UNITED STATES OF AMERICA + + + + + +

ADVISORY COMMITTEE ON HUMAN RADIATION EXPERIMENTS PUBLIC MEETING + + + + + + MONDAY, NOVEMBER 14, 1994

THE MEETING TOOK PLACE IN THE GRAND BALLROOM NORTH, THE RENAISSANCE TECHWORLD HOTEL, 999 9TH STREET, N.W., WASHINGTON, D.C., AT 9:00 A.M., RUTH FADEN, CHAIR, PRESIDING. PRESENT: RUTH FADEN, CHAIR KENNETH FEINBERG, MEMBER ELI GLATSTEIN, MEMBER JAY KATZ, MEMBER PATRICIA KING, MEMBER RUTH MACKLIN, MEMBER LOIS NORRIS, MEMBER NANCY OLEINICK, MEMBER HENRY ROYAL, MEMBER PHILIP RUSSELL, MEMBER MARY ANN STEVENSON, MEMBER DUNCAN THOMAS, MEMBER REED TUCKSON, MEMBER

ALSO PRESENT: BARBARA BERNEY, ACHRE STAFF DAN GUTTMAN, ACHRE STAFF JEFF KAHN, ACHRE STAFF STEPHEN KLAIDMAN, ACHRE STAFF ANNA MASTROIANNI, ACHRE STAFF RON NEUMANN, ACHRE STAFF GARY STERN, ACHRE STAFF JEREMY SUGARMAN, ACHRE STAFF SANDRA THOMAS, ACHRE STAFF JON HARKNESS, CONSULTANT NANCY KASS, CONSULTANT I N D E X

Introduction of New Staff Members ............... 10 Historical Relativism and Retrospective Moral Judgment, Ruth Macklin .................... 12 Report: Case Study-Radiation Research with Healthy Adults Testicular Irradiation of Prisoners, Steve Klaidman and John Harkness .......... 74 Report on Cincinnati Small Panel Meeting, Reed Tuckson ............................. 155 Report: Case Study-External Radiation with Patients (TBI), Gary Stern and Ron Newmann .................................. 189 Update: Research Involving or Affecting Children, Sandra Thomas .................. 254 Update: Ethics, Criteria, Jeff Kahn ........... 257

Update: Institutional Case Studies, Dan Guttman .................................. 259 Update: Biodistribution and Radioisotope Research, Barbara Berney ................. 261 Meeting Adjourned .............................. 265 P R O C E E D I N G S 9:00 a.m.

DR. KASS: -- Institutions where we're going to want to go interview. It is our hope that that will be the primary activity going on that will be completed by the end of December. Because of some of the delays we've had so far, we actually have been starting to draft materials that IRBs can use for models ourselves. The subcontractor also will be doing some focus groups which will be used to prepare the instruments actually used for our study itself and we're hoping that both of the instruments, the one for the short interview, close-ended component, as well as the semi-structured longer interview, will all be completed by mid-December, that the instruments themselves will be finished by then. We then hope that we'll be in the field actually conducting all of the interviews in January and that that will be completed by mid-February. The data entry will begin as soon as get any data back and we hope that the analysis will be completed

by the third week of February which will mean that we'll be able to have a draft report for you by the March 13 committee meeting. DR. SUGARMAN: Questions?

DR. MACKLIN: Have you decided yet whether on the initial interview you're going to do, I think we discussed before a group interview and then that would to an in-depth or are you going to do individual interviews and then from that group move to the in-depth? DR. KASS: The plan right now is to do individual, but much shorter interviews with a large number of people. We're hoping to do -- our goal is to do 150 at each institution, depending, obviously, on availability. From those people will be selected a much smaller number of people, 10 to 15, at each institution with whom we would do a semi-structure, longer, more open-ended kind of interview. DR. KATZ: When can we begin to see your drafts on the instruments and instructions and I mean real drafts so that we can have an input on the final instrument that you will develop because these interviews raise very serious issues, methodologically, results, etc., and I think that the committee should have as much of an input even if we get a new draft every other day from you. For once, fax machines are useful. I hate fax machines, but I really want to participate in this process as much as I can. DR. SUGARMAN: I think in answer to that, once the subcontractor gets on board, they are going to be lining up focus groups and I can tell you even before all the negotiations are completed, they have begun work on identifying focus groups. We have a draft that you have seen months ago that's going to be used as the script for the focus group. Once the focus groups have been conducted, we will be happy to circulate those and we may need to work that through in sort of a fax fashion with very rapid turnaround times. The reason why instrument development is going to need to be rapid is that we'll have to submit these materials to the IRBs so we won't have many opportunities, but if you are interested in that, I guess we'll work out a mechanism where those people who are interested in participating in this process will be very much in the loop, but it will be a very quick loop. Additionally, because we are all engaged and very busy, one of the things we have built in to the task order to the subcontractor is the identification of sort of an expert panel of methodologists who do this sort of research all the time. We realize we do this research a lot of the time, but we also thought that we're moving at a pace, we're loading trucks right now, and we want to make sure there's someone watching over that process to give us some input, removed from the process, just sort of strict methods critiques and we want to hear those up front as well.

DR. MACKLIN: One more question, have you or do you plan on building any redundancy into this system sort of as we've done for the protocol review, sort of assuming that we may only get 50 percent back of the IRB materials that will still leave us enough numbers to analyze in the same fashion? I mean you don't want to be too labor intensive, but if you built in redundancy you get held up by IRBs. DR. SUGARMAN: In terms of -- those are great questions -- I think there are two areas of that. One is have we built in redundancies first with respect to numbers of institutions and region, and second, with any institution have we built in redundancies because there are multiple layers. But those are the two big ones. In response to whether we've built in a lot of redundancy to region, no, because the amount of effort it takes to line up each of the institutions we are -- we can't do that and I think we'll have to ask some hard questions later on, if certain institutions let us in. With respect to have we built into redundancy at the next stage to fulfill response rates, there is leeway built into the task for them to stay at institutions long enough to accomplish the 50 short interviews in each sub-specialty, making 150. It is a descriptive project rather than sort of an intervention, so that whatever we describe will still be useful and we don't need to worry as much about the numbers. DR. MACKLIN: Actually, that's a good point. think a little bit more about that redundancy issue. We might

DR. SUGARMAN: We actually have built in and tasked the possibility of a fifth geographic region that if we decide we want to do that, the mechanism is in place to have funds available to have the subcontractor do that sort of work, so it's also a discussion that would need to take place if you think that's important for us to do. We can certainly build that in, but we thought about this in a lot of ways. The task reads that there are several areas for additional work to be done. We don't anticipate that the subcontractor will do all those and we've made sure that they will not be paid for the work that's not done as well. DR. FADEN: Other questions for Nancy and Jeremy? Well, I thank you very much and we hope you can get it done. expect, we expect you can get it done.

We

I want to quickly introduce an agenda item that isn't here and that is we forgot to build in time, very briefly, for introducing new staff members. Let me ask Jeff to come up and tell the committee about anybody who has joined us in the intervening several weeks. DR. KAHN: Just for your own reference, Tab C has the shortened biographical sketches of the four people we've added

since our last meeting. Alphabetically, they are Steve Goodman - and maybe if you could just raise your hand so people will know who you are. That's Steve, who is a physician with a Ph.D. in epidemiology, and he is on the faculty at Johns Hopkins, as Jeremy mentioned, in a previous short briefing. Second is Valerie Hurt. There's Valerie. She comes to us having just left NABER, the National Advisory Board on Ethics in Reproduction here in Washington, where she was a research assistant. She studied at George Washington University. Third is Wilhemine Miller. Wilhemine is a doctoral student, a doctoral candidate, pardon me, at Georgetown University, specializing in ethics in public policy. She has a masters degree in Health Policy and Management from Harvard School of Public Health and prior to going to Georgetown, she spent 15 years as a policy analyst at the Department of Health and Human Services here in Washington. Fourth is Pat Perentesis. Pat is just leaving NIH at the Division of Nuclear Medicine where she is a clinical nuclear medicine technologist. She's also a registered nurse. She's joining us to help in the area of science and nuclear medicine. So those four are here to see what happens in the proceedings here today and will be around to talk with anybody who needs to see them. DR. FADEN: Thank you, Jeff. I think that given that Reed is not here we should do a major shift around. I'm eyeing Ruth. Is that all right? All right. So we're going to get to work -- oh, did Reed just come in? Reed, do you want a minute or do you think you can perform immediately? Why don't we just go ahead and rearrange the agenda, I think. I think that's fine and that way Ruth is prepared to go. We can get right into some substantive issues and Reed can relax a little bit from having rushed from the airport. I think it might be better, Ruth, if you went to the speaker's platform. DR. MACKLIN: This red light is still on from the last speaker. I have to apologize because I don't have slides or overheads and being very old-fashioned and perhaps in that regard only, I've recently been at several meetings in which people said "I couldn't follow your talk because you didn't have it all written up there." So I apologize. Maybe I'll have to change my ways. This is entitled, and it's very rough, that's my second apology, this is entitled "A Framework for Making Retrospective Ethical Judgments." There's some argument in here, but most of what I try to weigh out are different ways of thinking about

retrospective ethical judgments or judgments about history in the past. The work that's been done so far in this committee, very capable work by the staff, has looked at a number of the events and activities that the Advisory Committee is studying and judge them or sought to evaluate them using today's standards, that is, either today's ethical standards or today's regulations or both. I want to step back from that and ask about these kinds of judgments. There will be plenty of time for discussion because I'm going to talk for about 20 minutes. How do we judge historical examples of conduct that we now believe to be unethical? How should we evaluate the conduct of people in the past? Are retrospective ethical judgments legitimate and if not, why not? If so, in virtue of what standards or principles can we make trans-historical ethical judgments? Even if we judge past conduct to have been unethical, does it necessarily follow that the individuals who engaged in that conduct can be considered morally culpable? This analysis is designed to address these questions. The candidates for possible ways to make ethical judgments about the past can be located along a continuum ranging from very strict to very lenient criteria. Underlying these various criteria are some presuppositions about historical relativity and the notion of moral progress. Now first I'm just going to sketch these positions and then go into more detail, just a brief sketch. The most lenient position -- and we might be able to find better words for these - but the most lenient position holds that whatever the standards or practices of the time were, they constitute the only basis for making retrospective judgments. According to this view, the use of today's ethical standards, rules or practices, to judge the past is illegitimate. This position is one of extreme historical relativism. A second view admits a degree of historical relativity, but also recognizes as legitimate the notion of moral progress. According to this view, although it may be inappropriate to blame people in the past for not adhering to ethical standards or conduct that were not then articulated or practiced, it is nevertheless meaningful to hold that today's standards or practices are morally superior or more ethically advanced of those of the past. The strictest position contends that people in the past ought to have known or ought to have articulated or adhered to certain ethical principles based on other features of their culture or society that demonstrated cultural sophistication or intellectual development. For example, and this is outside the realm of ethical conduct, for example, in literature, art, music,

mathematics, science and government -- that is to say, cultures in which there was sophistication and development in these other intellectual and cultural areas, one might make the argument that they ought to similarly have developed ethical principles or ethical guides to conduct to mirror or match their sophistication in these other areas. Now there's a somewhat different basis for this strict view and it stems from evidence that some progressive thinkers of that time did, in fact, articulate such principles or criticize then existing practices on ethical grounds. So that's the very rough sketch and further refinements of these basic positions can be stated with the following five criteria and my analysis begins with a statement of the criteria, along with a few general examples and is followed by application to human radiation experiments. Now here are the five criteria and I'll have to keep repeating this initial clause. Criteria for making ethical judgments about past conduct could be based upon -- this is the phrase that's going to preface five different criteria -criteria for making ethical judgments about the past conduct could be based on (1) unarticulated, ethical principles, codes of conduct or rules that now exist, but did not exist at the time. It might be said that although no one at the time, in fact, articulated or propounded such principles or codes, people ought to have done so in light of their sophistication in other areas. For example, this might be said of Plato and Aristotle who defended the practice of slavery in ancient Greece. Aristotle's defense of this social arrangement was based on his view that some people are natural slaves and others are natural masters. Now, it may well be true that some people have personal traits that make them good leaders, while others have traits that make them good followers, but it does not follow from those observable differences that the former should be ethically permitted to own the latter and treat them like property. Aristotle made numerous distinctions in his ethical theory, including distinctions between intentional and unintentional conduct, voluntary and involuntary conduct, and he gave a finely-tuned account of human virtues. It seems fair to say that Aristotle and others of his time had a moral blind spot when it came to the enslavement of humans. Based on the sophistication of his own ethical theory, he ought to have seen that it is not ethically permissible for human beings to own other human beings like inanimate property. That's the first criterion. The second criterion, that is, a criterion for making ethical judgments about past conduct, could be based upon -- and this is number two, articulated, but not widely accepted principles, codes, standards or rules. Such views may have been articulated by critics of then-current practices, by philosophers or social reformers, those who held progressive views that later became accepted.

Such people are said, in retrospective, to be ahead of their time. Examples include criticisms of slavery in the Antebellum period in the South; early critics of racial segregation before the Civil Rights Movement; and, critics of torture and other inhumane practices regarding prisoners when such practices were widespread. The third criterion, remember, this is a criterion for making ethical judgments about past conduct, could be based on known principles, codes or ideals that were generally accepted in other spheres, but not applied to the particular type of action or practice in question. Examples can be found in the area of sexual conduct. Some examples, some of which remain controversial or current today. The legal and ethical doctrine of privacy was recognized in this country, in general, and in many spheres of life before it was applied to sexual conduct between married couples and the example I have in mind is the Supreme Court's decision in Griswold. That decision which was in early 1965, was it, that decision struck down existing laws that prohibited the sale of contraceptives, even to married couples and what was invoked there was the privacy doctrine. Now the controversial application today of the notion of privacy is the existence of sodomy laws that fail to recognize a right to privacy of consenting adult homosexual couples. Another example, one that bears on the requirements of informed consent in the biomedical sphere, is the long-standing recognition and acceptance of the notion that people may not be touched or have their bodies invaded without their permission. Although this ethical position was widely held in many areas of social life, medical practice seems to have been excluded from this ethical prohibition against unwanted touching, until the early consent cases, that is the Schloendorff v. New York Hospital in 1912 and the body of cases that first established the doctrine of consent, although as we know it, was not yet informed consent. These early consent cases established that doctors must have the permission of patients to invade their bodies, but not until the court cases in the late 1950s was it established that doctors had to provide adequate information to patients about what they intended to do to their bodies. The fourth criterion -- notice that these are getting weaker, these are more lenient. The fourth criterion is known principles, codes or ideals pertaining to the type of action or practice to which lip service is paid, but are not yet or are only rarely implemented in practice. So quite clearly these are known and articulated, but only lip service is paid. This can be thought of as the gap between what people think or say is right and what they actually do. The example most pertinent to the work of the advisory committee is that of

obtaining voluntary informed consent to research, after Nuremberg, but before federal regulations were put in place. It could hardly be said that no one knew of or heard of the Nuremberg code, and the ethical requirements of informed consent to research. This is perhaps, when I say this is perhaps, I mean I believe it is, the most appropriate criterion for an ethical evaluation of human radiation experiments in the years after Nuremberg and even before. It is more lenient than the aforementioned second and third criteria, yet it allows for retrospective historical judgments, including ones that assign blame to moral agents. Fifth and last as a criterion for judging the past is the actual practice of people at that time. This extreme form of ethical relativism is ethically unacceptable, since it validates any and all past practices and conduct simply by virtue of their existence. It is a simple application of the maxim, "whatever is, is right." Since this criterion precludes the possibility of making meaningful retrospective historical judgments, it deserves to be dismissed. Now applying these criteria to radiation examples, and this has a word about methodology, one way to determine which criterion to adopt might be to decide a priori, that a certain criterion is the right one. That is, we sit around, deliberate and make arguments and decide "let's pick this one." However, that's likely to lead to disagreement between those who favor a stronger criterion and those who favor a weaker one. A second way is to seek to determine whether the strongest and the weakest may be ruled out and then work towards the middle. I've already indicated my own preference or decision to rule out the weakest criterion, the one that says we cannot in principle make judgments about the past, except in terms of what was then practiced. But what about the strongest criterion which holds that ethical principles, codes of conduct or rules that now exist, but were not articulated by anyone at the earlier time may be used to judge the past. I contend, and I do this with some trepidation, that this criterion is useful for judging actions, but not moral agents. It is certainly meaningful to use ethical precepts currently accepted to judge past actions, that is to say that they weren't wrong, but it is a separate matter to hold morally culpable the individuals who perform those actions. If no one ever conceived of, or articulated, the notion that such actions could be morally wrong, how can we assign moral blame to the particular individuals who engaged in those actions? Fortunately, we do not have to use the strongest criterion to use the human radiation experiments. Criteria 2, 3 and 4, my middle

three, applied to one or another situation, provide grounds for judging certain actions to have been wrong in virtue of what was known or articulated between 1946 and 1974. I'm just going to repeat again those criteria because these are the three that I contend we should be thinking about and working with. First, the articulated, but not widely accepted principles, codes, standards or rules and I'm lumping these all together for this rough purpose here, that is, principles, codes, standards or rules. The second here is, the middle one is, known principles, codes or ideals that were generally accepted in other spheres, but not applied to the particular type of action or practice in question. And notice that the action or practice in question varies, depending on what we're talking about. One is experimentation on prisoners, two is experimentation on dying patients, three is experimentation on children and on institutionalized, fourth is intentional releases. That's what I refer to when I'm talking about the particular action or practice in question. And then the third of this cluster of three known principles, codes or ideals pertaining to the type of action or practice, that is, that would pertain to that particular action or practice, but ones to which lip service was paid, but were not yet rarely implemented in practice. The details of the application need to be worked out and I have not or not yet undertaken that task, but the following are the pieces of evidence and the kinds of pieces of evidence, documentation information that can be fit into this scheme and I'm going to do this in just a very truncated way. If this were a full paper, I would have all the quotes and the cites, etc., but this is just a mere list. And the details of this next -these next few are stated in the interim report on pages 12 and 13. First, in the case of the military, documentation of consent policies predates the 1947 creation of DOD. See footnote 11 on page 12 of the interim report which locates the -- which identifies the documentation of consent policies. You can never say there were no policies or that these didn't exist. Second, in 1946, the Judicial Council of the American Medical Association published principles that called for voluntary consent to research. The Medical Advisory Committee to NEPA, that was the first -- our glossary didn't put in the second one, right, Nuclear Energy Propulsion for Airplanes, recommended that these AMA principles be used to guide human experimentation under its auspices. That was 1946. So there we have a time at which something was stated, written down and documented. Next, AMA rules concerning, American Medical Association rules concerning human experimentation written by Dr. Andrew Ivy, including provisions stipulating informed and voluntary consent. That could be found in briefing book 7, Tab A, Attachment 2. In February 1953, the by now infamous Wilson memorandum, the policy adopting the Nuremberg code to the fields

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of atomic, biological and/or chemical warfare. And finally, in this batch, at AEC, evidence for a consent policy dates to 1947, the year of the AEC's creation. Were these policies enacted as formal guidelines or rules where they put into practice by AEC sponsored investigators, these are some of the factual questions that would have to be answered to see how far these went and who might be held capable. Now these items I've just mentioned and others that I'm sure the staff can add from memory, relate only to the statement or adoption of policies governing research by these federal agencies. That's only policy so far. Other evidence, and the evidence that we need to find for whether or not anything was ever thought of or spoken or articulated or propounded, not only from policy, but other evidence, other evidence comes from letters, memos, transcripts of meetings and published articles. Here are some examples: Shields Warren, Dr. Shields Warren's opposition to the NEPA proposals for human experimentation in 1948 and 1949, a letter from Shields Warren to Leslie Redman dated March 5, 1951. Now I found significant that this letter quotes another letter from Carroll Wilson to Dr. Robert Stone dated November 5, 1947 in which the statement prepared for the Commissioners by the Advisory Committee for Biology and Medicine is quoted as follows and I'm going to read the quotation because one can't ever say nobody thought of these things in 1947. Here's the quotation: "We believe that no substances known to be or suspected of being poisonous or harmful should be given to human beings unless all of the following conditions be fully met: (a) that a reasonable hope exists that at the administration of such a substance will improve the condition of the patient; (b) that the patient give his complete and informed consent in writing." Notice this statement in contrast to others that we've seen uses the words "informed consent." It just doesn't say consent or permission. The words "informed consent" are in there. And "(c) that the responsible nearest of kin give in writing a similar and complete and informed statement revocable at any time during the course of the treatment." So I note in this statement from 1947, the use of the words "informed consent" not simply "consent." And also the fact that this explicitly includes experiments on patients, not healthy volunteers. We have had some discussions about whether or not certain rules in the Nuremberg Code was thought to apply at the time, only to normal healthy volunteers, whereas quite clearly, talking about the patient, the substance improving the condition of the patient presupposes that you've got a patient there and the patient has some condition that could stand to be improved by this substance. Okay, here's a few more examples before I'm through. This is in today's briefing book, the Jackson letter to Casburg regarding the requirement of written consent dated October 22, 1952, that's in the section on the origins and drafting of the Wilson memo and subsequent DOD policy.

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Another example, the Armed Forces Medical Policy Council Memorandum to the Secretary of Defense, dated December 21, 1952. And Andrew Ivy's article which was published in Science in 1948 stating that the most important ethical requirement is that subjects are volunteers under no undue pressure to participate. Another item and I'm coming to the end here is the special article in JAMA, February 14, 1948, "Ethics Governing the Service of Prisoners in Medical Experiments." This is again in today's briefing book and it refers to ethical principles including the following three, that all subjects should be volunteers in the absence of coercion in any form; two, before volunteering they be adequately informed of the hazards, if any; and three, that the choice of volunteers be made on the basis of established criteria. So in concluding this rough presentation here, some additional points that we need to keep in mind if we're going to be applying this framework: the Committee has to decide which of the above-noted criteria for retrospective judgments should be used to evaluate radiation experiments before 1974. Now I've already just asserted that I think the weak criterion, the practice of the time, should not be used, that that should be dismissed. And that the first criterion, the strongest, today's standards, doesn't have to be used because two, three and four are applicable, namely, these things were articulated, there were policies, there were views that were expressed. A second question is to whom the criteria should be held to apply. For example, those who ordered the research to be done, those who actually carried it out, or some intermediate level of supervisors, if there were such. I mean assuming that there was some hierarchy of organization, they were the people who approved the research, the people who ordered it, the people who did it, etc. A third point is to devise appropriate categories within which the retrospective judgments are to be made. For example, the presence or absence of adequately voluntary informed consent is one category. An assessment of radiation risks to subjects is a second category and a third is the selection of subjects, prisoners, mentally retarded youth, children and dying patients. This is all familiar stuff, but if we're going to apply criteria for making retrospective judgments, we have to separate these out because we may have different answers or different levels of sophistication or compliance. A fourth point in applying the criteria is for analogies elsewhere in medicine, that is outside area of radiation research. Are there any analogies that the conduct of radiation research departed from other areas? the search the specific to indicate that in

One item that has been suggested is the long-standing practice of medical researchers using themselves as subjects before subjecting others to experimental risks. Was that

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routinely or ever done by researchers in the radiation experiments? So that's just a start and it's admittedly rough, but I propose it as a possible framework. DR. FADEN: Let me just say that I hope that we're open for discussion and we do have a lot of time. This is important and I'm going to start looking for hands and let me just say again, we're going to have, we will not exhaust, we need not totally resolve this today. We will resolve it totally, hopefully in December, but we'll continue the discussion, but we should have a good hour now. I've got Henry, Reed, Jay and Phil and Nancy and let's follow our informal rule. If you have a comment that's exactly on point, break in. If it's really not going to advance the point being debated, please wait for your turn. Okay, Henry, you've got the floor. DR. ROYAL: Okay, a couple of things that I'd like you to expand on. One is you said one of the principles was this gap between lip service and what's actually done. It seems to me that in our own behavior, in the behavior of others, there's always a gap between what's ideal and what we'd like to be and what we actually do, so that it's not a -- we really all meet the idea, meet all of the ideas in our own personal behavior. How does that fit in? DR. MACKLIN: Shall I answer? This is absolutely right and none of us is a saint, if that's the right word or the perfectly ethical individual. But to the extent that we can criticize -- this doesn't distinguish historical judgments from contemporary ones. That is to say at best we approximate an ideal. We probably none of us ever fully lives up to the ideal. So to the extent that we can either judge ourselves, that is, each of us as an individual or judge others for failing to live up to approximate the ideal, those judgments are meaningful and sound, so this then becomes a question of drawing lines, that is, where you draw a line, given that no one is likely to be perfect in adherence to ethical standards, but we're assuming that people know what's right, but don't always adhere to the most scrupulous details of ethical conduct. This is a line drawing problem, not a problem in principle. The question is how far away from the ideal does one become or how far away is the lip service from the actual conduct before we can say this person can be blamed for failing to behave ethically? Now there's no general answer to this. As in many areas and places in ethics, there is no general answer. I can't give you a formula, but what we have to do is look at the conduct, look at the behavior and then try to make some kind of judgment in context. DR. ROYAL: When we make that judgment about the

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distance between how big the gap can be, is one of the things that we're going to consider is how big the average gap was during that period or -DR. MACKLIN: That might be. In fact, how big the average gap is, in other words, was everyone doing it this way? The answer then is yes, if everyone was. This is perhaps an example in which we can say the conduct was wrong, but the individuals could not be held as morally culpable as, for example, outliers. So if everyone is getting informed consent and some guys don't, right, then you can blame the guys who don't. If no one is getting informed consent or properly informed consent, although the actions can be still deemed wrong, and the people can, as a group, be faulted in a sense for not living up to it, if that was the average conduct and behavior and no one did otherwise, let's say no one did otherwise, you can fault the conduct, you might even argue, this is even going into another area, that people ought to be in some way compensated for failure, for having been wronged. But yet, you might not assign strong blame to the individuals. I'm very hesitant giving general answers to these because we really have to look at the conduct, but I think the difference is, is everyone doing it, is no one doing it, and what is the level of awareness? DR. ROYAL: DR. FADEN: DR. TUCKSON: clear and cogent. DR. MACKLIN: Thank you. Reed? Wonderful presentation, I mean, just very

Thank you.

DR. TUCKSON: Help me to understand the references that we cite that lock in a particular presence of a reasonable, moral, ethical consideration at a historical time, you cite various letters, memos, things like that which we are aware of, so that we know that there was thinking that existed. If a person is aware by being in a meeting of that, of that discussion, while they're not codified yet, but you're in the meeting and these issues are being discussed. They're not codified, there is a certain level of awareness. If you are in a university and issues are being discussed at national meetings, but it may not have filtered down to you or maybe a phone call that says Bob Smith is thinking about so and so, boy, the implication of this is going to be pretty severe, I guess the question becomes is how do we grapple, and this is a process issue not a -- I'm subscribing to your outline, essentially. The process question is how do we begin to grapple with the diffusion of thought into some relevance to daily life at a particular historical moment? DR. MACKLIN: Let me understand, is this how we ascertain that the principle or type of behavior is adequately diffused? I mean are you asking how do we determine when it's widely enough spread or is it another question, how do you

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actually, how does the process take place? DR. TUCKSON: Thank you for clarifying. It is more of how do we ascertain that the individuals conducting experiments would have or should have been sufficiently aware? The fact that -- the plans for the submarine and the helicopter were developed by 18 billion years ago by that genius, I forgot his name already. That's how smart I am. Da Vinci, thank you. (Laughter.) I knew that Henry would know that, that's why I turned to him. But very few other people knew that you could have a thing called a submarine, so I wouldn't hold other folks, the shipbuilders of the time faulty for not thinking about submarines. DR. MACKLIN: Right.

DR. TUCKSON: How do you get a sense of when these ideas or these people that seem, that are important ideas are diffusible enough so that it should have affected the behavior of individual people? DR. MACKLIN: That's a really hard question. I mean there are some relatively obvious easy answers, that is, if there is or when there is a federal or institutional policy, and when I say institutional policy or federal policy, there's something that's written down that is held to apply. At that point, you can argue that anyone who doesn't make himself or herself aware or you might even blame the people who are responsible for making others aware, let me give an example. I think the level of sophistication about ethical matters is higher among people who sit on IRBs than it is on researchers within the same institution who do not sit on IRBs. They're not -- the same federal regulations are out there, but I don't think people sit and pour over these with their morning coffee, and it often comes as a surprise to me, but because of where I'm located, how ignorant people are of today's IRB, the regulations, that is, the federal regulations. So one might then say that the presence of the regulations or the existence of the regulations doesn't guarantee even the diffusion of all of the notions that are in there, but one would surely expect IRB members, many of whom are medical scientists who do research to know and to adhere to those precepts more than someone who doesn't sit on the IRB. DR. TUCKSON: That's precisely it. I'll be listening for how the discussion evolves, the conclusions of our discussion in terms of staff were because I fear for the amount of -- the next stage of discovery that staff will have to do and that is essentially, it seems to me two things, one, helping us to try to understand the degree to which those important stake points, the memos that you cite were generally and widely understood or known by people doing this kind of work. I mean that's going to be important.

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Secondly, the implications that came out of the answer to Henry's question which is the sense of what was the standard in general terms, not just in the radiation field, it seems to me, but in medical science, in general, in terms of how far was the practice from the ideal and what was the nature of that delta. Not only, it seems to me, that that would be important to understand in this particular matter of radiation, but at the time in other areas of investigation the question becomes how do we learn and understand that so that to these people, and this you'll get -DR. MACKLIN: And I don't know even the ability to get at the answers to some of those, the promulgation and dissemination of the policies. You've got a bunch of people sitting in a room talking about these things and you have these documents and the questions that follow were all questions -- it was in the interim report, a series of questions on page 12 or 13 that the report posed about how far those were disseminated and who had them and whether people below the superior officers had them and I mean ideally that would go a long way to answer your questions about the dissemination, but we may not be able to -DR. TUCKSON: I promised not to do this, later, teach me then later about if we -- then it comes back to, I guess, another conundrum for us which is obvious and that is, if we cannot determine that then what do we do? What are the implications of not knowing that and I'd love to see that. That becomes an ethical conundrum for us. DR. MACKLIN: Well, one might make at least -- you can draw some conclusions about what can be, what is condemnable and what is not because of ignorance, that is, if people, who sat around talking about these things wrote memos to one another and developed policies, failed to implement those policies, then at least those who failed to implement them and to inform those who were responsible for carrying them out made an ethical error of omission, okay, what we can say about anybody else we may have to be agnostic and say we just don't know. DR. FADEN: Jay?

DR. KATZ: You opened up for discussion enormous problems and we should get copies even of these, of what you said as soon as possible so we can think about them. Let me make two quick points. You're quite right in letting us know that we have to be quite careful as to what kind of criteria we apply for making ethical judgments, but I would suggest a prior question, with respect to the past, do we want to make any kind of ethical judgments? Do we really want to be much more descriptive, look here, this is what went on. This is what happened. We probably can get away from some of us letting our feelings come through, but we don't really want to condemn. We don't want to pass severe moral judgments, particularly because it's much more important to really look at the present. And your last criterion

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of having knowing standards and paying lip service to them is to my mind what's going on in the '90s, in the United States. But that is one person's view. So the question is what kind of ethical judgments do we want to make about the past. If we really want to come down hard, then we may have to take your criteria very, very carefully. We may still have to consider them, but in different ways, if we just want to be more descriptive as to what happened and not condemn and not to heap too much blame on actors in the past of what use is it. The issue is what can be learned from the past. DR. MACKLIN: I think that's an important point and this, I think, goes -- we can make this distinction, I think, by again distinguishing between condemning the conduct or finding the conduct wrongful and finding the moral agents wrongful. Now let me say what I think and I'm saying this very hesitantly. It's just my own view. The committee, of course, has to discuss this. What I think follows from being merely descriptive and not making any judgments about the past, if you cannot determine or if we will not or decide not to make judgments that certain kinds of conduct were wrong, regardless of what we say about the agents, then we can't talk about anyone having been wronged by the conduct and we can't begin to talk about remedies. Now that's what I think follows, from a purely descriptive and nonjudgmental account. However, what we might decide to do, I mean, following your suggestion what good is it, I've just tried to answer what good is it, it's good, the good is for people today who are the victims or families of victims of wrongful conduct to locate and to provide criteria for claiming that the conduct was wrong. However, the next step, blaming the individuals or as you put it, Jay, in your inimitable fashion, heaping blame on the people, we may decide to refrain from that and that will be a judgment that the committee will make based upon possibly some of these criteria. So I think we have to distinguish between judging the conduct to have been wrong and blaming the people who acted in that way. DR. KATZ: Just in passing, but I'm sure others know more about it, even -- and your points are well taken, even with respect to certain issues, we may not be in the business of blaming. This does not necessarily mean, I think, that we cannot create remedies because it's blamed for a different purpose, but anyway, the other thing, very, very briefly, I'm not convinced and this needs to be discussed at greater length, that the pieces of evidence that you quickly shake off really colors anything of any moment. That consent was talked about, we have no idea what they meant about consent. The Judicial Council's pronouncements on the conduct of human research were enacted overnight because Ivy took a plane to the United States and said "look, you will be embarrassed. I'm going to testify at the Nuremberg tribunal and the AMA has no guidelines on human research. You must enact something."

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(Laughter.) And the AMA did overnight and then Ivy falsified the record at Nuremberg by saying in his testimony that these were principles that had existed for a considerable period of time. Thirdly, the Wilson document is, in a sense, not worth the paper it's written on. It was promulgated by lawyers who knew nothing about human research. The Department of Defense is the only agency in the world that ever took the Nuremberg court seriously. The AMA rejected it. Helsinki rejected it. Nobody accepted and it was a document that without any kind of elaboration and commentary, wasn't worth the paper it was written on. I could go on. I am just saying the piece of evidence, I think, won't help us very much. DR. MACKLIN: I think they help -- I think I can say with some confidence they help in one small step and you are making an argument that they're not going to help us beyond that step. They help in one small step. It could not be claimed, looking back at the past and at this evidence and documentation, no one could claim, it could not be claimed that no one ever thought of these things, no one ever had any of these ideas, no one ever articulated a principle of getting permission or of informing people about the hazards. So the strongest criterion, how could you expect anybody then to have done what they do now because nobody even had it in their heads to do it. This at least takes the step, yeah, it was in someone's heads and in some debates and on some pieces of paper. What goes beyond that, I think, we'll have to debate. DR. TUCKSON: One last point, I must say that Jay's last comment was said so extremely forcefully with such great certainty and the implications of it are so profound that I really do hope that we might get an analysis of those comments that if that is true, I mean I will find myself very much influenced by that statement and given that it was given in response to just a conversation and so forth and so on and because Jay is such an articulate speaker, I really would like to make sure that those on the staff that have had an opportunity to understand that can get with Jay and I think that requires some further analysis. DR. FADEN: I made a note, Reed, in line with that on the three or four things that we do discuss in December, we need finally to confront what does all this mean? So looking to Jay in anticipation and others who would like to present positions, as well as staff work so that we can say okay, what have we got here and can we reach some understanding about what this means. It's interesting because it may or may not bear profoundly on what we do, Reed, depending on whether we end up making this distinction between wanting to make judgments on actions and policies and not about actors and agents, in which

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case we may not have to hang so much on agreeing about the role of the Wilson memo and other documentary evidence. But nevertheless, I have the same sense that you did, Reed, and have had for some time. So whatever else is on the agenda for December, this debate and those of us who want to get situated in relation to it as well as staff, should be prepared to speak to it in December. DR. MACKLIN: DR. FADEN: Could I just make one other point? Sure.

DR. MACKLIN: I think this goes back to Reed's questions and observations about dissemination. I mean let's take it out of this fear, I mean, because Jay is so invested in this. Let's take it out of this fear and see what one would say. For example, some constitutions around the world that specify human rights of the citizens and yet they are violated left and right and everybody knows they're violated right and left. What we say about those situations is that here are the human rights standards or ethical principles of human rights set down in a document like the Constitution, but it's blatantly ignored and the society that promulgates it, but doesn't implement it is blameworthy. Now that would be one way of looking at some of these things, I mean, just using that other analogy. On the other hand, your point seems to be very different. Nobody even knew what they were saying, when you say -- lawyers wrote it. They didn't even know what it meant to do these things and furthermore there was no dissemination into the research or medical community. So that's very different from the Constitution which is up there for all to see, but it's being violated right and left. I think we have to look at those two. DR. FADEN: Jay, did you want to respond? I know that Phil wants to come in right on this point, but you'll be ready in December, hopefully, to respond? Good. We will get a more fleshed out -- which is what Reed is asking for and then a more fleshed out -- communally, we'll try to flesh out what the meaning is because it's not clear. We may agree about the historical interpretation and disagree about the significance for the ethical analysis of the historical situation or we may have different interpretations of the history, and/or both. So it's going to be an issue. Phil, do you want to get right in? DR. RUSSELL: I want to thank Ruth for putting into a framework for analysis issues that I have struggled unsuccessfully with previously and I'd like to -- well, I would say I disagree with both Ruth and Jay on the previous issue of the Wilson memorandum. I think the existence of a major policy statement by the Secretary of Defense is a very, very important document and

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it obviously has to be understood in how it came into being because even though it may not have been enforced, and it obviously was not disseminated and its operational value may not have been great, its existence is incredibly important because a major policy document like that cannot come into existence unless there's a big community of folks that have supported it through the debates and the policy councils. And, if my understanding of the events that preceded this, it was the medical community, I think it was the Armed Forces Medical Policy Council, at the time, that promoted this and brought the issues to the attention of the Secretary. That's very clear evidence from my perspective that there was a broad-base of support within the service medical departments for these policies and to go back further, the Surgeons General of the Armed Services who were the proponents for this policy came out of their service medical communities and most of them had spent 25 or 30 years in those service medical communities so they knew what their medical communities were thinking about and they promoted these policies. So I think if you try to analyze these issues under the criteria number 3 that Ruth related, it comes out that there were some generally accepted principles here that were probably widely accepted, at least in certain aspects of the medical field, not all. That brings me to the other issue of dealing with this. It was quite clear that there were differences between medical fields, both in terms of practices and perhaps assumptions on what were the proper courses of action. A lot of the prisoner issues came historically from use of prisoners in infectious disease research. Infectious disease communities stated they had used some level of informed consent since the turn of the century, but at the time we were talking the risks and consequences of an infectious disease, whether contracted naturally or induced, were known to most lay people. You knew that if you got a severe case of pneumonia you were likely to die in the pre-antibiotic era. The knowledge, it was general knowledge that malaria was a fatal illness in some instances. So the infectious disease volunteers, even though they may not have been informed by the investigator of all of the consequences, did know that they were taking high risks and indeed risk of dying and indeed some of them did as a matter of fact. But this didn't transfer readily, these kinds of practices and these kinds of understandings didn't transfer to the radiation field because nobody understood the risks. I'm sure that the infectious disease physicians assumed a lot of background knowledge when they did their experiments, didn't feel that they had to write out and provide extensive -- because of the extensive information on the risk. It was quite well understood. Walter Reed's volunteers knew that Yellow Fever had 20 to 30 percent fatality rates. How we're going to transfer these issues from one field to another is going to be very difficult. I think the historical studies that -- and interviews that Sue Lederer's group is going to do is going to be very, very helpful in this regard.

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Thank you. DR. FADEN: Thank you, Phil.

DR. MACKLIN: Can I just make one point? First I want to say that when Phil says he disagrees with Jay and me, I may change my view after I hear -- you know much more about these things than I do and your point about the significance of the Wilson memo, despite the fact that it might not have been implemented down in lower levels is instructive to me, so I take your point about the significance. The question of differences in different fields of medicine and the risks known in infectious disease, but unknown in radiation, doesn't get people off the hook, I think. One reason is that the obligation of physicians, I mean people still quote the ancient Hippocratic maxim, "do no harm" which is of course, ludicrous, because everything physicians do does a little bit of harm. The idea is to do more good than harm. I mean do no harm though is meant as a grand statement "don't go mucking around with people when you don't know that how much or if at all you might harm them." So the fact that the risks of radiation were not, in fact, known, but so very much more was known about the harms and the risks of infectious disease should have led to caution, one might think, and given the fact that all of the people doing this research were doctors, even if the field of clinical investigation was not as well developed as it is today, the practice of medicine and those precepts handed down throughout the ages were ones that should have governed the behavior of doctors when they were looking at the patients or healthy volunteers. So not knowing the risks is not quite an excuse when one could say there are unknown risks and therefore we have to be even more cautious. DR. FADEN: Henry, are you on this point?

DR. ROYAL: Yes. There have been a number of statements that we knew the risk of infectious disease and we knew the risk of radiation and I don't agree with that. The reason that we're saying that we didn't know the risk of radiation is because the risks from radiation were much more subtle, people don't drop dead from having been exposed to radiation like they die of pneumonia. Radiation was first discovered in 1895. There was a long experience prior to this time with radiation effects. One of the things I have been amazed at being a member of this Committee is looking back at documents, like a document that's in today's agenda book, about the effects of radiation from 1957 and I'm amazed that the information in that document is almost as accurate today as it was back then. So I think -- I don't want anyone to get the idea that being exposed to radiation is anywhere near as risky as being exposed to malaria or being

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exposed to an agent that might cause pneumonia and subsequent death. I think that that was known at the time. DR. FADEN: Phil, did you want to respond?

DR. RUSSELL: I didn't imply that it wasn't known. My statement was that the average lay individual, the American, the prisoner in Statesville knew a lot more about infectious disease than he knew about radiation and how to -- a life experience, understanding of some of the risks. I agree with your concept that the medical community had a tremendous amount of knowledge and they should have been able to impart in the course of these experiments and perhaps in part because of the procedures for obtaining informed consent were not put into any kind of a systematic practice at the time was at fault. DR. FADEN: Jay, you wanted to get in on this point? He's waiting patiently. DR. KATZ: Phil is quite correct in saying that I didn't pay any attention in my statement that of course there was the Wilson document and it was a major document. But then I think we part company because here we have this document. I'd much rather wish there hadn't been this document, but here we have this document and it was, I believe, guarded as it had to be. It was not paid any attention to because if it had been paid attention to all kinds of -- many of the eleven provisions would have had to have been construed because of just by leaving it in one sentence in sound bytes it was an unmanageable kind of document. Consider also, to be sure, outside of the Department of Defense, this was '53. In '53, we had the Tuskegee syphilis study still going on. Nuremberg Code promulgated by the Allied Military Tribunal; the AMA Judicial Council making statements about voluntary consent goes until '70. In 1966, Henry Beecher, in The New England Journal of Medicine, just taking one or two medical journals, described an ethical research 17 or 24 examples, so it may have been a major policy statement, but it was written to the stars and it was not written for us human beings who have tried to manage to live life in experimental life on earth. DR. FADEN: Nancy?

DR. OLEINICK: Well, much of the discussion so far has dealt with the issue of the passage of these grand ideals down from the top to the physician in the trenches and I would just like a little discussion on what responsibility that physician has in seeking the kinds of guidance that would be necessary and I guess what comes to mind is the one memo we have of one of the folks in the Army who was asking for some guidance in terms of the human experimentation. I don't know how much more of that is around, but I remember that one memo. I guess my analogy for this is, for example, in my own laboratory, I sort of try to set the tone of the kind of research that we'd like to see done and I give specific assignments to people, but I should certainly hope

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the students and post-docs in the lab are going to read the literature and going to independently bring new ideas to the research and not depend upon me to do it for them. And so I'd like to hear a little more about what kinds of responsibility that physician has independent of having guidelines from on high to seek out the correct procedures for conducting the research. DR. MACKLIN: That's a very good question and I certainly don't know what to say about the past or how people behaved, but we can use a couple of kinds of examples from the present. There are investigators who come to the IRB on which I serve and present protocols or plans for research and try to do as much as they can get away with. There are other people who call me or the Administrator or others on the committee in the process of writing the protocol or developing the ideas for the research and ask "what do I do about this?" Now this may be with today's sophisticated -- granted, but I'm just trying to make the analogy, so whether they call a colleague or someone who now holds this dubious title of ethicist in an academic institution, at least there's an attempt on the part of someone designing research or about to carry it out and an alertness and an awareness that leads the person to say that I want to find out more about this, I want to discuss it either with the colleagues or with the committee or whatever people have come prospectively to the IRB. They've written a little statement, "I plan to do this. I don't want to work up the full protocol, if you're not going to accept this. Can you give me some guidance on it?" So people who care about these things and think about these things will seek the guidance or might initiate that quest wherever they may be. On the other hand, there are people to whom it never occurs or people who want to go ahead and do something and hope nobody is watching or nobody is listening, so I think that you could probably find such analogies in the past, although I don't know what to say about how or what people did. But you gave one example of someone saying, "hey, what are we doing here and can I get some guidance?" DR. FADEN: Now, are there more -- Lois?

MS. NORRIS: I just have one quick question. How does the national security cold war sense of urgency need to know greater good of society picture come into play in making these judgments? I mean does that factor in there anywhere or -DR. MACKLIN: I didn't take it into account in making this presentation, that is, I was looking at this as if we're talking about research practices or practices related to research without regard to the specific purpose or the motives. I think that becomes an additional question. If we could, and I think

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it's going to be an awesome task, but if we could come to some consensus and agreement about the standard to be used and judgments to be made, if any, then I think we add as an additional constraint on that analysis, now does the purpose, the Cold War, the urgency, the need to know, make a difference in what we might consider relaxing these standards. In other words, under what circumstances can one excuse or mitigate responsibility when there are other urgent circumstances or needs and here again, I think we'd have to do this with analogies, not just by looking at the Cold War, but look at other kinds of analogies. For example, in times of national emergency, in times of natural disaster, to take that kind of example. I mean in war time in the conduct of hot wars and in times of natural disaster, other liberties, freedoms and privacies that people have are curtailed because there are overriding goals or values. So whether it's rationing of food or quarantine of people or various things that take away people's liberties and invade their privacies, they are held to be justifiable because of the national security or the natural disaster. So that might be an overlay, something that we would have to ask, but of course, in those circumstances, the ones I just gave, people are told, right, "we got a war going on and so you got to use these blackout shades and you can't go out after dark and you can't have sugar and you got to ration this that and the other." Or "we've had a flood here" or "we've had a volcanic eruption and earthquake and you've got to do this, this and this. You can't water your lawns" or something. But people are told and they're told why. And of course, what happened in these circumstances and the nature of the case, you'd have to make the justification for the secrecy itself. DR. FADEN: Henry?

DR. ROYAL: A dimension that you didn't discuss in the five different criteria was the severity of the transgression. There are some things that we pay lip service to, but that we don't do, but that are minor transgressions and there are some things that are major transgressions. How does that all fit in? DR. MACKLIN: It fits in when I said afterwards, it wasn't embedded in my discussion of the criteria, but after I laid out the criteria I had some additional points to note in applying the framework. And I think your point, even though I didn't state it explicitly would have to go here, namely, the point is to devise appropriate categories within which the retrospective judgments are to be made, the presence or absence of consent, and assessment of radiation risk, the selection of subjects and so on, that is once we specify the categories in which transgressions occurred, we would, using the same kind of analysis, we might then look at the severity. So I mean again, you ask very good questions for which there are no general answers, but surely the severity has to be factored in, in the analysis.

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DR. ROYAL: I guess within the category of getting informed consent, is it equally bad to not to have gotten informed consent when there's minimal risk versus a lot of risk? DR. MACKLIN: Well, I'd say yes, but let me put the -make it somewhat clearer in a different way, namely, I mean the reason I say yes is that you're wronging someone by not informing the person, even though the level of risk might be low, but the wrong in using someone for a purpose other than that individual's direct known or believed benefit and not telling the person that you're doing that is a wrong even if the risks are slight. But on a scale of how you would determine it, I mean if doctors lied to subjects, if they lied to patients, so for example, and again let's use an example from somewhere else, the Jewish Chronic Disease hospital case where doctors withheld from patients the information of what they were injecting them with was cancer cells. They used some gobbledy-gook technical term to describe what they were doing and they didn't tell them they were injecting cancer cells into them. They say "oh, we got their consent, but obviously we couldn't tell them we were going to inject cancer cells, then no one would have agreed." They said, right? Which is one of the points of informed consent. So if, in fact, doctors withheld information that was material because otherwise people wouldn't have consented or if they lied to them and said we're injecting a harmless dye which, in fact, they may have believed was harmless, but failed to mention that it was a radioactive dye, then that's more culpable in a way than other transgressions regarding informed consent. So your tying the importance of the consent or the level of the transgression to the degree of potential harm and I would like to separate those two because I think beyond a certain point the investigator or doctor may be culpable for subjecting the individual to great risks regardless of whether you get the consent from people, but as a separate ethical category, because it rests on a somewhat different principle, respect for persons dictates that you don't use people to your own ends without informing them and getting their permission. DR. FADEN: Phil?

DR. RUSSELL: I had two questions, Ruth. One is the issue of culpability with regard to the different classes of participants in these issues. There's a strong issue of accountability for persons and positions of some power and especially in government service. There's also an issue of accountability for the physicians or researchers, research scientists involved which stems from a different source, a different basis, but perhaps equally, maybe even more strongly related to the culpability issues and I'd be interested -- you kind of slipped over the issue saying they were important issues without giving us your views on -- is there a hierarchy of culpability, accountability of these experiments?

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DR. MACKLIN: There probably is but again I think we'd have to have the details of any one in order to evaluate it and I would certainly look to your knowledge before I make any stupid comments about -- or ignorant, not stupid -- comments about accountability. I mean for example, one thing that's not going to be acceptable and we can take the threshold question is "my superior ordered me to do it." Regardless -- I mean that defense against wrong doing is no longer acceptable, if it ever was, but we've certainly heard it. So accountability, if you've been told to do something, it may require a higher level of moral courage for somebody down the line who has been told to carry out an action that failure to carry it out may have some consequences for the individual than the accountability might be somewhat different from the person who orders it in the first place. But I would like to -- these are important questions and I don't think I have anything to say about them out of context. What I would agree as a general matter is there are degrees of accountability, degrees of responsibility and degrees of culpability and one would have to look at the two elements that you just -- in detail and accurately, the two elements you just cited, first, investigators or doctors conducting research on human subjects and secondly, government officials in their roles. DR. RUSSELL: I guess the other question I had is the question of how are we going to deal with the reasons for doing the research and acquiring the knowledge, whether they are medical or fundamentally non-medical. Some of these experiments were experiments in physiology, human physiology that weren't done for the purpose of acquiring medical knowledge, were done for the purpose of acquiring knowledge on the ability of the human individual to sustain the insult, fundamentally, for military purposes. Now the question of informed consent are equal, but are there reasons to ethically discriminate among the -- if the same experiment is done for medical reasons versus an experiment that's done to understand physiology and the limits of human tolerance, are there ethical discriminations made there? DR. MACKLIN: Well, I wouldn't make that discrimination because let's use the word "biomedical" in order to embrace both. That is to say, important contributions to knowledge that flow from -- to biomedical knowledge, that flow from research in which the subjects are normal, healthy volunteers is one of the bases for contributions to knowledge upon which people build for all kinds of purposes. So I would never want to argue, since I'm basically pro-science, not anti-science, I would never -- and this would be an argument against certain kinds of basic research, that is basic biological research, base line data, physiological information.

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What you did in your comment was link the quest for that kind of knowledge with certain military purposes in a war or Cold War setting, but one doesn't have to link it with those purposes. One can think of other kinds of purposes. I mean there are investigators who come before our IRB all the time doing things to normal healthy volunteers that lead me to shudder somewhat, namely, why would anyone volunteer for this and yet the IRB, and they've managed to convince me as well, when I ask enough questions "what do you hope to learn from this" and what they describe in terms of important knowledge of cardio-vascular functioning, even though we don't know now what application it might have, is enough to justify it if it's scientifically welldesigned and it stands to contribute to human knowledge. So I think the distinction here between physiological and medical can't by itself make the ethical difference, unless you want to say the only kind of research that can be justified ethically is ones where we know directly what the applications are or are likely to be, but then I think we might cut out a lot of basic science research on ethical grounds and that just doesn't seem right to me. DR. FADEN: Pat?

PROFESSOR KING: I'm sorry, I missed your presentation, Ruth, and actually you may have covered this in the presentation, but I was troubled when you responded to Lois' question about what relevance is the national security considerations and the context because I interpreted and perhaps I'm incorrect, your response to along the following lines, that we understand or may understand some moral principles or ethical precepts and we will deal with the question of national security in terms of justification or as exceptions to that. It seems to me and when you talk about emergencies that was made clearer in terms of how your behavior may differ in an emergency, but also how are you also able to tell people that -well, everybody knows you're in an emergency and how you respond differently. It seems to me that that approach assumes that there are indeed principles clearly understood that move across time so that you can then talk about exceptions to those principles. I'm concerned about the fact that maybe there may not be, and I want to know if you address the question of whether we think about ethical precepts and principles, maybe not always articulated the same way with respect, for example, to informed consent then and informed consent now in terms of practices, but that there are some principles generally understood that if we can find evidence of them being generally understood would work. I guess my question goes to the question of relativism and how you separate out national security and the Cold War climate of the times and make an exception rather than being something that informs not as an exception, but the articulation of the ethical precepts or understanding of the time. Am I too obtuse? I'm really struggling with his --

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DR. MACKLIN:

No, I think --

PROFESSOR KING: -- Because it is a question to me how to handle this relativism versus some generally understood set of principles that cut across time. DR. MACKLIN: Well, I think what is relevant here is that you missed the presentation because the whole presentation was about relativism. It was about historical, ethical, relativism. I mean my answer to Lois, Lois asked a question that I didn't deal with in the presentation, that is, how to factor this in. That's sort of the next step, but what I tried to do is to present a framework for making retrospective ethical judgments and built in there into that are some -- the notion that there are some enduring ethical principles or ethical values that enable us to judge the past. I want to hear your question again after you've had a chance to look at this. DR. FADEN: We're at 11 o'clock and my intuition is if Reed does not mind that we not do the presentation -- you'll do it, you'll do it. Hang in there, Reed. But rather than interrupt the Committee's being engaged in thinking about these issues, I'm inclined to think we should take a break and then immediately get into a case where we can continue to be working with this material in the context of some real time situation. If it's all right, I think people would really would love to read it as well as -- so we will make it available. We can make the discussion available. The transcript is available, but what we can try to do is make the discussion here, make it a high priority so that we can read each other's comments as well. (Off the record.) DR. FADEN: Please come to the table, we'll try to resume. We have so much to read, I think people, as Jay put it, are ready to talk. Let me just refer you to Tab E in your briefing book. Please. MR. KLAIDMAN: Let me make just a few prefatory comments. Four of us prepared this study. John Harbert did the medical science analysis. Jon Moreno did the ethics analysis. Jon Harkness did the history of prisoner experimentation and I did a narrative of the Oregon and Washington cases which we are looking at specifically today. And Jon and I are going to divide up the presentation. I drew the short straw and do the science. I'll make it very short. John Harbert is here. If there are questions that go to the science analysis, they can be directed to him and Jon Moreno is here as well.

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The only other note that I would make is that I would try to keep this very short because over the weekend I received a new batch of documents from the archives in the State of Washington and they are right on point with respect to the earlier discussion of retrospective moral judgment and I would just like to read some of that material because I think it's a fascinating indication of the kind of debate that went on that ultimately shut down the Washington experiment. Briefly on the science, the investigators' objectives were to assess the effects of acute radiation on various aspects of testicular function, including spermatogenesis and Leydig cell function. Animal studies had been done. The data was needed on man. Dr. Carl Heller, who was the principal investigator in Oregon said that man was unique in being able to submit to a series of biopsies without excessive damage or biopsy-induced artifacts. Sperm count reduction and recovery is dose related, a key finding. There are no documented cases of testicular cancer in subjects of these experiments, but there are a lot of subjects who have not been followed and so it's not clear what that means.

Potential oncogenesis from testicular radiation is thought to be low or unobservable. In that context, from the new documents, the radiation safety committee at the University of Washington in 1969 told Dr. Paulsen that the risk of 30 Rad. of exposure to the testicles for the 24 patients he was then planning to irradiate would be a risk of malignancy, of carcinoma, of one in a thousand. That is the only indication of a risk level from this body. The risk of acute orchitis from repeated biopsies may be greater than the radiation hazard and nothing of that kind was ever specified. Now let me briefly just recount the narrative. You have this in pretty good detail in the written material. There were different versions in how this experiment got started. Dr. Heller and Dr. Paulsen both were doing similar work. They got started at the same time. Dr. Paulsen says it was his idea that resulted from his having been called as a consultant to review the case of three workers who were exposed to radiation at Hanford and he made the proposal. Dr. Heller's assistant, Mavis Rowley, says that the AEC initiated the research proposal and contacted both Dr. Heller and Dr. Paulsen. It's not absolutely clear what the AEC's interest was in doing these experiments, but there are hints of various kinds including here again one that comes from the new documents. In November 1964, a notice was placed on the bulletin board in the Washington State prison which specifies that they were concerned with exposures of workers in atomic steam plants is the language that's used. The question of selection of subjects and consent procedures, we have a number of consent forms which you have in your attachments and there are three from the Heller experiments, two from the Paulsen

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experiments. In the Heller experiments, the middle one is the one that appears to be the most explicit with respect to chronic risks. There is a list that appears on the back of the form. Oddly, the front of the form which doesn't list the risks is signed by the subject. The back of the form, the one copy we have is signed by the researcher, Dr. Heller, and there's a 10month gap between the two signatures and we don't know what that signifies. It's just not clear whether the subject saw the front and back, why the subject signed the front and not the back. We don't have that information. In the case of the two Paulsen consent forms, neither one specifies any chronic risk. With respect to shutting down the programs, it's absolutely clear, it was absolutely clear to us at the time we wrote the report that in the State of Oregon they were moving toward shutting down all experiments using prisoners as subjects. This was not nearly so clear in Washington and this is what the new documents help us with so much and I will get to those after making just the final point which is that follow-up, medical follow-up of these subjects has been an issue in both states. In Oregon, the documentary evidence strongly suggests that the principal investigator and his assistant supported the idea of follow-up. They had some lawsuits in Oregon between 1976 and '79. That got in the way of the follow-up process. Lack of funds apparently was a problem and Jim Ruttenber who designed the follow-up plan that was delivered to the State of Oregon in 1990 says that lack of funds was the reason his plan was never put into practice. In Washington, Dr. Paulsen has said pretty much from the 70s on that he promised his subject population privacy and therefore he is not providing names of prisoners to anyone unless the prisoners come forward and say that they would like their names to be released. What I have here is a very briefly report written at the request of the Governor of the State of Washington which describes why the program was shut down there and some letters and supporting documents that spell out, I think, in very interesting terms the quality of the ethics debate that was going on at the time, and I will just selectively in just a couple of minutes read you some of the most interesting material here and then the whole packet will be copied and distributed. This is from the report itself which was written in 1976. It begins by quoting the very brief protocol that Dr. Paulsen submitted and he said that his concerns were questions like "what is the maximum dose of radiation that will not alter spermatogenesis and what would be the maximum dose of radiation that affects spermatogenesis, but only temporarily?" I read you that quote because later on the woman who was running what, in effect, was the human subjects committee of the Department of Corrections in the State of Washington suggests that these initial studies should have been done on primates and not on man.

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In June of 1969, that woman, Dr. Audrey Holliday, Chief of Research for the Department of Institutions became aware of the x-ray experimentation for the first time. What we know from Dr. Paulsen himself is that the only review prior to this review by the Department of Institutions, as they're called in Washington, was reviewed by the Human Subjects Committee at the University of Washington in 1963 and 1966 and that was review was conducted in the form of a couple of telephone conversations between Dr. Paulsen and the chair of that committee. This goes on to say that it's significant to note that neither the 1963 outline of the research project nor the November 1964 announcement to residents of the state prison makes any mention of a requirement that volunteer subjects undergo a bilateral vasectomy. This feature of the research project was apparently added after the 1964 solicitation of volunteers. This is new to us as well. It was not clear before that prisoners who volunteered for the project in the first year and a half or so were not advised that a vasectomy would be required to complete the project. It goes on to say once again there was not any recorded review of the project by Department of Institutions personnel until mid-1969. It says "the Committee definitely recommended" - this is after its 1969 meeting -- "that Dr. Paulsen's request for continuation of the study be rejected as it was found to be inconsistent with standards for the protection of the individual as a research subject. The essential issued by Department personnel was that of informed consent. There is serious question whether an individual in custody is truly free to participate in experimentation which may affect his or her future physical well-being when agreement to do so may be perceived by that person as operating in their favor in terms of release consideration or privileges while in custody. Acting upon the review committee's recommendation, Dr. Conte agreed that the temporarily halted irradiation phase of the study should be discontinued permanently." I'll go on now to -- this is from a memo to Dr. Holliday from the human research committee. It says "it seems clearly" -- talking about the study, this is 1970. This is 3/13/1970. It says "it seems clearly" -- and we're talking now about Dr. Paulsen's study. "It seems clearly inconsistent with the standards laid down by the Nuremberg code. These standards state that 'persons involved should be so situated as to be able to exercise free power of choice without the intervention of any elements of force" and so on. "It is the committee's consensus that within the context of Dr. Paulsen's project, it is doubtful that prison volunteers are psychologically able to 'exercise free power of choice' or that they are able 'make an understanding and enlightened decision' when they volunteer for irradiation and subsequent vasectomy." In other words, the committee feels that within the context of Dr. Paulsen's project it is largely irrelevant whether or not a volunteer declares his "desire to undergo vasectomy" since there is no assurance that his real reasons would be ethically, morally acceptable or that his

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reasons, whatever they may be, will stand the test of reality after release. The suggestion being that this is not a binding agreement to have a vasectomy. Finally, from a letter to Dr. Conte from Audrey Holliday on March 18, 1970, "there is no question but that the federal government has made considerable investment in this project. The federal government, however, as a reading of any newspaper will show, has supported a number of projects over which there have been many moral ethical questions, both large and small raised. For example, nerve gases, toxins, etc. I remind you that the federal government is not responsible for care, safety and safeguarding of human rights of populations under the purview of the Department of Institutions. That is a responsibility we must discharge regardless of the amount of money that the federal government is willing to invest in a project. There is no doubt but what the prison setting is an ideal setting for this type of research. I suppose concentration camps provided ideal settings for the research conducted on persons in them. If, in fact, non-inmates were to volunteer in the substantial numbers of persons Dr. Paulsen needs, then I would have less qualms about offering up a captive population for this research. That is, I would have some evidence, assuming the volunteers were in fact normal, that non-captive populations might make the same decision as the captive population." There is more here of interest, I think, but let me stop there and turn it over to John. DR. HARKNESS: Thanks. I should preface this by saying that I have not had the benefit myself of looking at the documents, but they are obviously of importance. These experiments which began in 1963 and ended in the early 1970s, and one of them at least began to end in the late 1960s, in my judgment bridged a transitional period in the history of the use of prisoners as medical research subjects in this country. During World War II, the practice of the use of prisoners as research subjects became firmly embedded in the structure of American clinical research. Immediately following the war, the use of prisoners as research subjects received a powerful endorsement in the form of a report published in The Journal of the American Medical Association and we've provided you with copies of that report. Now this report is the product of the work of a committee chaired by our friend Andrew Ivy, who is from Illinois and as we've discussed this morning already, was the chief expert witness at the Nuremberg trials, was the author of the AMA guidelines on human experimentation, and in large part was the author of the Nuremberg code. Andrew Ivy and his committee members in this report pronounced the experiments on malaria that had taken place in Stateville Prison ideal in their conformity with the guidelines of the AMA. So Steve has just read us a work from the -- a memo from the 1970s stating that prisoner experimentation is in fundamental conflict with the Nuremberg Code. Andrew Ivy, who could be called the author of the Nuremberg Code, presented experiments on prisoners in Illinois as

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ideal. Whether we agree with that or not it seems to historian, significant that this judgment appeared in of the American Medical Association under the name of held as much authority as Andrew Ivy did at this time of medical ethics.

me as a the Journal someone who in the role

In 1963 and before, '63 being the date these experiments started, the most common, publicly aired objection to the use of prisoners as research subjects did not have anything to do with exploitation or coercion, rather these objections were related to the idea that a prisoner who had participated in experiment and had been rewarded was being excessively rewarded for merely participating in a medical experiment and indeed, I gave you a copy of a resolution passed by the AMA in 1952 stating that people who had committed particularly heinous crimes should not be granted the opportunity to participate in medical research because of the possibility of excessive attendant rewards. And I would go so far as to say and others might argue with me on this that a virtual constant in the history of prisoner experimentation has been the fact that many, and perhaps even most, although that might be stretching it, many prisoners have viewed the opportunity to participate in experiments given the extremely limited opportunities open to prisoners. Prisoners have viewed this as a good opportunity. Indeed, racism at work behind bars combined with this favorable internal view of participation experimentation has historically worked for an over-representation of white prisoners as subjects in medical experimentation. I think that might come as a surprise to some people who, looking at the predominance of blacks in prison populations and these overt racial exploitation of experiments such as the well-known Tuskegee syphilis study has sort of leapt to the conclusion that oh, experimentation in prisons, we must be doing all sorts of research on black prisoners. There's still racism at work, I would argue, but the racism has a different result. The story behind the end of prison experimentation which is encompassed within the years of the testicular irradiation work is perhaps a bit better known to the members of the public and the members of the committee. This story is intimately tied to the Civil Rights movement, the prisoner rights movement, the general questioning of authority that was so predominant during the 1960s and as has been so common in the history of human experimentation, public press reports of scandalous activity have galvanized public attention, have prompted official inquiry and have resulted in significant change. Perhaps that's why we're all here today. Of particular importance in the journalistic realm was an article by Jessica Mitford, a well-known investigative journalist, which was published in a January 1973 issue of the Atlantic Monthly and I've handed that out in our break for your review. Mitford presented the use of prisoners as systematic exploitation and coercion of extremely underprivileged class and she did this in a very compelling terms as was her general style. The early 1970s, 1972 to be precise, Tuskegee hit the

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news. The Mitford article was in the news in '73 and Edward Kennedy held Senate hearings on prisoner experimentation. Those Senate hearings resulted in a formation of the National Commission, and the National Commission, among other responsibilities, was specifically assigned to investigate the use of prisoners as research subjects. The National Commission, and I'll refer to Pat King in the discussion since she was a member, the National Commission in the end decided to recommend not an absolute ban to the use of prisoners as research subjects, because of a concern that such a stance was excessively paternalistic to say that a prisoner by definition was incapable of volunteering for something was seen as too paternalistic for the tastes of the National Commission members. Joseph Califano who was Secretary of Health, Education and Welfare at the time was required to respond to the recommendations of the National Commission. Among those recommendations, the Commission stipulated that prisons should be -- in order for experimentation to take place in a prison, a prison should be certified as a legitimate locus for experimentation. It should be characterized by a high degree of openness I think the phrase that was used and Califano, in an attempt turned to the American Correctional Association to see if the ACA would be willing to serve as a certifying body to identify prisons for experimentation should take place. The ACA turned Califano down. The ACA had just recently at that time decided that prison experimentation was wrong because it was exploitation and coercion, based on exploitation and coercion. So Califano directed Education, Health and Welfare reg writers to come up with regulations that varied from the recommendation of the National Commission. Those regulations stipulated that -- I'm summing here -- that non-therapeutic experimentation wasn't appropriate in a prison unless that experimentation might serve to benefit prisoners as a class which was a -- which is a very small number of medical problems. So that was the -- more than the beginning of the end. That was the middle of the end of prisoners as research subjects. I would now like to turn to an attempted summation of Jonathan Moreno's work on sort of the ethical analysis as he sees it as an ethicist of these experiments. And I'll refer you to his work, but here's my attempt at summarization: he takes a look at the harm-benefit balance in these experiments and I think it's safe to say that he sees a tilt toward harm. There was a -at the time I think a general awareness of the link between radiation and cancer, seemed to suggest at least that the risk of malignancy associated with these tests, this risk does not seem to have been very well communicated to the subjects involved. Another risk which does not seem to have been well communicated but which John Harbert has explained to us is that there was a serious risk of infection associated with testicular biopsies that were conducted as a standard part of these experiments. The risk that was communicated was skin burn and the researchers, I think there might be some exceptions to this,

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did fairly frankly raise the question of chromosomal damage and thus required or at least strongly urged subjects to undergo a vasectomy. Now on the benefit side of things, some of these prisoners viewed a vasectomy as a benefit. They wanted a vasectomy. Others, of course, lost their fertility, could be perceived as a harm. Now the chief benefit of this experimentation and I think all would agree on this, subjects, researchers, etc., was the financial, the monetary reward. This monetary reward from a prison perspective is seen as too great in the context of the prison environment. Now subject selection. There does not appear to have been an overt coercion in the process of subject selection. I do not know of any instances of that as an aside in the history of prisoner experimentation. A warden was saying to a prisoner, "you prisoner number so and so have to participate in this experiment." Prisoners who participated in these studies seemed to have stepped forward after learning of the experiments through prison grapevine or bulletin board announcements. That sort of thing. Finally, there's the question of information disclosure or I guess not quite finally, but close. As Steve mentioned, we've found five consent forms and the level of disclosure suggested in these forms ranges from the very difficult to assess claim that the nature and consequences of these experiments have been verbally communicated to the subjects. Now as a historian, I'll step aside again and say this sort of language is very common in consent forms at this time, but it's impossible for us to know what was verbally communicated, of course. The other end of this spectrum is this double-sided consent form which lists on one side a fairly extensive lists of risks and yet with that particular form there's some question as Steve mentioned whether or not the prisoner/subjects ever saw these risks. The question of prior review. In both cases, prior IRB review, I think, was less -- IRB didn't even exist as a term at the time, was less extensive than current regs would demand. There is some evidence that Heller, in Oregon, did make a sincere and fairly extensive effort to seek the opinions of his peers, but less extensive than we would now expect. In sum, these experiments, I think, would definitely not receive IRB approval today. The level of compensation was too great. There are serious questions about the nature of information exchange between researcher and subject. There are no provisions for follow-up and non-therapeutic experiments that would not stand to affect the well-being of prisoners as a class would simply not be approved. That's it.

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DR. FADEN: Thank you. Even thank yous have to come up with a red light. Thank you. There's a lot to discuss. I'm looking for hands. Let me just point out, distributed as we are sitting here, is a list of three questions that are just intended in case we had a lapse or pause to stimulate discussion. It doesn't look like we need it, but there are questions that were thought perhaps to be helpful in thinking through the project. I see hands. Jay, Duncan, Nancy, Mary Ann. Let's start with that. And Lois. And again, please feel free if your comment is immediately on point to just interrupt. Henry? DR. ROYAL: It's been difficult for me to focus on what the central issue is here. It's not clear to me if the central issue is the use of prisoners in medical experimentation and their ability to give informed consent, or if the central issue here is something specific to these radiation experiments. I think it's important to try to decide what the central issue is. If the central issue is the former, informed consent from prisoners, I would have thought that that issue has been resolved, has been studied and I guess I would encourage the committee to move on, if that's the central issue. So I'm interested to hear what the central issue is. DR. HARKNESS: I don't know if that's a question most appropriately addressed by me or the -DR. FADEN: I think this is struggle we're still going back and forth with. The straight-forward approach was to say okay, against the standards of time let's state, let's make it more explicit. Against the current regulatory expression of contemporary standards, would this research be permissible and I think your point, Henry, if you're going to it is that this is one of the easier ones in my view, if we simply go by current regulatory requirements, these experiments would not now be permissible. It's a separate issue whether ethically they would be justifiable today. I'll just express a view and say no, today. And whether we could discuss that or we could continue our discussion now, but I think your point is well taken that in this instance we have a regulatory position with respect to these prisoners. We may not all of us agree with that regulatory expression but it's currently in place and we have to deal with it and say look, this would not be permitted today, period, end of discussion. We then will have to entertain, do we want to look back in the light of the discussion we have before the break and make some judgment about how to look at those experiments at the time that they were conducted. There's also the issue and

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that's why the questions were circulated, whether the central ethical problem with these studies or the only major ethical problem with these studies is that they were done on prisoners and that's why the first question, the first -- the second question, that is, if this was not a prisoner study would this have been, would this be ethically permissible today? Would it have been ethically permissible then which is to isolate whether the fact that this was a prison population is the major source we're all concerned about this work or was it work that should not have been done even if it had been and I didn't have benefit of this new document either, even if it had been a study done in a free-living population in which people were solicited. So we can decide how far we want to take this discussion, but I would agree with you that we could -- if the committee wished to stop solely with the question of whether by today's standards as expressed in regulation, this is permissible work, we could just stop and say no right now. It probably is going to be one of our clearest examples of that. DR. ROYAL: So yes. I guess the additional issue is whether or not this is an outlier in terms of prison experiments. DR. FADEN: At the time.

DR. ROYAL: At the time, but it's not clear to me where the discussion should be focused. DR. FADEN: Pat, do you want to come in? One of the questions raised -If the button

PROFESSOR KING:

DR. FADEN: Could you punch the button? is not on, the mike is not.

PROFESSOR KING: One of the questions raised is, as I understood the presentation, is whether medical monitoring at this stage is justified. It seems to me that how you answer that question or if indeed you want to answer that question depends very much on making retrospective judgments of some sort, although I could probably be creative and justify medical monitoring based on just what we know today. I mean I don't think we have to necessarily go back, but I think that for a medical monitoring form of redress if the Committee thinks that is appropriate, I think that part of it requires that you go back and make some kind of judgment about the study at the time. I mean I don't think it's going to be enough, frankly, to say that it doesn't meet the standards of today. DR. FADEN: Henry?

DR. ROYAL: The link -- I'm glad you made the link to medical monitoring because that actually was another issue that I had wanted to talk about. If this Committee were to recommend medical monitoring, I think it's important for us to explicitly understand what it is

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we're trying to accomplish when we make the recommendation of medical monitoring. Do, in fact, we really believe that patients are going to benefit by the medical monitoring program that's described in our agenda book for these patients with testicular irradiation and is there valid scientific evidence to support that belief that patients will actually -DR. FADEN: You mean the former prisoners?

DR. ROYAL: Former prisoners would actually benefit and in what way would they benefit? What is it that we actually think the benefits are? Or, is part of the enthusiasm to do medical monitoring that it is in some respects an experiment of opportunity? It's kind of interesting to go back and see what happened to hormonal function and testicular size and those sorts of things over time. It's very unclear to me when we recommend medical monitoring precisely how it's supposed to be benefitting the victim and we should be very explicit when we propose this to people who are victims. We should be very explicit to them about what their realistic expectations should be if they participate in this medical monitoring program; what should they realistically expect the benefits to be. DR. FADEN: I hate to get us off that topic because I believe that is one of the keys to be debated in the context of this research, but maybe we should see what other issues people want to debate and make sure we return to the medical monitoring consideration and justification. Jay? DR. KATZ: Well, I'll be brief, of course. I believe, you know, that this should be included in some form or another in our final report. How we do it, I think Henry raised an important question that has to be carefully thought through. After all, this was a very important, is a very important experiment. It was the Cold War, investigators, soldiers, what is more priceless than one's testicles, and in the end we had to get answers very quickly to the question, under what circumstances will our testicles, be affected both for reasons of pleasure and procreation, so an important study. So we went to our prisons. What's interesting in reading particularly the deposition of Dr. Heller, and I would very much like to see the whole document before the U.S. District Court, the most telling statement that I found in the materials made available to us is the statement he said well, he was asked, "did you tell them about the possibility of cancer?" And he said, "no, I didn't want to scare them." Well, this still happens today. I have evidence from the '90s where doctors didn't want to tell patient subjects about regression to severe levels of schizophrenia because it might scare the subjects and they wouldn't participate. So then the whole question of in what way should

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prisoners be used? Would it have been all right to have them participate in these experiments if an equal number of normal persons, I mean, in non-prison populations, would have agreed to participate in these research projects? Is one of the -- one of my arguments with respect to using prisoners in research has been that since we now have so many of them that they should be used in proportion for certain experiments as non-prisoners are used in experimental study. I don't like the new regulations for the protection of research subjects. I think they went overboard in the other direction, but did exclude --they said you can only use them for if it is to their own -- if it is in some way for their own benefit, but excluded from it were studies on alcoholism, drug addiction, sexual assaults, etc. These kinds of study are only for their benefit or very much more for our benefit. It is an open question. I think prisoners under certain circumstances should be allowed much more wider access to participation in research, but with safeguards that now do not exist. Now whether we want to get involved in all that is another question. We have limited amount of time. There was this big debate in the '70s about prisoner participation. I was involved in it to some extent and the prisoners themselves feel very upset still, still today, and even filed a lawsuit in the '70s, I think in Pennsylvania, that their rights to participation in research and make their own decisions had been abrogated, etc. etc. etc. So there are important issues here, but we need to talk about it. One final point is that wonderful document that the two of you prepared. For the moment, I have only one comment to make about it, but it has wider implications. You mentioned the powerful concerns expressed by the American Medical Association about participation of prisoners in research, but let me remind you that they were only concerned about murderers, rapists, arsonists, kidnappers and other heinous crimes. Those they didn't want -- they wanted to have locked up, but they said nothing about ordinary prisoners. Apparently, as far as that statement is concerned, I've read other versions of it. They weren't against prisoner research in toto, they only wanted certain prisoners to be excluded. DR. HARKNESS: Well, they only wanted certain prisoners to be excluded and actually this is, I'm virtually certain tied to the impending possible release of Nathan Leopold of Leopold & Loeb fame from prison in 1952, as a result of his participation in the malaria experiments in Stateville Prison and the Illinois delegation that the AMA became quite exercised about the possibility of this, of Nathan Leopold specifically being released from prison, so the AMA delegation formulated this resolution which was passed by the AMA in general. DR. KATZ: But they didn't take it as an opportunity to speak against all prisoners. DR. HARKNESS: No, no. They were for prisoner

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research. They were for prisoner research, but they were not for heinous criminals being rewarded excessively for participation in prison research. DR. FADEN: point? DR. RUSSELL: Only to say that I think the prisoner issue is not the most important one in this set of experiments. The prisoner, use of prison volunteers was widely accepted at the time and the investigators, I don't believe, can be held culpable because they couldn't -- these experiments couldn't be done today in prisoners. On the other hand, the informed consent issues are so overwhelming in these instances that I think there's -- we're missing the central issue, I think, by bringing in the prisoner issue. DR. FADEN: That's the force of the second question. If we did a counter factual and pretended these were not prisoners, how would we look at this study, assuming we don't want to take on the larger issues of prisoner research now and then. Steve, did you want to get a clarification? MR. KLAIDMAN: Yes, I want to add a factual point which is that these are two experiments in which there are a great many living subjects and these are people who can have wrongs redressed, indeed if wrongs are found, and the quality of consent, it seems to me is an area in which this could happen. DR. FADEN: Did you -- Ruth? Phil, did you want to comment on this

DR. MACKLIN: I just want to remind us, as I'm reminding myself, when we talk about the problems of informed consent, we need very importantly to distinguish between the information provided and the understanding that the prisoner or the subject was able to have an the voluntariness of the consent since the voluntariness or lack thereof was precisely the reason why the National Commission and those who became opposed to prison research were questioning the ethical acceptability of the research, but the question was there sufficient -- would it be permissible today if the subject population were not prisoners doesn't have to do with the voluntariness, but may very much have to do with the quality of the consent, I mean the information that was provided. And just one other little point to back up on Jay's question and the response here. There's a certain irony in the fact that both the AMA in its statement, its resolution that sought to prohibit at least a certain class of prisoners from being subjects and the National Commission in its reasoning to just want to withhold participation of prisoners altogether. Yet, they're focused on exactly the same point, the benefits to the prisoners, that is, the benefit to the prisoner was the very reason why the AMA said "uh-uh, we don't want to benefit these guys" but they have been perfectly willing to allow prisoners to be research subjects, if, for example, there was no promise of parole and there were no benefits given even for that

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specific class, whereas it was precisely the prospect of those benefits or the actual benefits that led to the question of whether it's an undue inducement. So when Jon described the shift in thinking about prisoners, I think it's an important thing and one that we'll have to grapple with when we talk about changing standards of the time. I mean, on the one hand what was viewed as an unacceptable reward to these guys who did heinous crimes, later became an undue inducement and therefore both the same element became a reason for not involving these prisoners, but with opposite reasoning. That's just an observation about that fact. DR. FADEN: Henry, is that on that point? No, then I'm going to put you back on the list, if that's all right. Duncan? DR. THOMAS: I just wanted to ask Steve to clarify something that I heard go by very quickly at the very end of yours when you were quoting from some document and I wrote down it's something to do with the Department of Corrections or perhaps it was the Federal Government at this point is not responsible for human rights protection. What was that all about? MR. KLAIDMAN: What that was about was Audrey Holliday responding to her boss who was the head of the Corrections Department making the point emphatically that their Department was responsible for the well-being of that prison population, not the Atomic Energy Commission which funded the experiments or the Federal Government, but that Department within the State of Washington. DR. FADEN: Nancy?

DR. OLEINICK: Yes. My question in some sense relates to the issue of what is the central issue? Whether it is is there prisoners or is it informed consent and Henry brought up is it radiation? I don't really think it is radiation. I think radiation is almost a side issue here, but it's very telling that it's at least helping to evolve some of the standards. There is this very interesting letter from the Chairman of -- it's not an IRB, but whatever it was at the University of Washington to John Totter of the AEC in which at that time which I believe was 1969, the Committee had decided to disallow the neutron experiments that had been proposed, but to allow the continuation of the xray experiments. And as I read that letter it wasn't quite clear to me what the reasoning was, was it that they didn't think there were going to be enough men who were going to be exposed to neutrons to begin with to actually do the experiments or was it that this was the beginning of the end. They were going to clip his wings a little bit and then the next year they actually ended the experiments.

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So I was wondering if we knew anything more about what that reasoning was that they decided to disallow one set of experiments, but allow the continuation at that time of the x-ray experiments? MR. KLAIDMAN: I can tell you the little bit that I know about it which is that Dr. Paulsen himself says that he believes for reasons that are not clear to him and remember, his field is not radiation, that they were afraid of neutrons, that somehow they felt that neutrons were worse than x-rays. Going back to his original grant proposal, you will see that he was proposing radium and neutrons. He was not proposing x-rays at all and he had his neutron machine. He bought it, it was out there and he believes to this day, at least, this is his account that they were afraid because they thought neutrons were worse in some way, inexplicit. DR. FADEN: Mary Ann? Lois?

MS. NORRIS: I apologize for taking Committee time for my own education, but I simply am going to ask two questions of fact. One of them, then this deals with whether or not -- these prisoner experiments could be done today and under the research regulations of today, do the provisions of 45 CFR 46 subpart C, which provide the additional safeguard for the protection of prisoners apply to research funded by agencies other than DHHS? It's just unclear to me whether this applies across -DR. FADEN: Your question is whether those provisions were adopted as part of the common role in 1991 and the answer is no, so your point is technically correct. I think it is the case that most IRBs have extended the requirements under the additional subparts to research regardless of the source of funding, but as a matter of policy -- is that correct, Anna? It's our understanding the other departments have not adopted the prisoner regs as department policy, but we can clarify that. MS. NORRIS: That's the way it appeared to me when I was looking at the material. Thank you. And then I had one more question. And this is really of Steve, like Duncan, something sailed by me rather rapidly and I think I heard you mention that in the Paulsen experiments the vasectomy question came up later after the experiments had started or was it just the informed consent? MR. KLAIDMAN: No, it appears, and it is not absolutely clear because there's still a fair amount of missing documentation, but the first point at which we have documentation referring to vasectomy is late in 1964. What preceded that is unknown. The reviewer for Governor Evans in 1976 drew the conclusion that this was probably the first mention of vasectomy, but we cannot say that conclusively.

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MS. NORRIS: So the original program did not, probably did not anticipate vasectomy as a requirement of participation? MR. KLAIDMAN: MS. NORRIS: DR. FADEN: That's correct. That much we know.

Thank you. That's for Washington only. Washington only.

MR. KLAIDMAN:

DR. FADEN: Because in Oregon, it's clear from the beginning in the original proposal that they had always anticipated that the men would have a vasectomy. MR. KLAIDMAN: DR. FADEN: DR. ROYAL: Question 2. DR. FADEN: DR. ROYAL: and yes. (Laughter.) Let me expand on those two answers. A lot of what determines whether or not studies are permissible are not just cold scientific facts and are not just ethical principles. There's a certain gut reaction to certain things and if you calculated what the risk benefit ratio was of the testicular irradiation experiment, I doubt that it would be very different than experiments that are permitted today. However, because of the imagery and emotional overtones, it's clear, I think, to everyone that you would not go to an IRB and suggest irradiating testicles. It's just too powerful imagery. Just to give you another example, Alar on apples. Alar on apples is too close to motherhood to be okay, so we have this problem of things which have very strong overtones that affect our judgments and they're not judgments that are made purely objectively. So I don't think that the experiment could be permitted today, whether or not that's a rational decision or not is unclear. DR. FADEN: Could I press you? Let us engage for a little while in even more a counter-fashion. We put away the prisoners and we put away the consent issues and we focus only on the harm benefit calculus. Are you suggesting then if we looked only at the prospect for medical harm and we'd fold in the multiple biopsies in the infection -- it would not just be the irradiation risk, but we folded in the risks that prisoners -and it's never been clear to me what the average number of That's correct.

Henry? I'd like to be extremely brief and answer

Good. And I'd like to answer it in two ways. No

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biopsies were that the prisoners had, but we know it was -MR. KLAIDMAN: DR. FADEN: it seems like two to three.

Two to three. Yes.

MR. KLAIDMAN:

DR. FADEN: So the sense is that that risk of harm or that potential for harm, both from the irradiation on the one hand and from the multiple two or three biopsies on the other against clearly no benefit to the prisoners, no medical benefit to the prisoners, but the hope of answering a reasonable prospect of answering a useful scientific question that putting that together with the view, the put aside questions of consent, put aside selection of subjects, that that is a risk of potential for harm, potential for benefit calculus that would seem permissible? DR. ROYAL: I would like to see the calculation done explicitly. For example, I don't know how to weight getting a testicular infection following biopsy relative to getting testicular cancer and so I think when you try to do trade-offs, if you're doing it in medicine, a cost benefit relationship, you have to somehow equate different outcomes and I think it's a very complex issue and I couldn't do it in my head. My guesstimate is that if you did the calculation and you compared the harm which the prisoners were accepting and you compared them to harms of experiments that are being done today in normal volunteers who are healthy, that they would be similar. That is what my guesstimate is. DR. FADEN: Pat?

PROFESSOR KING: How can you ask that question in terms of trying to compare harms to benefits unless you also have some sense of how important the question is? DR. FADEN: That's part of folding in the benefits. That's the only benefit we're talking about. PROFESSOR KING: What counts as a benefit? But I see how important the question is. If it's nontherapeutic research and a part of the justification is a perceived critical need to know some answers to these questions because of people who will be possibly exposed to radiation and who will worry about their testicles, as Jay put it so graphically, how can -- first of all, I don't think we can make that judgment today. I'm having a hard time because I can't get out of my mind that we don't want to know the answers to the question today perhaps in a way they wanted to know it back in the 60s, because I have a hard time seeing the significance apart from the context. I think I'm making your issue more complicated. Now I could see it if we were just talking about a scientific benefit, something that's going to contribute to what we know about mediation.

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DR. FADEN:

Going back to Phil's point.

PROFESSOR KING: Right, that I can understand. I can do that probably today if I had the necessary information and do it then if I had the necessary information. What I'm having trouble with and this is always complicated for me, is that the way to make the risk benefit calculation? Can you make it and leave aside why the question is being asked in the first place? DR. FADEN: question. PROFESSOR KING: That's important to us. We need to be clear about what we're counting as benefits and how we're approaching the upshot. I think it's easy to figure out what is being counted as a risk. DR. FADEN: Henry's answer, I think, was on the harm side only. And I think that that was the first part. Let's look at the level of risk of harm. Is that out of line with what we ask healthy volunteers do today? That's not trying to make it minimal risk or more than minimal risk or any of this. It's just -- it may be that we ask healthy volunteers to assume too much risk today. I don't know. That's not the issue. The issue is just to get out a general sense how do we situate this? Then you raise the complicated question okay, if it's not out of line with the sorts of things and Henry, I'm understanding you're saying you want to qualify that, to think about it some more and the rest of us who have less background clearly can't answer it. Let's assume that's right. Let's assume it's roughly not out of line with the kinds of things we ask healthy volunteers to do today. Then you move into healthy volunteers, where the question is important enough. Well, how do we understand how important the question is in a context where the research has no prospect of benefit for the subject and then you get into all the issues that you've raised. Ruth? DR. MACKLIN: I want to ask Henry a question about the way you put the concern in the "no" answer, that is yes and no. The no part was no one would present to an IRB a proposal to do such research because of the likely response. Now I want to know whether the -- or the emotional reaction. I want to know whether it's, that it's risk to testicles, whether it's radiation or the combination of the two. In other words, what is it that would give rise to this emotional response in this kind of research whereas IRBs may be confronted in a whole array of other research with things that a perception of harm like sticking wires into hearts with no benefits to patients, the IRB would accept? So what are the features here? DR. ROYAL: I don't understand why some risks have much And the importance -- it was placed on that

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more emotional baggage attached to them than other risks. DR. MACKLIN: Yes, but is your perception of what that emotional response is based on the combination of irradiation on the one hand and the part of the body which is being irradiated? DR. ROYAL: I think any experiment involving radiation is looked at more carefully and other experiments that have equal hazards and I think any experiments involving testicles are looked at more carefully than experiments having a equal hazard in some other body part and I think putting the two together makes it even more emotion lead ins. DR. KATZ: these matters. (Laughter.) DR. FADEN: (Laughter.) DR. FADEN: Yes, Phil? We'll have that be a chapter of the report. Men just shouldn't be allowed to vote on

DR. RUSSELL: Henry's view of the value of the information sought, both the perception of how valuable it's perceived to be -- how valuable the information might have been perceived to be at the time and in retrospect was it a reasonable harm/benefit relationship? DR. ROYAL: I think one of the most commonly asked questions about radiation exposure is how is it going to affect my fertility, even today when we talk to patients. One of the biggest concerns I have is how is it going to affect my fertility. DR. GLATSTEIN: Yes, and this particular reference is about the only damn reference you can quote. There's virtually no other source of information. DR. FADEN: Steve, did you want to cite a document?

MR. KLAIDMAN: Yes, John Harbert passed me a note earlier and it's relevant at this moment on the follow-up. One of the two reasons he cites for follow-up is prisoner peace of mind and given this discussion to have some resonance. The other one is cancer epidemiology. DR. THOMAS: I haven't seen the risk calculation or attempted it myself either. It wouldn't surprise me if Henry is right, that the risks in relation to the long-term risk of radiation carcinogenesis may be in line with what we accept in other acceptable radiation treatments, radiation experiments along these lines, but I really don't think we should be focusing just on that risk. I'm very much more concerned about the acute

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affects, the risks that we've talked about, the risks of infection, just the discomfort of the procedure itself. I haven't heard a lot of that discussed. I don't know whether these testicular biopsies have been under anesthesia. Probably somebody could tell me that, but it doesn't sound to me like a very pleasant procedure. DR. ROYAL: Again, we're talking about testicles and biopsying testicles and somehow different in getting paid from biopsying some other organ and I don't think that in any sort of objective scale of pain that that necessarily is true. DR. FADEN: We've got Phil and Ruth. Let me just throw in one comment while I have the mike before I turn my light off. The other potential harm that we have not -- that I didn't fold in to my question to Henry and I withheld it intentionally was the potential harm of subsequently being infertile which is one of the key, I think, debated parts of this study and on the one hand on one reading it looks like they were fairly careful in attempting at least in, I believe it was Oregon -- which one had the psychologist talk to the prisoners. In Oregon, about do you really want to have the vasectomy, do you understand what this means? On the other hand, we're talking about young men, many of them young men, I presume some of whom or many of whom were not fathers; some or many of whom would subsequently be released from prison, may find themselves very much regretting having allowed themselves to lose that potential. So I didn't fold it into your question because it's one of a debated area. It's a classic apples and oranges sort of issue, but another big ethic contention. It is when you ask someone as part of a research participation to make an irrevocable or nearly irrevocable or largely irrevocable, depending on your view of reversal of vasectomy, decision about something as important as being able to be a parent. That's a big deal in my view, regardless of the context and everything else. Phil and Ruth? DR. RUSSELL: I gather from Eli and Henry's response that the information that was obtained there was enormously important to the radiologic community. Then I would have the question of is there enough parallelism with large animal experiments to use that as a basis for moving ahead and getting the additional information and at the time these were done what was the perceived status of parallelism between large animal experiments and human experiments? DR. GLATSTEIN: Like a lot of the questions in biology, there are basic similarities, but there are plenty of differences between large animals and man and when you get down to specific issues of how much, how long and so many quantitative issues, you cannot extrapolate, period. Now you say this is of enormous value, I wouldn't say enormous, but it's the only data that you can quote to people about is this exposure going to sterilize me.

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There are no other data. Virtually, every other time you get involved in the issue of radiation to the testes, there are complicating factors like chemotherapy. There are no other data for radiation alone, period. DR. KATZ: Well, is it still true and I think we can ask that question, is the longevity of radiation therapists four years less than it is of physicians? DR. GLATSTEIN: life insurance policy. DR. KATZ: whether the -If that were true I'd have a different

So it isn't in the report and I wondered

DR. GLATSTEIN: I think these days the issue of radiation safety is enormously different today than it was in the first half of the century. The data that we're quoted before by the shortened life expectancy really based on cause of death as reported in The Journal of the American Medical Association, that's what they used as the basis for qualifying that, that no longer holds. DR. KATZ: Oh, I'm so glad you mentioned it because -I'm expected to live to a ripe, old

DR. GLATSTEIN: life. DR. KATZ:

I feel better.

Thank you.

DR. MACKLIN: I want to go back to Pat's point which is important before we lose it and just to put it on the record here. There are two things that are important to address here. One is the reminder that the ethics in using, talking about risks is always balanced against benefits. That's the way the regulations read and that's the way we've come to think about this, namely, are the risks reasonable in relation to the benefits. Now one might be able to make an argument, an independent argument that some risks are so high that it doesn't matter what the benefits are, but then you'd have to make an independent argument and take it out of the framework of the regulations, so that's the one point. The second, and I think intriguing part of Pat's question is that benefits may perceive to be quite different at different times, that is, the benefit today of such research out of the Cold War framework would be judged to be much -- would be likely to be judged much less than the benefit then. So how then does one fold in the benefits and is it from today's vantage point or from the vantage point then? I think there is an answer to that question and may be an unfortunate answer and it flows from the way the regulations read and that is it's the benefits as perceived at that time including not only biomedical, but social benefits and here when

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you look at the regulations, there is this asymmetry in what an IRB may take into account with regard to the harms and what the IRB may take into account with regard to the benefits. The IRB is allegedly precluded from taking into account social harms that may come as a result of the findings of some research and I think probably the best single example to bring home, what is intended there is research that is designed to give an answer to whether or not there is intellectual inferiority in certain racial groups than others. The IRB is precluded from taking into account the potential social harms that may flow from doing that research and finding an answer. However, the IRB is not precluded from taking into account the benefits that may accrue from doing certain kinds of research. Now that asymmetry, I think, is significant in response to the question of how you look at the benefits and are they contextual and are they time-dependent? So I think if we were to look at, if we had to look at the risk benefit ratio, we couldn't use today's perceived benefit, but would have to look at this contextually if we're going to think about what the regulations say. We may have another argument and we may want to reject those regulations or that feature of the regulation, but if we look and this shows the difference between looking at regulations and as ethics and trying to make an ethical critique of the regulations, Jay is very famous for making ethical critiques of regulations and we're now questioning whether this feature of this aspect of the regulation also is worthy of some kind of criticism. So this is more of an observation than anything, but I think we should be bearing in mind that when we ask questions about would they be, would the research be acceptable today, we have to specify by today's regulations, as properly interpreted or in the way we've come to think about some of these. DR. FADEN: If we stay with, by today's regulations, properly interpreted though, it also would require, I would imagine contextualizing the risk as well. It's this sort of notion that it would have to be the risks or the harms as they would have reasonably been understood at the time, even if we're looking at it from the perspective of today, it would seem bizarre to hold an investigator. It depends on the purpose for which you're doing this, but we'd have to be thinking about that and holding it in our minds and being clear about which we were doing as we were looking at the research. The problem, of course, always is maybe not in this case, but in some cases there may be better answers now to the issue of the relationship between radiation exposure and cancer in this particular context. What if there were? What if we now know it was 20 times more terrible than they thought then? Or conversely, what if we now know it's nothing to worry about but then there wouldn't have been the evidentiary base for concluding it? We have to factor that in. If we start making judgments about actors or policies at the time, rather than simply looking at the research itself. I'm not making this very clear, but I think it's very critical with what purpose we use the apparatus of regulations. If we use

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the apparatus of the regulations to look at the research today, what do we mean by that? PROFESSOR KING: DR. FADEN: Can I make an add on? I would not --

Is your mike on, Pat?

PROFESSOR KING: Yes. I think that the issue is not so much purpose and relationship to today's regulations. It is purpose in relationship to this case study. The reason that I think I get frustrated at the discussion is because it seems to go around in circles. It is sort of going -- in my mind, maybe other people don't have this problem. The cause, it seems to me that when I look at -because Henry's question restated, when you look at this case study, why are we reading it, if we had some sense of why we are reading it, what we are trying to relate it to, whether it relates or not we might reject it. If we had some sense of why we are looking at the case study, we would be able to then make some sensible judgments about whether we want to make an ethical statement about today, a statement in relationship to the regulations today or whether how important it is to understand what went on back then? I mean I'm frustrated because you can look at this from any number of angles. The question is where do we think we are going. Now I am most comfortable, but I'm a lawyer, I am most comfortable in looking at the case study from the perspective I understand best, which is, I want to know, discuss medical monitoring and I want to know why is it with all the research that goes on in the country that people may have psychological psycholie too, etc. Do I want to take a look at this one to even consider the possibility of medical monitoring, and even before I get to what medical monitoring consists of. So I'm looking at this to say to myself and I'm not making a legal judgment, I want to be clear about this. This would be for me an ethical judgment. I want to know why -- I'm going to look at this case study, what do I want to get out of it. Am I trying to ask was this unethically conducted? Am I asking myself does that make any difference at all if we've got living people who had their testicles radiated, who may have some fear -- am I being clear? I need to know a little of the discussion about where we're going in order to make some connections. DR. FADEN: It would be nice, wouldn't it? I think this is a generic problem we have with all the case studies and we perhaps should have had that discussion before we went on to do so much work with case studies, but I think we sort of had, we'll try to continue this on Tuesday afternoon, but we did start out saying that one question we had just for openers was for all these case studies would the current regulation as it stands, the current regulatory structure permit this work or not? That's just a question and it's directed toward ultimately being able to make recommendations about the current regulatory structure and we started out early on saying look, that's an easy one for this study. Right now, we know the current regulations today wouldn't

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allow this research to go forward. Now it may be that not everybody here agrees that that current regulation governing prisoners is a good one, but we got the answer. The answer is today, you couldn't do this work. End of story. After that, we sort of fall apart in terms of what we want to do here except with respect to the question of medical monitoring. I believe, in part, because we haven't answered the questions Ruth posed to us about what do we want to do with respect to making judgments about the past, beyond being able to say whether today it's -- from today's vantage point, it's permissible or maybe more profoundly ethically acceptable or not. That's sort of where I think we're stuck. We're stuck, in part, because we haven't grappled with how we want to confront the actors of the past, on what grounds we want to meet them, theirs, ours, something in between. PROFESSOR KING: If one of the reasons for asking could we do -- would we do the study today, would it be permissible to do the study today is with respect to making some regulations, some observations about the way research is currently conducted, then we really haven't answered that question yet because the question then is not a prisoner question. Then it seems to me for the purpose of this Committee, whether this particular issue -- it keeps pointing to, this particular experiment, could be done outside of a prison. DR. FADEN: That's why the other question --

PROFESSOR KING: Because that is the only way to answer the radiation question. Would it be important to have -- well, there are lots of ways I could structure it, but we need to ask that not in relation to the regulations, but we need to ask, because the regulations would say no, because they're prisoners. We need to ask about the study to find out if we found another population, could we do it because we want to know about radiation. So it would be useful just to ask it that way. DR. FADEN: That was one of the questions. That's what I was trying to do, exactly. You've just given it better expression than I did, but that was part of the reason for pushing it because we are not a committee designed to address the question of whether or under what conditions research should be done in prisons. Those remain live issues and we touch on it, but that's not what we're constituted directly to grapple with. It's a tangential, important, but tangential issue for the Committee. Tangential isn't the right way to put it. It's essential to these case studies, but we were not set up to answer the question whether the current regulations governing research involve prisoners are adequate or inadequate and to what extent they should be revised. That, I think, we are not constructed to do unless we all reach agreement and wanted to make a comment which we clearly could.

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PROFESSOR KING: If you'll forgive me, I hope you will forgive me. The second question -DR. FADEN: I'll never forgive you.

PROFESSOR KING: The second question that flows from that if we're going to try to get back to try to understand what we're doing would be if we ask that question that way, as you just expressed it and now we have trouble trying to answer the question that way because in trying to answer the question we would have to further specify for our purposes at this stage how we want to think about benefit. I think more than how we want to think about risk for the reasons that Ruth has stated, so it might be useful if the committee would focus on for those purposes with those goals in mind, how is it -- in what way should we characterize benefit just for this purpose? What should we do, but not -- I think Ruth has already pointed us in the right direction because the regs reflect a real debate in another context about how you think about risk benefit. And there was quite a debate about how you conceptualize it. So maybe we have to do a different conceptualization for now. Does that make sense? DR. FADEN: Yes, it does make sense.

MR. FEINBERG: Again, I look at it from a lawyer's analytic, compartmentalized perspective. (Laughter.) And to me, I defer to Ruth and the other members of the Committee, for the time being at least, I defer to them, on what the substantive prospective ethical guidelines should look like, taking into account risks and benefits. As a lawyer, I say that the value of examining past conduct even in the light of today's present standards is very, very useful for two reasons. First, retributive notions of justice tell me that if at the time, at the time the conduct was engaged in, it did not violate ethical standards, substantive standards, even if that would today, that's useful information. It's useful information in deciding, for example, what remedy, if any, should be available to those people. If at the time that the experiments were engaged in, looking back through the prism of today, looking back to 1950, '60, whenever, if one concludes today that at the time no ethical standards were violated or that the conduct engaged in was reasonable to use a legal phrase, then it seems to me that guides me somewhat in establishing retributive notions of what a remedy ought to be because the culpability, the injury is vastly different than what it might be in 1994. On the other hand, it's also very useful because if, in fact, we are going to promulgate or fashion prospective remedies, to guide government policy makers in the future, then it seems to me we build on the past in developing prospective guidelines which after all are a blueprint hopefully to prevent repetitive

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situations from recurring on the basis of what we know today. And it seems to me -- so that's not really a remedies question. That is an issue that goes to deterrence. And how do you deter people in the future, in 1995, in the year 2000, from engaging in conduct unacceptable conduct? That to me, and that's what history is all about, I suppose, but that to me is a quite different question. So it seems to me we have to know, we have to evaluate 1950s, 40s and 60s performance in order to deal with (a) retributive notions of what we're going to recommend in the way of remedy for these people, but at the same time we have to be always thinking about that chapter of our final report that is going to, I hope, articulate guidelines, regulatory guidelines, ethical guidelines to guide future decision makers in the area of experimentation. So that's the way I sort of evaluated this and finally, if Henry or Ruth say to me, and convince me that at the time it is difficult to find wrong doing, at the time, it seems to me that that is very, very useful to know in terms of deciding what remedy, if any, such individual "victims" are entitled to. At the time it helps me enormously in evaluating in 1994 what differences there are in our promulgating guidelines that might act as a blueprint for future policymakers. That's quite a different role. DR. FADEN: I'm thinking as I hear Ken talk that not only do we in December need to have a big chunk of time to continue with the discussion on historical relativism and retrospective moral judgment and a big chunk of time to continue discussion about remedies, but a bigger chunk of time to talk about the relationship between the two, the relationship between whatever framework we set up for retrospective moral judgment and its implications. I think it's got to be an iterative process for how the remedy section then would be structure because it's unclear to me this may end up being one enterprise, informed by two perspectives, an ethical perspective and a legal perspective. This actually I find quite exciting. If we can pull that off, that would be really impressive. Ruth? DR. MACKLIN: I just wanted to ask Ken there may be a divergence because you're very precise when you say "speaking as a lawyer". There may be a divergence between what ethics and law holds with regard to the appropriateness of remedies. Now when you say retributive, I take it you're including from what you said, I'm inferring that you're talking certainly about the remedies to those people who were harmed or wronged, but also possibly to some kind of blame, that is retributive is backward looking and could involve blame -MR. FEINBERG: Culpability.

DR. MACKLIN: Culpability. Now the questions I have about the way the law looks at these things are really too -- do individuals have to have been harmed or might they have been wronged without being harmed in order for there to be appropriate

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remedy? MR. FEINBERG: PROFESSOR KING: Clearly the latter. Battery, battery, come on.

MR. FEINBERG: Clearly the latter. It does not have to be -- in your distinction between harm and wrong, there does not have to be harm. A culpable party can be found liable in the criminal and in the civil law even if there is no impact on the alleged victim. DR. MACKLIN: No impact, so for example, if someone, if there was not inadequate informed consent or no informed consent and no demonstrable harm, the person was wrong to being used as a subject although not harmed. MR. FEINBERG: This whole argument has been made in subcommittee, that the fact that the person was not given adequate information prior to the consent is itself a harm, his integrity or her integrity has been harmed, but medically, at least, I think that the requirement of some causal connection between the exposure and the injury is not required. DR. FADEN: This is, of course, anticipating the discussion we're going to have after lunch, but just reinforces my view that at some point, probably very soon, we don't want to have such separate discussions between the two. MR. FEINBERG: Patricia just asks the $64 question of you, Ruth, which is, you ask the lawyer a $64 question and I ask the other a $64 question, which is explain to me maybe during the break the difference between the harm and a wrong. PROFESSOR KING: MR. FEINBERG: In ethical terms. In ethical terms.

DR. FADEN: Okay, I'll tell you what, we'll do that. But let's do this, as a procedural matter, not having to do with anything other than people needing to eat, we are at the lunch break. I saw Phil and Henry and I personally want to express this sense of frustration that there's so much to do with this case study that we have not yet done, not to mention the real issues having to deal with medical follow-up in monitoring which I know are important to lots of people who are still around and want to know where the committee is going to come out on that very practical issue. We'll have to give some hard thinking of how to structure this in the future so that we can really move everything all the way through, but is it agreeable after Phil and Henry make their comments, we break for lunch and then we're going to pick up after lunch with the subcommittee report and a discussion about remedies. Hopefully, we can pick up the questions on jurisprudence and philosophy of law and so on, about harms and wrongs, so we'll have a good time with that and also move the

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committee forward as well. Is that all right if Phil and Henry raise their two points and if there is a response, we'll have it. Then we'll have a lunch break and we can still start on time if people are comfortable with the one hour lunch break as opposed to a one hour and 15 minute lunch break. Phil and Henry? DR. RUSSELL: This issue becomes more and more disturbing as we've analyzed the various pieces of it. The prisoner issue is deemed to be acceptable at the time -DR. FADEN: In the beginning.

DR. RUSSELL: The level of harm is then expressed by some as a medical harm within reasonable limits. The benefits to society were regarded by the radiology community as substantial. So then it really boils down to the informed consent issue and it seems to be, as we sit here now, unknowable. The investigator claims that he fully informed all those folks and then it comes down to the standard at the time was not to have a written detail of informed consent and what I originally thought on the face of it was somewhat clear has disappeared in the fog of all these details that we have nothing except the issue of the level of informed consent and how credible the statements are that these individuals were informed. DR. FADEN: In terms of your analysis of the conduct at the time which relates again to which of the standards or whatever standard you want to use for looking at it. We had to overlay Jon's point that this was a moving target, apparently, during this -- this being the views about the use of prisoners and the ethical acceptability of the use of prisoners was a moving target in society during the exact time in which these studies were carried out which adds a kind of an interesting overlay to whatever position we take in retrospectively looking at conduct. But I think your analysis -- yeah, yeah. I think your analysis is very concise and very -DR. HARKNESS: Just briefly, I would also like to hear the emphasis on the committee address that sort of disconnect between principle, as we now hold them, which I think most would agree, exclude the use of excessively rewarded prisoners with the practice, the common practice. This gets to Ruth's point earlier about is the Committee going to allow common practice to be the standard by which to judge experiments of the past. And if I heard Professor Macklin correctly, her answer was an emphatic no. DR. FADEN: Do you want to answer, Ruth? No. We have to think. Your point is well taken, Jon. We have to see if we can make the pieces fit. Henry? DR. ROYAL: This is a procedural issue. We've been setting up these analyses by asking the question would these be permissible by today's standards? And the thing that's unclear

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to me is that it somehow implies that today's standards are somehow better than standards in the future or standards in the past and I guess I sort of -- what I expect would happen with ethical standards although I'm sure there are other people on the Committee who have a better grasp of this than I do is that there's sort of a swing back and forth. We sort of heard that maybe the standard that's currently in effect now for prisoners is a little bit too excessive and maybe the pendulum is going to swing back the other way and it's going to be less restrictive. I'm not totally sure what it means when we say well, this experiment couldn't be done today so there's obvious a problem with it because I'm not sure -- I'm not necessarily sure that in the future the laws might change or the thinking might change and it would be okay. DR. FADEN: That's quite right.

DR. MACKLIN: I'm not sure it's quite right. And that is -- it equivocates between standards of the day and the letter of the regulations. The letter of the regulations prohibits, as we heard, the research on prisoners and less directly on things that have to do with them. The standards have to do with the voluntariness with which consent is given. I mean that's the standard. And there's the presumption that when you're in prison and there is even a belief of the hope of reward of some sort, even if not the prospect of actual reward, voluntariness is compromised. Now at the time there's ambivalence and the ambivalence lies in the fact that prisoners do not suffer a diminished capacity to consent. They suffer from a context in which there's diminished opportunity in terms of the voluntariness. So unlike what you might want to say about paternalistic protections of mentally retarded people or possibly psychiatric patients, in the case of prisoners, they were believed to be capable of understanding but the context of the prison situation calls into question whether or not they can consent voluntarily. Now the argument on the other side is unduly paternalistic. Why shouldn't the prisoners be the ones, let them exercise their autonomy, let them say whether they want to participate or not. So there's both a problem of the standard and identifying what that standard is, namely, no one do inducement which presumably would be a standard in the future too and also an ambivalence about whether or not prisoners are so compromised by their situation that they cannot properly exercise their autonomy. So it's complicated. PROFESSOR KING: There's dispute over what Ruth just said. That's the only point I want to say, that this is a fierce debate about whether prisoners are in a capacity to give voluntary consent is lacking and that's because some would attack this and say how different is it being in prison that if you are a poor person outside the prison walls who also is willing to

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participate in exchange for something and in the one instance the prisoner may exchange for one kind of thing, and the poor person on the outside may exchange for others, raising the question for some people that we have difficulty articulating what is the difference between an environment that is conducive to voluntary choices and one that it is not, so people draw the line at the prison wall. Other people draw the line in different places, that one can be seriously constrained in other contexts as well by one's position and place in society. So this is a hot debate which should probably go to lunch -DR. FADEN: Let me just try to take it back to Henry's point. I think what you're suggesting Henry, at least to me, needs to be confronted that there is an implicit assumption that somehow today's regs are better than no regs or what was around by way of guidance 20 or 30 years ago. That does not mean that they're necessarily good. There's an operative assumption that they're better and it doesn't mean that they won't become changed over time. Now it may be that even that assumption should not be -- if I was in California, I'd just assume that these were after shocks or whatever. (Laughter.) Given that we're in D.C., I think it's reverberations from the election. We'll take it that it is a reaction to our comments in any event. But I think you are right. You are correct to call us in acknowledging there's somehow some assumption that if it passes today's regs that is something better than failing it. That doesn't necessarily mean that it's on its own face ethically acceptable or in the reverse, ethically unacceptable, but it is somehow better to be able to be done today and pass the regs than not is kind of an implication. Now in the prisoners, one points to the fact that there are some ambiguities about the debate you're just hearing between Ruth and Pat and the discussion and so on suggests that clearly, there's an arena where people remain troubled about where the regs have situated the prisoner community with respect to access to participation and research. I don't know how to end this, Jay, do you? DR. KATZ: One 30-second comment to make lunch more indigestible. Pat, you know, by voluntariness of prisoners and that whole question, if one questions voluntariness, what about patients in hospitals? PROFESSOR KING: I agree.

DR. KATZ: And secondly, I think it goes to another important issue that people are really concerned about the adequacy of the informed consent process and that really underlies also the concern about using prisoners for research and I've now come in the last few months of conclusion that raises

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new problems, even about the kind of regulations. I think they place much too much faith in informed consent and we better take a close look at it and figure out where we go from here. That's wonderful Pat. We have to talk.

DR. FADEN: We are breaking for lunch. Let me just tell you, if you want to know where lunch is, I assuming. It is next to Cafe Florentine in the Florio Restaurant -(Whereupon, at 12:56 p.m., the hearing was recessed, to reconvene at 2:12 p.m., this same date, Monday, November 14, 1994.)

A F T E R N O O N

S E S S I O N 2:12

P.M. DR. FADEN: Okay, Committee, we need to start. We're coming to the table. We think we're coming to the table. We're working at it. We have a very full afternoon and if need be, some items will be moved over tomorrow or moved over to next month or moved over to a written communication. We'll see how it goes. I have some internal debate and ran by some of you whether we should switch the whole agenda around and begin with remedies in the spirit of the discussion that we just ended, but

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the sense was that it might be good to get another sort of heard and roughly debated and then look at discussion with two cases behind us just by way of since that's the order in which we planned anyway, we'd go ahead and do that with one exception.

case study the remedies back drop and we thought

You may recall from the morning that we moved Reed's presentation, his report on behalf of the group that went to Cincinnati to later in the day. The suggestion was made that that presentation go now before the biomedical -- the case study on external radiation research with patients which is basically the TBI studies and where the Cincinnati hearings bore, in large measure, on that discussion. So, Reed, if you're ready, if you could give us a report on behalf of you and Mary Ann and Lois of what happened in Cincinnati. DR. TUCKSON: Yes, I would. Thank you. First of all, let me just say this is a report on behalf of both Lois and Mary Ann. The three of us really had a tremendous experience being in Cincinnati. I'll make this report very brief, Ruth, just in the interest of time, but let me say by way of introduction that I think we all, all three of us and all the staff that went found the trip very beneficial, not only for its intellectual and its discoveries, but also on an emotional level. It was a very powerful day and I think it left us extremely affected. No question about it. All the people that testified in front of us and they really were quite a large number. I want this committee to understand that this was a very, very well attended meeting. We have great praise for the advocacy organizations as they worked hand in hand with us to make sure that this was a success. I want to thank publicly all the advocates who were so much a part of making that a successful experience for us and staff did a fantastic job as well. There were -- just again, this Committee and our Subcommittee, the Outreach Committee in particular, continues to be very interested in receiving first hand input from victims, from families and from advocates. We are, I think, we have made it very clear as a Committee that we take this very seriously and we continue to take it very seriously. There were -- the meeting began with Congressman Portman from we were very pleased to receive him talked about total body irradiation again very appropriate. in Cincinnati very briefly Ohio who had some, I think, as our first witness and he experiments and he was just

There were three kinds of people, groups of people that we heard from. First, the University of Cincinnati experiments group, very powerful, very emotional. The main points that I think we came away with was first the people that talked to us gave us a clear sense that there really was not available to them an organized medical care system, that there really were not people who were from the medical community managing their care, coordinating it and in fact, several people spoke very, very

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poignantly about their complete inability to reach a physician to talk with them about their general care, much less their specific experimental care. It put into mind, into some concern the statements about how informed consent was obtained, given that we have records that talk about an internist that comes around and counsels the patient and so forth and so on. The families really report no such intern. In fact, couldn't get anybody to just answer their questions whatsoever. It sounds -- there are very, very real issues that were presented about, just families being shut out of a general medical care, much less a specific experimental issue. So you'll have those transcripts to read and we will have to explore more of that. Also, much important were statements about the status of the medical status of some of the patients, not being end stage, not being terminal, but doing housework the night before they went to the hospital, being vigorous people and so this sense that they were end stage and terminal was in many, many cases thrown very much into doubt again and so requiring us to follow up. And then we heard a great deal of frustration about the difficulty in accessing medical records. We were able to have testimony from the President of the University of Cincinnati who brought with him the Chairman of the Board of that organization and they assured us and the families that they would do everything in their power to cooperate and get medical information and records to them. And so we are holding them to their word and we will, I'm sure, be getting follow-ups from the advocacy community as to whether or not that is occurring. The second group of people that we heard from -- oh, let me just say this in this regard, staff is certainly now going to, as a result of this, spend a lot of time, they're somewhat assigned now to Cincinnati to follow-up and do much more of learning of details and evaluating the material that we were given and so for the advocates and for the families, they should be aware that that testimony is not just going into the archives, but in fact, is the substance now of further work as we try to understand it better. Quickly, the second thing that we heard from military personnel and families exposed to atomic weapons and the clean-up at military test sites. The one thing again that comes through loud and clear from them is -- and it's consistent, over and over again, is a sense of what they believe is a betrayal. They are loyal, absolute loyal Americans who served -- their families and relatives served in the military and they just feel that they have not been well-served and there's a tremendous passion that comes through regarding that. There's a disappointment, a teariness in that disappointment that we were affected by. One of the substantive issues that needs to be explored a little further is the interaction between the V.A. and the military regarding the presentation and interpretation of records for disability determination. What we heard were people that discussed some tensions in that relationship and some confusion

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about how you're classified for V.A. versus what's in your medical record and how things from the medical record get into the V.A. record. Without belaboring that, it's just an area that becomes important, but what also is important to this Committee that we heard is a concern that the classification of disability by the V.A. may not truly reflect the real incidents of radiation exposure, that one man who in particular was getting money as disability benefits for radiation-related multiple myeloma is listed in the records as having a blood condition. And so that that blood condition doesn't, won't necessarily appear, if you go back into an epidemiological analysis and so that it throws into question some of the interpretation of numbers. There was no sense that it was deliberate. It was just a sense of dismay. I'm not trying to make it pejorative a comment, but something that just we should be aware of. The third group of people we heard from were people and this is a perplexing one for this committee to have to deal with and that's the occupation exposures, the DOE and the AEC contract facilities, particularly at Piketon and Fernald, a lot of workers who expressed in very graphic terms their experiences with blown decontamination pipes or uranium spills and that sort of thing and the way in which the medical care system in those complexes, those factories is not really available to them in ways that they thought appropriate. Again, they're very compelling. I don't know how we deal with it in terms of the scope of our work and as we continue to go around the country and elicit testimony, we're going to need to decide whether this is within our purview and if it is not, how we handle it since it has become part of our record. Certainly, we have an obligation to these people that have come to testify and I think we're going to have to honor that obligation in an appropriate and in a rather urgent way. We were given very stark testimony regarding claims of adverse consequences to whistle blowers, as well as issues of falsified medical records. We were also told of and this is interesting to us that many of their disability claims were sent to Dr. Saenger for his medical review and authorization and so there was this linkage that we were not previously aware of to Dr. Saenger being involved in these cases as well, and that requires us to look a little further. We also learned about the Department of Energy tissue sampling program. There was very graphic testimony given, what they call body snatching and this has to do, again, with the tissue sampling program that once people die to be able to sample their tissues to see what can be learned. There are issues of consent and issues of information sharing that are involved. But we had people tell us literally that the workers have literally stood guard over the bodies of their fellow workers who have passed, to make sure that folks from other agencies cannot get at those bodies because they don't trust the work. I mean, it was surrealistic to take that kind of testimony.

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Further, made even more surrealistic by the sense that they claim that they actually have sent such bodies out of the country for nuclear autopsies, outside the United States and then brought back, so there is a whole other kind of dimension to this work that caught, I think I'm sure, the three of us on the Committee, by some surprise. We didn't -- we just heard the testimony. Now what to do with these kinds of statements becomes a matter for us to consider. We'll hear a little more about this DOE tissue sampling when we go to Spokane next week and I understand that we will learn a little bit more about that there. Finally, we were urged by Jackie Kittrell of the American Environmental Health Studies project to go to Oak Ridge and to hear from the more than approximately 200 Vanderbilt University patients. It turns out that given that we're doing an institutional case study on Oak Ridge, we have, I think, reached a tentative decision on whether it's definite, Ruth, yet, to try to go to Oak Ridge, I mean to Nashville and to actually do another outreach effort in addition to the ones that are actually scheduled and I think we feel that there will be some utility in doing that and want to do such. So again, the transcripts will be ready. I don't want to belabor any of these points. I'll simply conclude by saying that first of all it's very important to do this and secondly, the follow-up is going to be important as well as we must make good faith with the people we are meeting and hearing their stories. I think we are doing that well with the Cincinnati experience. I think that -- and as well as with the military personnel. The question that I'm not so sure about, that I know the answer to, is how we're going to proceed with the atomic weapons industry personnel. So let me stop -- Mary Ann and Lois, please, if you have any additions. MS. NORRIS: As I might have expected, Reed, I think, covered it beautifully. Mary Ann? DR. STEVENSON: Likewise, I just want to reiterate what Reed said. It was very well-received and it seemed to be very, very important to the people in Cincinnati and people who had come into Cincinnati, that we were there and the format that was used, sitting there and listening and commenting when we felt appropriate worked very well and I just can't emphasize how important these kinds of days are despite the fact that they are a lot of work, I suppose, for the staff. They really are extremely worthwhile. DR. FADEN: Duncan? DR. THOMAS: Any lessons as to how you would do things We're open for comments and questions.

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differently for the next one in Spokane and in particular, did having a whole day of this public hearings enable you to give people, be more flexible in the allocation of time compared to these meetings here? DR. TUCKSON: I really think -- I thought we were able to -- we did not have to rush. We must have -- I don't know how many we heard from, but it must have been 30 people at least. We were not rushed. And the other thing, Duncan, was, I was surprised, all three of us were surprised, we didn't get tired. It was not a physically demanding experience to be able to give everybody the time, so I would say, we would do it just the same way. And the main thing we benefitted from again was prior preparation of the advocacy community. They really were the keys. DR. THOMAS: DR. TUCKSON: 5:30. DR. THOMAS: You get any input from anybody with the suggestion that that would have been helpful, if there were people who couldn't make it at that time? DR. TUCKSON: It was not expressed to us. Did you have any evening sessions? No. We were able to finish by about

DR. STEVENSON: We made it clear at the beginning of the day that we would stay almost as long as it took. All of us, it turns out, didn't leave until 9 and we slated to be available from 9 to 6 and would have stayed longer, if necessary, but it seemed to work out. DR. TUCKSON: I think the main thing, just to think to the future, continues to be the conundrum that I see is as we get more -- we're hearing -- the more people we talk to, the deeper we seem to be able to get in areas that we already decided to plow which is good. What just concerns me is as we open up and open up and open up is how do we make good faith with the newer information, particularly that comes up later in the process and that's -- as you all know, with the whole committee that's been obviously involved in the outreach effort as we take public testimony, and you know what it's like to look in the faces of people with the pain and hurt and once having made that relationship, there's -- and sometimes there's some implied sense of what do you do with that? You just can't go away. DR. FADEN: I'd like to respond to that, but I think we should hear everybody out. Nancy, and Eli, did you have a question? DR. OLEINICK: Just one question, was the whole day devoted to public testimony or were there any presentations? Did you find that the public, those that gave the testimony were very well aware of what the Committee was doing and had followed all

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the deliberations? Did you feel the need for any kind of a presentation of a summation of what the Committee was doing? DR. STEVENSON: Reed gave an introduction probably very similar to what Ruth had done in San Francisco when we were away from our normal venue, so it wasn't a long introduction, but it was explaining what our charter was, what our purpose was. DR. TUCKSON: And again, I'm glad for the question. That's why I said it twice and I'll say it a third time in terms of the advocacy community. It was very clear that everyone involved in the process understood, the level of education and prior preparation, not determining what they were going to say because people were from many different organizations, but the degree of sophistication involved in this was, I found, very, very great. DR. FADEN: Lois, did you want to?

MS. NORRIS: I just wanted to get back to Duncan's question. I think it was a good one. It's different, it's a far different thing from -- well, scheduling meetings for evenings, for the convenience of those people who may have daytime commitments is far different than telling people in a daytime meeting we'll stay as long as it takes to hear your testimony and Duncan, I think, I don't know if you were making a suggestion, I think you were making an inquiry, but it might be worth considering whether or not these small panel hearings should be expanded to evening hours to accommodate those people who have daytime commitments. DR. FADEN: I don't know the answer. Eli?

DR. GLATSTEIN: Reed, the business of deceased bodies going some other place, was this from TBI patients or was this from the workers? DR. STEVENSON: DR. TUCKSON: DR. GLATSTEIN: DR. STEVENSON: Workers. Workers. Workers. Right.

taken?

DR. GLATSTEIN: Where were those bodies supposedly Outside the country?

DR. STEVENSON: The tissue, it's Spokane, Washington initially, wasn't it, the DOE facility? MR. KLAIDMAN: Yeah, there is a tissue repository in Spokane that's run by the Washington State University, and in fact, the guy who runs it is going to meet with the committee members who go to Spokane in Hanford.

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DR. GLATSTEIN: DR. FADEN: DR. ROYAL: registry. MR. KLAIDMAN: -

Is that information classified?

Henry, go ahead. Yeah, I think that this is the transuranic

Yes, the transuranic, U.S. Transuranic -

DR. ROYAL: That used to be down in Los Alamos. And basically when workers who had worked with plutonium and other transuranics died, there was interest in knowing how much plutonium they had been contaminated with and I don't know that they took bodies. They took tissue samples. MR. KLAIDMAN: Right.

DR. ROYAL: At the time of autopsy and those were sent down and all of the results in the transuranic registry have been published in the open literature. DR. TUCKSON: There is a very, at least in terms of the people that spoke with us and they made it very clear that we received a point of view, a very definite expression of distrust with the process and very great uncomfortableness with it, so much so that again we are led to believe that there are people who literally guard bodies to prevent people from taking these tissue samples. DR. FADEN: Duncan?

DR. THOMAS: Did you hear testimony to the effect that the tissue sampling was done without the consent of the individual or their next of kin? DR. TUCKSON: It's a very specific question, Duncan, and I don't know -- to be honest, I'd have to go back and look at the transcript. Again, the issue that I remember and what I took away from it was the sense of distrust for the process and distrust for the people involved. So I mean the fact is you would stand guard over the body and not let anybody touch it says something about the issue of consent. We really have to -- it was at the end of the day and we really learn too much more about what they meant. DR. FADEN: Lois?

MS. NORRIS: For what my recollection is worth, they were claiming it was without consent, but I would not wish to be held to that. That's what I recall. I don't know, Mary Ann? DR. STEVENSON: Yeah, that was the impression. This

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wasn't just a one time occasion, but any time a nuclear power plant or DOE employee that had potential exposure to these elements may have died, their body may well disappear from wherever. I mean that was the claim. We didn't necessarily have written documentation to substantiate it, but as Reed expressed, and we all heard, there was a union worker actually who -DR. TUCKSON: Actually, a former union leader --

DR. STEVENSON: Said that they had to stand guard over a body so that it wouldn't be "seized by the DOE for these tissue sampling purposes" and in fact, the body had been sent out of the country for their own autopsy, because they felt the material -the issue wasn't so much that the DOE wanted to follow these workers and analyze their tissues post-mortem. It was that the information wasn't being exchanged and shared with the industry and because of that, they were sort of drawing a line in the sand. DR. THOMAS: On the other hand, does DOE claim that at some point in their lives these workers had signed some statement releasing their bodies for this purpose? DR. TUCKSON: I don't think, Duncan, to be honest, I don't think that the follow-up is yet done on that. I don't know whether staff has had a chance to -DR. STEVENSON: There was clearly discussion that the DOE had approached people obviously before they died with the idea that they would contract to take their bodies and be given permission to perform autopsies and the union worker discussed that. He said they had, as a unit, had refrained from agreeing to that, to those kind of contracts because they had distrust on whether or not they would receive information. But we don't have any more documentation. DR. FADEN: something on this? DR. MACKLIN: DR. FADEN: sorry. DR. MACKLIN: I just wanted to hear more, if you have more, to say about the whistle blowers. You mentioned that and it's something that we haven't, it hasn't come up as much in any other studies, but is presumably, potentially, I should say, a matter of some concern. Could you say more about who these whistle blowers were and what happened to them or what whistles they were blowing or did they swallow any whistles? DR. TUCKSON: I don't remember the lady's name, but again another one of the union leaders who described a climate of intimidation, a climate of essentially harassment, that it was very clear that at least their concerns for the health of their fellow employees were not the prime interest and in fact, it was Can I let Ruth in? Did you want to say

I had another question. Is it a comment on this? Okay, Ruth. I'm

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harmful to them and their careers to raise concerns and issues regarding the health of the people. Again, these are two people that testified to us who in positions of leadership as advocates for the workers. not like they say on March 3rd I was denied a promotion. a general sense of tension, a general sense of intimidation they present and we'll have to look very carefully. You'll the transcript to look at it. DR. FADEN: Pat. This is a different --

were It's It's that have

PROFESSOR KING: DR. FADEN:

Is your light on? This is on a different subject, is

PROFESSOR KING: that okay? DR. FADEN:

Related to -It's related. As long as it's related to

PROFESSOR KING:

DR. FADEN: Yes, of course. the Cincinnati panel.

PROFESSOR KING: As you know, I missed San Francisco, so I didn't have a chance to see for myself in San Francisco and Cincinnati would raise some similar problems for me. My question for the Committee is I have no -- there's no doubt in my mind that there's something very important and useful to be served by serving as a sounding board for people to come in and talk and express what has gone on. What I did not hear in Reed's report and anybody can comment on this, is specifics about what kinds of things we will follow up on that are relevant to something that we may end up doing and that is a concern to me because when you hear testimony you can't accept testimony. Either you've got to commit resources to tracking it down and trying to figure out exactly what is going on or you have to decide not to do that and for that you need some sense of what are you being told that relates to something that you're doing. And in Reed's words, my memory is terrible, this feeds into ground we have plowed, but I wasn't quite clear about what the reference was in the ground we had plowed. That's what I think is really important, because I'm trying to figure out. I just want to be careful, I think this will sound harsh to some, but it's not intended to be harsh. My real concern is that when you listen to people and you can't make the other things clear, that rather than doing a service sometimes, you do a disservice because you raise expectations and if expectations are dashed, then actually people who are tense, who have suffered, they come off feeling worse about the whole thing rather than feeling in a legitimate point that they want to

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make has been accepted. That's the thrust of my question to see if we are getting the clues, are we getting trends and things that we are going to turn into something for the committee so it won't look like we just -DR. TUCKSON: It's an extremely important point and obviously one that's on all of our minds. First, when we went out and we make our introductory comments, we try to be somewhat cautious about what we can deliver and it's a fine line, as you suggest. My comments, I said first, that the Cincinnati experiments, the information that we got there was absolutely pivotal in terms of understanding Cincinnati and we're making as a committee, Cincinnati a major priority for the group so much that we are committing staff resources as a result of what we heard. I think that it is very difficult to understand the documents that we have been given regarding the informed consent process, particularly the reviews by the American College of Radiology and other reviews, and you read that stuff and that's one thing. Then when you go and talk to the families and you hear the families describe what their world was like when you visit mama or visit father in the hospital, then you begin to say wait a minute, there's a disconnect here and it clearly gives and gives the staff, I think, very definite direction to proceed, so I think we better understand Cincinnati. In that case, that's ground military personnel in the test sites, testimony we took there is again work at and in other places and it will be terms of fleshing out. we've plowed. I think the those issues again, the that we're already looking an additive and helpful in

The area that I said in my comments though that I expressed, the specific concern of your question is in the nuclear workers because I don't know whether that's how -- how much of that fits into our scope and that's something we're going to have to think about and that's where I do say I am worried there as well about some of what we get. Finally, though, what is important and what was not appreciated as a group, as a committee wanted to start to understand the interconnectness between departments engaged in this so that we begin to set a climate was the sense that Dr. Saenger again is -- for the Cincinnati experiment to understand that the nuclear workers are being referred to the very same person that are cases for arbitration, for analysis, are being sent to the same person that's under concern in other areas. It may or may not be an important point, but it's an interesting point in which to be explored, and so I would say to you that when it comes to the nuclear workers, we've got to decide what our responsibility is and as we get that information, what is the appropriate thing to do with it, if in fact, it is not for us. I think there must be some reasonable way in which to respond to that, referring it to where some other place, but we've got to

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deal with it.

I agree with that last point. Duncan?

DR. FADEN:

DR. THOMAS: I share Pat's concerns about raising expectations and I've been worried about this right since the beginning and especially after San Francisco and it comes up with quite a number of groups, but let's take the occupational workers, the nuclear workers as an ideal test case in many ways. The Scope committee considered the boundaries of what we ought to consider and concluded, you may recall, that routine occupational exposures of nuclear workers had no experimental or even observational attitude towards them. It was just a routine surveillance of medical, of occupational exposures to make sure - with regard to compliance with federal standards. That was well outside the mandates of this committee. To the extent that superimposed upon that is an organized program of biomedical research, such as the body snatching program, to use that terminology, that I think could well fit within our mandate as a piece of biomedical research. The toughest line to draw will be purely observational epidemiologic studies which could be viewed as an experiment of opportunity, much as we're viewing the uranium miners. I'm not aware, well, I shouldn't say I'm not aware, I simply don't know whether or not there was epidemiologic research of that nature going on during the time period that's under study. There certainly are, in retrospect, studies, cohort studies underway today, many of them, in that population. DR. FADEN: Let me suggest this is a very tough issue for the Committee and also in the interest of time I think maybe two things are clear. One, advance work, obviously, in planning for anticipation of the field hearings is terribly important, but it seems that a critical component of that advance work is a clear message of where the Committee is and what its mandate is. I am also very worried about this issue of setting of expectations and then people come and the human response is to want to help and we are not positioned to be able to do that. The very virtue, by virtue of hearing someone speak to us you set up this reciprocal sense that now you're willing to do something with that information and we can't. I think we need to make every effort as we do the advance work for these panels, making it clear that our focus is what it is, the focus on biomedical experimentation and the confined area of intentional releases and once you move away from that, the extent to which the committee may be able to address your concerns, weakens dramatically. We do have these other areas we are considering, but I think we can send a message out that's clear as we can possibly make it and we know that we have people interested in persuading us that many things should be considered experimentation and research and that's -- they are

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free to do that. I mean they are free to come and try to defend the view that this should be considered experimentation, but I think we need to keep sending that message out in advance that that's -- this is who we are and this is what our mandate is. Beyond that, I'm not sure once you're out in the public taking testimony, we obviously can't deny anyone who wants to come talk to us to talk to us, but at least we can try as much as we can to explain to people, you may come, but please know this is what this Committee is about there isn't a match you might think there might be between your interest and the charge to this Committee. DR. TUCKSON: Ruth, I think that's important and I think one of the things this is a timely point to have the discussion. I mean one of the things that you don't -- that Duncan really related about very logically in the sense that the scope committee very clearly said this is not within scope. Now there is this sense that maybe there is something more in terms of an active experimental or investigational component to this which may not have been appreciated before. You don't know that unless you go out and you cast your net a little broader. We'll have a chance now to follow up specifically on this question in Seattle. We may very well find out then that this, in fact, does not qualify it for inclusion into scope and then we can have resolved it, but then we're still left with the matter of how do we at least -- do we refer it to anybody else to further their exploration. I guess the point is that we had to cast the net, I think, somewhat broadly to find -- because you don't know what you're going to catch. On the other hand, I think Patricia's point is right on as well. We don't want to do harm. The bottom line is we also would have done harm if we didn't cast a net because there's so much -- it's like if they didn't get a chance to participate in the process, then they take that with them and -DR. FADEN: Clearly, there's no simple way to do this, so we just have to try to be -- the only thing is to be as honest as we can, as frequently as we can as we reach out to people so people know that we're in a tough place too and we would like to help everybody that needs help, but we can't. That's not -- when we have something clear, we'll be able to help anybody. We hope we can, but we're only an advisory committee and it is very difficult. There's another proposal that implicitly came in here which was for another field hearing in Nashville. My sense is that if we have Committee members willing to go and there's a way to get it in, although we had an earlier discussion that we didn't have the time and so on and the resources, but if there are people who are willing to go and it seems to me it sounds like from informal conversations that there are, in addition to the two other field hearings that we already have scheduled, then

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I'm hard pressed to hear an objection. But we need, other than it's going to be one more thing we're going to squeeze into an already overcommitted kind of a -DR. TUCKSON: I just want to remind folks, the only reason I think we feel at least a little more comfortable in recommending this is that it is and since we're already doing a case study in that area so it's not as if we're again plowing a whole other field, we're already involved in it, so now we're just talking about making it a much more intensive public comment section to the work that already is intended to be done. DR. FADEN: Can I take it that there is agreement? Is there anyone who wants to argue against it? If not, we'll let people self-select. Duncan? DR. THOMAS: I just wanted to revisit the comment you made a moment ago about advance preparation for this. I would like to see this organized somehow or another and I would volunteer to work with Reed and maybe the three or four of us that are going to Spokane might be a logical committee, I don't know, a press release, or however you go about publicizing it. We need to word that really carefully though. DR. TUCKSON: Well, I think that's important and it makes sense and again, since I know they're in the audience maybe we can get some of the advocates as well to come and help us who are extremely skillful at being able to organize these things. DR. FADEN: So we have a mechanism. If it's all right, we'd like to continue again, expressing a great deal of appreciation to Mary Ann and Reed and Lois and we will express the same to the group that goes to Spokane next and then there's a New Mexico group and now we know there's going to be a Tennessee group. So presumably all of us will get a chance to go to at least one. DR. TUCKSON: DR. FADEN: here. DR. TUCKSON: We're the group who is going. By the way, I think she's going to be very angry at me, but I just want to make sure everybody knows that Ruth Faden just got elected to the Institute of Medicine and she's very wonderful. (Applause.) DR. FADEN: sweet. I'm just thrown off here. Let's see. We are going to go now to the total body irradiation case study which Gary Stern Thank you, Reed. Thank you. That's very Duncan, Henry and -- who is going? Who is going to Spokane? Susan, who is not

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and Ron Neumann are going to join us to remind everyone we agreed on a group to consider which is a case study group involving external radiation research with people who are ill, with patients in contrast to other, the other group we heard from this morning where the focus was radiation research with people who are well. Again, as in that first group, instead of doing the whole category, we picked out prisoners. We also could be looking at military personnel, students and laboratory workers and hopefully with any luck we will look at all of those, but we can only get that far with the healthy adult group this morning. Similarly, we will hopefully be looking not only at total body irradiation research with patients, but partial body and other lines of external radiation research, but right now we have the TBI case study and with that Gary and Ron? Tab G, Anna reminds me, also as a practical matter since we ended lunch late, I'm hoping that people aren't in need of a break at 3:15 as was originally scheduled. We'll go until longer, have the break and then do remedies and everything else that was on the agenda for today we'll drop out in order to accommodate ample time for discussion of -- at least not ample, but at least a longer period of time for discussion of the TBI case study and a longer period of time for discussion of the remedies. We will not have the smaller agenda items this afternoon, just so that everybody knows what's happening, we're going to do this, have a break, do remedies and then we'll be finished for the day. MR. STERN: I'll start just with a very brief summary of the memo and what it covers, which is essentially a review of the literature and government reports which we've received and have been accessioned on TBI, in which we've identified approximately 20 TBI studies from this information in the period 1940 to 1974. Nine of these total body irradiation studies involved treatments of so-called radio-resistant cancers and eight of those nine, we realize, were funded by the U.S. Government, at least in part, culminating in the University of Cincinnati experiments, which was the last DOD-funded experiment. And so the focus of the memo is principally on the DOD, and prior to that the Manhattan Project, sponsored-TBI research. What's important is that the military was primarily interested in the effects of total body irradiation on healthy persons. Nonetheless, they turned to ill patients to do their research. Accordingly it seems that they looked for those who were hematologically normal, i.e., people that had non-hematologic, generally radio-resistant diseases and people who were in as good health as possible, given their medical condition. We've already actually touched on some of these experiments in the previous memo from last July, particularly the three Manhattan Project studies were discussed. I just want to make one quick note on the one done by Memorial Hospital on behalf of the Manhattan Project. It was essentially a repeat of

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a prior experiment and work that they had done and failed in terms of finding any treatment. Nonetheless, they repeated the same procedure because of the military interest, it appears. Following the war, World War II, the first military interest in TBI came up in the context of the NEPA debate, that's the Nuclear Energy for the Propulsion of Aircraft Project. In the course of the debate, in which we have a lot of material from the Committee on Medical Sciences, in particular, Robert Stone, for example, stated that, in place of the experiments on healthy persons, they could use patient studies; in particular, that meant, in his words, "you can't pick lymphomas, but carcinomous types of metastases." Once again, that's a distinction between the radio-sensitive and radio-resistant. The Air Force, in response to this debate, then contracted with MD Anderson Hospital and the University of Texas to do TBI studies on the patients that they were seeing and to incorporate interest of the military, both in psychomotor testing, as well as in biologic dosimeter and other tests of that sort. MD Anderson was the first hospital to put into practice the newly developed high energy cobalt 60 radiation machine, and so that establishes a context there. For most of the nine institutions that were doing radio-resistant, most of them were also treating -- the radioresistant patients were a subset of a larger pool that also included radio-sensitive cancers. Basically, the only exception was the University of Cincinnati, in which virtually all of the patients they were treating had radio-resistant cancers. I think there's three with Ewings arcoma and perhaps two very early on, I think, with leukemia and lymphoma. Let me just make a very quick note about dose, and this is partly for my own edification and understanding. In reading through the literature and the documents, they reported differently, the early studies, particularly MD Anderson, Baylor, Sloan-Kettering, always reported dose in Roentgens, with the letter "r", in contrast to later studies, City of Hope and the University of Cincinnati, which reported them in Rads. The important distinction is that Roetgens are generally higher than Rads, so for example, MD Anderson reported its maximum dose of 200 R which is equivalent approximately to 130 Rads and Baylor used 250 R which is about 150 Rads. In contrast, University of Cincinnati, for example, used 200 Rads, which was the maximum dose in all but one instance, which is actually equivalent to about 325 Rs, so there's an important comparison there. With respect to the University of Cincinnati experiments, they are the most well-known throughout the past year in terms of media coverage and they're the ones -- because of that they're the ones we have the most information. So there's no question we know more and can analyze it a little more deeply. What happened at Cincinnati, precisely because they're more well-known, not only now but because they came into public attention at a time back in the early 1970s when there was a lot of public and media scrutiny going on about -- in particular,

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academic connections with the Defense Department and CIA and other government agencies and so that was -- that's partly what has brought this greater focus on Cincinnati. But the context in which they were exposed and the fact that others were not publicly exposed when they were being conducted or even since then and maybe until now, should have no bearing on the assessment of what actually happened. Just, I think, to reiterate Reed's point, we've learned not only from the patient families' testimony in the Cincinnati panel, but it also comes out in the reports themselves filed by the investigators to the Defense Department, that it does seem that many of the patients at the University of Cincinnati were not in state such that even though they may have had an incurable cancer, they were not in the final stages with only a month to live. In fact, some of the documents made clear they purposely picked patients who were in reasonably healthy condition and who were active and therefore were not at the point of dying at that time. As the memo describes to some extent, we looked into the question of essentially what was known by the investigators with respect to the dangers and what could they do about it. It seems clearly from the reports themselves that no matter what they were expecting when they started, within a reasonably short time, within two years or so, they knew that the high doses that they were giving to some of the patients were causing severe problems with bone marrow suppression and having a major effect on the health of the patients at the time. Therefore they began, but it took a long time, about six years, to I think, apparently to perfect the process of bone marrow transplantation to counter that effect. But in the meantime, they were still giving the high doses even without the bone marrow transplantation. In the mid-1960s, starting in 1966, there was a review, institutional review of at least an aspect of the treatments that were being given, and there were serious concerns raised by several of the reviewers. Two of five of the IRB subcommittee in 1967 made explicit note or concern about what they perceived to be a very high death rate and commented that if it's not disapproved, at least the patient should explicitly be warned about the risk of death. I guess in just very quick summary from the review of the studies on the radio-resistant cancers, it appears that very little real benefits were reported or gained on these particular patients. What was generally noted from the studies were comments like we need to look further or it's not really any more harmful than anything else. A point in comment was made by the Oak Ridge Institute of Nuclear Studies (ORINS), which is included in the list that we have here, but did not do any radio-resistant treatments or radio-resistant cancers. ORINS was actually in 1966 questioned, or a proposal from the AEC was made to them, that they should treat radio-resistant cancers. They declined to do so and made the comment, and I'll quote that: "there is so little chance of benefit to make it questionably ethical to treat them. Lesions that require moderate or high doses of local therapy for benefit, or that are actually resistant are not

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helped enough by total body radiation to justify the bone marrow depression that is induced. Of course, in one way these patients would make good subjects for research because their hematologic responses are more nearly like those of normals than are the responses of patients with hematologic disorders." I'll turn it over to Ron. DR. NEUMANN: I'll make several points, sort of an analytical summary to help stimulate your discussion and first I'll focus on the role of the federal government, i.e., the Department of Defense, in overseeing these experiments that we're calling TBI. First of all, there's a lot of confusion in that early literature, particularly in the NEPA literature about what, in fact, constituted an experiment and therefore was to be subjected to the various regulations like the Wilson memoranda and there's a discussion at one point as to whether or not treating sick people is an experiment. There's a confusion between again an experiment on a normal subject of physiologic measurement or whatever, versus an experiment that bridges clinical science and goes into the role of therapy in terms of individual diseases where there may be benefit to the individual subject. Second, although I think it's clear that the implementation of the Wilson memo that Nuremberg Code was supposed to apply to DOD and its contractors, we have at least reasonable evidence in the case of Dr. Saenger in Cincinnati that no instruction was given to contractors. He and his attorney have no records that were ever found in their extensive search of the Cincinnati files that suggest that it was any forwarding or of regulations or educational materials or instructional materials of any sort vis-a-vis how one is to do clinical research or human research at least in the context of a government contract in that period in time. So there's evidence from that one exhaustive examination, at least these regulations as you were discussing this morning were ever passed out to the contractors that any educational process went on. The other thing that struck me that Dr. Saenger has a long career in various appointments to government groups and subcommittees and even in his days in the Army in the beginning had no instruction in clinical research given him by the government. That's a fine point, but I think it's telling to the extent that the government, to my knowledge, still doesn't require acknowledgment of training to do clinical research. It does require, as we were discussing at lunch, certain certifications to use radio isotopes, for example, now, but there's still a broad area that allows a person to declare himself or herself a clinical investigator and other than today's IRB process, we don't have federal regulations that I'm aware of that discriminate the trained from the untrained. That was certainly true back in the period of time that's under discussion. The 1962 regulation that exempted clinical research

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from the Nuremberg Code regulations or the Wilson memo is even more telling and this has yet to be explored in terms of its purpose, but nonetheless, in terms of culpability that we discussed this morning, if one accepts that regulation, then that seems to state that if you're doing clinical research, you're not even to be concerned about the number of regulations and that these are only to apply to experiments on contractors, military personnel, etc. etc. which I find to be extraordinary. And the third point about the federal government's role is its lack of regulatory or review processes to look at the underlying scientific and biomedical aspects of an experiment often. The review process from their standpoint and justifiably so is done generally -- if you read the notes to accomplish the goal that the federal government has in pursuing and funding that research and if you look at TBI it was clearly to understand th effects of radiation and performance and perhaps to come up with a biologic dosimeter. It was not intended to find a new treatment for cancer and in the review process that you've seen, at least in Dr. Saenger's proposal, there isn't a discussion of whether or not this particular TBI experiment is going to achieve palliation much less therapy. There's discussion of whether or not he'll find the biologic dosimeter with some disagreement in the review process. So in the context of again coming back to these piggy backed experiments where you, in this case, have the government's purpose quite in a different direction from the investigator or patient subjects' purpose, one has great difficulty in understanding how a single review process at that level, done with the individuals that are often involved, can arrive at a correct decision. They're fundamentally not in the business of looking at the biologic or medical or ethical question. They're in the business of understanding what they need to know for military purposes in this case, can pilots fly these aircraft? Can submarine crewmen stand the radiation that they may be exposed to in a nuclear powered submarine? Now let me turn a bit to the role of the investigator and ask some questions or give you some summary statements again. We looked in great detail, as Gary said, at Dr. Saenger's experiments, not to necessarily single him out, but because the bulk of the research over the last 20 years has been done in that particular TBI experiment, he just offers or the Cincinnati case offers a number of points that probably also apply to many of these other experiments, so when I allude to Saenger of Cincinnati, again, these are probably no different in this instance than they were in the other experiments. But in particular, the treatment of these patients or subjects in Cincinnati is termed a palliative experiment, i.e., Dr. Saenger was looking to see whether he could find some way to lesson the pain and suffering of advanced metastatic cancer. And yet, there's never been uncovered evidence of a written protocol for that. He himself admitted that to us in his testimony. He did not have, could not produce a written protocol. To the extent that one doesn't have a protocol and

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perhaps it wasn't always required that such protocols be written, but I think that points to at best imprecise or sloppy clinical research and I doubt that certainly today one could enter into any sort of a human experiment without very precisely listing the various goals of the research, etc., all the things that go into a modern protocol. So to the extent that we can criticize it, I think even in that late 1950s time period, it probably was common practice to have an experimental design for one's human research and certainly for bench research as well. There is no evidence of any prospective control group of subjects, i.e., those individuals that would have been given even no treatment or perhaps chemotherapy which was also in its infancy in that time period in a prospective study to compare the effects of the total body irradiation as opposed to no treatment or to chemotherapy in its infancy. There's also, as I alluded to earlier, a real question as to whether piggy-backing of the two very disparate types of work that we're talking about is appropriate in any experimental protocol. I personally would find it difficult to address an issue of finding a biological marker at the same time I was trying to do something that had a different end point, i.e., palliation or treatment. I think there's again perhaps difficulties in try to accomplish too much within the confines of a single experimental group of patients. That's not to say it's not impossible and it often has to be done because of the limitations one has, but I think it raises difficulties when one attempts then to do what's best for the measurement of data leading to one end as opposed to a different end. The faculty report noted and given to you also called the Suskind Report, confirms my belief that the design of the palliation and survival data were probably not state of the art and perhaps poor, even for its contemporary time period. Another interesting aspect, however, is when one looks at the literature review, now we've attempted to reconstruct all the available literature on total body irradiation with the able assistance of the National Library of Medicine and it's an extraordinary difficult project because the data bases are not computerized back into this time period. References and citations do not indicate specifically whether humans are involved. You've heard all these things before, whether one counts a review article or not and only counts primary articles are all problems. I had a belief that we could establish some sort of prior literature base to tell us whether or not an experiment of this type in its time period was still necessary of whether sufficient data had been accomplished in earlier trials to suggest that total body radiation for this particular subset of patients was or was not -- stood any chance of being likely to achieve a palliative effect. That's on-going, but I'm beginning to believe that that is not going to be a useful tool. On the other hand, in U.S. medical research, all

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research and perhaps most aspects of American life, we kind of allow the individual who strikes out on his or her own to achieve a goal or an idea, to pursue that course, and although that's in medical research certainly constrained to a great deal by the IRB process, there is ample evidence that in spite of a preponderance of negative literature, people are not necessarily precluded from taking on a particular experiment and so even if we had shown that, for example, all the literature, the bulk of the literature prior to that period in time was in essence negative, I'm not sure that would have been sufficient reason to say, well, no one could do it again. Someone who thought he or she had a better idea or a different interpretation should not be allowed to do it. We simply don't have that, I think, as a way we do medical research with the exception, as I said, you certainly have to have your peer group accept and that's the funding peer group as well as the IRB peer group. That didn't exist, however, of course, in the late '50s. The other issue is to whether or not in the Cincinnati case again, the palliative effects protocol could have been carried out without the Department of Defense money because Dr. Saenger said to us again in our conversation with him that it was very difficult to get research money even in those days as compared to now and that, in fact, had he not had the Department of Defense funding, he might not have been able to carry out the palliation part of his research and that looks, I think, at the issue from a slightly different direction. If good is accomplished with funding, that may not in our value system be quite so good should we think about it any differently and that's something for you all to consider. Finally, let me say that it's extraordinarily difficult to prove and we've not tried to prove individual harm with any of the subjects in these experiments because the fundamental question comes down to again informed consent, as we heard this morning. It's not necessary to prove harm, legally at least, so that the question that is pivotal on all these is were the patients told about the risks they were encountering when they accepted total body irradiation and this, of course, predates written informed consent, so we have only the word of the investigator, the word of the families, that you heard in Cincinnati to base such judgments upon. I, for one, am glad I didn't have to make a determination because of all the vagaries of time and so forth when we don't have that extra bit of evidence, i.e., written documentation to help us. I must comment though that Dr. Saenger himself created an informed consent document after receiving a letter from a wholly different branch of the government after concern about the chemical experiments that were going on. He received a letter and decided that radiation wasn't too much different than drugs and that he would create his first written informed consent document and you have that, as well as the later ones in the materials that we passed out to you.

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In conclusion, I think, aside from the ethical questions and the informed consent questions, my summary would be to say that sometimes poor science is as harmful as bad science and if I had to make a summary statement on the aspects of the TBI, I think that the problems that I see in the way the work was carried out, the fact that it didn't necessarily lead to anything that is now useful with the exception that you might make the claim that it predates marrow transplantation, but I think that begs the issue, you had to have marrow transplantation available before you could use the radiation to sterilize the marrow. I find very little of use that came from this work and in fact, was astonished to find that most of it is not cited in modern military radio-biology manuals, for example, for field commanders, in terms of determining risk of soldiers out on nuclear or sailors out on a nuclear battlefield and that may be the most damning statement of all. If one does research that is not done in a context that makes it useful later, perhaps, that is an equally bad outcome. We've prepared a series of questions as well, that I believe were distributed for discussion purposes. MR. STERN: I just want to make one final comment, just to follow up on what Ron was talking about, on the issue of consent. I think actually in the Cincinnati case, at least, a lot is known about consent. We have the forms that were developed over several different years. There's no question and no dispute about some of the things that weren't said, and in particular, the issue about the risk of death from high dose and the bone marrow suppression. I think there's no question that that was not included and it was never told to patients. So regardless of what's known or not known about exactly who said what, that was not said, we know that was not said. It was raised, at least, in 1967, by some of the reviewers, but it was not accepted and it was not put into a form or told orally, so that's an important consideration. Also, I wanted to pass out additional, additional tables on some of the other studies included in the report that were not included as part of the original packet. DR. FADEN: The floor is open for discussion.

DR. GLATSTEIN: I just want to say that what you present is a virtual recapitulation of exactly what the criticisms were with the Oak Ridge experiments at the Gore hearings in the early '80s. The major problems, there was no documentation of goal, what the purpose was and it's essentially the same thing. I think that to put the mortality some kind of perspective, however, in that time period, if you had a patient with acute leukemia and treated with chemotherapy, but to what most in the early '60s that would have been probably the standard chemotherapy disease, acute leukemia, the mortality from induction was 25 percent and that was known, that was recognized

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and still is used frequently as the base of comparison in chemotherapy. DR. NEUMANN: Yeah, I think that's why as I said, it comes down to fundamentally were the subjects told about these risks because the science is a more difficult one. In spite of their apparent good health, they all did have advanced metastatic carcinoma of one type or another whose outlook long term certainly wasn't good. The other side of the argument, that the TBI shortened certain patients lives, there's also on that chart patients who lived 900 more days after it, so as statistical analysis of whether it was worse or not is very, very difficult. Also, midway through it, there's an attempt to bring marrow replacement into it after untoward results occurred in early patients and I think it's a very difficult analysis, if one attempts to do things like survival curves and so forth with the way the experiment was carried out, and I think that the discussion of it is fraught with difficulty if we attempt to do it on a medical or scientific basis. It's probably an ethical informed consent issue as were most of these. Now you could see the earlier experiments were our equivalent of Phase I where people learned what amounts of radiation were going to cause marrow difficulties and even in the discussion of the Cincinnati experiments, it goes back and forth as to whether these are extended Phase 1 experiments or Phase 2 experiments. But once again, without an experimental design it becomes very problematic to do that sort of analysis. MR. STERN: And I guess I would add, concerning your comment about equivalent death rate for acute leukemia, I guess my understanding as a lay person, is that even then the benefits for the treatment were recognized and well understood and there was an offset. But with the radio-resistant cancers, there wasn't at the time understood to be the equivalent benefit that would come. The earlier reports, where it was attempted, suggest quite in fact the opposite, that, in fact, it wasn't going to be positive. So I think it has to be understood in the particular light of the treatment of these types of diseases. Then, at that point, the question to raise should be have the people been subjected to that type of risk without knowing the risk clearly? DR. MACKLIN: Yeah, I have a brief question about something Ron said and a question about something Gary said that followed on what Reed reported. Ron, when you were talking about the training in clinical research and the government training, you made the observation that the government for its researchers or people doing research directly or under contract, that there was no training, the government provided no training in clinical research and there was no distinction, you said, between the trained and the untrained.

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Now since part of our task today's standards and also look back time, my question is, is it the case do clinical research one has to have research. I know there are research become fellows, research fellows and there isn't any requirement anywhere take, have any particular training. sees schlock and I mean schlock that from people who don't know how to do write, don't know about goals, etc.

is to look back by virtue of at what was common at the even today that in order to training in clinical fellowships and people those are the good ones, but is there, that anyone has to So for example, when our IRB comes in as research, it's research, don't know how to

So were you making the point -DR. NEUMANN: I contrasted it with the radiation. If you want to use radionuclides, internal radiation in human beings, you do have to present evidence of a significant amount of training. So it's the one area that I'm aware of where you do have to document training in human clinical research if you propose to use internal emitters. DR. MACKLIN: But see that's with a specific substance, I mean you're talking about research that shows knowledge

right? --

DR. NEUMANN:

A class of substance.

DR. MACKLIN: Right, a class of substances, but that the focus is on, but correct me if I'm wrong, on the dualing clinical research with that class of substances and not on the kinds of things that have to do with stating the goals, having end points, designing a protocol that is good science. DR. NEUMANN: It varies, I'm certain from institution to institution. But for example, one way to gain such certification to do that type of research is to present boards from the related specialties that you've passed these board examinations and in many instances, those boards have requirements for training in aspects of human research. It's an indirect process. Certainly, it's not a government regulation. DR. FADEN: I'm sorry, that was the one thing I was supposed to tell you. Your mike is supposed to be on, but just so people know, Ruth said -- I know you reserved another comment, but I saw Henry, Jay, Nancy and now Phil, just so people are on. Ruth, you've got the floor back. DR. MACKLIN: Yeah, my other question is more of an observation than a question, but it invites us to think about this. When Reed made the presentation of the visit and then Gary, you repeated the comment that not all the patients were dying, some were much healthier, some did housework or something the night before. The reason I bring this out is it makes a difference to be sure whether people are terminally ill or dying or not dying with regard to the level of risks, how we look at the risks and how the risks of being, getting this particular intervention compared with the risk of not getting it, if you're

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going to die soon anyway. But since one of the concerns that we had from the beginning, and again I will say from today's vantage point is taking advantage of sick and dying people to do research on them based on the view that wow, they're going to die soon anyway, so it's okay to do this research. We have to be careful we're not talking out of both sides of our mouth. Now my question that follows this is were the patient population in these experiments in some way represented either at the time or later retrospectively as being terminal or dying, that is to say, I mean is it that this finding that there were some people who were not sick and dying was contrary to what was otherwise believed because the researchers represented these experiments as ones that were done only on dying patients so that there wasn't that much to lose? MR. STERN: Well, to some extent, Dr. Saenger, in interviews with us, did describe patients as sick and dying and really, it was as if they had no other alternative. I think there's been that perception that these treatments were kind of last ditch efforts with nothing else available. I guess I would contrast it maybe with one of the other studies in here, the City of Hope study, which was the one that was not DODfunded, but still focused on radio-resistant tumors. They explicitly described, when picking those individuals, those people all have life expectancies of one month and were considered, I guess, truly end stage. Apparently, the survival times of those people, even post-radiation, were much lower. So I think that's an important consideration. But it's also a comment that advocates have been making and critics of the program: that in a sense without being given any consent, they were exposed to an extremely high risk at a time when they still were living lives and living productive lives, and that it was an overwhelming risk to be exposed to without being given any information about the risk that there was. DR. MACKLIN: Yeah, just to point out, I think that is important because it changes the objective, if it can be said to be objective, the objective assessment of risk benefit ratio. If everyone is sick and dying, although the risk may be high and the lack of informed consent is the same in all of these cases, one might say from an objective standpoint well, the risk benefit ratio was not as unfavorable as it was in cases where people are still living productive lives. DR. STEVENSON: I think there's another side that should be brought up about this and I think it's still true in Phase 1 and 2 studies that are being done today. Most studies require, and this is aside from judging whether or not this is actually legitimate, Phase 1 or 2 study, most Phase 1 or 2 studies, they require a reasonable life span, otherwise one can't actually assess potential toxicity or benefit. So -- and I don't think in my reading of the letters and correspondence back and forth between the Cincinnati review board and the investigators, they make it very clear they prefer patients that were initially, I think, slightly healthier because

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they were presenting it in light of being a Phase 1 or 2 study, that they're trying to assess, benefit trying to assess toxicity. I think you have to be a little bit careful in interpreting what the motives were in terms of whether the patients truly were. I mean there's a difference between end stage, in other words, they have failed conventional therapy and have no other options versus terminal, that they have very short number of days to live. I think that's to some degree a sliding definition. I mean all of us who have been involved in oncology know that there's an on-going dialogue between patient and physician as to when or when not treatment is advisable, both from the doctor's and the patient's point of view and that largely does have to do with quality of life that might be attained and quantity of life that's left for that patient to life. So I think all of those things have to be taken into account when you look at the patient population. DR. NEUMANN: Well, one minor point I think it points out the problem with allowing piggy-backing because the purpose of the biologic dosimeter measurements and the psychological performance testing required the patient be as nearly "normal as possible." On the other hand, the palliation or therapy doesn't necessarily require that you start, the fact that you're exactly right, we have to start in the most advanced, the more risky the procedure, the more advanced the amount of tumor. The two things are working at cross purposes again when you allow this type of piggy backing to go on. DR. FADEN: Henry?

DR. ROYAL: Ron, you made the statement that there was no written protocol for the treatment in that it was your impression that in the late 1950s that that was an aberration that most research studies would have had written protocols. In view of Ruth Macklin's talk this morning about judging the ethics of an experiment and determining whether or not a particular experiment was -- experimenter was an outlier, could you tell us what the basis of that statement that you think written protocols did exist for many other kinds of medical research? DR. NEUMANN: I used the word protocol in this context to say a plan. And that perhaps is what you're thinking about in terms of a full-blown protocol in today's thing. But I think most experimenters were taught to have a written plan for their experimentation. You create a hypothesis. If you don't write that down you can explicitly state it somewhere. You have a method by which you're going to carry out your experiment and again, if it is not written, you can tell that to someone later and you have a data set that you have somewhere and you have an analytical part and a conclusion, just like a scientific paper. I don't think that part of science has changed or was invented in the post-'74 period and Dr. Saenger, for example, himself admits to not having that. I don't know why. We didn't get into a discussion of whether those records were destroyed, but even in those earlier investigations by the faculty committee, the junior faculty committee in the ACR, he did not or could not produce

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that type of an experimental design, maybe is a better word than protocol. DR. ROYAL: Have we seen experimental designs from the other institutions that were doing whole body irradiation resistant tumors? DR. NEUMANN: No, I don't think we've seen the research papers, but I don't recall that we've asked for an experimental MR. STERN: Well, actually we have requested data from many of the institutions, well, all of these institutions and many that were on the list of 45, 46 from the Oak Ridge, NASA retrospective study. And generally, we have not gotten back any such design data from the institutions. All that seems to exist so far is what was either published in the literature or what was done in government reports that were obtained from the government agency. The institutions have not maintained any of the investigative research documents at all, so far and we're still waiting to hear from -- and some institutions are still looking in some places, but to date we haven't gotten, even though we've requested, any of that type of data which would be very useful. DR. NEUMANN: Part of it is certainly records and retrieval and retention processes, but again, what I was more referring to was I asked the question, for example, in our first interview with Dr. Saenger, how would you measure palliation which was the stated purpose and he said "increase longevity of the patients." Now to my way of thinking that's actually not palliation to begin with, but I would have liked to have seen a more extensive discussion had he been able to tell me verbally what he had in mind and again, I don't, I'm not claiming he never had this, I'm simply saying we have been unable to recover such a thing which certainly were at present, I think, would be to Dr. Saenger's benefit. MR. STERN: Could I just add, I don't think there's anything -- I don't think Saenger says there's something that he did have that we don't have now. I think we have a fairly full record of what even existed contemporaneously with respect to the University of Cincinnati program because it came to public attention and was frozen at a time when it was essentially ongoing. It was ended, in part, because of the public attention focused on it, so everything was preserved contemporaneously as it was on-going. That's not the case with any of the other studies or experiments. They're only being studied basically now, many times, 30, 40 years after they were conducted. DR. ROYAL: The last thing is the -- Gary, you gave the impression that you felt that more harm than good had been done to total body irradiation experiments and the only analysis that I have seen in terms of survival was the one that Saenger had done. In Saenger's analysis, either implies that there might be some benefit, particularly with colon cancer or that it was at

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least equivalent to whatever the alternative option was. Has the committee staff done an analysis of the survival data to suggest something different than what Saenger's analysis -DR. NEUMANN: I'll answer that by saying that the difficulty again, he doesn't establish what his control groups are and we do not have chemotherapy patients that he did his comparison to, nor do we have any untreated patients from that time and place in Cincinnati, so I have had great difficulty engaging a life survival curve epidemiologist to be able to produce anything like that. MR. STERN: Well, actually his comparisons were not to his own controls. They were to previously studied historical controls, previously studied chemo or nonpatients. DR. THOMAS: Let me first of all dismiss Saenger's own comparisons because they're scientifically complete bullshit. (Laughter.) DR. ROYAL: Well, that's why I was interested in seeing an analysis that was not complete. DR. THOMAS: Well, it's going to be tough to do, but the fundamental, there are two things that can be said about his analysis. First of all, any comparison against his patients against any literature controls raises the obvious question about comparability in terms of baseline prognostic variables. And no attempt was made to try to establish any kind of comparability, let alone adjust for differences in comparability in relation to selection factors which would determine your future risk. But a more damning problem with this analysis is that he compares survival post-irradiation in his group against survival post-analysis in the others. MR. STERN: No, that's not -- I mean his study in his 1973 paper, he compares the post-diagnosis data. DR. THOMAS: Right, I'm sorry, I misspoke. In both cases, a comparison is some date of diagnosis, but that's flawed in his case because the patients are already known to have lived to the time of diagnosis, so that they couldn't have died during that first time period anyway, so what's needed is a proper comparison of conditional survival, that is, the probability of surviving two various time points given, survival to this point in time already. So that completely invalidates the comparison for which he provides. In my view, the only sensible comparison is the comparison in which the junior faculty report attempted, but not particularly with state of the art methods, which is an internal comparison within this cohort under the assumption that allocation of radiation dose is independent of prognostic

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factors. Now that, of course, is also a leap of faith, but that's something for which -- that's at least a testable hypothesis. The data that's available, that I have seen so far which is reproduced in one of the annexes in this report provides essentially no useful information on prognostic factors. The only prognostic factors are how long you've survived so far and what type of cancer you had. No mention of age, stage or any of the other things you would like to know about. For what it's worth, one could still do a survival analysis and I even attempted to do that last night and just all you need to do is eyeball the table to see that there's nothing that jumps out as sort of a prima facie case, the people with the higher doses had shorter survivals. It would still be nice if these data exist to attempt to properly control internal comparison dose groups and I made a request which kind of got forgotten after our first or second meeting that universities try to provide us with the file which have all the relevant variables, and I don't know whether there's been any follow-up of that request. This is the list, this is the first thing I've ever seen produced in response to that. DR. NEUMANN: We don't have complete hospital charts on virtually any of the patients to my knowledge. We tried to produce that table based upon information generally furnished by pieces of charts that arrived through various offices, so we probably can't do it with what we have now. If they are able to find the intact patient charts at the University of Cincinnati, it might be possible, Duncan, but what we have in our possession right now isn't sufficient to do that. DR. THOMAS: University? That chart was produced by us or by the

MR. STERN: No, that chart is produced by us. It's based principally on the patient histories provided in the DASA reports by the investigators themselves in the ten reports: over a period of ten years, they do a short patient history and so most of the data came from that, as well as other data that we've got from the investigators, files that have been accessioned, include almost essentially the equivalent chart of date of diagnosis, date of radiation, amount of radiation and death. But we do have some of the patient records that have been given to us by patients and their representatives. My understanding is all of the patient records exist, I mean not all of them intact, but a large percentage of them do exist and, in fact, are held by the court and by parties to the lawsuit. There is a lawsuit involved in this and many of the ones to which permission hasn't been given, mostly because the people haven't been located, are not publicly available. Although a suggestion has been made, that if the Committee made a formal request to the court, the court might be willing to turn over complete records to the committee on the private circumstances with privacy considerations kept intact. So we haven't been able to look at the patient records. In the report that we presented to you, there is a section on patient

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survival that was clearly very crude and just focusing on the date, survival time from date of irradiation and comparison to dose. I guess I had thought there was at least some prima facie difference between high dose and low dose patients, and that there was a higher percentage of patients who received higher dose who died within the shorter time frame, generally associated with bone marrow suppression, than folks who received the lower dose. And that's what the JFA report attempted to do as well. So there's that admittedly crude sort of comparison. DR. THOMAS: I think the two of us ought to compare notes on our respective analyses and also what kinds of data are either presently available that we haven't yet tapped or could be made available, but I guess I do have some trepidation about whether or not this is an area the committee wants us to pursue. It isn't at all clear to me that (a) we are properly constituted to reach a sensible, scientific conclusion as to whether people were, in fact, harmed, i.e., had their lives shortened as a result of this and whether we want to open that even for the obvious purpose of making remedies, contributions, its implications for remedies. I think we should think very carefully before we undertake such an analysis. DR. ROYAL: I wanted to make it clear that there was no other data. Could I make one last comment and that is there's a document in the chart in the whole body section that mentions patients by name and has some personal information in it and I would hope that we have permission to -DR. FADEN: Okay, we missed it. We're going to We missed that so that will be

apologize.

-- that should not have happened. MR. STERN: Although many of the patients have, I mean, many of the patients' families have testified at the Cincinnati panel and named patients by name and I think, I believe that that document, all those correspond with patients who testified at the Cincinnati panel and just publicly disclosed the patient name and patient number. I'm almost certain. DR. FADEN: We'll check. I hope that's right.

DR. NEUMANN: We did receive portions of medical records from various sources, as I said. Now some of these, parties who are well-recognized as being interested in this, they assured us on the telephone that any records they sent they had releases from the individual attorneys representing these people, so to that extent we took them at their word for that if that's not the case, it certainly is. DR. FADEN: As a matter of course, we could have -- it wasn't helpful or necessary and we should have just moved. We don't need them for our purposes, so that was -- even if we had - it's just not necessary. It was an oversight on our part.

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Thank you, Henry, for picking that up. A practical matter, I've got Jane, Nancy, Phil, Ruth, Jay is passing, Nancy is passing, Ruth is back on, Phil. Phil, you have the floor. DR. RUSSELL: If these experiments were merely failed attempts at chemotherapy of malignancies, it could be added to the huge list of failed therapeutic trials, some of which aren't very elegantly scientific, clearly put together as Duncan so eloquently described, but one of the key issues in this one is the issue of piggy-backing, and I think we should be careful about saying there's something wrong with that per se, because there are a tremendous number of good, scientific studies that are done in which there are add-ons and I've seen some experiments in recent years, especially vexing trials where the protocol begins to look like a Christmas tree because of all the bells and whistles that are added on for immunologic studies and so forth which again, could be good science and frequently are. So piggy-backing per se is not a bad thing. As we also said, the fundamental reason for acquiring the information, whether it be medical or nonmedical is not related to the ethics, but I think we're really stuck with the issue of was the primary purpose of the -- or what was the primary purpose of the study and was that the purpose that the subject understood to be the primary purpose. I think in this case that becomes very much a key issue. I'd also like to ask, you mentioned that these experiments did not appear to contribute to the information base on which the current military manuals that relate to atomic battlefield conditions. My question is where is that data base? What do they refer to? What does the alternative body of information that gave us the same or the kind of information they were looking for in terms of the biologic dosimeter? DR. NEUMANN: Let me drop back to the first point about piggy-backing. I think in this instance it's not quite the same though. I agree there are many, many good designs where one does piggy-back work. Here, fundamentally, the Department of Defense's interest was in performance in dosimeters in healthy young males to the greatest extent. So to force the piggybacking issue by saying we have to now do these in advanced cancer patients does a disservice because you're not measuring now a group of people that you really want the information from and the two purposes, the palliation for advanced cancer and the biologic dosimeter in young, healthy males plus performance evaluation have separate experimental groups. By combining the two, I think it's poor science all around. DR. RUSSELL: DR. NEUMANN: DR. RUSSELL: So the issue is bad science. Correct. Not piggy-backing --

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DR. NEUMANN: Not ethics. example of bad piggy-backing. DR. RUSSELL: DR. FADEN: point and I saw -Bad science.

But I think this is an

I know that Nancy wanted to get in on this

DR. OLEINICK: Just one comment on the piggy-backing. It seems to me that in the question of the military purpose, Dr. Saenger had a protocol of sorts. He actually said the purpose was to find the biomarkers and he had a whole experimental design, whereas in terms of the therapeutic of palliative work there was no protocol. So I think when one asks what is piggybacking on what, it looks to me as though it's exactly the opposite of what we've been stating, that the primary purpose was the military. That's what it appears to me to be. Now that doesn't negate the statement about saying poor science and all of that. DR. NEUMANN: Well, I mean it's certainly in the eye of the beholder in this case because you know one of the defenses is these are advanced cancer patients and I'm trying to do my best for them and this money comes along and allows me to do it. The other interpretation is certainly correct to say I need to find this and if I get some palliative therapy benefit out of it as well, it's true. The second question though here, the manuals that I was able to find tend to refer to animal experimentation and I'm not certain whether that's done because -- for political reasons so to speak. They don't want to refer as much to these human experiments or why, but it is of interest that at least one book I recall very clearly, military radiobiology, references primarily large animal experiments that were done with total body irradiation. DR. FADEN: That's interesting. - do you have one more comment? Let me do two things -

DR. RUSSELL: One more point. In the peer review, I mean on the issue of qualifications of investigators, we have a standard for peer review and imbedded in that standard is the qualifications of the investigator, so I think our -- at least it should be in most instances, the peer review process deals directly and explicitly with the qualifications of the investigator to carry out the science and the medicine experiment. DR. GLATSTEIN: DOE did not do a good job of --

DR. RUSSELL: No, I'm just stating our current process does take that into account. DR. FADEN: Could I -- I've got Ruth and Pat waiting

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and then perhaps we should have a break, but I would please ask you -- it's not, there's not time -- to look again at the questions that were crafted to begin the discussion. The first three, actually, the first four deal with some of the nuance issues raised by the relationship of the Department of Defense's interests on the one hand in funding the work and questions of culpability and ethical responsibility and the implications of misdirection on the other, and perhaps as we work on this, as we revisit it, this is a strain or a line of thinking that doesn't normally pop out when we think about research ethics. This is in some ways a newer arena and unmined territory where I think this committee could make a very major potential contribution, unlike some of the other arenas, where we're following in the footsteps of other commissions who also addressed these issues, so I think we should think hard about these questions and having said that, we've got Ruth and Pat. DR. MACKLIN: When I made my -- this is an old point and then I want to go back -- I forgot to ask Ron this. You referred again to something we've heard in the past, namely the applicability or lack of applicability of the Wilson memo and the Nuremberg code to -- experiments on patients raising the question of the application to that class of research or experiments, as well as to the definition of experiment. Now my mind is at this point so boggled with all these things this may be a very easy answer for someone, but I don't get it. The question is this, when I cited this morning something that I found and I'll say what it is in a moment, that mentions patients, this was a DOD, this was the Advisory Committee for Biology and Medicine, that's AEC, but didn't we establish that there were people from other -DR. FADEN: Yes and no. That's part of the problem.

DR. MACKLIN: I mean I'm only raising this to say it's not as if -- look, if I'm wrong, maybe I"m wrong. DR. FADEN: No.

DR. MACKLIN: I'm trying to put together whose letters or whose things -- this was the letter from Shields Warren to Leslie Redman in '51 that quoted the letter from Carroll Wilson to Dr. Robert Stone, November 5, 1947. And at that point the statement that was prepared for the Commissioners by the Advisory Committee for Biology and Medicine mentions all of the following conditions, no substances known to be -- or suspected of being poisonous or harmful should be given to human beings unless all these conditions are met and it refers to patients, namely that the patient give his complete and informed consent in writing. Now, is that at all relevant to this today? DR. NEUMANN: Well, no. The distinction is that this group that you're referring to is dealing with control of

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radionuclides and their dissemination into research, both basic and human, and I think the record will show at the end of this Committee's work that that was better controlled or more regulated, certainly from its inception than the radiation by machine source like x-irradiation or cobalt irradiation. These regulations or rules or stipulations applied to those investigators using radionuclides for human experimentation. It was not the equivalent group thinking about x-irradiation at that time point to our knowledge. DR. MACKLIN: So it's reasonable to think that one group, even though they were dealing with different sources of radiation and different types of application, it's reasonable to think that one group considered it an experiment if it dealt with patients whereas the other didn't consider it an experiment? I'm just asking -DR. NEUMANN: It seems the case. I agree with you, it boggles the mind because many of these are the same individuals that meet one another professionally, but that seems to be the case. DR. FADEN: DR. MACKLIN: For what it's worth. It's hard.

DR. FADEN: Right, right, but it seems to be as best as we can and we have Jonathan speak to this more in the December meeting as we try to piece all of this together in the context of this debate about what do we make out of all of these documents, memos, policies and stuff floating around, just how coherent or incoherent was the world, in fact, in terms of how people understood what constituted an experiment and who was the subject. MR. STERN: And then the similar point was these were two different agencies we're talking about. Cincinnati and most of the other studies, except for Oak Ridge, were not sponsored by DOE, which just wasn't guided by that particular document you're referring to. DR. FADEN: Or discussion, whatever. Can we have Pat and then I think we should take a break and come back and do remedies which is, of course, unsatisfying because we by no means have finished with the TBI case study, but we knew that before we started. Pat? PROFESSOR KING: Just an early aside and that is even as late as the common DNA debates in the 1970s, the people who were working with recombinant DNA did not go to talk to virologists, for example, to find out how you control for risk in a time when we actually thought -- I think now that would be routine that you would go to people who are used to handling pathogens, if you were worried about those dangers, but we know that didn't happen, so I'm certainly not surprised at things that

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happened. stages.

People didn't talk to each earlier in much earlier

In reading this thing and in reading this case study, the first thought that occurred to me was a question about does the Committee have an interest in having every set of cases we have identified as thoroughly documented as possible? Is that something that the Committee itself wants to do as a service? I think that's a question we have to confront because our data is incomplete, at least in the studies I've heard, so that raises questions about how much of our resources and time and attention are going to go just for the purpose of careful documentation of every case. And I actually don't have a view on that, but I see that now becoming a major issue. The second reaction to this is along the lines that Ruth was suggesting. If the decision is we have no independent interest in having all of our cases carefully documented, rather than leaving some of this to people who come after us, in this particular case study, documentation that goes to what I think is Ron's conclusion about bad science, I would think is very important and the reason I would think it's very important is because I think that question 3, DOD's obligation with respect to the ethics of the work done by medical contractors is critical. It seems to me that agencies like NIH who fund medical research or diseases, basic science processes, etc., this idea that we're generating information for the health and well-being of us all constitutes one kind of research that's been our model and we know how to think about that. We think we know how to think about that anyway. I think that agencies and I suspect that this will occur more in the future, agencies that fund research where sometimes it's that model, DOD being giving breast study work, for example, and AIDS work, for example, as opposed to agencies that have mixed motives. I don't even know how to call them primary, secondary, because I'm not sure we'll ever be able to tease that out. I think the closest we maybe could get to it is mixed, where you can discern several different primary areas of motivation. The question to me becomes if that is the case, does that create a greater obligation on the institution as institution to insure that the research is conducted -- this is an ethical question, although it's not going to sound like it, is conducted scientifically and scientifically in a sound fashion. If I take it as a premise that exposing people to any risk at all where you have not set up a plan or methodology that will answer your questions so that that part is -- I would argue we should consider unethical, at least I know I do, and part of this is with respect to these mixed motives research, is there an even greater obligation to insure that your review process sort of goes beyond and your monitoring process goes beyond what we might expect if it were NIH funding, a researcher at a university and using a university IRB. I'm obviously not speaking about the past. I'm speaking about the future. I'm talking about research that doesn't go to benefit health and

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-- for lack of a better term, general health and well-being, where you have other interests that are work. It's clearest in the military because you may want to know something for military purposes that may also tell you about health and general wellbeing, but you really want to know it because you have a particular need to know it and it's not a health need at that time. DR. FADEN: There's also a way to turn it around and Phil, I know you want to respond on the clinical level and I've started to struggle with it. We, for a long time, have had discussions and debates about the extent to which there's a conflict between the physician's role as a physician and the physician's role as a clinical investigator. Now when the physician is a physician now and an investigator, at least in part or in whole, investigating issues that are not intended to advance medical science, does that make it any different or is the conflict less or whatever? PROFESSOR KING: separately. You broke out the physician's question

DR. FADEN: I'm starting to flip it over. I'm saying you can make the same -- you can raise the same issues and the answers may be no. It may be that it's just as big a mess that - the problem is having the two roles, researcher and clinician, and it doesn't matter what kind of research you're doing once you've got those two roles. We have those two role conflicts, but I don't know. PROFESSOR KING: There is guidance, however, I'm not aware of any for institutions, so that I think that's breaking new ground. There are already existing problems when physicians work for institutions, for example, just in the ordinary practice of medicine where an employer employs physicians to take care of workers, for example, where we have dual motivations in terms of what are the ethical obligations of physicians in those dual conflict situations, so this might be a dual conflict situation, but the institutional one which you appropriately have listed as a separate one, seems to me we may be breaking new ground because I don't recall ever really having to focus on institutional obligations with respect to sort of the mixed motive and I don't mean mixed in a bad sense. DR. FADEN: It may be perfectly fine. PROFESSOR KING: It may be perfectly fine, it's just that what does that imply, additional or lesser? DR. FADEN: sure? DR. RUSSELL: To clarify one thing that I think the Department of Defense motivation is health and welfare of a narrower population. Their fundamental concern is healthy Phil, did you want to respond? Are you

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manpower on the battlefield and so that there isn't any motive other than health in that and there's no ethical issue as far as I'm concerned. On the other hand, the -- you started out with the issue of do you need a different set of regulatory processes and the answer is yes. And that is because you don't have a small narrow, professional community involved. You have a much broader community who tend not to keep their focus on some of the biomedical ethical issues and do get into difficulties when their enthusiasm for getting the answer is overly aggressive. PROFESSOR KING: That's a good point.

DR. FADEN: That's a very good point and I keep saying we're going to end there, but I saw Mary Ann. DR. KATZ: I will be most brief. That's what I was going to talk about at greater length. I think the point that has been proposed in a sense poor Dr. Saenger was really a triple agent here. I talked about the problems of physician investigators being double agents, both committed to science and to the patient and here he's also committed to the defense establishment and I was struck, perhaps even more so than you were by his use of relatively healthy cancer patients. In the '50s, there was a great debate in terms of the ethics of research that was in the good old days before informed consent, is whether at first the sickest patients should be used for new experimentations and then work back and see how it affects. Here, the healthiest were used and consciously and unconsciously, in part, possibly, inference by the fact that the Department of Defense was concerned about using terminal patients for these studies because they didn't compare -- because they wanted to know how healthy soldiers would react. In selecting the healthiest kind of cancer patients, he hoped to give the Army better data which the Army was interested in obtaining. DR. FADEN: We may never end this discussion. Pat has one second comment, I hope. Let's just do that and then we will -- I don't know what else to do. Eli and then Pat. DR. GLATSTEIN: Very quick question, were all the patients from the county hospital in Cincinnati? MR. STERN: I believe all but five were from the county hospital. Three with Ewings were from the Children's Hospital. There were two who were private -- and those three, I think, were private patients referred and I believe there were two additional patients. I don't know which ones were privately referred. PROFESSOR KING: My comment, I don't want to get lost in a substantive discussion. Actually, I was trying to make a proposal, additional work on this case study, one of the lines of inquiry to be followed is to look for data that will help us focus on the questions that we have talked about here, unless we make some other decision that says we just want to pull exposition.

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DR. FADEN: Move to the institutional and role conflicts that are raised by the Department of the Defense's interest in a set of questions that are different from medical science questions that are claimed to have animated the research as well. DR. NEUMANN: We don't have time today to give the boron neutron capture therapy experiment introduction but we'll address a little bit of that because there it gets even more complex. One has political people involved in keeping facilities open in different parts of the country and allegations now that political contributions have led to selection of patients to restart, so that will almost be a five part complication. DR. FADEN: So now we have layers and layers. I apologize for the fact that we have to finish, but we need to move on. We'll take a very short break and then we're going to discuss remedies. (Off the record.) DR. FADEN: Okay, group, we have a change of schedule, realizing that it's already 4:20, 4:25. We're going to juggle things a little bit and defer the remedies' discussion until 9 o'clock tomorrow morning. Good idea? We're also going to worry about some people being a little -- brain dead is another technical term of art that we can introduce at this point, but a little too much overload. You know we discussed that and the awkwardness if we can't because we didn't announce it as starting early, so we will discuss maybe tomorrow afternoon the notion that the second day could start at 8 or 8:30 since people are already in town, rather than at 9, meetings from now on, to buy us more awake time in the future, that that may be a good idea. It's hard to do on the first day because people who are within short flights are coming in, in the morning. Are we staying in the same hotel? I don't know. Does anybody know?

Jerry, are the committee members staying in the same hotel as the meeting will be in next time? Okay, yes, so that would work particularly well because there's no transportation time, so for those, for the Committee members, we have an endorsement then that the second day from now on will begin an hour earlier which gives us an hour more awake time, plus we could have our breakfast while we begin the meeting too. We can munch on the muffins or whatever. So we're going to move things around. Ken, the remedy subcommittee presentation which Ken will make and then we will discuss, will be at 9 o'clock tomorrow morning. I obviously have no opening remarks, so that takes care of it. We're going to move some of these items around so that

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we can make room for that and we're going to do that by having -if you look at your agenda, and we'll try to do this quickly so that we will end certainly by 5 o'clock and perhaps sooner. We'll first hear from Sandra Thomas, who will give us an update on the project going on with respect to research involving or affecting children. Moving down to what will be tomorrow morning's agenda, Jeff Kahn is going to give us an update on the work that's going on with respect to ethics criteria. That will be followed by Dan who is going to give us a brief update on what's going on in institutional case studies, and we'll close with Barbara Berney, giving us an update on what's going on in the biodistribution and radio-isotope research groups. Again, these are brief updates for information only. Obviously, if someone has a question and wants to know how things are going, please ask questions, but this is by way of letting us know how things are proceeding. Sandra, if you could start? DR. THOMAS: Good afternoon. I'm here to update the Committee on the staff's work on the group of experiments that involved or potentially affected children. Although the work is focused on experiments prior to 1974, the issues surrounding these experiments are so very relevant to the present day. The most recent issue of IRB Journal contains an article on radiation research involving healthy children and includes invited replies. We have a copy here and these materials we included as part of the December briefing book. Two months ago, a preliminary identification of children's experiments were made. We have identified additional experiments through resources that were not available at that time and our current numbers are approximately 100. Many of our experiments have been identified through bibliographies and contain citations in the open literature. We have initiated retrieval of all cited documents with the assistance of our information management staff. As we get further information on the experiments, we plan to classify the experiments by subject type and research type and then generate appropriate ethical questions for each category. Our subject types include pregnant women seeking to terminate pregnancy, pregnant women seeking not to terminate pregnancy, healthy children and sick children. At the next committee meeting, we anticipate presenting at least one and hopefully two case studies to the Committee. The Vanderbilt Nutrition Study is scheduled to be presented. It represents the subject type of pregnant women not seeking to terminate pregnancy and it's a well-publicized case. In this study, approximately 829 women were given radioactive iron during pregnancy. The Fernald School Experiments are also scheduled to be presented. They represent the category of nontherapeutic research in healthy children and they're also a well-publicized set of cases.

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To the extent possible, we will embed an analysis of these two cases in the larger context of similar research at the time. Are there any questions? DR. FADEN: Thank you, Sandra. It's like when you get a grant the good news is we know what to do. The bad news is now we have to do it. (Laughter.) That's the scary part. We actually have to deal with all of this. This is a very challenging area and it turns out to have been probably a retrospectively good decision to have decided on, focus on children. If we can just get that going. Our next presentation update is from Jeff. Just to remind you, by the way, this is useful as we have our discussion tomorrow afternoon about subcommittees. The subcommittee for the children's project that Sandra mentioned is myself and Mary Ann and Ruth, so that's who is working on it now from Committee and you may want to think about whether you want to join it or whether it should be inflated or whatever. Jeff? DR. KAHN: Just to follow-up Dr. Macklin's presentation from this morning which obviously opened the discussion and got people interested, there will be a longer paper sent to you shortly after we all go home from this meeting prepared by Alan Buchanan with other members of this staff outlining the issues that Ruth raised in some greater detail. So that will be something that needs to be read relatively quickly and your comments received as quickly as you can get them back to us so that we can really get into that issue for the December meeting. So Ruth's presentation today was to open up the discussion, get you thinking and then we'll have a written document to be addressed at the December meeting, just by way of updating. DR. FADEN: So that's going to come to us?

DR. KAHN: It should come shortly after we all arrive back to our respective homes after this meeting. DR. FADEN: DR. KAHN: Oh good, can't wait. It's a longish document too.

DR. FADEN: A longish document. And everybody has received the comments and written comments which certain bear rereading and re-reading so you can put those pieces together and we will have to December, hopefully, well versed in the subtle issues raised by these tough problems, but my own personal

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comment, I think that it's so clear to me now to deal with the case studies that we must get straight on the Committee's position or positions, if we have more than one on the tough issues that Ruth raised before us this morning and the framework that Ruth provided us is a superb one for trying to see the extent to which the Committee has agreement or not, I think, personally. Okay, we're going to get a quick update from Dan. you do it from where you are? Can

MR. GUTTMAN: Yes, very quickly, we had talked about two major institutional case studies, the University of California and Northern California, appears to be very going well, working with DOE to -- the Northern California working with DOE. They've like there's going to be a hopefully Greg Herken will Study appears to be going very well got a terrific archivist and it looks lot of interesting documents and have a report at the next meeting.

Oak Ridge, as Ruth mentioned at the onset, a group of staff folks are down now retrieving what we hope is a very useful and diverse document collection from the Oak Ridge archives. In addition, not major case studies, but Gil was out in New Mexico last week working both in connection with interviewing someone who was in charge of the School of Aviation Medicine, Radiobiology Program and also spent some time at Los Alamos where we will be in New Mexico in January, so that we are proceeding with haste in big case studies, not lesser, but the other items we talked about. DR. FADEN: Thank you. Any questions for Dan?

Okay, then our last update, we'll get from Barbara on two groups. DR. BERNEY: The biodistribution group includes plutonium which you received a case study presentation and then the other transuranics thorium and uranium, plus several studies on cholesterol and lipids and chelation experiments. We are in the process of identifying the experiments and going to get the background documents both from the open literature and from the relevant institutions that participated in them. In terms of radioisotopes, we expect to be able to get a draft out in the next month. There are 111 experiments now in the data base and we're doing research in the available literature and in the AEC minutes and quarterly reports on isotope distribution. For both of these groups, we're hoping that the group now in Oak Ridge will be able to retrieve significant documents that will be very useful in preparing the presentations. The plan for radioisotopes is to develop a series of

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sort of mini-institutional case studies trying to look at the way the AEC distribution program worked. The probable institutions are the University of Michigan, the sort of Boston complex of Harvard, M.I.T. and Mass. General and Case Western, and we are planning oral interviews of researchers and some trips to those institutions to collect archival or other materials. DR. FADEN: questions? DR. KATZ: What are the chelation experiments? Thank you, Barbara. Are there other

DR. BERNEY: Basically, they tagged EDTA which is a chelating agent and studied the biodistribution and effectiveness of those chelating agents and their ability to remove radionuclides from the body and also other heavy metals that weren't necessarily radioactive. DR. ROYAL: Yeah, the chelating agents are not tagged. The chelating agents are used to remove radioactive materials from someone's body, so if there was an occupational exposure and someone had radionuclides inside their body, chelation agents are used to make those radionuclides come out of the body more quickly. DR. BERNEY: Yeah, in these experiments EDTA was tagged. They used calcium, radioisotope calcium in the EDTA. I'll show you the stuff on it. DR. FADEN: DR. KATZ: Anyway, whatever it is we're studying it. Are they risky or not?

DR. ROYAL: Are these chelation therapies routinely used for things like lead poisoning, any sort of metal poisoning? DR. BERNEY: Mercury poisoning.

DR. FADEN: Thank you very much, Barbara. My comment probably was a good idea, at least for me, to have the meeting end a little early. We're shutting down here, folks. We are going to end then now, except Ruth has an announcement she wants to make, so don't get up quite yet. DR. MACKLIN: The announcement consists of your homework. Since Ruth Faden didn't give you any homework, the Research Proposal Review Committee will be making a report tomorrow and what we have, I'm going to pass out now is a draft in capital letters, D-R-A-F-T, of an on-going -- I mean a document that is undergoing revision. This is going to be a coding form that will be used by anyone and everyone who is reviewing proposals in that project which is scheduled to begin maybe tomorrow. I don't know, I think we said November 15th. DR. FADEN: Did we run out of copies?

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DR. MACKLIN: There should be more. Duncan has left and Pat, I don't know if Pat will be back, but anyway, if you could look this over, what we propose to do, we're going to discuss this tomorrow, but we will not be going through it item by item. The subcommittee will, of course, be doing that and probably coming up with a fourth and this is the third draft, the fourth and fifth and sixth draft, I don't know how many until we're satisfied with it. What we would like, I'm giving it, I'm passing it out today so that you'll have something to look at or at least be familiar with the outline of and what we'll be soliciting tomorrow are only global comments, that is, comments on the format. You will have the opportunity, if you take the opportunity to comment and direct your comments to staff in detail, item by item, after this meeting, but just so we can, you can familiarize yourself with it and we can have at least a purposeful discussion about the form and format scope of it. Now remember, this is important for everyone since although there has been a committee that's been drafting this and looking at the designing and devising the research proposal review project, we have all agreed to sign on to be proposal reviewers, so each of us or all of us has to be satisfied that these questions are the right questions and that there's nothing omitted and that there's nothing that shouldn't be there, so that's what we're going to be looking at tomorrow. DR. FADEN: Thank you. So some homework and just a few practical announcements, the answer is yes to the question, materials can be left in the room and dinner is at 7 p.m. in the Barcello Hotel Restaurant which is where the Committee is staying. Any other announcements? Okay, we don't need Phil Kaplan today because we're not finished. Thank you all very much. (Whereupon, at 4:35 p.m., the meeting was recessed to reconvene tomorrow, Tuesday, November 15, 1994 at 9 a.m.)

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