to satisfy ourselves and may not have reported on all of it. Or where we reported it, sort of -- MEMBER THOMAS: I certainly would not want the report cluttered up with lots of things that you tried that were unenlightening. DR. GELLER: Right. MEMBER THOMAS: The report really does need to be concise and just focus on the things you really learned. I'd be very curious, and it would help me satisfy my own curiosity though for you to share some of those regressions. DR. GELLER: Well, okay, another one, which is one of our significant findings, was that more of the greater, if I recall right, more of the greater than minimal risk studies tended to be non radiation research than radiation research. Which is consistent with our findings that cancer and neuroscience research tended to be greater than minimal risk. So we did what quantitative people would call bi-buried analysis a lot. You know, we didn't get to the regression point, but we certainly looked at correlations between variables. CHAIRPERSON FADEN: The key issue is whether we want to do this. I'll state my position which is that I don't want to, okay. But if the view is that you want to try and do a quantified, a statistical analysis, this is what you described, we can. Now, what might be an intermediate step is for anybody who wants to see the raw data to take a look at it and see if you think -- Duncan, if you would like to, or anyone else who is so inclined, thinks that looking at it, it would indeed be useful or illuminating to do some, then we can certainly proceed that way. MEMBER THOMAS: But I am puzzled by your reluctance to do it in this project versus the highly quantitative treatment that the subject interview study gets. CHAIRPERSON FADEN: Because your ends are considerably different. You had 2,000, you don't do it for the qualitative way. MEMBER THOMAS: But I don't think sample size has anything to do with it -- CHAIRPERSON FADEN: And I also think -- that's fine, we can discuss this -- MEMBER THOMAS: You know -- CHAIRPERSON FADEN: -- I'm happy to try it. I have other reasons as well we'd be happy to try. We can try it. And if you would like to do it, that's fine, or you'd like to take the lead in guiding Gail to do it, we can do it. MEMBER THOMAS: I'm willing to not do the data analysis -- CHAIRPERSON FADEN: No, I realize that. But if you have specific ones -- MEMBER THOMAS: -- but I'll work with Gail, sure. CHAIRPERSON FADEN: -- you'd like to have done, we can try and do them. I would phrase it that way. If you look at the stuff and you or anybody else would like to see some runs done, we can try them and see what happens. And then we can see if in fact the inferences would be different. I think we'd get some more refined understandings and that could be useful. That certainly could be useful. The intent on pages 28, and it's certainly nowhere near right yet, 28 through 39 is to answer Phil's question as to say what sorts of factors gave the committee concern, and they were basically in a few areas, okay. And they are identified here, that the kinds of -- to give you an example, the one thing that's highlighted is reading level, okay. The reading level thing distinguished the ones from everybody else. This is just an eyeballing sort of thing, but it wasn't by itself something that gave you a low rating. So if you had a poor reading level for your consent form, that didn't give you a five. But on the other hand there was only one study that got a one that had a poor reading level kind of thing. So it sort of -- but everything else was sort of on a sliding scale. The worst you got in the three areas indicated here, in the view of the reviewers, the lower the score you got, and sometimes it was -- and the problem is that sometimes if you looked at these it was one study was just awful on one factor and therefore got a four or a five. Another study was problematic in two or three areas and got a four or five because it was a cumulative thing. But the areas which were consistently the same that gave people trouble and that's what's articulated in 28 through 38. You know, where people were worried a lot, the reviewers, they were worried about these sorts of things. They were worried about either the benefit was not properly characterized or the down-side of being in the study was not properly characterized. Or there was some issue about how people of questionable competence were being handled, and we haven't worked that one through yet. Those seem to be the areas where, you know, concern emerged. But now we're talking about two and three, you know, several of us looking hard at the fours and fives in reaching that conclusion. Phil, did you want to proceed? MEMBER RUSSELL: I was wondering -- CHAIRPERSON FADEN: Henry is waiting. MEMBER RUSSELL: -- are all of the problematic areas in the areas of communication or are there some that were downgraded because it was dangerous or totally inappropriate research or something that was substantive about the nature of the investigation rather than the nature of the communication or what's on the printed page? DR. GELLER: Well, as Shobita said, there was only one that was evaluated as scientifically questionable. MS. PARTHASARATHY: And even that one was just a health survey. I think in general even if they were "dangerous" or "risky" settings, the reason why they were downgraded or considered problematic was basically because the communication about danger, the communication of those risks was -- CHAIRPERSON FADEN: There is one big hole which I've already mentioned which we don't know yet. There is the several studies that appeared to have been downgraded in part because of how issues involving people of questionable competence were enrolled in the study. We haven't mined those yet. We have to go back to those and figure out more what was bothering the reviewers about that. But it's possible that in that area, okay, the issues are different simply than that the explanation to the potential subjects was inadequate with respect to the benefits or with respect to the down-side. So that's open yet and we haven't gone back and there are four or five of those. DR. GELLER: And also, Phil, there are some studies, and I mean I don't have the exact numbers, but there certainly were some where reviewers said that they were greater than minimal risk and the risk was not offset by benefit to the subject. Now, what conclusions you draw from that is a separate issue. I mean you may want to say that the fact that there were any that fell into that category is not acceptable -- CHAIRPERSON FADEN: Right. DR. GELLER: -- but that's sort of what we you say about -- CHAIRPERSON FADEN: Why you want to distinguish that from scientific merit. In other words it could have been an interesting scientific question, but to answer it the reviewer worried that from the subject's point of view it didn't look too good, okay. DR. GELLER: Yes. CHAIRPERSON FADEN: which is more than a communication. MEMBER RUSSELL: That's kind of disturbing that there were several that were -- DR. GELLER: But reviewers were not asked to say this should not -- that's sort of a conclusion that the committee gets to draw from the fact that there were some studies. MEMBER RUSSELL: Were those all in the category of four or five? DR. GELLER: Well, 40 percent of the studies that were considered greater than minimal risk or 40 percent of the reviewers felt that those studies where -- MS. PARTHASARATHY: 40 percent of the studies. DR. GELLER: -- the risks were not offset by potential benefit. But clearly 40 percent of the greater than minimal risk study is about 20 or 25 -- MEMBER RUSSELL: Potential benefits to the subject? DR. GELLER: -- yes, and there were 17 that got fours or fives, so there are some that -- MS. PARTHASARATHY: Close. DR. GELLER: -- yes, close -- CHAIRPERSON FADEN: I've got Henry waiting patiently, and Ruth who wanted -- no, okay. Did you want to pursue it further, Phil? Okay. Henry? MEMBER ROYAL: The words that were used for this contemporary project to describe the experiments are different than the words that were used to describe the experiments that happened in the past. Specifically what I'm referring to is the words "human radiation experiment" is used permanently for the -- CHAIRPERSON FADEN: Old ones. MEMBER ROYAL: -- old ones, and the words in this contemporary research project are very different. Maybe "very different" is an exaggeration. Are different particularly in light of our contemporary study -- CHAIRPERSON FADEN: Right, that shows the language we provide. MEMBER ROYAL: Correct. We need to either have a reason -- CHAIRPERSON FADEN: That's a good point. MEMBER ROYAL: -- for using different words or we need to use the same words. Let me see, there was one other comment, just to let the authors know, the box on page five needs some work. I found it interesting that the bio distribution studies in the second paragraph were characterized as the object of the study is potentially hazardous radioactive contaminants themselves, and then on diagnostic studies it's we're injecting radioactivity but there's no reference to the fact that the are hazardous, and I don't think that the body knows what the name of the isotope is, so I was confused about that language. CHAIRPERSON FADEN: Please edit it, Henry. That would be helpful. MEMBER NORRIS: I do have a question and I apologize because I did not refresh my memory on this, so it may be answered in here and you're going to have point it out to me. It seems to me that it was either Jay or some of the early analysis indicated that the group oncology protocols tended to be more problematic as a group than others. Is that borne out in here, is that reflected in here. And I don't recall why those protocols as a group were problematic. Was it because of risk or was it because of consent problems or both? MS. PARTHASARATHY: In general the oncology group protocols are basically all greater than minimal risk protocols, and therapeutic also. So that may be part of the reason why there were a lot of clinical problematic studies. We started out writing it and then we kind of edited it out as we went through. One of the big issues that we were trying to flesh out as being a major issue for the oncology protocols was the issue that generally the oncology group sends a clinical model consent form to the institution and that then goes to the IRB and, you know, subtle changes. And we were looking at the issue of there being a boilerplate of the entire -- you know, the entire consent form being boilerplate and that that may in fact be problematic. But we didn't actually include that discussion in this iteration of the draft. MEMBER NORRIS: Should it be? CHAIRPERSON FADEN: I don't think so. I mean not yet. It bears a little bit. Again, this is a judgment call. We can look hard at it. There are two kinds of issues. I mean the bottom one is how far we can go with these data and there may be lingering issues, but what it looked like was, you know, there was boilerplate that traveled from one to the other, but the problem is what it says. I mean it's not that it's boilerplate, it's what it says. And whether it came up in one place or it came up in several places is kind of what the concern is. So the ambiguity of the discussion we had last time about your doctor will explain this to you kind of stuff, and who is it, your doctor, and is it the investigator or all that kind of stuff, that shows up in oncology group forms, but it also shows up in other forms. And the issue that we couldn't -- the data that we have don't allow to address is whether there are sort of prescriptions on the extent to which IRBs are allowed to change. Risk statements for example in drug-sponsored research, which we don't have anyway, which is a whole other set of issues that we don't have to deal with in here, so on balance I think that the kinds of issues we saw, we saw other places too. But, you know, again, we could take a look at it again and see. I'm happy to have a group of us take another look and see if that's right. Jay? MEMBER KATZ: Could I just make really a very informal statement to all of you enlightening and unenlightening. Is first of all for the last four weeks I've really been out of touch with the staff on the protocol review. They've been so busy putting all this together that they had to work very very hard and I wasn't sure what they were thinking about and what they were doing and what they were writing. And I was confronted with the same document that you were confronted with. Let me just say it was interesting for me to learn of the agreement between what they were doing and what I've been doing, and even the greater agreement in the light of the statistics for whatever it's worth. And I'm sure statistically it's worth nothing, Duncan. Let me just tell you the way I worked briefly is, as I reviewed these protocols I was not particularly interested in evaluating scientific merit. Many of these studies I wasn't sure whether to test the impact of exercise on the future well being of people who had undergone an efactomy whether that was a scientifically great study or not great study or not. I didn't see any study, but it wasn't part of my interest, where I would say that's really horrible, you know, or that's really terrible. They seemed to be, you know, you've got to make a living somehow and you have to get support, so these are scientific studies. What I was interested in was the following, and it was based on my view of the federal regulations and what IRBs are supposed to do primarily. And what IRBs primarily are supposed to do is to review the research proposal and see whether they have various kinds of comments to make about the proposal and for modifications, etcetera, and things that they do not understand that are incompletely described. And then they are supposed to really take a good look, not at the informed consent process, but they are supposed to take a look at the informed consent form. In fact they spend an inordinate amount of time I think on the informed consent form, which they would spend less time on it, but they do, they see it as part of their charge and whether that product, that important product communicated anything. And these are the two things I paid attention to because since we were primarily interested in this project is how adequately from the information available, whether rights and interest of the research subject is protected. I found that in many of the research protocols I would have sent back to the investigators and said, I mean I used to serve on the review committee, we would do and say look, this isn't clear, this isn't understandable, this even doesn't make any sense, revise it and send it back to us. They were not revised. Indeed many times I had to comments of the reviewers and what was interesting about them, that all the things that I was concerned about didn't seem to be of any concern to them, but they were interested about by and large I thought of esoteric meaningless kind of issues. But so be. About these matters good people can differ. So I evaluated the research protocol again in terms of how in my view on the basis of the research protocol did the IRB really pay attention to protecting the interest of the research subjects. With respect to the informed consent form, I did the same thing. If reading the informed consent form, what kind of things were said in what way, what was included, what was omitted, and could on the basis of that informed consent form a person appreciate what was at stake. I did not take into consideration, and that's a separate issue, you know, which researchers always tell me, the latest mantra is that informed consent is not an event but it is a process, and that's fine, but what does it mean. But I would say, and my answer to them is at the end of the process it's the informed consent form. And if the informed consent form does not reflect what should be, what should have occurred in the process and that there is a great discrepancy, as I would think there must be, if we take the informed consent process seriously, which means the form and what was communicated, then I had problems. I can document all that on the basis, and maybe for the same or different reasons I came to similar conclusions as most of the official reviewers did, I didn't pay too much attention to the form that we sent out except in a very general kind of way because -- and I voiced it at the beginning, but I was outvoted, that I didn't like the kind of form that we constructed for the review process. But because I had problems, all kinds of problems with it, but low and behold the form was good enough that in a general way my non -- I apologize, Duncan, my non scientific way of going about it brought about similar results to the scientific way in which all of us proceeded in the official review. DR. GELLER: What's important to us as staff in part is it's my impression that we ended up, whether it was our intention or not, evaluating consent forms on very similar basis. If that doesn't come through in the chapter, that's a problem. MEMBER KATZ: It doesn't come through yet, but that we have to work on, yes. DR. GELLER: Yes. CHAIRPERSON FADEN: Duncan, did you want to respond? And for what it's worth, I would like it if people could take, when we're at the end of the meeting, a minute each of us to say what are we thinking based on reading this. That would be very helpful. What's your gut take? I would like if people would take a minute as we're closing to give their reactions to what they read. I mean what impression have you formed tentatively based on what you've read. That would be very helpful. So we can know how to proceed. Duncan? MEMBER THOMAS: Jay touched on something that I think is extremely important. If one of our purposes here is to review the IRB process, this project didn't really capture that very well. I too had noticed -- CHAIRPERSON FADEN: But, I mean in the chapter that we've received or in general? MEMBER THOMAS: No, the mechanism of the review process. MEMBER KATZ: Oh. MEMBER THOMAS: Didn't really give us the opportunity, there was nothing in the box, in the form. There was no box for us to question the adequacy of the IRB's review. And I too was struck in the few anecdote examples that I saw where we had ethical problems with the project that the IRB was concerned with, what did you call it, esoteric and trivia, and didn't touch on the things that primarily concerned us very much. And I wonder whether this is an experience that other members of the committee had and whether this is something that even though we may not have captured it in the data we have, it's something that we want to say. CHAIRPERSON FADEN: I see Ruth responding, and then I really would appreciate anybody who wants to volunteer a comment, that would be helpful. Ruth? MEMBER MACKLIN: Yes. This is going back to discussions we had several months ago, but we didn't design this in a way that could get at some of those questions even though we end up making inferences about the IRB process. For example we deliberately decided not to request the minutes of meetings, the correspondence and communication between the IRB and researchers and perhaps other administrative papers. Therefore, if we were going to do that, if one of the aims was to look at the IRB process, we would, it seems to me, deliberate have to have sought additional materials that we did not seek so at best we can make inferences about the incompleteness, about the lack of attention to the wording in the consent form, if it was so opaque that subjects could not hope to be able to use it. CHAIRPERSON FADEN: What we don't have. MEMBER MACKLIN: Let me give this kind of example because I think this is critical. On the question of balancing of benefits to risks, that could very well happen in a conversation that the researcher has when he or she comes to the IRB, and an IRB member questions the researcher and say I'm a little upset about this benefit risk ratio to me, could you say some more about what are the benefits of this research especially if they're not benefits to the subject. And the researcher might then exquisitely lay out the benefits on the contribution to knowledge and science which none of us in reviewing it could do. So in those protocols where the box was checked cannot evaluate, you know, are the benefits worth it in terms of the risk. Or even the scientific merit, there were lots of times when I and my co-reviewer checked "cannot evaluate," but that's because the people who were doing it lacked the specific expertise to be able to do that. So I mean the results could actually look better if one had information that could, you know, illuminate the question of whether or not there was a justification of both the contribution of scientific knowledge and the benefit risk ratio. CHAIRPERSON FADEN: Yes. Let me just comment that the one place where that's an exception of course is the consent form itself, because we have the approved consent form. MEMBER MACKLIN: Right, and that's the only -- CHAIRPERSON FADEN: That's the only area where if the committee concluded that the consent form was inadequate, that was the approved consent form so we have a disagreement that's clear. Other than that I'd express sort of to myself and to Jay, there are two rival hypothesis here. One is however we say the world is, one is the world is a lot better than this review suggests for the reasons that Ruth has just outlined. IRBs have access and it's here in the draft, "IRBs often have access to information about protocols they're reviewing that this committee did not have," that's what you're saying. So it's conceivable that in some cases in fact the IRBs had more information and the study looked better than what we got. The other rival hypothesis is that the world may well be worse than what we saw because what we don't have and what IRBs don't have is what actually happens between the research assistance and the investigators and the patients. So we have the consent form -- and that could go either way. It could be that in fact the dialogue and exchange with the patient or the healthy subject, the healthy person who is being recruited, is richer and more thoughtful and more respectful and more detailed than what this document before us suggests. And it's also possible that it's more manipulative and more cursory and less serious than the document suggests. So we have to remember that what we have is a base for drawing some conclusions but that the world could be better or worse than what we have evidence here suggests. That doesn't mean you can't say anything. It's just like everything else in life, it's not perfect and we don't have a total check. We have what we have and we should qualify that, but I think what we have is significant. I see Henry and then Jay. And anybody else who wants to say what they think this all means. MEMBER ROYAL: I wouldn't sell this study too short. I actually think we could say a lot. And one of the reasons why we can say a lot is we got to see consent forms and IRB applications from many different institutions. CHAIRPERSON FADEN: Correct. MEMBER ROYAL: And it really is striking the difference in the sensitivity that different IRBs have to the process. And one of the reasons why I think that's such an important finding is, you know, as much as I dislike paperwork, I think a strong argument can be made that the form itself is part of the educational process. The very fact that the IRB application for example is supposed to address the issue of what is the risk benefit of this experiment, it's supposed to address that explicitly, forces the investigator to acknowledge that this is something that he should think about and do. And it was surprising to me that ethical issues which we think are important in some IRB applications just that they're not referred to at all. The second thing that I think that we can say very confidently is the fact that consent forms don't communicate risk and benefits to patients very well. And if an investigator can't do that on a piece of paper, it's hard to believe that they're going to suddenly come up with the right words when they do it verbally. I mean the consent form is something they've had a chance to think about and presumably they've made an effort to communicate the benefits as risks as well as they can, and it's clear in many instances they do a poor job of it. So as said I think there are a lot of -- the one caution I have about the conclusions is I hope that we pick out two or three or four things that we really focus on as being the most important conclusions so that people don't get lost in the individual details like, you know, how many times a particular thing was checked off -- CHAIRPERSON FADEN: Right, right. MEMBER ROYAL: -- we really should try to identify the most important things that we think need to be done. CHAIRPERSON FADEN: Yes, that's very important. I'd like to hear from other people who have a -- Jay and then -- MEMBER KATZ: Well, I'd like to be -- CHAIRPERSON FADEN: -- Eli. MEMBER KATZ: -- I want to be brief, and will probably have to continue this tomorrow, let me make three brief comments. One with respect to the two hypotheses that Ruth advanced as a third hypothesis and namely that things of course are somewhat better than they were prior to 1974. But we now have a 21 year history of federal regulations. And, look, we may want to throw the whole study out because it's so flawed and say we just -- CHAIRPERSON FADEN: No -- MEMBER KATZ: -- no, no, no, let me finish, let me finish please. We may want to throw it all out because it's so flawed and that was a possibility, we had also sufficient time to look into this, into these matters. But if we stay with it, and speaking for myself however flawed the study is, what I've done and from what all of us have done, I've learned about the small steps we've taken, not a giant step to the moon, but small steps, you know, on the moon with respect to moral progress in the light of the result of the studies. Of the complex, risky kind of experimentation, 47 percent of them are seriously flawed. What does it say about IRBs, what does it say about informed consent forms, etcetera? I think, and now I am speaking for myself and then I will stop, that what part of the problem is that the federal regulations really need to be, and I've thought about it a lot, need to be revised, need to be changed. The IRB structure needs to be changed, etcetera, etcetera. And if we leave this in either as a group or for myself I want to make some recommendations about it that maybe the majority can join me in because unless I can persuade you that my reasoning is correct, but if you persist with the study, we have certain facts to take into account. And here it takes me back to this morning, that in light of what we wrote in the introduction to chapter five, about morality etcetera. We have to make some very very strong and serious concern about what's going on in today's world. CHAIRPERSON FADEN: I've got Eli and Mary Ann wanting to comment. Eli? MEMBER GLATSTEIN: I think that basically on one of the points that Jay has just made, where the emphasis is placed at each institution is on the IRB. And the IRBs are highly variable. It depends on the quality of the people who are -- and the leadership that one or more on that committee will actually express. And many of the IRBs have no leadership which is a serious problem. There needs to be some structure to educate them by. My old mentor used to tell me that when you read the papers you have to understand that the investigator will always present the data in their flattering way. Nobody will show you the data in its ugliest picture. What was interesting to me was to see that the investigators have gone one step beyond, because many of the consent forms were presented in their most flattering way also. It was disturbing to me to talk about radiation therapy and multi-agent chemotherapy and not clearly say that it is possible that these treatments can kill you, because they can. Now, it's not terribly likely to happen, but they can kill people. And to fail to express that in a very clear and unequivocal way I think is a serious flaw. I think that, as I said, I think we need some kind of structure by which we can give some leadership to the IRBs themselves who on the whole I think are going through the motions thinking they're doing a good job and in some instances they are, but in many instances I think there's some real problems. And I think the institutions as a whole don't recognize it. CHAIRPERSON FADEN: Thank you. I hope, is the transcription continuing because we want to make sure -- COURT REPORTER: Yes, it is. CHAIRPERSON FADEN: -- okay, thank you. Because we want to make sure that that continues even though we're going a little over 5:00. This discussion is so important. Mary Ann? MEMBER GLATSTEIN: There's more of a problem than I anticipated. CHAIRPERSON FADEN: I think that's the general. Mary Ann? MEMBER STEVENSON: Eli and Jay have expressed a lot what I was concerned about. But I mean clearly we've all recognized variability between the consent form and the variability or the deficiencies in the consent form are going to rise either because of the investigator's lack of knowledge and expertise and expressing the purpose and the risk benefit ratios, or the IRBs deficiencies in being able to catch it and send it back to the investigator. So Jay actually answered one of the questions as to whether or not the committee wants to go on record and make some recommendations as far as the IRB process. And I would raise the question of whether or not, and I think Jay has alluded to this in the past, we want to make a recommendation as to a need for some kind of formal training for investigators doing research. And that's something that has not, to my knowledge, been formalized in terms of medical school training, post graduate training. So those are the two ways you get to a good consent form. I mean ideally both of them are working and you get the best consent form, but either one will get you to a better product in the end. CHAIRPERSON FADEN: I see. I want to make one comment for what it's worth. It should be recognized, I think we had about 16 proposals that were more than minimal risk that goes on, which says, and Jay pointed out some in his review too, it shows, and this goes to the variable issue, this can be done properly. I mean we have -- it's not as if we can throw our hands up and say look this defies the human experience. No one could possibly construct a set of documents and a consent form in a complicated context that is ethically appropriate -- MEMBER GLATSTEIN: Least I sounded too negative, there were some outstanding examples. CHAIRPERSON FADEN: -- no, but the point is -- MEMBER GLATSTEIN: Outstanding. CHAIRPERSON FADEN: -- yes, there were. And the point is that the reason they're important is unfortunately first of all because they weren't the majority, but secondly it's important because it's as it can be done, okay. And it is being done in some places. Jay had some in his review as well. And while, even if there had been zero, that would have been worse, it would have at least raised the hypothesis of look it can't be done, you know, it's just impossible. We know it can be. We have evidence that it can be, and we can pull those out, you know, additionally and that's speaks to, you know, whether it's variability in the thoughtfulness of the investigator or in the significant, the hard work of the IRB, which is your point, Mary Ann. We don't know from this. I mean often we don't know whether it came perfect to the IRB and the IRB had no work to do, or it came sloppy to the IRB and the IRB worked with the investigator and it was good because of this, and who knows. Sometimes we have evidence of IRB changes and sometimes we don't. All we know is some projects got it right even in very complicated context and other projects, unfortunately a fair number of them, gave members of the committee pause. That's basically where we were. I forgot where I was. Oh, Phil wanted the floor back. I'm sorry. MEMBER RUSSELL: One of the unfortunate problems we're stuck with is that the investigators in the IRBs are all people and they have to operate within a structure. I think we have evidence that the system and the structure can work and it produces some very very good products. I would look to how can we make the current system work better, somewhat along the lines that Mary Ann looked at, rather than proposing a new structure that still will be flawed because it's full of people. MEMBER MACKLIN: Well, the one thing, Phil, though is to make this system work better, the current system work better, doesn't quite address the problem of the variability of the IRBs. And that was particularly distressing because it poses a question of justice. That is the current system is predicated on institutional IRBs that work within the institution and the regional or local level and that that's the appropriate place for final review of the ethics. But I think what we have seen, and in some of the examples that -- and others that the very same protocol, especially what you can see in the multi-center trials, is reviewed exquisitely and very well by one IRB and abysmally by another. Now, that is the present system and it's not clear what we could do to make it work better -- MEMBER RUSSELL: Centralization of those kinds of things will produce just different kinds of injustice. You know, struggling between centralized and decentralized authority and system management is the name of the perennial argument. MEMBER GLATSTEIN: My idea of a structure would be basically an annual meeting of some sort sponsored by the NIH. MEMBER RUSSELL: You're talking about an educational process -- MEMBER GLATSTEIN: Yes. MEMBER RUSSELL: -- to make the current system work better rather than restructuring, right? MEMBER GLATSTEIN: Yes. MEMBER RUSSELL: I can buy that. CHAIRPERSON FADEN: We're now moving, and this is important because this is now moving towards recommendations. There is also the common problem of what do we mean by the current system. You know, it's not one person's throw out the system and get us a new one is another person's overhaul of the current system. So rather than use the term "current system" throw it out, keep it, I would rather we have a discussion of what kinds of changes would the committee like to recommend and then somebody can judge those changes as throwing the whole system out and starting again, and somebody else can say those changes are refining the current system, and they can decide that later. But the issue is what are the changes that the committee thinks are worth making recommendations about, if we feel we're in a position to do that and not get hung up on sort of ideological views about changing the system, keeping it and making it better. Let's think about the changes people would like to propose and then see if that constitutes throwing it all out or tinkering, you know, making major changes from within, or whatever we end up concluding. I have Nancy and Henry and Jay, and we are overtime. CHAIRPERSON FADEN: We have to stop because we have to go soon. CHAIRPERSON FADEN: So maybe we stop, we can pick this up some tomorrow. I realize this is a very big -- this interpretation of what does this mean. I am hearing a lot of agreement and that's very important. We have to discuss specifically what people want to recommend. MEMBER KATZ: By the way could I just have 30 seconds. I did not mean to suggest I want to throw the whole system out. I want to make some radical reforms, but not throw it out. Indeed one of my recommendations would be that the IRBs should be 50 percent of the review task because they are reviewing much too much, much too many research proposals that are Mickey Mouse stuff and they shouldn't do that, and concentrate on more important issues. But then there are other kinds of things that I think need changing, but I'm not suggesting to go to the point which really would lead only to moral progress in the light of Phil's comment, namely ones that is decisive genetic change in the human brain, because probably when that is going to happen and there is all kinds of mutations, then there will be truly moral progress for-- MEMBER MACKLIN: A mutation can go in either direction. CHAIRPERSON FADEN: Nancy and then Henry, and then we are going to stop for today. MEMBER OLEINICK: Oh, all right. I think we're heading towards some kind of an education program and I would certainly agree with that. And I think it probably ought to begin with students and proceed through some kind of annual retraining. But the other issue that I wanted to just throw in here was somewhere there were chairmen of IRBs were polled or asked to write about what their thoughts were, and we sort of filled a form and said we wanted to see these, and I haven't seen anything. Is there any information? No, that was never sent to me. CHAIRPERSON FADEN: Neither have I. MEMBER OLEINICK: I did check that I wanted to see them. CHAIRPERSON FADEN: Okay, we'll get it. MEMBER OLEINICK: So I'm just wondering if there was information from, you know, these are the folks and the troops in the trenches. CHAIRPERSON FADEN: Them too. MEMBER OLEINICK: That that might go in here. Yes, we have that in -- CHAIRPERSON FADEN: All of this needs to be put together, that's the really scary part. Henry? MEMBER RUSSELL: Just two comments about recommendations I think that might get some change for a small amount of effort. I'm asking a favor of -- research effort. I think it's very important that they learn about clinical ethics. But because only a small percentage of medical students go on to do research it seems to me a better time to teach them about research ethics is at the time that they want to do research. So I would rather see whatever resources are available for the educational process be really focused on people who are actually going to be doing research. And I just would remind you that for radionucleides you cannot do research with radionucleides unless you're an authorized user, which means you get annual recertification. So this is not unheard of that you have some basic knowledge before you can do research. The second thing has to do with, you know, how we get informed consent. Right at the moment if a physician spends time with a patient and the patient ultimately says I don't want to participate in research, the physician sort of regards that as having wasted their time. If physicians were required as part of their annual IRB renewal to provide a list of patients who they spoke to about participating in a research project and indicate which ones agreed and which ones didn't agree, suddenly the fact that a few people or more don't participate becomes a good thing because now they now that they're not going to be accused of browbeating patients into participating in research. CHAIRPERSON FADEN: So it's -- MEMBER RUSSELL: Right. CHAIRPERSON FADEN: -- so that a refusal is not always defined as -- MEMBER RUSSELL: Correct. CHAIRPERSON FADEN: This will lead us into the discussion for tomorrow. Before everybody goes away, and thank you, Duncan, for reminding me or I would have forgotten, this is the stuff to talk about tomorrow. One stack is number situations. It's a very technical term. We've had situation 1A, 1B, 2A, 2B, this is the return of the situation. I feel like a horror movie, you know, "Bride of Frankenstein" and now "Frankenstein Revisited" and this is "Situations Revisited." These are the various attempts, iteration upon iteration for the committee to see if it can reach any kind of view about what should happen with respect to people who may have been wronged in the past, okay. This document is like a projective test. There are seven categories here where the committee is supposed to fill in the blank. The committee finds that with respect, with regard to contemporary human radiation experiments, the committee finds that, okay, what's the bottom line take-home message? With one exception I think Dan stuck in one or two. These are basically left open. So the idea is to think about this tonight, and if you had to write the one liner that goes into the press release, that's the projective test, if you had to write the one liner that goes into the press release for these seven areas, what would you have the one liner be. All right, now that's to see, to get us going, to see how we are as a committee with respect for findings, okay. And also if we think there should be a one liner on (X) and it's not in here, or I don't think we need, this doesn't rise to the level of core finding from the committee. So if you're going to write the top sheet on the executive summary of the major findings of the committee, that's where this is supposed to be, and we'll start that discussion tomorrow as well. So don't leave without two pieces of paper. MEMBER MACKLIN: Could you just tell us what else on the agenda, I mean among the chapters -- CHAIRPERSON FADEN: I know, I know, I know -- MEMBER MACKLIN: -- because things got shifted around so much. CHAIRPERSON FADEN: -- got dropped were basically, let's take a minute on that. The agenda for today -- just what's left. Okay, we're going to do situations and we're going to do findings. MEMBER MACKLIN: What about chapters? CHAIRPERSON FADEN: Chapters, okay. Okay, with respect to chapters I think we need a discussion on the observational studies, and we need discussion about radioisotopes. MEMBER MACKLIN: How about secrecy? CHAIRPERSON FADEN: We can try secrecy, if we can get it in. I don't know if we can. But those would be the candidates. Radioisotopes has never been discussed. I would hope it can be like a short discussion, not a profound discussion, but a short discussion. MEMBER MACKLIN: The secrecy one is very important. CHAIRPERSON FADEN: The secrecy one is very important. Maybe we should try to make sure that gets in. Observational studies is to get a sense of whether this new approach, which has been -- whatever, flown by, thank you, floated by a members of the committee who have really been investing in that part of the thing is acceptable to the whole committee is going to attempt to write, somewhat. So let's try to do redistribution -- radioisotopes, observational studies, and secrecy. We're going to really focus on this finding stuff and the situations a little bit. And we need time to talk about where we're going in the process. We haven't done our process discussion, how are we going to handle this from now on. So don't leave without two documents. Three, what's the third one? All right, it's three documents, the cover memo for secrecy, for situations, situations and the fill in the blank projective test. (Whereupon, at 5:20 p.m, the proceedings in the above-entitled matter were adjourned to reconvene tomorrow morning.)