Meeting Transcript
September 12, 2002

Hotel Monaco
700 F Street, NW,
Washington, DC 20002



COUNCIL MEMBERS PRESENT

Leon R. Kass, M.D., Ph.D., Chairman
American Enterprise Institute

Rebecca S. Dresser, J.D.
Washington University School of Law

Daniel W. Foster, M.D.
University of Texas, Southwestern Medical School

Francis Fukuyama, Ph.D.
Johns Hopkins University

Michael S. Gazzaniga, Ph.D.
Dartmouth College

Mary Ann Glendon, J.D., L.LM.
Harvard University

Alfonso Gómez-Lobo, Dr. phil.
Georgetown University

William B. Hurlbut, M.D.
Stanford University

Charles Krauthammer, M.D.
Syndicated Columnist

William F. May, Ph.D.
Southern Methodist University

Paul McHugh, M.D.
Johns Hopkins University School of Medicine

Gilbert C. Meilaender, Ph.D.
Valparaiso University

Janet D. Rowley, M.D., D.Sc.
The University of Chicago

Michael J. Sandel, D.Phil.
Harvard University

James Q. Wilson, Ph.D.
University of California, Los Angeles


INDEX

Welcome and Introductory Remarks

• Leon R. Kass, M.D., Ph.D., Chairman

Session 1: Toward a "Richer Bioethics" 4: Science and Society Discussion of Hans Jonas' Essay,
"Philosophical Reflections on Experimenting with Human Subjects"

Session 2: Regulation 6: Institutional Review Boards (IRBs)

• Ezekiel J. Emanuel, M.D., Ph.D.,
  Chief, Center for Clinical Bioethics,
  National Institutes of Health

• Peter D. Kramer, M.D., Ph.D.,
  Clinical Professor of Psychiatry and Human Behavior, Brown University

• Carl Elliott, M.D., Ph.D.,
  Director of Graduate Studies, Center for Bioethics, University of Minnesota

WELOCME AND OPENING REMARKS

CHAIRMAN KASS: I would like to welcome members of the Council and our fellow citizens to this, the Sixth Meeting of the President's Council on Bioethics.

I acknowledge the presence of our Designated Federal Officer, Dean Clancy, whose presence makes this meeting legal.

I would like to offer special thanks to the members of the Council who traveled here during this time of solemn remembrance. When we planned the calendar for this meeting, we weren't thinking all that carefully, and however eerie or odd it might have been for you to travel yesterday, the symbolic meaning of your coming to Washington at this time in the nation's service is appreciated here. I want to reiterate my personal thanks for your hard work, loyalty, and devotion over the past eight months.

Just a few announcements before we proceed: There are a few of our members who hope to be joining us at later times during the meeting. Jim Wilson will be here this afternoon. Robby George hopes to be with us tomorrow, and Elizabeth Blackburn, unfortunately, couldn't make it.

It is also with regret that I want to announce publicly that Stephen Carter, for personal reasons, has had to resign his membership on the Council. The letter was received with sadness.

I also want to mention that the cloning report, its final version will be published by the Government Printing Office sometime in October. And as I think I've indicated to you in communication, Public Affairs, an imprint of Perseus Books, is planning to publish the report in its final version, containing only a new foreword written by the Chair. That publication is expedited and should be out in the beginning of October and available, among other things, for teaching.

It is our hope, it is certainly the hope of the commercial publisher, that there might be occasions, from their point of view, to promote the sale of the book; from our point of view, to advance the discussion of these issues. Some of you have responded to my inquiry about your availability and perhaps even willingness to host events on your own campuses where these discussions can continue. If you haven't responded, if you would be willing to join in one or another of these public fora, please let Diane Gianelli know. Diane? There she is in the back, Director of Communications.

The next meetings of the Council will be October 17 and 18 and December 12 and 13. The date that we had reserved in November has been freed up.

CHAIRMAN KASS: At this meeting we continue our discussion of two topics that have been afloat for several months, topics under the general rubric of regulation, topics under the general rubric of enhancement. Neither of those titles are strictly accurate, but you all know what I'm referring to.

As an introduction in a way to the further consideration of both of these topics, I have asked Council members to read for opening discussion Hans Jonas' classic paper on "Philosophical Reflections on Experimenting with Human Subjects."

There are a number of reasons why we thought that this is a good idea. First of all, the ethics of experimentation with human subjects is a critical moral point in which science and ethics intersect and in which one has a look at the relation between the scientific enterprise and the social values.

The goals of medical progress run up against our concern for the inviolability of the human person, and this is a place where society, usually with more-than-willing collaboration of scientists and physicians, erect restrictions, mostly procedural, on what scientists and physicians may freely do to human beings.

Second, those institutional arrangements and procedures for protecting human subjects are also instances of the attempt to put principles into practice. The Institutional Review Boards, which will be the subject of our discussion in the second session, are the places where we try to give effect to the moral concerns that society has, concerns that express themselves in procedures for recruiting subjects, for securing consent, and for monitoring results.

It is well to keep in mind, as we think about current efforts to reform the Institutional Review Boards, what the moral principles and what the human goods are that we are eager to protect and promote. So that the first session today will be largely philosophical; the second one will be largely institutional. It is important, I think, as we think about each, to keep the other in mind.

Third, it does seem to me that both with respect to the ethics of experimentation, but also with respect to all of the things that are of interest to this body, it is important that we try to become self-conscious about what exactly it is that we are trying to protect in these discussions. Of course, we are trying to protect human health and safety. We are trying to promote medical progress. We are interested, of course, in not violating people's freedom, as expressed in our concern for their consent.

But the question is, is that the whole story? Are there other things having to do with human dignity that are of importance here? And that consideration is relevant to the ethical aspects of all of our work, including, for example, things that might concern us in the area of using mood-altering or personality-altering drugs, the topic of our discussions this afternoon.

So it seems to me, for all of those reasons, a look at the kinds of issues raised by Hans Jonas in this essay seems an appropriate way to begin this meeting.

Let me introduce the discussion of the paper with at least one person's formulation of what I think he's about in this paper. It's a dense paper, and it's not the easiest thing to read and follow.

But let me at least state what I take to be the question at issue and something of the way in which Jonas tries to work his way to an answer to this question, and then throw it open for comment and discussion and see where we go.

I think the point of departure is on page 107 in the paper, where Jonas points out that human experimentation, for whatever purpose, is always also a responsible, non-experimental, definitive dealing with the human subject himself, and not even the noblest purpose of such experimentation would abrogate the obligations that this involves.

So he wants to put the conflict in these terms: On principle, it is felt human beings ought not to be dealt with as mere subjects. On the other hand, these dealings are increasingly urged upon us by considerations also appealing to principles that claim to override the objections of treating human beings in this way.

And he goes on to state what is for him the most serious difficulty, down toward the bottom of the page. "What is wrong with making a person an experimental subject is not so much that we make him thereby a means, which happens in social contexts of all kinds, as that we make him a thing, a passive thing merely to be acted on and passive not even for real action, but for token action whose token object he is. His being is reduced to that of a mere token or sample."

And he goes on to distinguish being conscripted as a subject for experiment and being conscripted as a soldier for war, while though you're still subject to someone else's orders and are still a means, nevertheless, are still acting in the way in which you understand yourself to be acting and as an agent.

Now the question of the paper is: What in the world could be of sufficient weight to justify treating human beings in this way? And I won't rehearse much of the analysis except to say that he doesn't find the answer sufficient in the notion of a social contract or even in the notion of health as a public good, because averting a disaster is different from promoting a good, and that medical research, though it falls in between, seems to be closer to the second than the first.

That, to be sure, society has adopted medical progress as its cause, but that the goals, however important they are for the professionals and urgent for the patients, nevertheless, medical progress is societally gratuitous, however noble, and in an interesting move, suggests that even when one goes out to appeal for consent and solicit volunteers for research, one is engaged in something that he calls semi-conscription -- semi-conscription -- in which in fact, and he doesn't elaborate on this, but the moral authority of the physicians, the moral authority of the people in the white coats, and the desire to please those upon whom one is dependent for help makes this not absolutely a free and innocent request, however well-meaning.

And the solution is somewhere to be found in his remarkable discussion where he says, the ideal would be the self-recruitment of scientists and where there would be the maximum motivation, the fullest understanding, the freest and most spontaneous decision, integration of this choice into one's overall life project, and, most important, the identification of the research subject with the purpose of the experimentation. It's that last idea which seems to have gotten lost, speaking now editorially, from the concern purely with consent, which is the granting of permission.

There are things that follow for research, the descending order of who's available and the like; no research on diseases not relevant to the patient. But it points to a kind of ethics of research that goes beyond just calculating benefits and harms, and even beyond merely giving permission and consenting, to something that seeks to do justice to the human person whom one is, nevertheless, inviting into this project as perhaps a co-partner in experimentation.

I wonder, I mean I don't think that's an unfair summary. There's lots of richnesses that have been left out, but I think I take it that's the shape of the discussion. I wonder to what extent we find this paper, written now almost 35 years ago -- it was written in 1968, published in 1969 -- whether this strikes us as sound and whether it offers an adequate ethical foundation for thinking about this subject.

Gil?

PROF. MEILAENDER: Let me just pick up really with what you noted in the paper. I mean, this paper, it is one of those rare papers that at least I think is sort of so profound that one would be glad to die having written it, kind of.

But I want to think about the problem that you highlighted there. I mean, the way he puts it, the difficulty with recruiting research subjects is that it, as it were, "thingafies" the person, which is a little like the concept of alienated labor actually, I think, in the sense that the person is used for an alien cause, not fully one's own, in which he or she is not fully invested, something like that.

Then the question is, how can you make that a human endeavor that fully dignifies the person? And the interesting thing to me, you mentioned it, is that the Holy Grail of consent doesn't seem to be a sufficient answer, as far as Jonas is concerned. Not that it's unimportant, of course. I mean, he doesn't want to suggest that we should ignore it, but it is interesting to ask why it is insufficient.

I think it is, as it were, too negative. It only protects the person against abuse, and that alone doesn't overcome the problem of alienation, the problem of not being fully invested in the undertaking. That is where you get the principle of identification that you pointed to.

If you say, "Why is that so important?", it is because this descending order that he sorts out is a way of trying to see to it that we at least first attempt to recruit those most fully able to identify with the project, which is probably almost the reverse of the way we actually go about doing it most of the time these days.

I think he even says it at one point: that, I mean, really it comes up in the discussion of why you wouldn't use patients as research subjects on something wholly unrelated to their disease. It is because you would be tempted to use them because they're handy in a way. What you are trying to avoid is simply using someone because he's handy, because then that person is in a certain sense alienated from it. Only that principle, which somehow goes beyond just the sort of negative understanding of consent as protection, can deal with the "thingafying" problem.

I think that's, even apart from the context of research, an interesting notion to puzzle over and contemplate a bit. It may relate to a whole variety of other issues, some of which we'll take up, because in a certain sense we might describe Jonas as asking the question: How do we think about the presence of the person in what we do in or to the body, or in what we take into the body?

Overcoming the "thingness" is a way of asking about what it means to be personally present and invested, not alienated from, the action that we undertake. I mean, I don't know how to make all the connections with other questions, and maybe they can't be made necessarily in advance entirely, but that's an issue that has kind of a larger resonance than just questions about experimentation, and in that sense it seems to me we can think about what Jonas says with respect to experimentation, but he's also driving toward something that cuts deeper and will involve or will be involved in lots of other questions.

Thank you.

CHAIRMAN KASS: Paul?

DR. MCHUGH: I can't add a lot to what you've said already, but I want to just give a couple of examples of how at all of our hospitals there are monuments to people who were scientists and who did contribute themselves to this work.

At Hopkins there's a large plaque to Jesse Lazear, who was one of Walter Reed's group in the yellow fever expeditions and died as an experimental subject. He was a young physician from Hopkins.

But perhaps the one that's not known and yet is perhaps the most distinguished human subject at Hopkins was William Halstead, the first surgeon, who in his early career, interested as he was in peripheral anesthesia, did experiments on himself and on others of his colleagues with cocaine as a peripheral anesthetic, ultimately opening up the whole sphere of peripheral anesthesia and dental anesthesia for our benefit, but in the process developing tremendous addiction of himself and on some of his young friends, several of whom died. Halstead was fundamentally carried as an addicted victim throughout the rest of his career by people like William Welch and William Osler.

So the one great advantage of the lineage that Jonas lays out here is that it's been done, and in the process of being done, does show us what can happen to an experimental subject in the most dramatic ways.

We honor them and the plaques for Lazear and our knowledge about William Halstead, of course, encourage us when we're asking other people and ourselves to contribute to similar research.

CHAIRMAN KASS: Janet?

DR. ROWLEY: I'd like to take a somewhat different approach to this, and I'm sure it is because, though I do not myself treat patients, my colleagues do, and the patients they treat are those with cancer and leukemia. Very often, these patients have tried all of the standard treatments for their disease, which seems to continue sort of relentlessly progressing. They are often the main protagonists for what is new: What can you give me that might even give me some remote chance of cure?

So the patient as sort of a partial victim, as is portrayed, I think may be true for some studies, is certainly true for some studies, but I think that it totally loses sight of those cases in which patients are desperate for any straw of hope, and they are more than anxious to participate in experiments that might give them some benefit, but also benefit patients in the future who have the same disease.

Certainly, for the treatment of childhood leukemia and a number of other cancers, the remarkable treatment successes we have now are built on those patients. I think that's totally lacking in this analysis.

CHAIRMAN KASS: Just to this point, Alfonso, go ahead.

DR. GÓMEZ-LOBO: It is my understanding that Hans Jonas does take that into account. For instance, on page 127 he says, "Introduction of an untried therapy into the treatment where the tried ones have failed" -- where the tried ones have failed -- "is not experimentation on the patient." In other words, he excludes that as an instance of experimentation, it seems to me.

CHAIRMAN KASS: Gil, to this?

PROF. MEILAENDER: Yes, right to this. I think we would want to ask a question, Janet, in the kind of circumstances you describe, whether the person is, to use the language I used before, fully invested in this undertaking as a research subject or as a desperate person hoping for a cure.

If the researcher is involved in what he or she thinks is research, and the person is invested in it not simply as a research subject but as a desperate person grasping at a last straw, the researcher's purposes may be somewhat alien from those of the subject. I mean, so we still have to think about that concern that Jonas has.

DR. ROWLEY: But is that really -- I mean, I guess you are in territory where I'm on very weak grounds in terms of trying to think of the concepts, the nuances, and the dividing line between these. I'm not even sure that, for at least some of my colleagues in their work with untried, experimental therapies, but which have some rational basis -- I mean, these aren't just picked off of somebody's shelf; they've all gone through both a fair number of trials in other animals, in animals before you approach patients -- how to separate out the scientists' desire to learn and to see if this is going to be beneficial for the patient and his desire as a physician to do the best for that patient, that's a nuance I think I can't deal with.

PROF. MEILAENDER: Just really quickly, I mean I agree it is very difficult and probably can't be separated out and sorted out sometimes. All I wanted to point out was that nobody is handier than the desperate man.

Insofar as that's Jonas' concern, one would have to continue to worry about the intersection of those two sorts of roles, that's all.

DR. ROWLEY: Yes, but at the same time, if you're not desperate, you're not going to be willing to be a part of something that is experimental and untried, and things come with terrible toxicities, as we all know from any friend who has had cancer and been treated. So I don't know; it's a very gray area, I think.

CHAIRMAN KASS: Rebecca?

PROF. DRESSER: I was just going to comment that there's been some interesting research done actually by the University of Chicago physician researchers on Phase I oncology trials. I think the contemporary concept that people try to use in a formal way to go beyond just permission to be a study subject, it's informed and voluntary consent. I think in the abstract it sounds nice, but there are a lot of studies showing that many subjects don't have the kind of understanding that I certainly would like them to have.

In these Phase I trials, somebody looked at a number of trials and said they have about a 4 to 6 percent chance of directly benefiting the subject, and in terms of direct benefit, that doesn't necessarily mean extended life or even palliation. It's just tumor shrinkage. When they asked people who participate in these studies about possible benefit, many of them cling to that belief, that there's something in there that's going to help them as individuals.

Zeke Emanuel has written on this. So maybe he can comment. But this thing called the therapeutic misconception, where people who are in studies confuse what's going on to advance knowledge with their personal treatment, is a serious problem I think in Phase I trials, at least in actuality.

DR. ROWLEY: I think Chris Daugherty and others have certainly looked at this. See, I think, again, you have to put it in the context in which these studies are done. You're a physician; you treat patients, a very large proportion of whom are going to die. You are trying desperately to advance things. So it's true, you have a personal, psychological, vested interest in trying to come up with something miraculously which will change the situation, so you just don't go in and see one dying patient after another, which when my colleagues come off of the service, they're devastated emotionally for the trauma that they have experienced during the month that they've been on this intensive service.

So these are human activities carried out in very real, desperate circumstances. I think to dissociate the reality from, or to dissociate our dissection from the actual reality, makes this a somewhat unreal exercise.

CHAIRMAN KASS: Let me comment just briefly on that. I would underscore Alfonso's pointing to that place in the text where one acknowledges that desperate people in desperate situations, eager for cure, treated by people profoundly eager and willing to help them, can participate in things that are very risky with very uncertain promise of gain.

But even so, I guess the question is, in what way does one approach these people and what is it that one is -- what of their humanity, in addition to their pain and suffering, is one also trying to respond to? I think that's partly the concern.

If one simply says, "These are the only subjects that are possibly available to advance our knowledge," however true and necessary that is as a condition for using them, the question is whether it's sufficient and whether one doesn't want to try in some kind of honest way to elicit their identification with the enterprise and not simply exploit their desperation.

It's not an objection to proceeding with that research, but the question is: How should they be regarded? How should they be treated? How should they be spoken to?

I think Jonas is suggesting that merely getting the consent form filled out as a permission to subject one's self to the risk is a formal procedure that might point to something else, but by itself isn't sufficient.

DR. ROWLEY: Let me just respond to that because this is a situation where I believe some of his perspectives, at least in some circumstances or some hospitals and teaching centers, has changed. It is certainly true over the last decades that our own informed consent sheet that a patient signs has gone from a simple, one-page form to about a five-page form that you would need a college education to understand. You are dealing with many patients who do not have that level of sophistication.

We have specially-trained nurses who talk with patients, try to explain all of this, but it is not simple. I'm not saying that medicine and physicians and individuals conducting this kind of research should not be even more attentive to patients, but I have to say, as an observer of what goes on in hematology/oncology at the University of Chicago, that I think that the physicians and the nurses bend over backwards to try to make sure that the patient understands the risks. Of course, many patients decide they don't want to do that, and there is no pressure on those patients to participate if they say, "I've been through two years of treatment and here I am, and I accept my fate and will deal with it."

But I am also certain that there are many places where this has not been emphasized as much as it is in some of the teaching hospitals where these concerns are probably much more applicable.

CHAIRMAN KASS: Thank you. Alfonso and then Mary Ann.

DR. GÓMEZ-LOBO: I'm going to step back a little bit in the discussion and try to go back to the basic philosophical framework.

Needless to say, I was delighted when I saw that Leon had included the article by Jonas. I had the good fortune of hearing Professor Jonas deliver a lecture at the University of Turin many years ago, and I was very, very impressed.

Now this is a wonderful paper because here we have someone whose main concerns were really abstract, philosophical thinking, and he's invited to think about the problem of experimenting on human subjects. It's admirable how he carefully sorts out all of the different issues, different possibilities, and at the same time I think is very careful to preserve the genuine interests of promotion of medical knowledge.

Now reading this article in the present times, it seems to me that there are two very important differences in the setting for the paper and the setting in which we find ourselves. Let me just go into two of them: difference in the facts and difference in the ethical approach.

With regard to the facts, of course, we have gone already through the Tuskegee scandal, et cetera, and we all know that there are these very serious efforts to overcome questions of consent, informed consent, that the people know exactly what they are going to be subjected to.

Now this assumes that we are talking about adults as the objects of research in the paper. However, as we know from our previous discussion of cloning, the big problem today is having human subjects, say, at the embryonic stage, who of course would be experimented upon without there being any chance of consent or something of that sort. So that creates a totally new situation, it seems to me.

Now the second difference I think is this: Again, I point back to our previous discussions. All of these trials that Jonas has in mind are, of course, therapeutic, and he insists that there be therapy in the benefit of the sick person herself, and that's what prompts this extension of saying, well, in certain cases, when some therapeutic means have failed, of course, one goes further for some kind of experimental treatment. From a moral point of view, it seems to me that's perfectly reasonable and permissible.

But from the stem cell research issues that we dealt with, there we are in a different situation. The human embryos are being destroyed, which of course is very different from what Jonas had in mind. In other words, there's intentional action there of a sort that he never even imagined, it seems to me, at least from this paper.

Now the second area where I think it is remarkable and what a different situation we find ourselves is, as I said, on the philosophical framework. It seems to me that Jonas takes clearly a Kantian approach. He has the philosopher Kant in the back of his mind, because he assumes that the first principle is that one should not reduce a human being to a thing or mere means, not just means but mere means, and he says, well, in order to violate this, we need very, very, very strong reasons and unusual circumstances, and he adds lots of qualifications. That's why he mentions war and mentions such other things.

Now if we think about our predicament today, it seems that the reverse holds: that what is socially accepted is the goal of promoting health and well-being, and it is the other principle that then needs justification. In other words, how can you justify not using, say, certain human organisms, if or since they are going to lead to all of these benefits? So it seems to me that that is extremely important in order to understand the direction of the moral debate that this article generates. Thank you.

CHAIRMAN KASS: Gil, to this or what? Well, if this is a direct response to Alfonso, yes; otherwise, there was a queue. Okay, Mary Ann, I'll just put you in.

PROF. GLENDON: Okay, this is a somewhat different subject, but this article was written in 1969. So much has happened, not only in terms of scientific and technical advances, but also changes in the culture, that I would be curious to know -- and I think the other non-scientists would be curious to know -- about whether there have been significant shifts in scientific opinion on some of the problem points that Jonas raises.

I mean, to be quite concrete, when you get to be a certain age and you go to a physician, and all of a sudden your physician, she looks like she's 14 years old, but she's probably 30, but, nevertheless, you can't help but wondering, what kind of culture has she picked up in medical school and what does she think about these issues that Jonas discussed in a certain way in 1969?

So I have three points that I would be curious to know whether anyone can enlighten us on, whether there have been significant shifts in scientific opinion. The first is where he mentions, as a somewhat peculiar point of view expressed at a conference, someone said, "Society cannot afford to discard the tissues of the hopelessly unconscious patient." And he raises the question, well, wait a minute, what does that say about who owns these tissues, if you talk in terms of discarding and salvaging?

That put me in mind of the discussion that goes on in my state, Massachusetts, which I realize is somewhat exceptional. We have organ donor cards that we may sign when we get our driver's licenses where we can give consent to have our organs taken, but there's some discussion about whether it wouldn't be better to just have a presumption that people's organs are available unless they sign a card that says they don't want their organs taken. It really reverses this presumption that Jonas is talking about in the area of experimentation. So that's one point about which I'm curious, whether there's some widely-shared view about whose decision this ought to be and what the presumptions ought to be.

Then, secondly, Jonas proposes very strongly that, not only as we have been saying there's an ideal subject for human experimentation, but that there is a category of subjects that are the least morally-justifiably subjects and those are the people who are least informed and least free. I wonder there whether we are seeing an increasing sense that actually that last category is the one that's most available because, well, as Gil said, because they are available.

Then, finally, the definition of death and the warning that he issues that there will be enormous pressure to alter the definition of death, so as to make more subjects available.

CHAIRMAN KASS: Does someone want to join directly these questions? Interestingly, Mary Ann, those are all things that would fit with Alfonso's comment earlier, where Alfonso suggested that his view of the cultural shift is that what is taken as the given is in a way the imperative or the necessity of medical progress or the saving of lives, and that the burden now falls on those who would object in the name of, say, the dignity of the person, something of that sort. I think it would take all three of your examples and make those specific instances of where his claim could be tested.

Does someone want to join, respond to Mary Ann? Paul?

DR. MCHUGH: Yes, I would like to respond to both Alfonso and Mary Ann, but perhaps to begin, to say that I think that there has been an important and, to some extent, a very useful cultural change that has occurred over the last 50 years and that relates a bit to what Jonas is saying but carries it another step.

You see, I agree with you that there's a Kantian thing here, but Jonas is calling for virtues, and virtues, Aristotle said, are tied to practices. The practices have been enhanced. What Dr. Rowley was saying is that we have seen wonderful things happen for our patients and for our world and for ourselves, and in that process a lot of us, patients, citizens, as well as physicians, have said, "We want to join these practices because they do call for virtues." Yes, virtues of the doctor/patient relationship, but also virtues of the subject, and that we want to be part of that.

We want to have this grace or virtue that we'll take part in this great advance that has occurred for our patients, our cancer patients, our endocrine patients, our heart patients, our hypertension patients. I mean these are wonderful things that have come forward, and lots of us have begun to think about how we could be part of that virtuous practice.

In that way, to some extent, we can go too far. I agree with you, we can go so far as to sweep by the people who don't understand what we're doing.

Now in my case in particular, after all, I am often talking about asking patients who are mentally disturbed to help take part, and that's a big problem that Jonas doesn't take into account here. He never mentions it and the like.

I also agree that there is besmirching of this virtue when grants, indirect costs, paying of subjects, and things of that sort come into play as well.

But at an important level, the culture has changed, and changed to advantages, because of the things that we have worked on. We should be talking about the virtues that are implied in the practice of this kind of research and avoiding the pitfalls that are here.

CHAIRMAN KASS: Is it your suggestion, Paul, that for the most part subjects that are recruited or volunteer for research are really entering in the spirit of identification? When you say that they want to join in this virtuous activity, that it's not just they give permission to run certain risks, but that they become, to use Paul Ramsey's phrase, co-partners in the experimentation?

DR. MCHUGH: I think that's far more true now than it was 50 years ago, as people have heard about the things which are potentials and which are happening. I must say they can be greatly taken advantage of. They can be abused. They can be given consent forms that, as Janet said, require a college education.

By the way, I think all IRBs now know that fact and submit the consent forms to these computer techniques that tell you what grade level you have to have to understand it, and show you that, you know, that you can have really impressive ideas that are at the third or fourth grade level. I mean, the Psalms are a good example of just how wonderful they can be, but that's a sideline.

But I do think that the issue of virtue and the acceptance that we have been not only great beneficiaries, but in a sense a common legion to attack the problems of illness in our society, in our world, is a broad theme in the citizenry, and that many patients come forward with that sense of being part of the process with the doctors.

For all the things that Jonas warns us about, I do think that Janet is onto something when she says, gee, you know, talk about this context, and this context is very broad on our society.

DR. ROWLEY: Can I intrude and just ask, Dan, you're probably, along with Paul, a physician who is involved in teaching medical students. If you think of how some of these issues were discussed when you first started as a faculty person and as they're discussed now, I would be very interested in briefly your comments or perspective on this issue. It's not fair for me to put you on the spot, but I think, of all the people besides Paul --

DR. FOSTER: You're always putting me on the spot.

DR. ROWLEY: -- you really have practical experience and can comment.

DR. FOSTER: Well, the culture clearly has changed. When I started in academic medicine, you were either a basic laboratory investigator or you didn't work in a medical school, for example. I mean, there were very few clinical trials with humans which were going on. There were the heroic efforts in yellow fever, and so forth, where many physicians put themselves at risk.

You know, there were things that were going on, but clinical investigation is now a huge operation, both in the private sector for people who develop instruments and drugs, and so forth, but also in the context of teaching in the medical schools. So you find in all medical centers you have to have courses these days in understanding statistics, the consent, and all of those things.

Now do I think that the average -- that that intrudes very much in the four years that they are medical students? I don't think so. I mean, I think that it's those sorts of issues about partnership and consent have been cast more in terms of individual patient care than they have in terms of the larger issue of how one gets consent, and so forth. So the culture has changed.

I think I want to say that the sort of conversation we're having today does not intrude on the real world. I mean, one of the dangers is, I mean these sort of sophistications that we're talking about here are not real-world problems.

I once heard somebody in a counseling session say, if you're worried about what people are thinking about you, don't worry, they ain't thinking about you. That's sort of the situation here.

The issue of literacy has to do with just reading of prescriptions, and so forth. I mean, you really do have to cast these things in terms of just consents that are understandable. Many times the corporations, if you're doing a trial, the lawyers put in these things that nobody can understand. Most of the time -- we just had a grand rounds on this -- you have to communicate the level of the fifth or sixth grade for most things, just the instructions on it. So this kind of conversation doesn't have anything.

So I don't think that -- I mean, I think it's important to do because there have been terrible abuses of humans, and I think we need to focus on that. But I think that the effort -- I mean, I thought this was a very scholarly paper, sort of ethereal in some sense for most average people. They wouldn't really understand it.

But there seems to be, and I certainly don't want to say -- this is a warning -- I don't want to go back to the discussions that we had about embryos, and so forth. I mean, we've already been through that in great detail. I think we ought to talk about the real practical problems that we have here.

There seems to be built in a view that I kind of hear that anything that you want to do in terms with humans, regardless of the virtue, is either dangerous or shouldn't be done. I mean, it's very carefully said here, well, okay, if it's a desperate situation, a patient is dying from cancer, you're worthy of trying to do something.

But to find out about a drug that just shrinks a tumor, in the first place, everybody I've taken care of in an experimental drug, if they have a tumor, that gives them at least a month or two of joy. I mean it does, and that's part of the foundation to build up -- you know, it took 15 or 18 years to get Gleevec, or something like that. You know, you've got to get these small advances.

So I'm sort of rambling to say that I don't think that this enters into medical education in detail about consent until you get into start doing clinical trials.

As long as I'm here, I might make one other point. We began with talking about Kant and this issue of "thingifying" humans. That seems to be, for all the ethicists, sort of a holy grail about what we should do. But there is an element where in just clinical care the physician is more, or the scientist is more, than just an equal partner.

I want to illustrate that by a real-world case and then I'm through. I think that most people are happy to have somebody that they think they can trust to be working on things for their disease individually or for the long run.

The long-term editor of The New England Journal of Medicine, Franz Ingelfinger, as many of you know, was probably the most influential person during his lifetime about things. When he was a scientist, he had worked on esophageal cancer, and he got esophageal cancer.

He wrote an article in The New England Journal called, "Arrogance." That is the arrogance of the view that a physician should be not co-equal in terms of the care of the patient. Because he knew everybody in the world, he was besieged by: Should he have radiation first? Should he have surgery first? Not only that, he had kids who were physicians, and everybody -- he said he was just torn to pieces.

Finally, somebody said to him, "Franz, what you need is a doctor." And he said, "I followed that advice and turned to my internist and was at ease that he would take care of me, and then I got back to my usual activities of editing this Journal and giving talks," and so forth and so on.

In other words, his learning, his plea was not for -- I mean, he wouldn't consider himself a thing, but he certainly considered himself to be cared for by somebody that he trusted, and so forth.

So the bottom-line answer: The culture has changed, but it has changed mostly not in the undergraduate work in the medical school, but subsequently I think that there are very marked abuses that we have to limit. In the practical world, I think that consent is not simply a negative thing. I think it is a very important thing.

I am very worried continually about a subtle sense that medicine and medical science, which I consider to be a high and noble virtue, becomes cast in terms that it is automatically in some sense negative for those who are participating in it or those who do it. I would say that's not real world in this country. I think people who are sick want to do it.

If I had been prepared to say something, I would have said it a little better, but, anyway, I'm trying to answer your question.

DR. KRAUTHAMMER: Could I make a point on that, a response to that?

CHAIRMAN KASS: Charles.

DR. KRAUTHAMMER: Dan, I don't think that the issue is that we're casting advances or the noble or wonderful things that medicine has done as negative. I think what we're trying to do is to point out certain inherent difficulties and contradictions.

That is that when you do medical experimentation on humans, you necessarily introduce "thingness." That, in and of itself, is inevitable, and that, in and of itself, is a problem. It does not mean that you don't carry on that research, but it means that you have to be very careful and think about it.

We know what extremes of "thingness" can do. We saw it at Auschwitz. We saw it at Tuskegee. Those are the seminal examples which warn us that, however noble and beneficial medicine is and can be, the very nature of experimentation, which is to treat a person as a thing because we are studying it as a thing, is inherently dangerous. All that we're saying is, let's examine the dangers and ask what kinds of protections one has to introduce.

I was struck, incidentally, by the "thingness" of it. It always strikes me in blind experiments. We all read a few weeks ago about this new discovery that a certain kind of surgery for arthritic knees is useless, and it was discovered by having two sets of subjects, one-half of whom received sham knee surgery. It was shown that there was no difference in outcome between those who had the real and those who had the sham.

I always ask myself, how would you feel if you were the one who had that sham surgery? I mean, it's rather remarkable.

There's a more famous case, I think about 30 years ago, where that was done with heart disease. Also made a wonderful discovery of the uselessness of a certain kind of invasive surgery, right, with the mammary artery transplants which were useless. But it was discovered by doing sham surgeries on half of the patients, actually opening their chest, sewing it up, and doing nothing.

So we have here an inherent problem. That was a great discovery, that the mammary artery surgery was useless. On the other hand, we had real people who were wheeled in, anaesthetized, chest opened and closed, and nothing happened to them.

If I could make just one other point in response to what Paul had said about participation, being part of a great enterprise, I agree entirely that is the ideal. I think it's exemplified most dramatically when the physician himself engages and becomes a patient.

But consent is a separate issue, and it introduces itself here. There are three categories of patients in whom you can never really get true consent. That's children, the mentally disabled, and prisoners. Those are the classic cases.

Even if you exclude those cases, you have patients, adults, who are sentient and who are not in prison; you always have the questions of desperation and naivete. Those always contaminate, and I would contend that it is almost impossible to get a true consent.

Again, this doesn't mean that you don't engage in the therapy, in the experimentation, but it has to be a real caution.

DR. FOSTER: Let me just respond to that. I would be absolutely first in line to preclude the sort of issues that give interesting data but are totally unacceptable. I could probably spend a lot of time today, which I'm not going to do, giving you examples of things that have been done that I think are absolutely wrong. So count me as first in line for that.

I think that if we can bring some insight into that, but I just don't want to go over so far -- I mean apart from the dialogue, which I think, as I say, is ethereal for the average person. I mean the illiteracy in this country may be as much as 23 percent. I mean in the West you can't talk like this.

I think everybody understands about protecting subjects and getting them to do that, but I don't think that most people are going to be involved in the Kantian thing. I would rather us concentrate on how we improve the process.

CHAIRMAN KASS: Bill May?

DR. MAY: On this question of recruitment and depths of identification, I suppose the most obvious analogy is recruiting for armed services. There used to be the practice, as we say, of shanghaiing people for service in the Navy, and so forth. Informed consent or signing on was a protection against dragooning people into military service.

But there's the next category of, if one especially went after those folks who would be highly motivated, let's say immigrants or convicts maybe destined for execution, those folks that you would hope could recoup significance for a life in danger of losing or rapidly losing the capacity to recoup or signify, and, look, you can't become a citizen of this country, but join the armed services and you'll find your way into citizenship, and so forth. So you're offering not the inevitability of it, but the possibility of it. Then the question is, what degree of possibility?

The final level that Hans Jonas is talking about, and that Gil highlighted for us, is a kind of patriotic investment. I mean people who join the Army and the Navy for reasons of patriotism. But what lies behind that, it's a conception of the country. I mean, if they are disposed to sacrifice, it's not simply because just out of nothing they're disposed to sacrifice, but they belong to something; they're participating in something that in a sense they're joining a history of sacrifice.

This was talked about in terms of some idealistic physicians who felt themselves belonging to a tradition of sacrifice that precedes them. That tradition may not be very alive amongst us now.

The problem is, the larger problem is, we live in a setting of a society where we do not think of the society itself as founded in sacrifice. Its origin was a deal where you surrender something and you get something, and then the terms of that deal is, what allows the State to do things? It is the fact that it gives you something. In order to be able to give you something, it, of course, has to stay alive. So a fundamental warrant granted to the State is its capacity to conscript if its survival is at issue, and that's where Hans Jonas takes that.

But there are, of course, other old traditions of the origin of the State where the State was founded not on a deal, 17th and 18th century, but is founded on sacrifice, the sacrifice of the gods or magnitude of investments on the part of individuals, and so forth.

There's an echo of that, I guess, in immigrant folks who weren't dragooned to come to this country, but whose parents made great sacrifices to bring them here. In a sense one belongs to a tradition of sacrifice, so that what you do is simply your mode of participating in it.

It seems to me that is what is largely lacking in the particulars of professions or the kind of warrants that we can present to people. So we have to suppress that speech. Hans Jonas gives us an illustration of that speech, almost mockingly, because you know it will chill people. They will not act, because the ordinary terms of relating through such an undertaking, such an enterprise, is signing on. Then the question is, what will I get out of it? That's understandable.

CHAIRMAN KASS: I have Rebecca and then Bill Hurlbut.

PROF. DRESSER: One interesting thing about that sham surgery study was that, as part of it, they made people write down, "I understand that I am going to go through surgery and they might not do anything to me." They lost a lot of people after they said, "Yes, I want to do this," but then they had to write this in their own words, and people said, a certain percentage said, "No thanks."

I think this paper is brilliant and timely, and it really forces us to step back from something that we accept so much as a society today, this idea that progress is not optional, but it's nearly mandatory and this kind of sense that we are in a war against disease and we must go forward with research.

So progress is almost mandatory, and progress of a certain sort, progress in the form of advancing knowledge to produce miracles or unknown effective treatments, as opposed to progress in providing measures that we have available today to more people, such as established health care and even more basic things, like decent housing and education, and so forth. So it's we must make progress and we must make progress in a certain way and not another way.

Then it becomes interesting, why do we see it this way? Why is our culture at that point? You know, I don't know; I think we've gotten more that way than we were when Jonas wrote partly because of the patient advocacy movement, which started with HIV/AIDS activists where they started presenting research not as something to be afraid of, but something that we will demand. "You must do research on our disease." Then women and other groups got involved in saying you must study women because we want to know whether to take an aspirin, and all this sort of health advice that's being given to men.

So research is seen as a benefit, and that view is really, I think, promoted through patient advocacy groups and also through journalism. I really think the way that research is reported on reinforces that image.

But I'm not sure if those are cause or effect. So I would be interested in hearing if anyone else has thoughts on that.

CHAIRMAN KASS: Bill and then Gil.

DR. HURLBUT: What interests me about this essay most strikingly is the way Jonas puts the ethical, foundational, central significance and progress as contingent upon the preservation of the ethical.

Central to the essay is a dignified and exalted view of human beings and a recognition that the ongoing existence of society and the progress of science depend on this view of humanity as the source of something that can't be legislated or enforced.

The progress -- it seems to me in his essay he says it plainly -- progress is not the highest concern, that progress flows forth out of a society where you preserve humanity's central core of individual dignity and its commitment to personal devotion, what he calls authenticity and spontaneity.

In an interesting way, this places the essay as a hinge-point between our previous six months and where we're heading next, because our disagreements and discussions at least hinge to a large extent in the first half of the year on the question of how to preserve this humanity that we're trying to promote, nourish, and heal.

The thing that strikes me about this essay so strongly is how Jonas acknowledges the central concern for all of the other benefits of society of the preservation of the crucial qualities at the core of humanity. In that sense, as we go forward now, we talk about enhancements. The issue is, how do we preserve this crucial, ethical quality within human beings, this central core on which all things depend, both meaningful individual existence and social cohesion?

He speaks of a sphere outside the sphere of social contract, of public rights and duties, of a trans-social upwelling of personal idealism, the noble of grace, not decree, and intangibles even of a religious order, and what Bill was saying of self-sacrifice.

It strikes me as an interesting place to start our discussions of where we are heading with our progress, that we need to preserve these qualities as central. Just to give a couple of his own words, he says, "The ethical dimension far exceeds that of the moral law and reaches into the sublime solitude of dedication and ultimate commitment, away from all reckoning and rule, and shored into the sphere of the holy."

And he says, "A society cannot prosper without this. It must draw on them, but not command them."

And then he goes on to say how this source is powerful and wells up from natural humanity. All we have to do is be sure not to preclude or quench it. He says, "We have laid down what must seem a forbidding rule to the number-hungry research industry" -- in his essay, that is -- "having faith in the transcendent potential of man. I do not fear that the source will ever fail a society that does not destroy it, and only such a one is worthy of the blessings of progress."

I found this a very striking essay for that because it called me back to that commitment to the central significance of the ethical in not just the individual, but the whole outplay of social process; that we need to be concerned not just with what we preempt, but what we promote as well and what we preserve, perhaps more centrally.

CHAIRMAN KASS: Thank you. Gil.

PROF. MEILAENDER: I want to go back to Mary Ann's comment quite a while ago and make my way from that to Dan's, in order to try to persuade Dan that this really is the real world here.

At least as long as some of your fellow human beings seated around here obstinately intend to talk about it, Dan, it's going to have a certain kind of reality. We're just going to keep beating you over the head with it.

DR. FOSTER: I wouldn't have been in this discussion if it was not for Janet. Okay?

(Laughter.)

PROF. MEILAENDER: It's her fault, that's right.

(Laughter.)

The interesting thing, in terms of the three kinds of issues that Mary Ann raised and just inquired sort of how things had or had not shifted in the roughly 30-year period, say, since Jonas wrote, is that in fact I think I'm right to say that a lot of people worried about those questions, and that the increasing attention to consent, you know, free and informed consent, the increasing kind of codification and requirement of consent was precisely designed in many cases to deal with some of those issues that you raise, and does deal with it in many ways. I mean this was Paul's sense that something good has happened.

The peculiar thing is, though, that I think if you took those three, you would see that they all remain quite contested areas actually. Indeed, for a while we thought consent solved the problem, and I think you would say that many aren't so sure that consent has solved the problem, partly for reasons Rebecca referred to in her comments.

See, that brings me back to the, to me, interesting thing about the Jonas article, is that you somehow have to dig a little deeper than just consent. Just a notion of consent won't turn out to satisfy us in terms of the sorts of issues, and the enormous amount of attention that's been paid to it in the past 30 years and real concern about those issues and progress in certain ways still doesn't turn out to solve it entirely.

That brings me to Dan's comment. I think part of what Jonas is getting at, and part of the reason for that, is this is not just a concern about researchers out there, Dan. We love them all, though they are, of course, subject to all the vices and temptations that the rest of humanity is.

The concern is not just that they might misuse their research subjects or their patients or those desperate people, or whatever. The concern is that we might being using the researchers as our instruments.

I mean, we do all, to some degree, live off of each other, of course. But we don't just want to live off other people. Insofar as we all benefit from what medical research does, we do need to think about whether what that really means is that some of us benefit by living what others have largely done.

What Jonas forces us to ask is, to what degree those people off whom we are living really thought of themselves as sharing with us in some kind of undertaking or to what degree we're simply living off them with nothing more? So it's really not just a question about what researchers are doing, though if their consciences bother them, you know, that's good and they should worry about it, but he is really getting at kind of what all of us do in benefiting from research.

I will say, I mean, if you go to a teaching hospital and you look around at the people who are there, it ought to lead you sometimes to worry about whether you are living off some other people who are very unlikely to have some sense of sharing in a joint venture.

So that's where I think Jonas ought to point us. If that's not a real-world problem, then I wouldn't know what an important real-world problem would be.

CHAIRMAN KASS: Dan?

DR. FOSTER: Just one quick comment: I mean, I think your concern about living off others is not limited to biomedical research. I would wonder about the stock market and everything else. I mean it seems to be sort of a systematic desire for a few to live off others.

I mean, I think that one cannot eliminate the human need or evil, or whatever you want to say, to live off others in that sense. I accept your comments, and I love bioethicists, too, even though they are often ethereal, as I say.

(Laughter.)

CHAIRMAN KASS: Alfonso?

DR. GÓMEZ-LOBO: Just a little clarification for Paul, if I may, on the question of virtues. But let me start from what Charles said because Charles -- it happens to me very often -- expresses with great clarity what I would have liked to express, but never managed to do.

What we are talking about here is a question of caution, of being very careful with what we're doing when there's research with human subjects. Now that can be expressed either in terms of respect for the dignity of persons, but it can also be expressed in terms of virtues.

One of the key and fundamental areas to deal in virtues is, of course, the virtue of justice. One could say the endeavor here is this: that in the overwhelming majority of cases there are no violations of justice, I presume, but we should be very careful in these very special cases that justice is being done. So I don't see it as mutually-exclusive. By the way, Kant does have a very strong theory of virtues as well.

A further remark is this: We hear in the paper and in Bill May's remark the constant parallel with conscription. I find it a little bit unsatisfactory myself because I'm not sure that all instances of conscription are morally justifiable. I think that a case can be made that in certain instances it's morally wrong to conscript young people.

Now the extreme case would be, of course, the conscription of young Austrians to fight for Hitler in World War II. Some young Austrians drew that conclusion, and they were duly shot, of course.

CHAIRMAN KASS: Paul, and then I'll have a comment, and we'll break.

DR. MCHUGH: I'm always in your debt, Alfonso, to explain to me these differences amongst the philosophers.

But I think we're all at least talking in similar ways about what we want to do as practitioners. I want to get away from this idea that it is ethereal, Dan -- I have to speak as the psychiatrist here -- that it's ethereal to work in a full and expanding consciousness. That's really what I want to do as a doctor, and I think that's what you want to do.

All of the activities that I do every day I want to have in full consciousness and appreciating my place in this community, because it's the community issue that I believe the virtues ultimately emerge in, in the practitioners who are fully conscious of what they're doing all the time and who are listening to people like Jonas and others about how they should think.

But I still want to come back to the idea that the full consciousness of a community does come in advance and does advance along with things which a community accomplishes. The tremendous accomplishments of things in medical science, along with, as Gil said, refinement of our research procedures, has been a tremendous uplift to what we can accomplish as members of a community, whether we are subjects or whether we are investigators.

I also agree that we haven't ever completely answered all of the issues that Mary Ann raised, because these are always vexed questions, and there's, to some extent, an asymptotic approach to the justices in them in which we can't be completely satisfied that we have an absolute forum.

Now Charles wonderfully explained that there are three groups of people in whom research is -- well, he said it shouldn't be done: children, the mentally disturbed, and prisoners. I want to salute that. I want to get up and say, "Right, I'm all for that."

But then, gosh, wait a minute, I want at some time to be able to talk about why I might want to persuade people who have mental disturbances to work with me and to be pa

I'm also losing it a bit, but it was this idea that this is too ethereal. It is not ethereal, I think, to anyone who believes that he should, or she should, be acting in his practice in full and advancing consciousness of what is happening and finding the words that deal with the feelings that he has, or she has, when he asks patients and subjects to commit to being in part a "thing" in this work.

DR. KRAUTHAMMER: Leon, I must make a clarification here. I didn't say that you should never experiment on them. I simply said that you could inherently never have informed consent --

DR. MCHUGH: Right.

DR. KRAUTHAMMER: -- which is why you have a difficult problem of delegated or implied consent or proxy consent, and there are all kinds of regulations which, in fact, in a previous life, a quarter of a century ago, as a psychiatrist working in the Carter Administration, I worked on those regulations.

But these are three categories of people which make the problem of informed consent very, very clear, since it is impossible to get that kind of consent out of them. So you have to devise a mechanism to get around it. It is not as if you can never have experimentation. I would never argue that you can't have experimentation on children.

DR. MCHUGH: Yes, fine, thanks. Thanks, Charles.

I think my point continues just in the same way, that that kind of discussion, that kind of interaction, that kind of explanation of and misunderstanding makes my life and my practice more enriched. That is the whole reason why I want to do it.

CHAIRMAN KASS: Okay, we're coming up on break. Let me make a couple of comments. A lot of people stirred me up, but I will just be very, very brief.

It does seem to me that, however abstract the text is and however philosophical, and, therefore, seemingly remote from everyday practice the article is, and certainly can be a big jump from this to talk about the regulations and the IRBs, it does behoove us, I think, to think very hard about what it is we are trying to protect and preserve in all of these arrangements with our patients, not just as experimental subjects, mind you, but in all the human encounters.

If it turns out that the attempt to protect these things produces documents of five pages long, which one needs not just a college education, but a legal education, to understand, and it is in fact the lawyers who have seen to it that it looks like that because they're interested primarily in protecting the institution, and not necessarily protecting the things that we are interested in, then it seems to me one might have gone off the road.

It ought to be possible to explain to someone with a fifth grade education but with a human heart what it is that one is trying to do here in the same way as one could explain to them what one is trying to do in all other kinds of human relations.

Jonas is, I think, trying to get at something which lies beneath and ought to inform the procedures and the human interactions, and I think not just in the experimentation, in the area of human experimentation, using human subjects for research.

It seems to me both Gil and Bill Hurlbut in their own way called attention to the fact that the principles that are operative here will be relevant for the discussions that we are going to have this afternoon, and they ought to at least be in our mind -- I'm not sure we've clarified them yet -- but ought to be in our mind when one thinks about trying to adjust the procedures that are, in fact, meant not just to encourage the research to go forward, which we all want, but in fact to protect, whether it's human dignity or human virtue or the sense of community or the notion of paying one's price for the benefits of having a community and the sacrificial norm that Bill spoke about.

Those abstract things are, nevertheless, tacitly present, and we probably, at least the presupposition of this conversation is that we would be better off making them not just tacitly present, but, as Paul says, matters of consciousness, when we try to fiddle with various things.

We have gone over a few minutes, not too bad. Why don't we reconvene at 10 minutes before the hour, and Dr. Emanuel will join us?

CHAIRMAN KASS: In this session the Council returns to the general topic of oversight and regulation of development and uses of biotechnologies, a subject of interest to us in general and also, I remind you, in relation to our work on cloning and stem cells, in which many of the people on both sides of the aisle on the cloning debate were interested in exploring the prospects for and the principles of regulation.

In previous meetings we have been looking both at what other countries are doing and also learning about the current regulatory activities in the United States. So far, we've had an overview of what is happening around the world with Lori Knowles and a report on the Canadian practices in reproductive technologies with Patricia Baird. We've had three sessions domestically on the patenting of living organisms.

Tomorrow morning we will hear from Professor Simitis on Germany's practices and policies, and today we will be looking at the Institutional Review Boards, those local bodies that are now charged with oversight and approval of all federally-funded research involving human subjects.

We are very fortunate to have as our presenter this morning Dr. Ezekiel Emanuel, physician, oncologist, Doctor of Political Philosophy, Chair of the Department of Clinical Bioethics at the NIH. His paper he wrote with co-workers, Ann Wood and Christine Grady, entitled, "The Crisis in Human Participants Research: Identifying the Problems and Proposing Solutions," was distributed to Council members in advance.

I remind everyone present that the opinions expressed in this paper and in this presentation are those of the authors. They do not reflect any official position or policy of NIH, the Public Health Service, or the Department of Health and Human Services.

It's a special privilege for me to welcome Zeke Emanuel here who I first met when -- I shudder to think when -- he was still a student, a senior at Amherst, and I was a much younger fellow.

Zeke, welcome and thanks for being with us.

DR. EMANUEL: My speech coach always tells me to stand and never sit. So I hope the Council will indulge me in that.

It's very wonderful to be invited here, and many of the Council members have been my mentors, many are my current colleagues, and many are people whose writings and work and research I have admired over the years.

I think it's fair to say that everyone seems dissatisfied with the current system of protecting human research participants. Many of our researchers find the system onerous and more of a hurdle to get over than something that is value-added.

IRB members who serve on the oversight bodies -- IRB stands for Institutional Review Boards -- find the regulations quite opaque, feel in a bind between federal oversight and what they're supposed to do for their institution. The pharmaceutical and biotechnology industry finds the process very time-consuming, very inefficient, and very resistant to innovative and novel approaches in research.

Regulators feel frustrated. They get criticized by the federal government and the public for not doing enough. They get criticized by institutions for being too intrusive.

And the public is afraid, uncertain. They believe greatly in biomedical research, but recent polls have certainly shown them to be much more concerned than they ever were. I think the cover of Time magazine over the summer that showed a human subject in a guinea pig cage attests to this concern.

I don't think it is misplaced. Since 1999, the federal government oversight body, OHRP -- that is the Office for Human Research Protection -- has stopped or suspended research at 13 major research institutions. This includes two of the top ten medical centers in this country, and a third of the top ten medical centers in this country had a major scandal involving the death of a patient, but was not actually closed.

Now that dissatisfaction has led to tremendous activity to respond to the problems. You can see all those acronyms up there. You know you're in Washington; it's alphabet soup time.

Recently, there was the creation of this Office for Human Research Protections during the end days of the Clinton Administration that reports directly to the Secretary of the Department of Health and Human Services.

At the FDA there was the creation of the Office for Good Clinical Practice to oversee all their ethical issues. The NIH, my employer, has issued requirements on training and education of investigators and one-time grants to improve the function of IRBs. There are new initiatives for accrediting IRBs, which I'll talk about in a moment. And there's introduction at least of two bills by Senator Kennedy and Representatives DeGette and Greenwood in Congress for reforming the system. This attests to a huge amount of activity.

I think there's a problem, though, and a lot of this activity really tends to address specific problems without stepping back and assessing the whole system. In the next few minutes I really want to sort of systematically delineate what I take to be the problems of the system, evaluate how the various proposed reforms address or don't address those problems, and then I want to float for you a more comprehensive solution.

It is at this point which I want to just reiterate Dr. Kass' disclaimer for me, which being a federal government employee I always do at every talk, which is that these are my opinions and the opinions of my colleagues, Ann Wood and Christine Grady, and our Department, and these are not the official opinions of anyone else.

I can tell you, having circulated the manuscript you saw inside the NIH, many people certainly disagree with, but they also thought it was important that these issues be aired and discussed. I greatly appreciate their commitment to free inquiry.

For those of you who aren't sort of up, as it were, on human subjects research and the regulations, I thought a brief historical digression would be helpful. From basically the mid-sixties to 1972, there were a series of research scandals in this country that really began in 1966, where Henry Beecher, a Professor of Anesthesia Research at Harvard Medical School and the Mass. General Hospital, published a very important paper in The New England Journal of Medicine that delineated 22 violations of research ethics at major research institutions.

He said he culled these 22 from a further 50 cases which he couldn't produce because of reasons of space, and that was from a further 100 cases. He made very clear that these events were occurring at the premier research institutions in the United States: Memorial Sloan-Kettering, NYU, Harvard, the NIH.

For the next six years a series of scandals happened in the country, culminating in the Tuskegee syphilis study, which was stopped in 1972 by the then-Department of Health, Education and Welfare after it was revealed in the press, although it is important to emphasize Tuskegee was not hidden; it was not done surreptitiously. Papers were coming out annually from that. As recently as 1969, just three years before it was stopped, it had been reauthorized by the Public Health Service.

Tuskegee led directly to the appointment of a National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research in 1974. That was chaired by Dr. Ken Ryan, an obstetrician and gynecologist at the Boston Lying-In Hospital.

Over five years, the National Commission issued some very major reports, including reports on research with prisoners that has already been mentioned and many other topics. Its probably most enduring report is so-called The Belmont Report, which established the sort of framework, ethical framework, for research ethics.

Soon thereafter, the federal regulations on research -- that should say, "on research" -- 45 CFR 46, were enacted in 1981. In 1991, they became what's called the Common Rule, when 17 federal departments and agencies adopted them, although it is important to mention that there are some federal departments that still don't adhere to these rules, notably the Department of Labor.

What's cut off (referring to the viewgraph) should say that the FDA maintains similar but slightly different rules regarding research that is being applied for approval as a drug or a device.

All right, the Common Rule focuses predominantly on local institution-based IRB review of research protocols and continuing review, at least annual review, of those protocols. It is also relies on informed consent of individual research participants, and there are special rules that have been in place for research with children, prisoners, and pregnant women.

With that brief historical background, I want to try to systematically and coherently look at the problems of the system, because I think a large part of the debate, certainly inside the Beltway, focused on one or another of the problems, but not on a sort of overall structure to the problems.

I think the problems can be divided into sort of three domains: structural, the whole system is laid out in the regulations; the IRB review process itself, and assessing the performance of both clinical research and that process.

Before I proceed, I would need to insert two caveats. The first is that there's a serious paucity of data documenting these problems. We just don't have a lot of studies of the whole system and of clinical research and how it is performed. So my claims here that there are problems is born of my experience as a clinical researcher and as an IRB member, discussion with lots of clinical researchers and IRB members, collection of the limited available data that's been published, and we'll look at the actions by the federal oversight institutions.

I also personally think -- and I'll get back to this at the end -- that the absence of performance data on the system is also an indication of serious defects. If Ford didn't know how many defects there were in its cars, you would think there was something wrong with their production system.

Second, while the review of the problems here is systematic, I don't by any means suggest it is comprehensive. There are lots of other problems I'm not going to talk about, such as the application of the regulations which were originally created for biomedical research to things like social and behavioral research and whether they fit or don't fit very well.

So with all of those caveats and hesitations, I want to talk about some structural problems. The first structural problem is that it may strike you and the public as ironic, but not all research, biomedical research, in this country is actually covered by the federal regulations. Research that's not funded by the NIH, research that's not seeking FDA approval doesn't have to get, isn't covered by oversight. This covers some very important research.

A lot of reproductive research falls into this category, and, in addition, research such as on dietary supplements isn't covered by federal regulation. Research on surgical procedures that aren't looking for approval as drugs or using devices is not covered.

Second, currently in the system there's no mechanism in a systematic way for addressing major ethical issues in research or for assessing the social value of research. There was a national commission; there was a President's commission; there was NBAC; there is this Council; there is another group called NHRPAC, which has just been disbanded -- for occasionally looking at major ethical issues in research, but these are stop-and-start events. They're not systematically organized.

Importantly, assessing the social value of research -- Is it really going to contribute that much? What are the down sides of research? Is it designed so that it will affect the most citizens? -- is not systematically evaluated in the system, and to some degree is discouraged from being evaluated.

The third problem: We rely on local institutional-based IRBs. When this was developed 25 years ago, that might have been reasonable when a lot of the research happened at our major academic settings like Johns Hopkins, the NIH, Harvard, UCSF, but in fact a lot of research, or maybe even today a majority of research, has now filtered out into private practices, clinics, and a lot of other organizations. There is a mismatch, many people feel, between the fact that we have institution-based IRBs, but a lot of the research isn't even occurring anymore at institutions.

Fourth, even within institutions there's no dedicated funds for IRBs. When the NIH gives out grants for research, there is no extra money for the IRB function. It comes out of what's called indirect money, and there's not even a line item in there.

Many IRBs, certainly before these recent scandals, were resource-starved, I think is an accurate way to put it. Now the scandals have gotten the attention of many institutions, especially if you can close down Johns Hopkins, and Johns Hopkins has announced or indicated that they have doubled the amount of money they devote to their IRB. But I think in general there's still a lot of lack of resources there, and, importantly, IRBs have to compete with all the other demands for medical institutions that are under increasing price pressure.

Fifth, there's a lack of attention to institutional conflicts of interest. One of the problems of having your IRB be institution-bound is that the IRB is actually regulating the research within the institution that is paying the IRB. That is an inherent conflict of interest. I, myself, have twice experienced some of the pressures that can be brought to bear by reviewing research done at the institution and people, powerful people, in the institution having some interest in getting that research going.

Sixth, there's a very poorly defined mechanism for investigator conflict-of-interest rules and the IRB's role in enforcing those rules. An investigator in this country can be subject to as many as five different conflict-of-interest rules: one from the institution where they work; one from the NIH; one from the FDA; one maybe from their professional society, and if they work at a state institution, there's frequently state conflict-of-interest rules.

They all differ. It is very unclear how to follow them, and it is very unclear how that is matched with submitting a protocol. The IRBs also don't know what they are supposed to do.

Seven, there has been inadequate education of clinical investigators and IRB members. The NIH has recently mandated that for its grantees there be education and training, although there's no curricula requirement; no one knows what the content is supposed to do, and, importantly, therefore, no one knows what the sort of core material they're supposed to understand and any way of assessing whether it works or not. This, by the way, is in marked contrast to animal research.

Eight, the system is replete with repetitive reviews. So, for example, if I do a research study, which I once did at Harvard, involving five other cities and hospitals in all those other cities, and ultimately there were 40 different hospitals, I actually had to get that protocol reviewed at 42 different places to do the research, all of them looking at the exact same thing over and over again. Sometimes this process can take a year and involve a lot of people's attention and energy. I know that another project I am currently involved on, we have one person who is full-time, worked for a year, just in getting all the paperwork together.

Those are structural problems. Now I want to shift to the IRB process problems. I think it is fair to say that a lot of the attention that we have today is really focused on these IRB process problems. A lot of the legislation, the accreditation process, really take these as key. I, myself, think they're important, but I don't think they're the whole story, and that is one of the reasons -- and the previous eight problems are a large part of that reason.

Getting your research approved is a time-consuming process. It has become longer and longer. I will say that most investigators are increasingly frustrated. Six months from submission to approval is not unusual. You often have to go through scientific review, which can take several months. Then the IRB frequently meets only monthly, and if you don't get on the schedule, the IRB frequently has corrections or modifications they want made. You then have to go back in front of the IRB. It is a very lengthy process.

Ten, there's poor quality control of the IRB reviews. One of the things we learned from the Johns Hopkins episode is that the investigator submitted information about the drug being used, but it wasn't complete or comprehensive information. The IRB relied on that information, did not proactively investigate further. This happens frequently.

Sometimes the IRB will get a protocol in an area. There's no one on the IRB who's an expert. Well, IRBs always could get ad hoc members, could actively investigate. That requires time, resources, and it is frequently not done.

Eleven, there's is excessive focus on the informed consent process at IRBs and excessive focus within that just on the document and what is, I think, derisively but not inaccurately called "wordsmithing" of the document. Now some of that wordsmithing is important to make sure that the language and the level of comprehensibility is correct, although we don't always get it right, but a large part of it is just altering words for preferences without any real focus on its importance.

There is good reason why this is true. Frequently, IRBs have been criticized by federal regulators for leaving out something when a scandal happens. This happened at Johns Hopkins. But a large part of the deliberations are about the document and really ignore many, many other important aspects of the research.

Twelve, there's substantial deficiency on how IRBs monitor research and conduct these continuing or annual reviews. It's frequently said, and very accurately said, it seems to me, that IRBs see the research protocol at the start, and then the ball rolls down the hill. They have no idea whether the research is actually being implemented as stated, and continuing review, the annual review, is a very perfunctory thing, done frequently in just a handful of minutes for very complicated studies. This is a very, very serious problem.

I think one of the most serious problems personally is we have a very inefficient and ineffective adverse event reporting system. Adverse events are those problems that arise in the course of a trial, people having reactions to drugs or complications that need to be reported.

It is now required that every IRB get informed. The FDA has a very strict timeline, a strict rating criteria. The NIH is a much more loose, very undefined system.

More importantly, if you have a large trial with lots of centers, you have to send the same information to all the IRBs and they have to make a decision, each individually, what to do, frequently without knowing how many people have been enrolled, are these three cases a large number of cases, a small number of cases, how serious. It is a very time-consuming process, but doesn't do a lot to protect the people on research studies.

The last two problems I want to talk about -- cut off at the top, unfortunately (talking about viewgraph) -- are what I call performance assessment problems. I think these are extremely important and not very well-appreciated.

We have almost no data about IRB function and how well they do their function, and whether, in fact, they actually protect patients. We don't know a lot about what goes on, where they spend their time. Is there a relationship between bad continuing review and harm to patients?

Fifteen, probably more serious is no one in this country, not the Director of the NIH, no one at Pharma or at Bio, and not the commissioner of the FDA, can tell you how many research trials are going on today in the United States, how many people are enrolled in research trials, how many people experience serious toxicities, and, indeed, how many people die on research trials. We don't record that information anywhere.

Again, it seems to me it is hard to know whether the system is better, worse, going in the right direction, going in the wrong direction, if you don't systematically, regularly, routinely even know how many people are on research trials. We don't even know how much we spend on it. I might say we don't even know exactly how many IRBs there are. I am sure General Motors knows exactly to the number how many dealerships it has. We know that there's somewhere between 4,000 and 6,000 IRBs in this country.

Let's talk about the reform proposals now. There are a number of reform proposals: accreditation of IRBs, which I'll talk about in-depth; credentialing of IRB professionals, which I won't talk about because I think it addresses a very small number of these problems; some of these legislative proposals, which I'll talk about. OHRP, again, that federal oversight body has some quality improvement initiatives and conflict-of-interest initiatives. There's been an effort at the National Cancer Institute to create a central IRB, which is in a pilot phase, and I won't say more about that. In a few months we think the Institute of Medicine is to report on its view of how to change the oversight system.

So I want to say a few words about accreditation of IRBs. There are two accreditation processes, again the alphabet soup here. NCQA, the National Committee for Quality Assurance, was hired by the Veterans' Administration to reform and look into and to accredit veterans' IRB programs, and AAHRPP -- and I can never even remember what all the initials stand for -- is an independent group that is doing voluntary accreditation of institutions and research hospitals.

There's some overlap in what they are evaluating. They are looking at the educational programs of these institutions. They are looking at the specification of IRB membership qualifications, how they're trained, how they're kept current. They are looking at policies on conflict of interest in other areas that the IRB has to deal with, and they are developing guidelines and assessing how many resources are provided to IRBs.

At the request of the Department of Health and Human Services, the Institute of Medicine, as the first part of its oversight, examination of the oversight system, reviewed these projects on accreditation. Basically, they said that the standards being developed do not apply to all types of research in all types of settings, that they really focus on biomedical research in the academic setting.

They argue that neither set of standards is tested or ready, as it were, for prime time. They said that accreditation is really best viewed as a pilot project, to be evaluated over a substantial period of time.

I would say -- and this is my summary; they didn't put it in this language -- at best, the IOM gave what I would call tepid support for the accreditation initiatives. It was certainly not wholehearted.

Importantly, which we can confess to you we just learned yesterday, as of April 17th, the Veterans' Administration suspended the NCQA accreditation process because of concerns about the standards and the process itself. It is anticipated they will resume in January, from what we have heard.

Part of what is happening is that the number of standards is being decreased from 130 to 100, and the revised process is supposed to be more VA-friendly. It was felt that the accreditors were not, in fact, very sympathetic to the institutions and that any deficiency on any one of those standards flunked people.

Now accreditation might affect a number of the concerns and problems I raise, such as resources for IRBs, some of the conflict-of-interest issues by forcing policies, some education issues, quality control, but they, by and large, concentrate on the reforms about the IRB process. They cannot affect the structural issues and do absolutely nothing regarding collecting performance data.

I want to talk a little bit about legislative proposals, and those of you who know about these things are much wiser than I about these. But these are proposals. They're clearly going to get reformed as they work their way through Congress. They may never get passed. We know how these things happen.

But both Senator Kennedy and Representatives DeGette and Greenwood have introduced bills into Congress, and they overlap in many ways. They have some individual characteristics. All the proposals want to apply the federal regulations to all of human research regardless of the funding or the location of the research. All mandate investigator education. Both of the bills mandate disclosure of investigator conflicts of interest. They permit central IRB review for these multi-center trials, so that you don't have the repetitive review process, and they mandate collection of some basic performance data.

Senator Kennedy's bill would require accreditation of IRB six years after passage, and the DeGette-Greenwood bill talks a little bit about requiring institutions to provide some money for the IRBs and funding, although it doesn't actually say where the money is supposed to come from.

Now, again, these legislative proposals I'm sure are going to change as they evolve, but they do some important things, but they obviously have some deficiencies, again, when we look at all of the problems we have in the system. While they will cover all research regulations and they will shift slightly away from reliance on local IRB review, they do at least nod towards providing some resources for IRBs, address issues of conflict of interest and repetitive review process. There are still many issues they don't address, such as the larger ethical problems that IRBs are going to confront and need to confront.

Finally, OHRP, the federal oversight body, has undertaken several initiatives, including a quality improvement program and to get conflict-of-interest rules. As I understand that, the conflict-of-interest rules are awaiting the Department of Health and Human Services' final approval.

The quality improvement programs are an important self-assessment program for institutions where they provide a survey that institutions can do for themselves and see where they are deficient. This at the moment is sitting at the Office of Management and Budget and, as I understand it, hopefully, by the end of the month, will be approved.

They also offer some site visits to particular institutions to address particular problems, and they are beginning a program on continuous quality improvement, which I think is quite innovative. But this is really their form of accreditation.

The conflict-of-interest rules, at least as gone up to the Department, apply to institutions, investigators, and IRB members. Again, at best, many of these initiatives will concentrate on the process problems, not really on the structural, and certainly not on the performance assessment.

So those of you who know me as always being bold, a little reckless, I thought I might offer a more comprehensive reform proposal for this Council to consider and to enliven the debate. I, again, hasten to add that many of my colleagues at the NIH don't agree with me, but they think it is important to elevate the debate and to begin to consider all possibilities.

So I want to suggest an alternative reform of the current system that would have these qualities: It would extend federal oversight regulation to all research. It would abandon local IRB review. It would create Regional Ethics Board to conduct all independent review of research studies, monitor research, train investigators, and formulate ethical policies and assess the value of research studies. It would entrust to a federal agency coordination of these Regional Ethics Boards.

We imagine that the Regional Ethics Boards would be geography-based in this country, that there would be 10 to 20 to cover the whole country. They would have something like this structure:

Each Regional Ethics Board would have a number of Regional Review Committees. It would have a liaison between the Board and particular institutions. It would have ombudspersons to interact with research subjects, and it would have an Ethics Policies Committee that would develop comprehensive policies.

There would be a federal oversight body, as I said, that would coordinate and monitor the function of these Regional Ethics Boards. The federal oversight body would collect data, publish performance data, and I give you some suggestions as to what I think that data should include, so that sometime someone in this country can actually say something authoritative about the clinical research landscape.

Importantly, it would also coordinate the Regional Ethics Boards to share best practices, to share operating procedures and, I think importantly, share ethical policy reports, which we really don't have today.

At the heart of these Regional Ethics Boards I think would be Regional Review Committees. There would be multiple Regional Review Committees per Ethics Board, I think possibly specialized and focused, so you would have one on cancer, one on heart disease, one on eye diseases, one on infectious diseases.

At least a quarter of their membership should be lay people. They should meet very frequently, weekly, not monthly, and they should conduct all prospective reviews of research studies in the geographic region.

Importantly, I think each research study should be submitted to one, and only one, Research Ethics Board. The Research Ethics Board in the geographic region of the Chief Investigator should review the study, and approval by that should be sufficient for doing research anywhere in this country.

Importantly, I think one of the things we don't have, and I didn't mention this as a problem but I think it is an important problem, is we need an appeals process for any adverse rulings by a Regional Review Committee. If you are going to concentrate power, you need an examination of that decision.

So I would suggest that if a Regional Research Committee rejects a study, the investigators should have the option of appealing, and that the federal oversight body should assign that research study to another group.

Importantly, I think the Regional Ethics Boards would collect data from investigators and report the number of people approached to enroll in research studies stratified by key variables like race, sex, age, diseases, number of people who actually enroll, number of participants removed from research and the reasons why they were removed, number of people who stopped participating in research, number of people who experienced what we in the industry call grade IV and V toxicities -- that's serious, serious toxicities, usually accounting for removal, but not always -- number of participants who died in research.

I also think that these Boards would be responsible for developing educational material and educating all the investigators in their Region.

I think all of the Regional Ethics Boards should have to establish a Regional Ethics Policy Committee that would create a forum to examine major ethical issues arising in research. Again, right now we do that haphazardly. We do it on a national level, very distant from people.

The kind of problems or issues I have in mind are: Should we pay children to be on research studies? A lot of studies do, probably unbeknownst to you. What are the ethics of it?

What about xenotransplantation, transplanting tissues from animals to people? What about having children to provide therapies for a sibling, conceiving and having a child? These are big issues that we really don't have a sort of systematic forum for addressing.

These Regional Ethics Policy Committees should engage the public in thoughtful discussion of the issues and develop coherent, consistent policies. Again, part of the issue is to educate the public and elicit their views. They could convene public deliberations, develop a draft report that could be the focus of public discussion, revise the report, establish a policy, and begin sharing the policies. This is a way of bringing the public into these discussions, educating the public, but also developing policies in areas where we have no policies today.

We also think that institution liaison is important. If you remove this review process from institutions, you need to connect with them. So we think each Regional Ethics Board would appoint individuals to serve as liaisons with major research institutions and probably liaison with smaller research institutions and physicians who individually in their practices conduct research.

Their responsibilities would include coordinating submission of protocols, clarification of policies, feedback, alerting the Regional Ethics Boards about problems and deficiencies.

Finally, I think an ombudsperson is very important. Right now if you get a research trial, if you have a problem, the number on the research form given to you to contact is the principal investigator. That's the person who you contact. We think there should be an ombudsperson who provides an independent view, so people who participate in research can contact them about any concerns they have about a research study.

Now any reform is going to have a lot of problems. I, by no means, catalog all of them. But I think it is very important to keep some in mind.

Again, I have mentioned the distance from and resentment by investigators is possible. At least if it is in the institution, the people you resent are your colleagues. If it is 100 or 200 miles away, it is some bureaucrat. I think that can cause a lot of resentment.

The concentration of power, I don't have to tell this Committee, can lead easily to the abuse of power. That is definitely a potential problem.

Uniformity of policies among 20 Regional Ethics Boards can certainly lead to rigidity, and that I think is also a problem.

Finally, no doubt, some people are going to worry about the high cost of having multiple Regional Ethics Boards. Cost is always a problem. Clinical research in this country is estimated to be a $40-billion-a-year industry. That is the research part of it. It seems to me a few hundred million dollars is not too much to pay for protection, and that is probably what we're paying now, although it is very hidden.

I thank you for your time and attention and welcome discussion.

(Applause.)

CHAIRMAN KASS: Thank you very much.

The floor is open for discussion. Michael Sandel.

PROF. SANDEL: I would first like to ask one or two naive factual questions, and I may be the only one who doesn't know the answer to these questions, except maybe my friend Gil. I hope maybe he doesn't either.

(Laughter.)

The IRBs, as they currently exist, that's only for federally-funded research?

DR. EMANUEL: It is a little more complicated than that. It is for federally-funded research and research that is seeking to get FDA approval for device or drug.

Now the federal oversight body has used its authority to mandate, to create agreements, for example, with Harvard that any research done at Harvard, even if it is not NIH-funded or if it is not seeking FDA approval, will still abide by the rules. But those are voluntary agreements. There's no law that requires them.

Furthermore, there is a lot of research, research that's not seeking FDA approval, like on dietary supplements; research that is not NIH-funded, such as many reproductive research studies, that don't have to abide by those regulations.

PROF. SANDEL: If there's a private company that doesn't take federal money, they don't have --

DR. EMANUEL: And not seeking FDA approval.

PROF. SANDEL: They don't have any IRB?

DR. EMANUEL: They might.

PROF. SANDEL: They might?

DR. EMANUEL: They might, but, again, the issue is whether they are legally required to.

PROF. SANDEL: And the people, let's say there's some biotech company someplace that has an IRB. Can they just appoint employees or do they have to appoint certain people to it?

DR. EMANUEL: Usually companies don't appoint or have their own IRBs. What they do is they contract out with proprietary or for-profit IRBs, some of which are probably the best IRBs in this country actually. So there is a private IRB market out there, as it were.

PROF. SANDEL: And it only applies to research on human subjects? IRBs don't deal with ethical questions of research apart from research on human subjects?

DR. EMANUEL: Right, and human subjects are defined in the regulations. They, for example, don't include dead people, are not human subjects.

PROF. SANDEL: And just one last question: This is no longer now in the category of the naive factual questions, but about your proposal. The thing you're proposing, that would apply, that would look at ethical questions beyond necessarily human subject research?

DR. EMANUEL: That would depend on what's crafted, but it seems to me one of the -- it would certainly be more than enough ethical questions regarding human subjects research. Importantly, how human subject research interfaces with many other aspects of clinical care and society are important issues that we haven't looked at.

The inclusion, in our view, of the importance of examining what we call social value of research, that's widely considered to be part of the ethical requirements of research. It would be wrong to do research that has no social value. It's now currently not systematically looked at at all.

PROF. SANDEL: And for your setup, are you only interested in the ethics of research, human subject or otherwise, or are you interested in the ethics of biomedical practice, and is there a clear distinction between the two? The reason I ask is that you gave the example of people conceiving a child for a blood match or a bone marrow match, or conceivably, as we'll discuss later, sex selection.

Suppose an IVF clinic wants to engage in various practices like those, not research practices but clinical practices. Would your proposal cover those, too?

DR. EMANUEL: You're getting to the issue of what distinguishes research from practice --

PROF. SANDEL: Right.

DR. EMANUEL: -- and there's not a -- I mean there's some stipulative definitions, but it's an open question as to exactly what the criteria are.

Certainly the early cases of conceiving a child for therapy were done on research studies. My current conception is that this is related, ought to be related to research, but, obviously, the considerations and the rules that you set down and the research setting would have some moral force, it seems to me, to extend beyond.

One isn't going to engage necessarily in some of these things in the clinical setting before you do it in the research setting. So it's very frequently, it seems to me, that you will address or at least confront the issue in the research setting before you get to the clinical practice setting. Certainly you ought to.

CHAIRMAN KASS: Let me follow on this, too, Zeke. I mean, I'm mindful of the fact that the talk is about the reform of existing institutions that are problem-ridden, and much of what you say in the proposal and the summary makes sense to me. But what's missing in the discussion, and what is somehow tacitly assumed, is some notion of what the goal of the IRBs or of your Regional Ethics Boards would be. If they remain defined as the protection of individual human subjects of research, then it seems to me you have -- I don't mean inappropriately, but you've limited only one piece, you've limited off only one piece of the larger ethical issues that, for example, concern this body. Point one.

There is for many people a sense that the crucial ethical issues in biomedical technologies are, in fact, the research ethical questions, and one will try to force almost all of the other questions into that model, and we had our hand at that actually earlier this year.

But if you then go on to say, as the statute does, that what you mean, what you're looking at, the protection of individual human subjects, that you will consider risk-benefit analysis, that you will consider questions of subject selection, and that you will see to it that there is informed consent, that is a further narrowing even perhaps of what it is you want to consider when you're taking account of individual research subjects.

So the large question is, the largest way to put the question is, assuming you wanted to design a system that would in fact protect the individual subjects of research in as rich a way as you can, would such an institution devoted to those goals be reasonably expected to address some of the larger social and ethical questions or do we need something different to do that?

DR. EMANUEL: I don't think I said anywhere that these groups should limit themselves in the way that current -- that we simply should take the way current IRBs limit themselves to individual research subjects and simply protecting them as necessarily the paradigm. I don't think I meant that, and I certainly don't take that to be the case. I'm very much on record in getting at, among other things, concerns about how research affects communities. It's very important and underplayed.

Second of all, it seems to me that many of the questions that ought to be taken up do go beyond a narrow conception of either risk or subject selection. Let me just point out the way I conceive it, and maybe we're talking here a little orthogonally.

If you take the question of, should we pay kids to participate in research, now you can conceive it very narrowly, but you can also conceive it much more broadly. How does it express how we value children in our society? How do we understand the relationship between kids and their parents, if you pay the child independent of the adults? What kind of payments communicate different things? What's their both material and symbolic value?

It seems to me you can't answer those questions in any narrow way, and part of my alluding to the kinds of things that I think are on, or would have to be on the agenda, this is a burning question for lots of IRBs, I take it, I know, in this country.

I would tell you that there are probably only two things written on paying kids in research. We've written one of them, and the American Academy of Pediatrics has written another. Actually, the European Union has a third. But that's it. I think discussing the underlying values of what you are trying to achieve in policies is absolutely critical. That's part of the reason for having an ongoing body.

Similarly, other topics that would have to be taken up that are burning issues today have broad social meaning. For example, what are the obligations of researchers from this country who are going overseas to developing countries to provide medical care beyond the end of their research for the people who have been involved in their research studies? And maybe not just on the disease that they've looked at, but on other diseases. How long does that occur? Who is supposed to shoulder the financial obligations? You cannot answer that kind of question in a very narrow frame of just protecting subjects.

Third, it seems to me that when you include the notion of assessing the value of research, the social value of research, you go to the heart of the question: Why are we doing this? One of the things we have certainly learned over the last decade or 15 years, and I think was alluded to by Professor Dresser, was a lot of the research we had structured was very narrow, you know, assessed only white males between the age of 50 and 59, and had no greater social implication, or couldn't be extrapolated without significant danger.

How we understand the research we're doing, make sure that it is maximally valuable to society, I think is very important. Again, it is widely recognized as an ethical requirement for research and simultaneously widely ignored in any review of research. It seems to me that's exceedingly important for us to examine.

So I think it is hard to see how, if you take one of these issues seriously, if these Ethics Policy Committees took it seriously, how they would stick to the narrow question of just protecting individuals. Almost all these questions open up larger questions of social values.

CHAIRMAN KASS: Just a very brief followup: It does, then, seem to me that you've got enough trouble, I suppose, peddling this proposal as it stands, but I think it would be enriched if it began really with an articulation of the kinds of things you're now saying, where you somehow talk about your perception of what it actually means to call something a Research Ethics Board as opposed to saying Institutional Review Board, and to make some of these tacit goals explicit and call attention to what might be different in the overall ethical and social intent of this, I mean if you mean it.

DR. EMANUEL: Yes.

CHAIRMAN KASS: So that it becomes -- people will see really what's at issue. They may not like it. The individualistic focus is very prominent in the society; communitarian perspectives have an uphill battle. But, nevertheless, it does seem to me that the proposal itself could be enriched upfront with some kind of discussion that doesn't begin just that there are dissatisfactions with the way the system works, but to talk in a more positive way about what one is trying to accomplish.

PROF. SANDEL: Okay.

CHAIRMAN KASS: I'm sorry. Charles and then Michael.

DR. KRAUTHAMMER: Michael Sandel said he was asking a naive practical question. My job is to ask the naive philosophical questions.

Why regional and not national? I know that obscenity is defined locally and regionally in this country. Is ethics also defined that way?

DR. EMANUEL: Well, I think moving to a national body would be, for practical reasons, unwieldy, just sheer volume and considerations of that. I think many of the standards are universal and aren't particular to a region. So part of the regional focus is a practical focus.

It is also an attempt to try to avoid the rigidity problem. While I think having 4,000 to 6,000 IRBs is probably more akin to chaos, having 10 or 20 think through some of these problems and some of the implications is probably a good way to keep the pot stirring and keep innovative ideas.

I think in this country I don't have to tell you, a better historian of American culture than I, national things obtain a lot more resistance than even local things.

One of my colleagues did ask a similar question, which is, well, then, let's look at the Ethics Policy Committees, why are they regional and why that could be national. I would consent to that.

DR. KRAUTHAMMER: Am I overinterpreting you to say that this is more of a political, practical, what-is-feasible consideration rather than philosophical? If you were creating a system from scratch and had no political constraints, would you have any -- is there any reason in principle, other than the idea of the laboratory of democracy, different regions learning things and teaching each other, other than that, which I think is a consideration?

It would seem to me more logical, if you were going to have a set of ethical regulations and people applying them, that it would make sense to have one system or at most one or two or three regionally. But I don't quite understand, other than what you're saying, that it is politically impossible to go the other way. In principle, would it not be desirable to have as few as possible?

DR. EMANUEL: I guess I am somewhat of a student of political history. Concentration in one place I think does tend to ossify. I think that is not a trivial concern here, especially as research progresses in some areas. I am not a big believer that it raises, you know, the argument that it raises new questions, but it certainly puts them in different lights and makes different kinds of challenges.

I think in that light, having everyone having to troop to Washington or Chicago or something, it is probably a much better idea to have different places looking at things.

DR. KRAUTHAMMER: Could I just have one quick followup? So, in practice, if you have an investigator who's headquartered, say, in Boston, under your proposal he goes to the regional one there, but he might involve a hospital in San Francisco that is operating under a different set of rules. Yet, that protocol, as practiced in San Francisco, would have to adhere to the Boston rules rather than the local rules. Wouldn't that lead to all kinds of jurisdictional problems?

DR. EMANUEL: It might lead to jurisdictional problems, but I think I don't see the different rules per se; there might be different interpretations of some rules. But, again, I think that's possible, but it is a problem that is better lived with than either the current system or one system.

PROF. SANDEL: I hadn't thought about this before Zeke's presentation, but one argument in favor of having Regional Ethics Boards might be to allow not just a laboratory of democracy, diversity for that reason, but different arguments to be developed and positions taken on ethical questions, analogous to the way it works with federal district courts and courts of appeals.

Now there is a Supreme Court. And one question you might have put to Zeke was, why not have a Supreme Ethics Review Board to handle the appeals rather than some other regional one, which is what I thought you were going to ask?

But there is currently the law now, as a result of regionally-based federal courts of appeals, that you are allowed to count race in admissions to law schools in Michigan but not in Texas, because the courts of appeals have come out with different positions on affirmative action. The Supreme Court could take those cases up to resolve it, but so far they haven't.

There is something to be said -- I don't know if it is enough to be said -- for having debatable questions like these medical ethics questions and like affirmative action be reasoned and debated differently by different regional courts.

DR. KRAUTHAMMER: But, Michael, that structure really only makes sense because you ultimately do have a Supreme Court which will in the end adjudicate on the critical issues. If you didn't have that, you, I think would agree, that having a system, a legal system in America of circuit courts and no Supreme Court would be incoherent and ultimately hard to defend.

PROF. SANDEL: Well, incoherent I'm not sure. There are those who defended the federalist system who would say there's something to be said for that degree of decentralization.

But you could add to Zeke's thing a Supreme Ethics Review Board.

DR. KRAUTHAMMER: But you would have to find a better name.

(Laughter.)

CHAIRMAN KASS: Mike Gazzaniga.

DR. GAZZANIGA: There are efforts going on, or about to go on, to address some of these things. I know that Dartmouth just received a large grant to start a database of all the IRBs that are funneled through the NIH. So some of these coordination efforts are started.

But I have three questions for you. One, are you knowledgeable about any cross-cultural models that might help us think about this?

Two, have you really thought about the time to study? I'm the clinical investigator who uses the current system, and I'm about to inherent your system. Have you thought it through to what's involved there?

Three, a little more thought, apparently, you're in total agreement on this, but the monolithic problem of an agency with an ethic. If I have learned anything in the last six months, there's no one ethic; there's all kinds.

The ossification you talk about I think is a huge problem. Science, for example, if it only had one vendor, one source for all money, the beauty of the process would come to a screeching halt.

Lastly, I don't think that local control is all bad. I see in our IRB process that people learn quickly who is responsible, who are good. Whereas, if we mailed this off to somebody in Manchester, New Hampshire, or to Boston, or whatever, it sounds like a nightmare.

So, as a friendly skeptic, maybe you could comment on some of those.

DR. EMANUEL: First, in the cross-cultural models, all through Europe there's different models. Some countries have a national system, like Denmark. Some countries have a regional system like this. I think it is fair to say that there is a European directive now; they want to facilitate review, and review is in a few years going to be required to be 60 days, no longer than 60 days.

Places like The Netherlands are fulfilling that review by basically getting rid of all IRBs at the bottom end, that don't deal with a lot of protocols, don't have a lot of experience, don't have a lot of standard operating procedures. They've acknowledged that essentially it is going to be a regional system.

Second, I think we actually have home-grown examples of how this might work. The proprietary IRBs are, in fact, a model of a regional IRB system. At least in this country, as I alluded to, they are quite good.

Now those people who are at academic centers I know are quite skeptical of this, but, in fact, we have some good data about that, because every time the federal government closes down a major research i