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Meeting Transcript
April 21, 2006


Edmund Pellegrino, M.D., Chairman
Georgetown University

Floyd E. Bloom, M.D.
Scripps Research Institute

Nicholas Eberstadt, Ph.D.
American Enterprise Insitute

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

Michael S. Gazzaniga, Ph.D.
University of California, Santa Barbara

Robert P. George, D.Phil., J.D.
Princeton University

Alfonso Gómez-Lobo, Dr. phil.
Georgetown University

William B. Hurlbut, M.D.
Stanford University

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

Peter A. Lawler, Ph.D.
Berry College

Gilbert C. Meilaender, Ph.D.
Valparaiso University

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

Diana J. Schaub, Ph.D.
Loyola College



DR. PELLEGRINO: Good morning.  We've got some members missing but we'll just move ahead.  When they hear our dulcet voices, they no doubt will come in, as long as we keep it dulcet.  This morning our first speaker is Tom Beauchamp.  Tom is a member of the Kennedy Institute of Ethics but more famously the co-author of the most popular book in biomedical ethics in the world, I guess, and of course, beyond that a Yung Scholar as well.  But I'm not going to go into all his credentials.  As you know, that's available and we'd like to keep our introductions short and I know Tom appreciates that as well.

We've asked Tom, who was a member of the Belmont Report Committee, played a prominent role as you all know, to give us the present status of the Belmont Report, what's happened since then, with particular emphasis on children, our concern this morning.  Tom, can you take it from there?

DR. BEAUCHAMP:   Is that all right?  Can you hear in the back, Marti?  Good, okay.  Many of you know that I have had a long association with Ed and Alfonso, a member of my department for how many years, Alfonso? 

DR.GÓMEZ-LOBO:  Thirty or so.

DR. BEAUCHAMP:   Thirty, right, and also with Rebecca Dresser, my dear friend and co-author and I believe Rebecca will not be here today, as I understand it and I'm very sorry about that.  I'd like to tell you that when Ed called me I was really very worried about what time he was going to call this meeting, because Ed just decided we'd find out when we were free during the day and Ed would say, "Well, I'm here at 5:00 o'clock, how would that be?"  I was afraid he was going to ask me to be here at 5:00 o'clock this morning.  So this is a very decent hour to get started. 

I should also say in the spirit of disclosures of the sort we're supposed to make these days, that I have a long, long, long history with Bob Levine and that history is, in some respects so close that we might even sound like we're speaking from one voice.  So it's not as though you get very different characters when you have us around at the same time.

All right, so let's get down to business.  I'll stay fairly close to my text.  I like to do that because otherwise I depart and stray and digress and I don't want to do that.  This morning you've given me a time limit and I'll try to stay within it.  I trust you being very good about time, you'll nudge me if I'm going on too long.  Okay.  Ed and Dan have asked me to discuss my quote "Views on the Belmont Report as the ethical basis for the regulatory framework governing clinical research in this country" and then to generalize beyond that circumstance to the quote "regulatory framework governing clinical research ethics" and then to include my own view of quote "the current state of the ethics of research with human subjects", and I understand that that means in terms of the historical continuity with what happened back in the 1970s.  So I will try to stick reasonably closely to this assignment.

I will state what I believe really happened when the Belmont Report came into existence, how it captured some reasonably deep and significant themes in research ethics and how some of this might still be of help today.  I will then, at the end, as I understand my assignment, offer you some recommendations based on what I have said.  Recommendations are, of course, just that.  They're recommendations.  So let me talk first about the National Commission. 

As is reasonably well-known, the National Commission was established in 1974 by the U.S. Congress with the charge to identify the ethical principles, that was in the charge, that should govern the conduct of research involving human subjects and to develop guidelines for the conduct of research.  It was hoped that the guidelines would insure that the basic ethical principles would become embedded in the research oversight system of the United States.  Its more than 100 recommendations, the Commission's recommendations for reform, went directly to the desk of the Secretary of the Department of then Health, Education and Welfare and many were codified in federal regulations.  You know them all well, there's US 45 CFR 46. 

The Belmont Report is not itself written in the style of federal regulations or anything even approximating it and was never so codified.  The Belmont Report is a tiny philosophical document for the most part.  Carol Levine offers the following sobering but I believe accurate statement of the historical context in which the National Commission deliberated.  I quote her, "The Belmont Report reflected the history of the 30 years immediately preceding it.  This emphasis is understandable given the signal event and the modern history of clinical research ethics, that is to say Nazi experimentation.  American public opinion was shaped by the revelations of unethical experiments such as the Willowbrook Hepatitis B Studies, the Jewish Chronic Disease Hospital Studies and especially the Tuskegee Syphilis Study.  Our basic approach to the ethical conduct of research and approval of investigational drugs was born in scandal and reared in protectionism.  Perceived as vulnerable, either because of their membership in groups lacking social power or because of personal characteristics suggesting a lack of autonomy, individuals of that sort were the primary focus of the Commission's concern," close quote.

I want to go now — I want to go in a moment directly to the Belmont Report but I know that you are now thinking about children and I want to start with the Commission's Children's Report, still a document, I believe, well worth your reading, and a problem in that report that kept coming back over and over again during the National Commission's deliberations.   This problem was never resolved adequately or fully or whatever the term should be, nor is it likely that you will resolve it here during your deliberations.  It is a deep problem that will always be around. 

But it captures, I think, one of the great questions of research ethics and one with which you must grapple because it's unavoidable.  I will not summarize or interpret any document.  I want to go to the moral heart of what I understand the debate to have been about and in this way to offer you an understanding of what the Belmont Report is about.  I think this problem could easily become the center of debate for you as well.  But historical understanding is important in its own right, a view that I have always shared with both Alfonso and Ed.  Alfonso, as  you may know, is a historian of philosophy and so am I, in our own way.  I take historical analysis of that sort with very great seriousness and I think it's important to look at the history of bioethics in much the same way. 

So I take fidelity that history is my first obligation in what I'm about to say.  In 1975/'76, the National Commission deliberated on the topic of research involving children and eventually produced a volume on the subject, one written and published well before, before, the Belmont Report.  It is easily the most important of the Commission's 17 volumes for an understanding of why Belmont takes the shape that it does.  Belmont was forged in the context of discussing research involving children.  I know that because I wrote it.  I know exactly how the context was forged.  Without this background, I think you lose something.

By the way, I wrote almost all the Belmont Paper.  Bob Levine wrote the section on boundaries in that paper so that you know how the authorship — because it was revised many, many times by the Commission.  You know the process well.  For about a year, no exaggeration here, the Commission found its deliberations grinding to a halt over a significant moral problem; how much danger or risk could justifiably be presented to children in so-called at that time non-therapeutic or non-beneficial research? On one side of the debate were the apparent defenders of research.  They argued that severely restricting the involvement of children would bring pediatric research to a standstill, with, of course, grave consequences for children who would be sick in the future. 

On the other side of the debate were the apparent defenders of research — I'm sorry, children.  They argued that openly using children with exposure to significant risk when the intervention was not therapeutic or of direct therapeutic intent, was to use persons without their consent to the ends of science.  Children would be, in short, exploited without any benefit flowing to them for their sacrifice.  During this debate, most Commissioners found themselves somewhere in the middle of the two sides and reluctant to choose sides.  So how to bring a very long body of deliberations to a conclusion?

Ultimately the defenders of research would be, so to speak, victorious although I'll be careful about that word in this debate, but with two dissenting votes among the 11 Commissioners and two dissents filed.  The most difficult ethical issues for the Commission arose with respect to research presenting more than minimal risk, where there is no immediate prospect of direct benefit to the individual children involved.  Some members of the Commission urged that the limit for such research remain at the level of minimal risk.  Others pointed out that such a limit would almost certainly eliminate much research that has genuine scientific significance as well as the promise of substantial long-term benefit to children in general.

Ultimately the Commission decided with two members dissenting, that if three conditions are satisfied, research in this most difficult class of cases could be justified.  First, the risk must be only a minor increment beyond minimal.  Second, the procedures to be used must be reasonably similar to those with which prospective subjects have already had some experience.  Third, the research must be likely to yield generalizable knowledge important for the understanding or amelioration of the specific disorder or condition. 

Thus, foreseeable benefit in the future to an identifiable class, class, that was the key notion that was landed on, of children was held to justify a minor increment of risk to research subjects.  Dr. Robert Cook then Chancellor of the Medical System in  the State of Wisconsin, objected vigorously to these conclusions and, as I understood him, he objected to the moral premises underlying them as well.  He wrote as follows in his formal dissent.  Quote, "In the ethical justification of its recommendation, the Commission can invoke only the principal utility.  This, in itself, does not constitute any breach of ethics but it does indicate the perilous nature of the recommendation and the ethical uncertainty of the Commission."  Lawyer, Robert Turtle, was even tougher on his fellow Commissioners.  He says in his dissent, that the Commission notes that it was, and I quote, "Impressed by reported examples of diagnostic therapeutic and preventive measures but," Turtle says, quote, "that rationale provides no basis at all for segregating children in to separate classes.  The rationale is strictly utilitarian.  I do not believe a strictly utilitarian rationale can provide adequate justification for a policy creating a doubly disadvantaged class of children, doubly disadvantaged because they're already sick and you — they're sick and then you add an additional risk on top of their sickness."

I agree with the minorities' interpretation, the Commission had reasoned heavily by appeal to considerations of public utility, but this was certainly not the only evaluative commitment of the Commission and it would misunderstand the deliberations and its moral commitments to cast its conclusions in this narrow way.  The historical record and transcript clearing indicates that the National Commission, was very concerned throughout its work that it had become too easy in the biomedical world to use utilitarian justifications of research.  The Nazi experiments, Tuskegee and Jewish Chronic Disease Hospital case, all the cases that were very much on the horizon and being examined at the time, had left a legacy of being driven by a very utilitarian view of social beneficence, the justified using human subjects on grounds of benefit to the broader public.

That is, a major purpose of the report, of the Commission's Report, was to properly balance the rights and interests of subjects with those of science and society.  Considerations of autonomy, justice and risk control were set out to limit utilitarian balancing, explicitly so, that's why these considerations are there, not to promote utilitarian  balancing.  However, it is doubtful that the question of how best to control utilitarian balancing was ever resolved with the Commission and, in truth, I do not believe that it has ever been resolved by anyone in bioethics.  That is the theme, so to speak, of my talk today to the extent that it has a theme that cuts across all of its sections. 

Now, to the Belmont Report.  When I wrote most of the Belmont Report for the National Commission, what I have just explained to you was the framework of deep issues that was always before me.  These concerns had already been laid out by the history of the Commission's deliberations, most clearly, I believe in the children's report.  So it was easy for me to grasp the nature and importance of these questions, in other words, people have already done the work for me.  I never forgot this context for even a single sentence when I was writing that report.

But before I explain this background further, I should state what the Belmont Report is known for and how to interpret its framework of basic principles.  These principles are still today referred to in many contexts as the Belmont Principles and rightly so in my view.  The Commission identified three general principles as underlying the conduct of research; respect for person's beneficence and justice.  These principles, though often quoted in bioethics have often not been well understood because the historical context has been dropped in the invocation of the principles.  I will cite a simple example which will be readily understandable to you and it will also, perhaps, motivate you to find the historical context I'm now drawing out a little better.         

On page 19, Roman 19 of your Volume "Being Human," there is a brief discussion of these principles.  And I think you wrote that, Leon, am I right or did you all write it together?  I'm not quite sure how that worked.

DR. KASS:  The report?

DR. BEAUCHAMP:   Yeah, the introduction to the report.  It doesn't matter.  That was my understanding but it doesn't matter.  The principles that are there said to be; and I quote, "The major principles of professionalized bioethics."  The principles are then explained.  They are explicated wholly in terms of the patient, for example, as discussed here, patient autonomy, and also in terms of distributive justice in the health care system as well as in terms of public health.  There is no mention of research, not even a hint of it.  The oddity of this to me is that these principles were born and bred in a research context.  That is where they came from. 

The concerns were not about patients, per se, but about subjects.  The concerns about distributive justice were entirely about the fairness of the selection of human subjects, not about distributive justice in the healthcare system.  In other words, the embeddedness of these principles in the history of research in the 1970s is easy to lose and it has for the most part simply dropped away in the contemporary understanding of what these principles are.  And yet, if you're going to understand that Belmont Report, that is the only way, I believe, that it can be understood.

And so if we're to understand the National Commission and what it brought to be codified in federal regulations, as well as the connection of this history to the development of research ethics over the course of the last 30 years, it is truly important to understand not only the principles but what gave birth to them and the original context of their birth.  This is what I'm trying to accomplish now.  There's a key organizing conception underlying the Commission's presentation of their principles and use.  The simple conception is the principle of respect for persons, commands in the research context, obtaining informed consent, be it first party or be it third party.  The principle beneficence commands that a risk/benefit assessment be done and that it not be a narrow one but a broad one. 

Justice demands that you pay — the principle of justice demands that you pay very careful attention to the way in which subjects were selected so that that selection process be fair.  That's in outline, the essence of what the National Commission was about in constructing these principles as the framework of what it had morally done.  In this way each principle makes moral demands in a specific domain of responsibility for research.  Here is what is noteworthy.  Beneficence in the world of biomedical research is very different than beneficence in the context of patient care where it is confined almost exclusively to the medical welfare of the patient.  In the research context, beneficence has to be understood and should be understood in terms of benefit to the public and the social imperative, so to speak, of biomedical research.  Quite explicitly the principles of respect for persons and justice in the Belmont Report are not in any respect whatsoever to be allowed to be brought under the context of or to be subordinated to public beneficence.  That was the architectonic of the document. 

Those two principles, axioms and the framework, so to speak, are erected intentionally at the heart of the National Commission's moral framework to serve as moral constraints on beneficence, to be just as important as social beneficence, what some philosophers like to call the ontological constraints.  The whole point of this framework is that neither of these principles is to be compromised or lost under public beneficence, medical research, ambitions and the like.  The Commission spent a huge amount of time on the place and purpose of informed consent. 

In historical context, there wasn't much informed consent at the time or much of an understanding for the notion, for that matter.  The Commission insisted that the purpose of consent provisions is not protection from risk.  Indeed, that risk/benefit and their balance is wholly the wrong way to understand the place of informed consent. 

I've heard it often said in both the United States and Europe that there has been an over-emphasis on autonomy in the frameworks spawned by the National Commission, sometimes expressed in Europe as an American obsession.  I think this is false to the historical facts and I think it shows no insight into the history of bioethics.   The National Commission was as concerned with personal dignity as it was with autonomy and this is one reason why its first principle is the principle of respect for persons.  However, I don't want to carry on about this subject as at this point, it would take us too far astray.  Back to the main theme.

We have seen repeatedly throughout the history of research involving human subjects that we cannot avoid coming to some form of delicate balancing of the human values that we attempt to collect and then distill in the form of principles expressed in the biomedical — in the Belmont Report.  We then must contextualize balance and specify their significance when we confront particular issues such as those that confront us with children.  The Belmont Report was written in significant part to try to insure that we appropriately balance appeals to social utility in the justification of research together with respect for persons and considerations of fairness. 

If you lose that perspective, in my view, you lose almost everything of real and enduring importance about the history of the National Commission and much of the history of recent research ethics.  The whole of the work of the National Commission, all 17 volumes, came to one fulcrum; how to balance and specify the moral considerations that it called, following the mandate of the U.S. Congress, principles, as those principles could be brought to bear in problems arising from research involving vulnerable groups, that is after all what we were up to: embryos, prisoners, the institutionalized, mentally infirm, children and so on. 

I want to say just one more thing about the Commission's framework, by the way, how am I doing on time, before ending this first part of my assignment?  The principle of justice in Belmont requires fairness in the distribution of both the burdens and the benefits of research.  The Commission insisted that this principle requires special levels of protection for vulnerable and disadvantaged parties but that attention to questions of distributive justice should always remain at the forefront of research ethics. 

This principle demands that researchers first seek out and select persons best prepared to bear the burdens of research, for example, healthy adults, and that they not offer research only to groups who have been repeatedly targeted, for example, mentally retarded children.  The Commission notes and laments that historically the burdens of research have been primarily placed and indeed heavily so on the economically disadvantaged, the very sick and the vulnerable, owing to their ready vulnerability and availability.  Yet, the advantages of research are calculated to benefit all of us in society.  The over-utilization of readily available, often compromised segments of the US population was a matter of the deepest moral concern to the Commission throughout its deliberations.  The theme of justice and the proper selection of subjects was Belmont's way of saying that since medical research is a social enterprise for the public good, it must be accomplished in an inclusive and participatory way. 

If participation in research is unwelcome and falls on a narrow spectrum of citizens because of their ready availability, then it is surely a questionable enterprise.  Sadly, the Commission never got much beyond these themes of justice but what the Commission did is still a good start and I will return in a moment to these questions of justice and explain this a little further.  I conclude this little historical discussion as follows.  The Belmont Principles are in some respect present in every document the National Commission published.  These came to be the backbone of federal law in the area.  From this perspective, as Christine Grady has observed in her recent book and I quote her, "Probably the single most influential body in the United States involved with the protection of human research was the National Commission."  I believe that she is right.  Biased as my judgment may be, I think Christine is right about this.  But whatever the influence and enduring legacy of Belmont and the Commission's other reports, it is not clear that scientists who today are involved in research with human subjects are really familiar with the Belmont principles or understand them or for that matter actually use them. 

When the National Commission deliberated it seemed to many at the time that the general system in the United States of protecting human subjects was in need of serious repair, that research investigators were not educated about research ethics and that subjects were not adequately protected.  To some observers, the system still seems today caught in a notably similar state of disrepair, I mean right now.  I am not here today to make any judgments about this claim as I'm really unqualified to do so.  It takes a different kind of knowledge.  I say only this; it would be a shame if you, a great national deliberative body, could not find the time to figure out where we are today and to do as much as possible to remedy defects in the system.

With this general perspective now out in the open and before us, I will turn to my recommendations to you based on what little I do know of the system today, what might be important to you and the history that I have just sketched.  So at the risk of reducing myself to a kibitzer that you, perhaps, think I am anyway, I have several things to recommend and in four areas.

First, the research oversight system; some in bioethics have argued that problems with research ethics are largely a matter of getting just right how to adjust the present oversight system for clinical research in the United States, which supposedly protects subjects against excessive risk and exploitation while demanding scientific rigor and promise.  If the system fails, this view goes, then to avoid moral problems, we need to patch up or reform the system.  This view puts tremendous weight on the oversight system that we have and it is this that I suggest you be cautious about.  There is no evidence that research oversight systems have a particularly good grasp on various moral problems of research ethics.  And in any event, I don't think the oversight system is the only way to process or to present these problems.

Moreover, in a globalized world, one needs to think globally irrespective of a particular country's system of oversight.  There are many oversight systems.  I do not, myself, assume anything about the adequacy of oversight systems in thinking about research ethics and I recommend that you not make any such assumptions either.  Frankly, many people now believe that the system of protection we've erected in the United States stinks and is in need of deep reform.  I take no position on that issue before you today.  If you wish to get into this, I would applaud the effort.  At the same time, I do not think that moral problems should be confined to this arena.  Performing the IRB system and the like could wholly consume your time for months and months.  Try to think far beyond this to the underlying moral views and how to present them clearly. 

Second area, problems of justice which I said earlier I would return to.  The National Commission came into existence in the aftermath of public outrage and congressional uncertainty over the Tuskegee Syphilis experiments, the Willowbrook experiments and other apparently questionable uses of human subjects.  The socio-economic deprivation of the  subjects who had been enrolled in the Tuskegee experiments and involved at Willowbrook made them vulnerable to overt and unjustifiable forms of manipulation at the hands of health professionals. 

What we know today about the recruitment and usage of human subjects is less than I would like us to know, at least I believe it to be.  What do we know about that system, including how children are used in it?  This is an empirical question that I hope you spend the time to investigate.  I am not an empirical scientist but I suspect from a survey of the literature that less is known than people often believe.  Since I am no expert, I say only this; consider what we know about economically disadvantaged persons in the United States today.  Several issues are apparent.  Are those persons, when used as subjects, vulnerable to morally objectionable forms of involvement in research?  What kinds?  Where, where does this occur?  If so, what is it that renders them vulnerable?  Is it morally permissible to trade off some level of risk and research for some benefit such as money or health care? 

Answers to these questions are not readily available and they are difficult.  It is also not clear which populations, if any, if any, should be classified as vulnerable.  Discussion of issues about the vulnerability of research subjects, so-called vulnerable groups, have historically focused on embryos, fetuses, prisoners, children, psychiatric patients, the developmentally disabled, those with dementia and the like.  Until recently, relatively little attention had been paid to populations of persons who possess a capacity to consent but whose consent to participation in research might, nonetheless, be compromised, invalid or unjust.  Prisoners have been the most frequently mentioned class of such persons but there could be many other such populations, especially among the economically disadvantaged.  It is known that persons of this description are involved in some research in North America though the extent of their use, I believe is not well understood.  It is also known that persons of this description are used in other parts of the world, sometimes in so-called developing countries.

The scope of their use there is even less well-understood and reported and I believe that to be the case with children as well.  I recommend that you look into such questions with some care but these are not the only issues of justice that you may wish to consider.  One of the major problems of research is the potential injustice that occurs when a benefit is generated for the well-off through a contribution to research made largely by disadvantaged members of society including potentially many children.

Research, as currently conducted, places a minority of persons at risk in order that all, sometimes only the well-off, might benefit, but how the burdens of research involvement, if they are burdens, if they are burdens, a much under-discussed problem, are to — how those burdens are to be distributed across society has never been established in any authoritative code, document, policy or moral theory known to me. 

Nothing in federal policy, to my knowledge, speaks to it.  The notion of equity, commonly invoked in these discussions, is poorly analyzed and even more poorly implemented.  As a result, it remains unclear and controversial when a practice becomes a morally objectionable marginal form of coopting the economically disadvantaged for the benefit of the privileged.  I strongly recommend then, that you do your very best to understand this situation and provide remedies as it is possible for you to do so.  Considerations of justice suggest that society should take a far greater interest in these individuals than it often does, not because they have become or might become research subjects but because of their status as economically disadvantaged and exploitable members of society at many levels.  There are here many unresolved questions.  For example, there are questions about the disproportionate use of the economically disadvantaged, emphasize disproportionate there. 

It may be appropriate to have selection criteria so that the research enterprise does not so frequently use the economically disadvantaged or any vulnerable population for recruitment of subjects and that it set, as a goal, that the percentages of the economically disadvantaged subjects in research be restricted while insuring that research subjects are drawn from suitable diverse populations.  This was a great concern to the National Commission but frankly, we never adequately resolved that problem or, in my view, addressed it.  I'll say something more about that in a minute.

This does not imply that it is always unfair to recruit even heavily from an economically disadvantaged population.  I suggest only that certain patterns of recruitment and enrollment introduce problems of distributive justice.  Diversity in a subject pool might protect against several conditions that might otherwise too easily be tolerated in the research process; for example, that studies would be conducted in dreary, inhospitable and even inhumane environments.  That the same subjects would be repeatedly used in such studies and that a dependency on money would set in so that subjects would become dependent on studies for their livelihood.  A related problem is whether it is problematic for individuals to be repeatedly involved in multiple studies, a problem that presumably would be exacerbated as financial inducements are increased to be involved in those studies.

Let me conclude about this part about justice with this confession to you and that's what it is.  I find it somewhat painful to admit but it needs to be said.  The idea of justice in the Belmont Report and throughout the National Commission's work is deeply under-analyzed.  The problems are not well-developed and the answers are thin.  This is my own personal failure as well as the failing of the Commission and I take full responsibility for it. 

What I am recommending to you is that you take care not to find yourself in the situation I now find myself before you today some years down the road.  These are powerfully important issues and they are difficult ones. 

The third area I want to say something about, informed consent; among the great worries about research at the very heart of what the National Commission did or worries about inadequate or compromised consent, the typical concerns center on whether the consent is adequately informed of whether subjects have the ability to give an informed consent.  I'm not concerned now with the ability to consent.  That won't be where my comments go but rather with the process used in the research context to obtain consent and the ways in which consent can be compromised.

The most frequently mentioned problems of consent in research are concealed data and inadequate discussion with trial participants about risks and inconveniences, a common complaint.  Some practices of obtaining consent are clearly shams, where consent is invalid even if a written consent document exists.  However, there are many more subtle and difficult problems of informed consent, including ways in which information is presented initially and then throughout a clinical trial.  Without appropriate monitoring of consent, even an initially informed and legally valid consent, can become uninformed and invalid at least morally.  I don't want to get here into the business of constructing an appropriate framework for obtaining and gaining consent in research but I do want to appeal to you to keep practices of informed consent at the center of your investigations of research ethics.  The research enterprise and many of its parts still must learn that informed consent, properly so-called is very often not a single event of oral or written consent, but a supervised multi-staged arrangement of disclosure dialogue and permission giving that takes place far beyond the point of adequate oversight of a protocol. 

I am not convinced that this model is deeply embedded in the research system in the United States still today or elsewhere and I recommend that you look carefully at the problem, including issues of consent or perhaps assent as we used to say in the National Commission, by children themselves.  Research that proceeds without a voluntary and informed consent is simply an inexcusable disregard of the right of subjects.

A final comment, I want to say something about the political context of contemporary bioethics since you have to operate in them, in some context of bioethics.  I have a longstanding disagreement with some of even my best friends in bioethics regarding whether or not National Commissions, Advisory Committees, Presidential Councils and the like have been and/or must be political bodies.  Crudely stated, the argument to this goes roughly as follows. 

The political views of Commissions reflect their political appointment sources which always have some political edge to them, whether it be the President or Congress or whatever.  Whenever an issue turns in a political direction, it is reasonably predictable what the outcome will be.  There might be something to this view, especially if it can be made subtle so that it is not cast too broadly.  Discussion of it needs to be placed in historical context and made specific to particular issues, but this can be done by an historically sensitive scholar.  However, I do not, myself, believe that this position is historically accurate or that things need to be in this way as some people have told me they are.

I believe deeply that such a characterization of the appointments to and the deliberations of the National Commission is false to the historical facts.  I believe it is historical imagination getting in the way of real historical understanding.  But now, pertinent to your context here, it is surely good advice that you protect yourself against the possibility of such an interpretation of your work, most especially in the context in which your charge is the protection of the interests of children and research subjects in the United States. 

Few things could be more distasteful even disgraceful than a political arena for such discussions.  I do not believe that Ed Pellegrino would tolerate it for a minute.  Indeed, I do not believe that he would tolerate it in any arena.  The problem here, of course, is that there is, I quite agree, a sort of political dimension to the work that you do.  You can see that clearly emerging right now, for example, in discussions of the TGM-1412 case of the six London Hospital patients so tragically effected by an experiment gone wrong.  This is real human tragedy and what happened in London spanning across four countries has to be sorted through very carefully.

We do not yet know, I believe, what happened here.  It is too early for judgment.  But listen now to the cacophonous voices reaching for judgment and speaking to the press with their opinions.  Look carefully at what has been said by so-called bioethicists and others about this case.  Watch the political jockeying that is every day in the newspaper.  It will pay you dividends to watch this and not to make similar mistakes.

What I am recommending to you is that you take every precaution not to find yourself in a comparable circumstance.  I think that is not as easy as it sounds, although I'm personally pretty confident here about Ed Pellegrino's leadership skills.  So what I've been trying to tell you is how it was at the National Commission and that's the way I deeply believe that it was.  This was not a political body ever.  It was an anguishing grinding struggle over the importance of scientific research and the imperative to protect people from undue risk, but the National Commission left many stones unturned. 

There is a great deal for you to look into  and much hangs on it.  Do it well, indeed, do it excellently.  I'm sorry, I couldn't avoid that last line, given so many Aristotle scholars around the table.  Thank you, Ed.

DR. PELLEGRINO:   Thank you very much, Tom.  Dr. Beauchamp's talk is up to discussion and I have Dr. Gomez-Lobo, Alfonso.

DR.GÓMEZ-LOBO:  Thank you very much, Tom.  That was a very clear and affirmative exposition.  Let me start with an information question.  And it has to do with the following; I was wondering if we're so far away now from Tuskegee and Willowbrook, et cetera, that some of the historical assumptions may have changed.  What I have in mind is this; yesterday, we heard basically from Dr. John Lantos the following and I'm sorry I didn't have a chance to have him give us a broader view of this, but his claim was nowadays that the participation in a research project may not  only not be as risky as it was but even beneficial and his claim was that in pediatric research subjects, that seems to be the proper word, would fair better or did, in fact — do, in fact, fair better than people who might have qualified for the research and didn't.  So there is this presumption that because of the care, because of the concentration of efforts, probably as a result of Belmont Principles, the scene may have changed and I would like to hear more about that as a point of information about what's going on in research.

DR. BEAUCHAMP:   I'm sure things are better and I would like to think they're better because of documents like the Belmont Report.  I would enter a discussion of this with some skepticism about the point of view being quite as sanguine as you just laid it out as being John's view.

I think actually we know very little about this.  How much does anyone know about what actually goes on out there?  We tend to pay attention to things like hospitals, academic research context, clinics and universities.  One of the things that drops out of sight, would be very easy to drop out of sight with you, for example, is corporate America.  Stunningly little discussion of what goes on in corporate America, but there may be — and even in the case of a single CRO, there may be at any one time, as many as 100,000 subjects arranged for by the — at least these are the figures that have been given to me. 

There's a huge number of human subjects involved in the research enterprise in this country.  How much do you actually know about that and I think the answer is relatively little.  I surely hope that things have been made much better in the last 30 years but this is an empirical question.  I can't really answer it, because, I mean, I'm not an empirical scientist.  I haven't empirically studied this and that's the kind of question that I see it.  I think, though, when you see a case like the TGM-1412 study that I just mentioned, you see what can erupt at any time in the research context.  Things can go very badly wrong.  And you may even not be sure why they went so wrong in that context.  So though I'm sure there are many, many studies where people are benefitted by being in the studies and, of course, you can certainly imagine to be not only in the case of the United States but in many other countries as well, I'm sure there are such circumstances.  I would ask — I mean, I would be very reluctant to frame it in that way.

I would ask, yeah, but what about the other circumstances? 

DR. PELLEGRINO:   Peter, Dr. Lawler.

DR. LAWLER:  So I was — to follow up on what Alfonzo said, I was thinking about the happy conclusion that Dr. Lantos gave us yesterday that if you're in a heavily regulated environment you're safer.  So I will be safer later on this afternoon when I'm flying back to Atlanta than I am sitting here right now because then I will be in a more heavily regulated environment.  I mean, there's some truth to this.  The studies do show, so to speak, the safest place you can be in the world is on a plane flying, okay.  But this seemed — I agree, your skepticism concerning this finally, that this doesn't simply resolve the situation so we can now put burden in quotes, "the burden" of being a research subject because it's not really a burden because we should all want to be research subjects.  It couldn't be this simple.  

So if I understood the beginning of your presentation correctly, there is an irreducible conflict between what's best for the individual, what's best for the person, and what's best for scientific research.  There is no way of coherently resolving this on the level of ethics so all you can do is balance it in such a way as to minimize the problem.

DR. BEAUCHAMP:   Be constantly on guard for it, yes, that's right.

DR. LAWLER:  Right, so in other words, there's no coherent ethical resolution to this problem given that both of these interests in isolation are valid, the interests of the individual person and the interest of science to progress which everyone benefits from.

DR. BEAUCHAMP:   Yeah, if I can comment on that critically, I'm often astonished at the literature of bioethics and the attempt to what we sometimes call hierarchically structured principles or something else.  I'm just astonished at the idea that — this is not a knock at you — beneficence should be above everything else or that justice should be above everything else or autonomy above everything else.  It's not the world and never will be.  I'm sorry.

DR. LAWLER:  Right, so that seems very reasonable.  So your concern about justice confuses me a little because —

DR. BEAUCHAMP:   Confuses you?

DR. LAWLER:  Confuses me.  I think lurking in your presentation is this premise, that citizens have a duty to advance scientific research.  That premise must be there because you were against giving incentives to people to participate in scientific research because that then would have too high a proportion of the disadvantage —

DR. BEAUCHAMP:   I'm sorry, I didn't say either of those things actually, but go ahead.

DR. LAWLER:  No, no, the — well, I think you did implicitly because diversity is a goal in terms of subjects.  How exactly would you achieve this given that if you offer incentives, those who are disadvantaged would be more likely to accept the incentives?

DR. BEAUCHAMP:   Well, I have a 30-page unpublished paper on the subject that I will send to you if you would like to see it.  I think it is an extremely difficult problem.  It is way more — there's vast literature on undue inducements and undue influence and that kind of stuff in bioethics, most of which I find so confusing or incomplete that I really don't know quite what to do with it.  And I don't think it's something that we can really get into.

I'd be happy to e-mail with you and, you know, talk about it at some length.  It really is a subtle and difficult problem, more — way more nuance, I think than most people have appreciated but no, I don't hold either of the views that you're attributing to me, that you thought you saw in my talk, sorry.

DR. LAWLER:  Well, then I'm relieved, thank you. 

PROF. GEORGE:  Dr. Beauchamp, I want to take you to those comments that you made at the end on  the — well, really I think you're warning against the vulgar politicization of advisory councils and ethics councils and so forth and I thought your sound and subtle distinction between that and the sense of working in a political environment that was inevitable and not of itself something that needed to be rejected in any way.

A council like ours or any of these councils, our predecessors, other councils does work in a larger environment where there are particular elements of the society who are paying particular attention.  I think in the case of a council like this and our predecessors one is particularly aware of the academic world and particularly the bioethics academics who are interested in the work of the Council, commenting on the work of the Council and so forth and also the media.  I mean, we'll open the newspaper on a given day after a meeting of the Council and you know, there might be a report, something in the Washington Post perhaps, something in the New York Times and so forth. 

Now, plainly you're right, I don't think anybody would disagree that a council like ours really needs to be careful to avoid politicizing itself or being politicized in that vulgar and bad sense. My question is not about that.  It's about the steps that I think you were implicitly urging us to take to avoid not only that vulgar politicization, but the appearance of vulgar politicization.  Now that, too, sounds right to me, since the effective work of the Council depends to some extent not only on doing our job well, but being perceived by opinion shaping elements of the society as doing the job well.

But I would just ask for your reaction to the following thought; it's not as if there are neutral observers standing apart from a political environment and free of political convictions and concerns of their own who are then assessing the question whether the Council is politicized in the vulgar sense or is doing its job well or is doing its job less well than it should because of vulgar politicization.  Rather there are political realities that are describable about the people who are paying attention and writing and seeking to shape opinion.

And my own experience with this Council is that in the end there's very little that you can do that will enable you to avoid an allegation of vulgar politicization where at least as in this case, you're talking about a council whose members are appointed by a President who holds very publicly and defends certain views which are just out of step with major constituencies who are paying attention to the Council and commenting on it in the public media, whether people who are themselves professional pundits and commentators or people who are in the academic world and particularly with the world of bioethics.

Now, I guess I would not suggest that that doesn't mean that the effort should be — that doesn't mean that the effort should not be made, and by the effort I don't mean simply the effort to avoid vulgar politicization, I think there's no doubt that I mean, just as a matter of morality and virtue, that should be avoided.  I'm also saying, I guess, I don't think it means that the effort to avoid the appearance of vulgar politicization shouldn't be made, but I simply have my doubts about how much can be done to avoid that. 

Now, I could go through and cite examples and give you chapter and verse and so forth, but I think you know what I'm talking about and I'm wondering if you just have any reaction to that thought and any concrete advice about whether there are — whether I'm wrong and perhaps there are some steps maybe things that we haven't thought about that could be taken on the appearance question.  Have I made myself clear?

DR. BEAUCHAMP:   Yeah, I guess I'd like a more richly drawn description of — it's almost as if you're saying at one point in your comments you think it's difficult to transcend the political context and I'm wondering, I guess, what the underlying interpretation is there and what you think about that?  Do you think that the context is so political and you have to have arrangements with such and such, the media, with let's say the White House or whatever, such that you're unable to transcend that political — to use the language of neutral observers was it, to become a kind of neutral observer of your own situation and/or the political context?  Am I following you right?  Is your view that strong?

PROF. GEORGE:  I don't — perhaps I haven't made myself clear.  Whatever we do is going to be observed and commented on by people who are interested in it.

DR. BEAUCHAMP:   That's a given.

PROF. GEORGE:  Okay, that's going to be a given.  That is, itself, part of a larger political world, the elements of that commenting society.

DR. BEAUCHAMP:   That's a given, too, but not a world that you have to, so to speak, conform to.  You have to conform to its expectations and —

PROF. GEORGE:  It's certainly true and we haven't.  I think it's fair to say we haven't conformed to anybody's expectations.  The Council has been, you know, quite publicly very divided on many, many issues.  We have managed to achieve sufficient consensus to get out some reports that are valuable but in very many cases, what the reports are doing is not defending a single view, but putting forward the best arguments that we think are available for competing points of view and the reason we're doing that is that those points of view are represented on the Council.

But even those efforts seem not to be able to persuade significant commentators on the work of the Council that the Council is avoiding the kind of vulgar politicization that you're, you know, rightly warning any council against.  And I think that's because people have political views and people have political agendas beyond the — beyond the Council and there's really very little we can do about that.

DR. BEAUCHAMP:   There's nothing you can do about that.  You're stuck with that problem.  I mean, you just have to remain true to what you know are the right values, the right kind of information that you should assemble, be sure you have proper discourse and something that I personally think is very important is not to be in any way intimidated by or unduly influenced by any kind of political constituency and after that, what more could anybody really expect of you?

If people then draw the conclusions that they wish to draw because they have an agenda of some sort or an ideology or whatever, there's nothing you can do about it.  They're free to say whatever they want to say.

PROF. GEORGE:  Yeah, I think that's a good answer and I think it's in a way a very important answer as well, because it strikes me that there is a danger, your last comment really highlights it, that a concern to avoid the appearance of politicization in a certain sort of environment, might very well lead you to take steps that are out of line with your substantive mission to give the best possible advice on bioethical questions that we're facing.  And so, while the concern for the appearance of doing a good job is important, you can't let that deflect you from actually doing a good job.

DR. BEAUCHAMP:   That's right. 

DR. PELLEGRINO:   Dr. Eberstadt and then Dr. Meilaender.

DR. EBERSTADT: Professor Beauchamp, I realize that statistics and quantification may not be your metier but it's —

DR. BEAUCHAMP:   That's for sure.

DR. EBERSTADT: — but it's kind of my thing so let me torture you just a little bit or avoid torture as the case may be.  When we talk about minor increments beyond minimal in terms of acceptable risks for subjects, patients, is there, in practice any sort of literature that would indicate what is taken as acceptable and what is taken as not acceptable risks in practice?  A subsidiary question there.  I thought we had a very illuminating and valuable discussion yesterday about the differences between harms and wrongs. 

I can see how harm is amenable to quantification.  I'm not sure that wrong is amenable to quantification in the same sort of way.  Any thoughts about that?  And finally, just as a general observation, the mortality levels for children in most developed societies are vastly lower than mortality levels for adults.  Does that suggest to people who are looking at the question of minimal acceptable risk for children the standard for children in absolute terms should be a much higher threshold than for adults?

DR. BEAUCHAMP:   A three-part question, I guess.  On minor increase beyond minimal, I would be embarrassed to try to make an answer to your question when one of the world's leading authorities is sitting in the front row back there.  He knows more about this than anybody that I know.  But I will tell you this; it was the view of the National Commission that it was not our job to try to fill in exactly with great precision what that means.  That was the job of the IRB.  That was the whole point of coming up with the conception in the first place, which is to say, if you want to put it, you know, rather negatively, nobody really knows what that means.  It has to be decided at the IRB level in the research context.

On harms and wrongs, it's always been a very important distinction to me. It's a subtle distinction.  I think it's beautifully analyzed in the work of Joel Feinberg, if you want to know sort of where I am on that issue and I guess I would agree with what you said about that. 

And the other was about threshold of —

DR. EBERSTADT: Minor increment beyond minimal, acceptable, minor increment beyond — should there be a stricter standard for children?

DR. BEAUCHAMP:   The way the National Commission went at that was to say we ought to use healthy adult populations first.  Now, is that the right view?  I don't know.  I don't know that that is always the right view.  So to harden that principle may be the wrong way to go.  Still, you've got to see children in most contexts as more vulnerable than a healthy adult capable of consent, knowledgeable about the situation, and so I don't really know what much more to say about it than that.

DR. PELLEGRINO: Gil is next.

DR. LAWLER:  Although his question was literally because children are objectively less vulnerable the standard should be higher.  They're more likely to die just hanging around —

DR. BEAUCHAMP:   That doesn't mean they're less vulnerable, yeah.

DR. PELLEGRINO:   Gil, Dr. Meilaender.

PROF. MEILAENDER: I won't ask anything statistical, so —

DR. BEAUCHAMP:   I wouldn't expect that of you.

PROF. MEILAENDER: — so we're okay on that. 

DR. BEAUCHAMP:   Maybe something Lutheran?           

PROF. MEILAENDER: Not for today, I think.  We'll see what your answer is, you know, and where it takes us.

Two questions.  The first is just a kind of — it may just be a personal curiosity for me but when you were talking about the importance of seeing the Belmont Report embedded historically in a context where the issue was research and so forth, I mean, I don't dispute that but I just have the feeling that there was a sub-text that I was missing in a way.  I mean, after all, there is that well-known book "Principles of Biomedical Ethics" that has some kind of historical relation to the Belmont Report, which —

DR. BEAUCHAMP:   But nothing what people usually think.

PROF. MEILAENDER: Well, but which isn't confined to research ethics, right, and a somewhat similar structure morphs out in a way to deal more broadly.  So I mean, if I was missing something, if there was something really important about locating the Belmont Report in that historical context, I'd just appreciate it if you could say a bit more about why you emphasized that so much.  That's the first thing.

The other sort of less just kind of personal inability to get something, the notion of this sort of unresolvable and irreducible tension between respect for the individual and concern for the well-being of society, and the just sort of inability to get over that, there would be sort of two things I'd say about that.  One, you — when you were talking about it in your talk, you used at one point, I wrote it down, in terms of these several different principles and some constraining others, you used the phrase "balance and specify the moral considerations."  I would have thought that balancing and specifying are not the same thing in the way one goes about dealing with sorting out conflicting principles.  I never — I never know what balancing means actually.  I have some sort of idea what, you know, Henry Richardson means by specification and so forth.

So if you could illuminate the balance metaphor a little bit, I'd like that.  And the other thing is, I don't know why we should necessarily think this tension is irreducible and unresolvable.  It depends a little bit on what you think a person is and what you think a society is and what the relation between the two might be.  And on some views of the relation between the person and society, there wouldn't be — the tension needn't be left to stand.  Certain views might clearly, you know, give primacy to the claims of the individual and the well-being of the society would just have to suffer a bit. 

Other views would think of the person as more a part of a whole, who's good had to be taken up in that.  So the tension is only unresolvable, I think, if one's just kind of willing not to push farther on some what I admit are sort of quasi-metaphysical kinds of questions, but if we push on those questions, we might well get some kind of answer to it or so it seems to me.

And I just wonder if you think I'm mistaken about that or if I'm right but you'd just prefer not to push on those questions or sort of how you come at that.

DR. BEAUCHAMP:   Well, that's a heck of a set of questions.  It would take a lifetime to get to all of those adequately but let me say something about it.  The main point that I wish to make about the three principles is that in order to understand those principles and what is the meaning of those principles, it has to be understood in the historical context.  It cannot be understood in any other way, I believe, and understand that because it's been presented as a framework of principles.  Understand that framework of principles requires a historical understanding.  Of course, you could take respect for persons, do what a lot of people do, which is to give it say a Kantian spin or a Kantian interpretation.  This is most certainly what the National Commission did not do.  In fact, I tried that with the National Commission.  I tried to explicate Kant and build it into the document.  They said, "We don't want that.  We want plain talk so that the entire American public understands it."  So that really the larger point that I was making is that that framework is a historical framework. 

If you don't understand it in its origins, you just abstract it out and you say, "Well, here's what respect for persons means," and then you go and you read Ed Pellegrino and you say, "Well, this is what beneficence means," and then you go and read Jack Rawls or something like that about "This is what justice means."  You just won't get it.  Right, you don't understand what's going on.  Moreover, there's been a tremendous amount of confusion of the very sort that you elude to, which is between the principles of biomedical ethics and the principles that are present in the Belmont Report.  People are so confused then that what they've done is to interlock the frameworks.  Of course, they don't interlock, they're incoherent actually.  So those are the kind of concerns that were in the back of my mind.  I've taken a long time to sort of unravel that.

On balancing and specifying, it's a hard question.  I've struggled with this.  I've argued with Henry Richardson about it.  I have argued with David DeGrazia about it.  I have argued with Jim Childers about it.  It is a difficult problem.  I agree with you.  I can tell you Jim Childers agrees strongly with what you were saying but it's not easy to get out and the reason it's not easy to get out is because you get more and more into the theory of what happens with specification and it looks more and more like you're balancing.  That's the logic of the problem.

In simple terms, I think of it in this way; it think balancing occurs in judgments that are made in specific context and it is something that we have to do and we don't have time to specify, we don't have time to think about the consequences and the implications of the kind of thing that goes on in specification.  We have to make judgments and we do the best that we can to balance the different considerations that are present in that context.

Specifying, I think of largely in a policy context.  We are able to sit back and think and figure out well, what if this and what if that and what if the other thing and try to articulate what the policy would be under those different contingencies.  But it's — I think it's a deep problem and I most certainly don't think that I've resolved all the questions.

Now, metaphysical questions; gee, I'm really reluctant to say anything with Alfonso in the same room with me.  It might come as a surprise to you  to know that most of my own teaching career has dealt with metaphysical questions.  These among them, but many other metaphysical questions as well of the sort that say Alfonso and I would deeply share.  So I have the deepest kind of respect for pushing in the direction of metaphysical questions.  At the same time, the most influential philosopher on me, and I don't know on Alfonso, but the most influential philosopher on me is David Hume.   And Hume asks you to approach metaphysical questions with a certain — a certain carefully edged skepticism and I do.  I am very skeptical to go directly to the concept that you mentioned which is a concept of person.  I'm very skeptical that that concept can be explicated, theorized about, and presented in a way that resolve, I think, exactly the kind of questions that you're talking about. 

Now, there may be other ways to go at those questions but I am very skeptical that metaphysics persons will do it.  That's another long paper as to, you know, what the skepticism is and how it would be manifest, but it's the long and the short, I think, of the answer.  I don't discourage anybody ever from engaging in metaphysical thought.  Just understand that it may have limits.  It may have deep and sharp limits and not be able to get you, especially in the area of ethics, to the conclusions that you want to reach.

Is that okay, Alfonso, or am I making a fool of myself? 

DR.GÓMEZ-LOBO:  I think the key metaphysical issue is the issue of community rather a common good rather than persons in Gil's question, if I understood it correctly, right?

PROF. MEILAENDER: I would have said the relation between the human being and the community.  I mean, on a type of person of language here, actually I should prefer human being language, but one might find arguments suggesting — actually, we could find some in Luther by the way, but I won't trot them out right now, suggesting that there's a sense in which the human being transcends the community and cannot be understood to the whole extent of his or her being to be a part of that community.  That kind of approach might begin to suggest a certain way to resolve the tension and not leave it unresolvable, for instance. I mean, it's just an example, so I would have said that what I had in mind was, yes, it is community but it is the relation between the human being and the community and how to understand that but it does seem to me that different ways of understanding that might lead to different resolutions of this tension rather than just leaving it to stand alone.  That doesn't mean it will persuade everyone but I never worried about that.

DR. PELLEGRINO:   Dr. Hurlbut and then Dr. Kass.

DR. HURLBUT:  Why don't you go first?

DR. KASS:  Just a couple of comments and then a question, just sort of try again on something that was in Gil's — part of Gil's question.  I appreciate the historical context of Belmont Principles.  That's a very valuable addition to our consideration.  I also share — sympathize with your frustration about how a careful piece of work has been misunderstood, confused by others and abused.  It's an occupational hazard.

DR. BEAUCHAMP:   We all have our sensitivities.

DR. KASS:  And you can fill in the blanks as to why I and members of this Council might have some sympathy for that concern.  We are in part responsible for the way in which we are misunderstood and in the field of bioethics generally the Belmont Principles, not by us primarily but by many people, have been taken, expanded and used beyond the research context and there are also people who try to push almost all kinds of ethical questions into the research analogy.  So — but I think — I mean, on balance, I think this is a very valuable revisiting and clarification of what those principles are about.

Second, I appreciate that the principles are intended not as a licensing of a simple utilitarian approach to research with human subjects but in fact, to introduce non-utilitarian considerations.  I appreciate that but I think part of the reason why the charge that this is somehow in the service of utilitarian, of a utilitarian consideration in the end, comes through the balancing — through the metaphor of the balance.  The metaphor of the balance presupposes commensurables, presupposes some kind of measure, presupposes an adjudication amongst competing goods, but the — you don't balance the right against the good on the same scale if there really is such a thing as the right. 

And there are people who think that there are certain kinds of inviolable — that there are certain kinds of conduct that simply should not be done and cannot be balanced, this would be an argument, cannot be balanced by certain considerations of social good or what have you.  So I guess I wonder — I wonder really about the sort of underpinning of this notion of the need to balance and whether that doesn't finally contribute to a view which will eventually lean harder and harder against those kinds of restraints in the name of the good and in which you don't sort of say no matter how much good comes from this, this is — you're somehow traducing something deeply important about human beings.

I didn't put that very well, Tom, but I think you get the gist of what I'm talking about.

DR. BEAUCHAMP:   Leon, you always put things well.  I think that the essence of that last part which might be the most important part is about what I've referenced in the language of the paper as  deontological constraints.

DR. HURLBUT:  Right.

DR. BEAUCHAMP:   This is maybe, maybe the most important discussion and philosophy of the 20th and 21st Century as ethical theory unfolded.  And I would be very, very reluctant to try to say anything about how you resolve it.  I do not think it is a simple question and no one has ever convinced me that there are clear deontological constraints that one must follow wherever they take you irrespective of the consequences and that's where the balancing will come back in.  As the consequences are upped and frankly, as what might be at stake under the rubric of these deontological constraints are reduced, there may come a point where you say, "Well, even though ordinarily it would be very wrong to do this, in this case I think it is the right thing to do."

Now, I know these are very abstract notions and philosophers divide heavily over this.  I do think the notion of a deontological constraint is a terribly important one and you could probably tell that that's the way I'm representing how I understood the National Commission as putting forward views about justice and respect for persons as precisely as deontological constraints.  I don't know how to push harder on that without getting deeply into Thomas Nagle's theory of this and that sort of thing, which I don't think would be the right way for us to go.

DR. KASS:  Could I just a small thought?  Let's assume that there are constraints which are not always but for the most part, and that you might imagine yourself saying that, you know, the rule against adultery is more or less absolute but if it's necessary to provide an heir to Queen Elizabeth I to avoid civil war, we make an exception, et cetera.

But would you then be thinking of what you're doing under the metaphor of balancing?  I mean, are you sort of creating a — or is the very notion of balance a kind of homogenization of the various considerations such that you can get them on —

DR. BEAUCHAMP:   Yes, I would think what you're doing is balancing.  The problem there is you have to articulate some kind of an account of what it is to balance and what it is that are the balancing considerations in these cases.  Yes, I think that's in part what you're talking about exceptive case kind of circumstances or counter-examples or something like that and playing that game, which I personally think is a very important game or strategy or whatever in moral theory, I believe it inherently involves you in balancing considerations all along the way.  You can't ultimately escape them.

PROF. GEORGE:  Could I follow up very briefly on this, just to get clear on the distinction between specification and balancing?  I can understand, we could argue it every step of the way but I can make sense of the idea that it's specification at work when we move, for example, from the principle of respect for persons to the norm against direct killing of the innocent.  It also strikes me as pretty clear that what we're doing is specifying when we move from the norm against direct killing of the innocent to the principle of noncombatant immunity even in justified wars. 

Then if we get into a debate about exceptions to the principle of noncombatant immunity, I can understand how that would be a debate between people who say, "Well, you can't balance a principle like noncombatant immunity off against other considerations," you know, even prevailing against a wicked enemy and so forth and so on, and how other people would argue, no, no, there you do have to balance.  I mean, noncombatant immunity is for the most part and usually but there comes a point at which. 

But I thought that at one point you were saying that the idea of specification itself becomes problematic, so that in moving from say — now these are my examples, not yours obviously, from respect of persons to no direct killing of the innocent or from no direct killing of the innocent to noncombatant immunity, what looks like specification does, itself, even there involve balancing.

DR. BEAUCHAMP:   That's right.  It may be very hard for you to articulate — I mean, specification is progressive specification in the way in which I believe you are suggesting.  So as you progressively specify, render the principle or the norm more and more specific, it may be impossible to do that without bringing balancing considerations into the focus of what you're doing, at the very base of what you're doing.  That's what I was suggesting.

PROF. GEORGE:  Okay, I mean, I understand the position.  I would want to argue against it.  It would be an interesting argument there.

DR. BEAUCHAMP:   Yeah, these are hardly settled matters.

DR. PELLEGRINO:   Dr. Hurlbut?

DR. HURLBUT:  Several times you mentioned the questions and problems associated with international considerations and I just wanted to generalize this discussion a little bit to a few practical and theoretical problems just to get your insight from your experience, a reflection on these kinds of problems.  The Belmont Report is, by its own admission, your writings, provides general guiding ideals and sort of a general analytic framework for reflection and it seems to me that at the best, that will work well within a context where there's a certain cultural center of gravity to draw your thinking down to consensus. 

But now we're facing the strange problem of what you might call the outsourcing of ethics, a troubling dilemma of not just US scientists being lured overseas to do work that is proscribed in the United States, but also the hints of corporate commercial interest by outsourcing clinical trials and so forth.  And I think there's a really big problem brewing here and the problem is exacerbated by our own inability to find tangible kind of structure or skeleton to our own ethical thinking. 

I know it's a vague question but I'd just like your reflections on this.  It seems to me the three major zones where we are going to have to face up to some difficult dilemmas and the first one is the one that's the least troubling and the most troubling to me, it's the question of when you have a possibility of doing a clinical study in a population that is so wracked by disease and so under-served that you may be bringing the only medical care they have to the community, the only supervision.  You know what I'm talking about.


DR. HURLBUT:  So that's one thing.  And especially with regard to children, you can imagine that you could do both a lot of good and a lot of harm in that context but then there are the practical problems associated with competitive commercial advantages, but overarching all of this is the more metaphysical concern with the question of pluralism and I just would like your — I know that's another very big set of questions but can you give us some reflections on those concerns?

DR. BEAUCHAMP:   Tell me what worries you the most about them.  Is it competitive commercial concerns or what worries you?

DR. HURLBUT:  Well, I'm not accusing anybody of anything in saying this —

DR. BEAUCHAMP:   No, I understand that.

DR. HURLBUT:  — but I'm worried that if one country has different standards for what's acceptable practice and research ethics that they can test drugs more quickly and more efficiently on poor human subjects, unhappy situations.  There are rumors of such things and I'm not saying they're true, but if it's true that drugs are being tested on prisoners of in orphanages for example, that would provide a very troubling foundation.  It would be a very efficient foundation for later testing in above board transparent ways and it might increase the efficiency of your success in filtering drugs, but it wouldn't be good for human dignity and it wouldn't be good for individuals who are subjected to it.

And likewise, I can imagine situations where scientists go places where they're allowed to do things and I mean, we're now arguing in this country over the stem cell issue and the 14-day limit on the use of embryos but there might very well, I'm not saying any of our scientists want to do this, I'm not making any accusations, but there might very well be some people somewhere who want to use embryos later than 14 days if it could be done and it probably can be done technically some time.  So, I mean, from a purely scientific standpoint, we would both want to know the science of embryo genesis after 14 days, plus it might turn out to be an efficient way to get cells, more advanced cells, tissues and organs for therapeutic use. 

So I just — I know this is a very vague question, but it worries me a great deal that we're now becoming a global civilization.  We're gravitating toward a globally standard material culture, but we don't seem to be able to find a moral culture of similar — of a similar uniformity. 

DR. BEAUCHAMP:   I guess I think what you are doing is rightly placing on your own shoulders a  certain responsibility for creating such a moral environment because major public policy groups or bodies such as your own really do have that responsibility.  I think it's built into the fabric of what you do.  You started, I think, with the international domain.  Let me first say that Bob Levine is one of the most distinguished figures in the world in international research ethics and again, I'm sort of reluctant to move into territory where he knows so much more than I do and he's sitting in the front row here.

But I've watched some of these things and been to some of these places and I've come increasingly to the view that there are a lot of American biases that — American biases, that's not — some are American biases and some are biases that come from institutions and so on that we should be careful about. 

For example, a lot of people seem to reflect in conversations I've had with them, the view that well, of course the United States, we're very careful about human subjects and we have such a great health care system that will back up anything that goes wrong, and so on and so on.  And in these other countries, well, of course, they don't — I'm not so convinced about that, that that's just even factually the case, that the healthcare systems in many, many, many countries in which the research is done quite as bad, and in fact, might be even better in some cases than the opportunities that we can provide them in this country.

So when you go to disadvantaged populations, there are disadvantaged populations in virtually almost every country of the world, I wouldn't leave the United States out.  I wouldn't be so worried about say a population in China or India or something like that thinking that somehow inherently they're more disadvantaged than populations here.  I worry about them in all of these places and what happens.

Another bias that has disturbed me over the years and might deserve a little bit of reflection on your part does come through your language of competitive commercial, I believe was the wording that you used.  My own view, for what it's worth, I just give it to you for what it's worth, is that people who come from universities have a deep bias in thinking that, of course, their work is completely free of bias and so on when they do research and so on.  And then there are these commercial interests where things get out of hand.  Is this sort of, should I say hubris, Leon, would that be the right word to use in this context?  It's certainly a kind of presumption here that I've personally not found to be borne out.

I should have to tell you, I was not raised in an academic home or environment.  I was the son of a CEO of a healthcare corporation, a non-profit one, but that was the way in which I was raised and I came to deeply respect that culture.  Now, things do get out of control, but they also, I think, also in our academic work and the research that we do, things can spiral out of control and we can misuse populations and so on.  So I would be careful in understanding the context, careful in what your expectations are for certain groups and the like, but I don't have any cosmic solutions to these problems.  They are not atypical, just a lot more complicated, I think, than people usually think they are.

I certainly do think that your reservations are well-taken.  I guess I would just try to broaden them, contexturalize them a little bit.

DR. HURLBUT:  I certainly think that the issue of commercial competition has its parallel at the level of individual ambition for which academics as well as other human beings are vulnerable.

DR. BEAUCHAMP:   Exactly.

DR. HURLBUT:  But still, and I wasn't even accusing commercial interests from our country to export their problems or outsource their ethics, I was just saying that regardless of who the originating source is for the decisions to do research of a certain type on — say on children, you can see how unless you — when you dispense with ethical concerns, you can do — you probably could do science and biomedical science particularly more quickly and efficiently but that's — the whole point of ethics is to put into the equation the more fundamental concern that to my mind has primacy actually, the protection of —

DR. BEAUCHAMP:   I couldn't agree with you more.  Sometimes that gets a little out of control.  We think ethics always has primacy over everything else.  I'm not so convinced that's true, but, yes, there is kind of a basic primacy to —

DR. HURLBUT:  Well, if you see ethics in a broader context rather than just the frosting on the cake, but the very substance of the cake itself, the thing that knits the pieces together, the coherence of life, then it's — then it does trump everything else because without it, you have nothing.

DR. PELLEGRINO:   Dr. Foster?

DR. FOSTER:  I'll be very brief, I know we're at break time.  I'm concerned about two things, Tom, about the practical things that you've talked about.  It's certainly is clear.  I've read the Belmont Report and all of those things and I get different insights from what you've said and the problems, you've hinted that there's sort of a loss of understanding about many of these problems of human research.

And I should say, I've never done human research.  I mean, the most sophisticated animal I ever worked with was you know, a mouse or a rat, you know, or something, so I don't do this kind of research.  But there is a huge increase in — with the NIH emphasis on translational research.  You're going to see more and more human research coming along which means more and more problems we have to say.  And we don't — in the first place about the risk; in 2004 there were 550,000 papers published in the 4,000 journals at the National Library of Medicine archives.  Okay, that's one paper a minute, okay, just to keep up with risk.

I saw something this week that in all my life I have never seen and there are three cases in the literature of something that's such a common disease that every physician knows about it and it comes up, I mean, you can't predict always what risks are going to happen even with the Internet.  So people who work on these things have a huge burden to try to comprehend — let's say only one out of 1,000 of those papers are important, that's still 500 major papers you have to learn about and so forth.

So there's not much time to spend on learning more about deep ethics and so forth.  I mean, I don't understand a lot of the dialogue that goes between — you know, about specification and all these  things, you know, and I don't think the thousands of people who are actually doing the research and the IRBs on which they serve have the slightest inclination to study in deep detail the sort of things that would be very important to you and to other ethicists as a discipline which should be but in terms of just running a clinical trial, I mean, it's not possible to do the sort of informed consent that you have described that's ongoing, reaching in great detail.  Many times people can't understand the simplest thing. 

If you've ever tried to talk to a very sophisticated professor of medicine and get them to take a drug that they need desperately, like a statin or something like that, and they've read the PDR and they've read every possible negative thing that can happen and you can't get them to, you know, give consent to do that.  How am I going to do that to somebody who's got a grade school education?  You know, I mean, so there's the problem in — there's a problem in carrying out this research is that there's not an inclination or the time for either all the knowledge — I mean, you have to try to do it.  I mean, one of the things I know a lot about is diabetes. 

I can't keep up with just the papers on diabetes mellitus, you know, that go on.  So the question I want to ask to you, isn't it sort of unreasonable to say, as we've heard in some of these things, that we need to deepen, broaden the time and  intellectual expenses in trying to do things more perfectly and more in accord with what the wonderful report Belmont meant?  I mean, is that really possible?  I can tell you very frankly as a chairman of medicine who deals with people who do all these things all the time, I think that's absolutely impossible and unrealistic and one of the thrusts we heard yesterday, we need to try to diminish the safeguards that are coming up with the IRBs in order to get a better assessment of what the true problems are.  That's — and I don't want you to answer much about that except — because the time is up, but that's what really worries me.  It's in seeing people who are actually doing all these things and on occasion you get heinous mistakes and some of them are deliberate, you know, that people have done wrong things but I don't know how — I don't think we're going to have a discussion in IRBs like we've had here this morning.  I just don't think there's a chance in the world that that will happen.

DR. BEAUCHAMP:   Dan, I don't have much to say about that.  I agree with you wholly and completely.  You are a — you're still a Donald Seldon Professor of Medicine; is that right?

DR. FOSTER:  Sixteen years and I've passed that on.

DR. BEAUCHAMP:   You've passed that on, okay.  Well, let me say there are only a few Donald Seldons.  Donald Seldon, for those of you who don't know him, is one of the great Professors of Medicine of our time, Dan's predecessor and he has the capacity to consume all of this literature and process it, but he is just about the only person I have ever known in my life who can do so.  I agree with you wholly and completely, and therefore, the system has to find some accommodations and it has to be streamlined in certain ways.

One of the things that we looked at when I was on the Institute of Medicine Committee looking at responsible research, was how do you take what is clearly a broken backed system, the IRB system, and try to reduce the workload to straighten it out so it can do its work properly.  That in itself is just a huge, huge chore and so what you've got here is you very nicely lay out the tip of an iceberg that we have to deal with. 

DR. PELLEGRINO:   Dr. George.

DR.GÓMEZ-LOBO:  Can I make a — sorry, thank you.  Just a quick remark, but isn't that precisely the reason to have something like distribution of labor?

DR. BEAUCHAMP:   Absolutely, absolutely.

DR.GÓMEZ-LOBO:  Because of course, the clinical physician, of course, can't do all of this but there has to be someone thinking through these problems it seems to me.

DR. BEAUCHAMP:   No, no, let me give you an example.  One of the things that we talk about a lot at the Institute of Medicine was the problem of conflict of interest by contrast to the work of IRBs.  Quite a few institutions throw several kinds of conflict of interest onto the IRB.  The IRB should not deal with conflict of interest.  That should all be handled, done and over with before they even begin to process things.  In other words, you should have a separate conflict of interest committee.

Now, I personally think that conflict of interest is a deeply under-analyzed notion not well attended to particularly non-potential conflicts of interest.  That, then becomes itself — can become itself a major preoccupation.  Most certainly IRBs in my view should be shielded from it.  So yeah, of course, I'm going to agree with you.

DR. PELLEGRINO:   Dr. George?

PROF. GEORGE:  Yes, I've been —

DR. PELLEGRINO:   Last comment.

PROF. GEORGE:  Yeah, and thank you for the third opportunity.  Sorry to take us beyond the limit but just I'll try to do this quickly because Dr. Beauchamp's comments as I've been reflecting on them brought a question to my mind about how we think about the common good and how we think about what you've been referring to as deontological constraints.  

In professional bioethics, I think a lot of people conceive of the common good or social benefit in utilitarian terms.  So they think that there's a common good and they've got a conception of the common good and that conception is a utilitarian conception.  Now, for bioethicists for whom that is just part of a larger or more comprehensive utilitarian approach to ethics and to life, that's the end of the story.  But there are other people in professional bioethics who aren't satisfied with the utilitarian story as a comprehensive approach to ethics and, therefore, they see a need for constraints on thinking of things in utilitarian terms and ordinarily those constraints are matters of protecting individuals who could be sacrificed in a way that would be unethical for the sake of the common good where the common good is conceived in utilitarian terms and where they're prepared to conceive the common good in utilitarian terms.

And then you have a debate between utilitarians and non-utilitarians.  But of course, there are alternatives to thinking of the common good in utilitarian terms.  I mean, there could be, for example, a purely deontological theory.  I think it would be problematic.  There's no doubt about that, it would be problematic but there could be such a way to try to solve the problem that you've identified as the problem that nobody has solved and probably nobody will solve, thinking about individual interests and the common good.

But in addition to that option, there is the kind of conception of the common good, I would say a non-utilitarian conception of the common good, that's part of a longer tradition, you know, going well back before the great founders of utilitarianism, and which still has very articulate exponents today, I mean, some in this room like Gil and Leon and Alfonso.  I mean, the way their thinking and I, myself, try to think about the common good is to begin with a non-utilitarian conception of it and on such a conception, rightly or wrongly, there may be all sorts of problems with this, but on that sort of conception, what you are talking about and what a lot of professional bioethicists talk about in terms of deontological constraints on the pursuit of the common good, are really conceived as aspects of the common good.  So there's not a contrasting of individual interests or rights with the common good, so we would never think with Ronald Dworkin in terms of rights being trumps on the pursuit of the common good conceived in utilitarian terms.

But rather we would see those individual interests, there's... one might even say individual rights, as aspects of the common good itself.  So that there's an attempt, at least at seeing individual interests and the social good in more of a harmony and when we would restrain ourselves from certain courses of action that might otherwise be regarded as ways of advancing the common good, we wouldn't be, even on our own understanding, sacrificing the common good for the sake of deontological constraints or the individual or individual rights.  We would be pursuing the common good, because the common good itself included a concern for the dignity and worth and rights and welfare of the individual.

DR. BEAUCHAMP:   I think I agree with you completely.  Let me only add that sometimes you find your situation is one of strange bedfellows.  And it should come as no surprise here, I believe, that that's so.  My own greatest teacher in philosophy, including in matters of this sort was David Hume and  Hume's fundamental commitment was to the common good.  But the moral theory doesn't really turn on the common good.  The moral theory unlike what many people have said about him turns actually on the theory of the virtues.  And so what's buttressing and supporting the over-arching view of what is in the common good is that ethics originates only in the bosom of a conception of common good as fostered in a society is the importance of virtue.

Now, the funny thing there is so many people have interpreted Hume as a utilitarian.  I personally think that's a difficult interpretation to get out of him, but what you're saying could easily be explicated along the lines of Hume's view.  What you're saying could easily also be explicated along the lines of John Stuart Mill's view in many ways.  One possible way to understand Mill is his doing exactly what you just laid out.  Now what a lot of people want to say, "Oh, yes, but he contradicts himself along the way.  He screws up." 

Well, maybe he did.  Maybe he did, but I think he has in his philosophy in mind exactly the objectives that you have in mind and by the way, sometimes when I hear Edmund talk about beneficence and the common good, it sounds an awful lot like Mill to me, talk about strange bedfellows.  But that's at any rate — I mean, we need to frame these things in terms of what people really held and what these frameworks are in a broad way committed to.

PROF. GEORGE:  Yeah, I take your point actually about Mill.  I remember reading years ago when I was doing my own doctoral work, a very interesting book by John Gray, one of John Gray's early works trying to harmonize the Mill of "On Liberty" with the Mill of "Utilitarianism."

DR. BEAUCHAMP:   Yeah, that's exactly what you have to do, yes.

PROF. GEORGE:  Yeah, and I thought it was actually a persuasive case.

DR. PELLEGRINO:   Thank you very much, Tom, and the commentators.  We're a little bit overtime so that we'll have our break and return at 10:30.

(A brief recess was taken at 10:12 a.m.)

(On the record at 10:35 a.m.)


DR. PELLEGRINO:   This session, this last session of the morning, will be a little bit different.  This is the first time we're trying something of this order and we'll invite your participation.  I'm speaking to the members of the Council.  In fact, the emphasis will be on your continued participation.  I'm very pleased with the way the Council has taken part in every discussion and we fill every moment of time with their discussion, which I think is crucial and important and relevant.

But we've asked Dr. Bob Levine to present a case, maybe our clinical colors are beginning to show but I think you may find this a very interesting way to look at some of the problems we've been cogitating over the last several days in a particular circumstance.  And while bioethical issues must rise above individual's general perceptions and concepts, nonetheless, they come back to individuals and this is the final point.  It's really the moment of truth to see how a principle or a rule or a policy effects the person who is ill or the person who is a subject, how it effects individual human beings. 

Forgive me for that interest as a clinician.  I hope you'll find that it is not irrelevant to the larger issues we've been discussing.

So Bob is going to present a case and then he's going to involve the Council members and then make some comments and if I can restrain myself, I will not make too many, but I probably will make a footnote here and there.  I've been practicing restraint in the interests of maintaining a little bit of neutrality.  Bob.

DR. LEVINE:  Thank you very much, Ed.  Here I am again.  I thought the first half of this morning was a very interesting and important discussion and when Tom Beauchamp said that he and I speak as if with one voice, I thought, "Don't I wish?"  The case that you have in front of you, Ed has asked me to just go through it, not read the whole case to you but go through it to pick up on some of the important points and then to turn this over to you for discussion.

This is a case that was published in the IRB Journal about 15 or so years ago.  In the publication, which is footnoted at the end of the second page, in case you want to read the full case, there's a careful analysis of the ethical issues.  When I recommended this case to Dan Davis, he decided to use it and I want to congratulate Dan and Ginger Gruters for a very skillful job of restoring this case to its original position, that is in the form that it was presented to the IRB rather than after the IRB did its work and wrote its interesting ethical analysis.  So I congratulate and thank them.

I think one of the interesting things about presenting a case is that some of you are clinical scientists who probably have complained about all of the things the IRB has asked you to be responsive to.  It's my experience, though, that when we all get together and review a case as if we were an IRB, you will find emerging from your respected colleagues some of the things you've been complaining about that the IRB was doing.

Without further ado, I will get into this.  The study is a proposal to investigation mechanisms of diabetic instability in children.  The study uses techniques that are very well-tested and have been used extensively and safely, but in adults.  The study requires — well, first, it's necessary to look at young people.  Yes, sir.

DR.GÓMEZ-LOBO:  Could you define diabetic instability for the lay person?

DR. LEVINE:  I don't dare with you sitting next to Dr. Foster.

DR. FOSTER:  It's difficulty in controlling the blood sugar.

DR. LEVINE:  Thank you.  They want to look at very young subjects.  They want to see if there are any changes that are related to the changes at puberty.  So it's important for them to look at children from the age of about eight until about the age of 18.  This is quite a span.  The studies will involve diabetic children, children with unstable diabetes, insulin dependent diabetes and it will also involve their siblings.  Siblings are designed to give them normal control information. 

They justify involving the siblings because according to the regulations, if you want to do studies of this sort, you must be developing information that's responsive to the condition or disorder that the child subjects have.  And they define the condition or disorder as being situated genetically as having about a 25 percent risk of developing diabetes themselves.  This distinguishes them from the mainstream of normal children.

They recognize that this is a compromise, that siblings who are somehow genetically pre-disposed to develop diabetes might have some abnormalities of glucose metabolism but they felt this was the best they could do.  The studies involve a 48-hour admission to the hospital for each child.  The first day they will have a 24-hour profile of blood hormone levels and this requires the insertion of an intravenous cannula, a small plastic tube put in their vein and then they can periodically attach a syringe to that tube and pull back a little bit of blood.

On the second day, they plan a four-hour hormone sensitivity test.  For the clinicians here, the test is called a glucose clamp or a hyperglycemic clamp procedure.  The procedure will require that the child be immobilized in bed for four hours with his or her arm on a board, taped to a board to keep the elbow from flexing.  In this way they can continuously monitor blood levels of sugar and insulin. 

There was concern, not so much, for the risk of physical injury.  The probability of a physical injury in this procedure is vanishingly small.  What they are concerned more about is the possible emotional effects on the child, what is the  meaning of a child, of taking him or her into the hospital for an overnight stay?  What is the meaning for a child to be confined to bed with the arm extended and an intravenous cannula in place with infusion of — actually, during the hyperglycemic clamp procedure, two intravenous cannulas; one to put things in and one to take things out?

I think what I've done — oh, according to the investigator's initial assessment, the diabetic children were accustomed to being in hospitals.  For some it was an unpleasant experience and for some it was a pleasant experience, but they certainly would understand that invitation to spend time in a hospital and have the arm extended and so on.  They would be very well situated to give a knowledgeable consent or assent or refusal.  The siblings, generally, had never been in a hospital before.  And so they might not be able to really appreciate what was in store when they were asked for their assent.  The parents were going to be encouraged to attend any and all parts of the child's admission in the studies.

They were going to make determined attempts to keep the patients entertained during the infusion study, providing them with books and even having somebody turn the pages for the child or DVDs or movies or whatever, video tapes.  So that's the case.  I would like to now turn it over to you to see what you think might be the major issues in deciding whether or not you will approve or disapprove this research activity.

DR. EBERSTADT: Could I ask two questions for clarification?  Are the children to be immobilized just for — the arms immobilized just for the four-hour second intervention or is this 48-hours of immobilization?

DR. LEVINE:  No, no, no, four hours of immobilization.

DR. EBERSTADT: And the second question of clarification; are the parents — the parents are invited to be — participate in all this.  Does that mean the parents could stay overnight, for example?


DR. EBERSTADT: I see, thank you.

DR. LEVINE:  And they can — the parents would also be put on notice that in case they think the child is experiencing anxiety or discomfort that they have the authority to put a stop to the study of their child.  Yes, sir.

PROF. MEILAENDER: Also, just a question of clarification.  It says right at the start and you mentioned it that the techniques that they're studying are well-tested and have been used extensively in adults.  How were they developed for use in adults?

DR. LEVINE:  May I once again defer to Dr. Foster.

DR. FOSTER:  I haven't read the whole thing but — you'd think after four and a half years I'd learn to turn on the light, but I've always been a little slow, so — the glucose clamps, I am a little puzzled as to why they wanted to do this particular — the hyperglycemic clamp, if that's what Bob said they're doing is you raise the blood sugar to a given level, and they're infusing insulin and the sugar to keep it at a fixed level and probably looking at hormonal responses during this period.  So it's just like having an IV in the hospital.  I mean, there's no risk at all. 

I mean, you know, you may get a bruise if you — you know, from putting the needle in but there's really not anything there at all.  This is usually — the hyperglycemic and insulin infusion clamps are usually used to assess insulin resistance.  In other words, if you infuse insulin and you have to infuse more glucose in one patient to keep the blood sugar that the fixed level than you do with another, it means that the one that you had to use more insulin for was resistant to the action of the insulin.

So usually, this is a measure of how well insulin is working in the intact human.  So that's — and then I don't know what else they were going to measure in the test, what other hormones and so forth.  So does that answer your question?

PROF. MEILAENDER: Well, what I really want to know was when these techniques that they're now going to be testing on children were developed to use in adults, were they developed through the use of controlled trials analogous to this one or were they developed more retrospectively through, you know, treating diabetic patients and learning how to do it and so forth?

DR. LEVINE:  No, this is not a matter of treatment.  This is a matter of studying basic physiology.  When they do it on normal or, I don't know if we can really define what normal is, when they do it on people who have no known disease, they're studying basic physiology of carbohydrate metabolism.  When they do it on people who are diabetics, they're still looking at basic physiology.  In most studies of physiology, you would want to have a simultaneous control population.  With adults it's easy.  They tack up a sign on the campus bulletin board and see who walks in, often a lot of students.

DR. FOSTER:  I've been gone for so long, I don't even remember when the first studies were done, but I'm sure that they did exactly that when they started off.  I mean, it's such — in the language we've used before, it's a minor increase risk of doing nothing, you know, I mean —

DR. PELLEGRINO:   Dr. George?

PROF. GEORGE:  Do I interpret this correctly under subjects and controls as saying that the subjects in the experiments will all be either diabetic children or their siblings or any relatives?  So there will be no going beyond that pool of people?

DR. LEVINE:  I also learn slow.  We are not going beyond — actually, the way it ultimately turned out, they narrowed it even further to use only siblings.

PROF. GEORGE:  Only siblings, okay.  And no one is being compensated for their participation in this in any way.

DR. LEVINE:  No one is getting paid.  The parents might be given a bit of money to cover their taxi fare or babysitter fees or something of that sort.


DR. PELLEGRINO:   Peter, Dr. Lawler.

DR. LAWLER:  So the premise of this is these relatives would have a higher, much higher than normal chance of getting diabetes themselves, so they would stand a chance of benefitting from the results of this study. 

DR. LEVINE:  That's the premise.

DR. LAWLER:  But —

MALE PARTICIPANT:  Is it stated?

DR. LEVINE:  It's here, yes.

DR. LAWLER:  But it seems to me there are many problems with that, including this.  Presumably, the purpose of the study would be to figure out better how to treat diabetes around puberty, right?

DR. LEVINE:  Let me clarify that.  They're not trying to figure out how to treat anything. They're trying to get — contribute to the basic fund of information of how do diabetic children metabolize carbohydrates?  What is their hormonal response to maintaining a constant high blood sugar level and do any of these things change during and after puberty.  Now, based on this information — I mean, we did studies.  I used to do studies.  We do studies all the time that are attempting to get basic information with no particular vision of how that information might be used in the future to better treat or diagnose diabetic children, but very often it does lay the ground for some new understanding and it very often — it may contribute to an improved diagnostic ability or therapeutic ability. 

DR. LAWLER:  So it's unlikely these particular children who are participating in this study would actually benefit from it.

DR. LEVINE:  It's — let me put it this way; it's unlikely that these particular children are going to benefit or derive any benefit from the results of this study. 

DR. PELLEGRINO:   At the moment.  They might in the future.

DR. LEVINE:  It's not impossible, but if they're going to benefit, we can't specify how.  The apparently normal siblings would have an even lower probability of getting any benefit because only one out of four of them, more or less, will ever develop diabetes. 

PROF. GEORGE:  But there's an explicit — there's a sentence under subjects and controls in the first paragraph that says, "Moreover, since the risk of developing diabetes is greater than that of the general population, these children," I gather the siblings, "have a correspondingly greater chance of benefit from the results of the investigation."

DR. LEVINE:  Yes, it is greater.

DR. LAWLER:  Is that consistent with what you just said or am I missing something?

DR. LEVINE:  Yes, it is much greater but it's still very small. 

DR. LAWLER: I think it's highly unlikely that they'll benefit from this study, right, the control group?

PROF. GEORGE:  This is where — now to move from questions and clarifications at least to start, in my own case thinking about how I would evaluate this from an ethical point of view, it does seem to me relevant that they could benefit and if, in fact, that opportunity or chance or likelihood of benefitting is very, very, very small to the point of being negligible, then that would erase that positive factor. 

DR. LEVINE:  Not negligible.

PROF. GEORGE:  Not negligible, okay.

DR. LEVINE:  It's small.

PROF. GEORGE:  Small, but not negligible.

DR. LEVINE:  Yeah, and let me say that in the normal population if you did these studies —

DR. HURLBUT:  Well, it specifically implies, though, that they could benefit because it says the opportunity for further diabetes education will be used and we're not talking only about medical benefits here.  Understanding their sibling and having the general knowledge of what a hospital is like, I mean, it does seem to me there are arguable benefits here.

PROF. GEORGE:  I would add another point on top of the benefits just to get my own cards on the table here.  It seems to me because of the natural relationship of siblings and familial obligations and so forth that it counts very much on the positive side of the agenda, at least as far as I'm concerned, that we're using siblings here and not just children off the street. 

DR. LEVINE:  Let me add that the statements you are reading are statements that were made by the investigators who were proposing this study to the IRB.  There is invariably a tendency on the part of investigators to over-estimate the benefits of their work and you know, they need this to get out of bed in the morning.  They've got to believe they're going to do something important.  But the IRB is experienced at ratcheting these things down.

PROF. GEORGE:  So it's like letters of recommendation for undergraduates applying to law schools.  The professors know they have to exaggerate and the admissions committees know they have to take into account the exaggeration.

DR. LEVINE:  I think you've got a nice analogy there.

DR. FOSTER:  Let me just help a little bit in this.  You can — no matter all the studies that you do in animals, they're different in humans.  So you always ultimately have to do physiology in humans, and you can never understand a disease or normality until you understand normal physiology.  Most people think about Type 1 diabetes which is what they have here, the autoimmune form, think of it about being a deficiency of insulin and then we give insulin and then sometimes the blood sugar gets too low and then it goes too high and so forth.

It was — I don't know how long ago this was, but we now clearly know that there are six hormones involved in the control of the blood sugar day to day.  I mean, insulin is on the one side.  It lowers the blood sugar, makes fat and all that sort of stuff.  And then there are five hormones on the other that protect you against hypoglycemia.  That's what keeps us alive every night.  Yeah, it is.

It keeps us alive every night because our brain has to have either oxygen or glucose and it doesn't.  So what happens is, every night when we're not eating, insulin drops and these so-called counter regulatory hormones come up and make the liver make glucose to protect our brain.  In the diabetic state there is always a relative or absolute deficiency of insulin and a relative or absolute increase of the major counter-regulatory hormone which is glucagon.  The others are secondary things.  And so it's well-known that in both types of diabetes that you — if you just have a deficiency of insulin and glucagon, if you just take out the pancreas, you don't have much in the way of diabetes, because you've got to have that glucagon elevated.

Well, this is potentially — people have been working for a long time on trying to get a blockade of glucagon which is high in all forms of diabetes.  You've got to understand this.  It may be that they — that some of these children may be unstable because their glucagon is not as high.  So when you give them insulin, they get low blood sugar.

So this is studying physiology that will be applicable and has to be done in humans to ever look at therapy and but it's not — I agree that the chance for the siblings — and I think most people would say that in Type 1 diabetes, there's maybe a 15 percent chance, 10 or 15, not 25 percent chance.  In Type 2 diabetes the genetics is overwhelming, it's almost 100 percent.  So these are things that are relatively safe, but I don't think in this particular case — the children themselves, you might get an immediate benefit if you saw how they handled, you know, insulin infusion, and that they were too sensitive to it or they were less sensitive to it, you might alter your therapy in that diseased child, but not likely in the sibling.

Now, maybe you'd learn something if we get a glucagon antagonist later on that would help, but I hope that clarifies a little bit as to what they — you know, as to what's going on here. 

PROF. GEORGE:  But Dan, you interrupted yourself in mid-sentence just on the point I think that's relevant.  You were about to say what the percentage chance was, I think, for the siblings.

DR. FOSTER:  I thought I said — no, I can't say — I don't have an idea.  I think the —

PROF. GEORGE:  A ball park figure?

DR. FOSTER:  Less than one percent.

PROF. GEORGE:  Oh, less than one percent, okay.

DR. FOSTER:  That's what I said, the 16 percent or 10 to 16 percent is the inheritance, and it's also — there's implanting of genes and so you're more likely to get Type 1 diabetes if you get the genes, the HOA genes and so forth from the father as opposed to the mother and so forth.  But, no, I think it's very — probably considerably less than one percent that the siblings would get any immediate or short-term.

PROF. GEORGE:  That sounds to me negligible.

DR. LEVINE:  Let me say that when I recommended this case, I did not know Dr. Foster was a member of your group and I'm so grateful that you are.

DR. FOSTER:  Thank you.

DR. PELLEGRINO:   Dr. Bloom.

DR. BLOOM: Bob, maybe, Dan has purposely simplified the protocol description but it would help me elevate the benefit to risk ratio if I knew what they were going to do with the blood samples and how many of the hormones that were just eluded to are going to be measured and in terms of the puberty question, whether they're also going to measure gonadal hormones and where would the sibling be relative to the proband (phonetic) in terms of advancing into or coming out of puberty.

DR. LEVINE:  These are all very good questions.  Let me tell you that this case was published in 1985, so the work was probably done in `83 and at that time there was certainly not an awareness of six counterveiling hormones in this.  As far as the details of what they were going to measure, I don't remember.  I think, though, what I would like to do is all of these questions about details are very important and the real IRB experience, we would probably write a letter to the investigator saying, "Exactly what are you measuring here, are there any gonadal hormones, et cetera."

And at the end of this exercise, I'm going to ask you to come up with a decision on how you would like to — whether you want to vote this up or down, but part of the — one of the contingencies might be we'll vote to do this if, and only if, they're going to measure gonadal hormones.  That's one of your options.  I think Leon won by one millisecond.

DR. KASS:  Yeah, this is more — I'm holding back because I'm hoping that after all of these throat-clearing questions of clarification, somebody is going to take a seat at the IRB and offer an analysis of this and I'm hoping that, in fact, some of the clinicians might give us the benefit of their thoughts on this, but would it be welcome, Bob, or to the group, if we sort of tried to bracket some of these details which might sooner or later make a difference, and stipulate for the sake of the discussion of this case that we're not counting any benefit, any likely benefit to the siblings?  We'll just simply dismiss that as a way of making it either more complicated or easier and also stipulate that this is terribly important work for understanding if not immediately, fairly soon, understanding how one can help these unstable juvenile diabetics regulate their insulin, so that the importance of the work is not in contention.  The necessity of the control group for understanding this work is not in contention and that we don't somehow try to lard up — to weigh up lots of potential benefits for the siblings and then simply ask the question, is this a reasonable use of those siblings for this study.  Doesn't it come down to that or am I being —

DR. LEVINE:  I would be very happy if the group agreed to stipulate one, that there's no likely benefit or no likelihood that these particular siblings will derive any direct benefit, health-related benefit from participation and two, that — stipulate that it is important to have this information in order to better understand unstable diabetes around pre, during and post-puberty but I would ask for a third stipulation, that you have a good account of the physiology of unstable diabetes unless you have some control group to compare it with.

So basically you are saying if we want to really deliver the fullest benefit to the unstable diabetes group, we've got to have controls.

PROF. GEORGE:  That's fine, Dr. Levine.  On the point about the benefitting though, for the diabetic children themselves, we're also stipulating that there is a substantial likelihood that them or some of them will benefit, 25 percent or whatever it is.  Is that right?

DR. LEVINE:  I need a philosopher to help me define "substantial."

PROF. GEORGE:  Well, not negligible.  I mean, that there's a good chance that some of these kids themselves — they're not going to go through this just in the hope of benefitting future diabetic children.

DR. PELLEGRINO:   There's a reasonable possibility.  Would you agree?

DR. EBERSTADT: One last question of clarification, at least as far as I'm concerned; the consent process, is it the parents who provide the consent for children ages eight through 18?  Do the 18-year-olds provide their own consent?  Do the eight-year-olds provide their own consent?  What's the process there?

DR. LEVINE:  The process is necessarily this; and what I'm about to tell you is required by regulation.  Every child who comes into the study will be called upon for assent.  The eight-year-olds will be able to give you a much less sophisticated assent than the 11-year-olds.  And between 11 and 14 you've moving into a range where they can manipulate extractions that approaches the ability of an adult.

By the time you're — you generally recognize the authority of adolescents to override their parent's approval even when what you want to do is evaluate something that's good for them.  So certainly, they will have complete authority to veto this and in fact, even the eight-year-old will have the authority to veto. 

Now, in addition to the assent, which looks for all the world like consent except it's not legally effective, the parents must give their permission and their permission is obtained through a process that is exactly like consent, informed consent.  It's just that the Commission said it's not consent unless you're talking about yourself.  We will call this instead permission. 

DR. EBERSTADT: And the children will not go into the — it's a double or nothing situation.  You want to have a controlled child without diabetes in addition to a child that is diabetic.

DR. LEVINE:  No, no, it's not a paired control.  So we might have a half a dozen diabetic children whose siblings don't go out — or don't want to do this.  They would prefer in the case of the siblings, to always have a diabetic sibling being studied at the same time.  And the reason for this is to give the child a sense of familiarity.  You know, this child might say to his or her diabetic sibling, "What is the meaning of this tube in my vein?"


PROF. MEILAENDER: I know we keep asking these questions, sorry, but is it possible to give me an idea of what we're going to say to the children in the control group when we seek to get their assent to their parents?  In particular, I mean, what are we going to — are we going to tell them that — are we going to say that we need some basic physiological knowledge and this will help us get it?  Are we going to tell them that it may — that we're not only going to learn that but we're learning something that may be of help to other children who are diabetic or even more specifically that it may be of help to, you know, their sibling, who's a diabetic or their child and so forth?  Can you give me an idea of what we're going to say to them?

DR. LEVINE:  Let me say, this case coming from 20 years ago, I don't remember exactly, but in general, what they would be inclined to say is, "We want to do some research and it's to get information about people who are like your sibling and we hope that some time in the future this information will help us diagnose or treat people like your sibling."  One thing we rule out, it's a no-no, you can't say, "If you get in this, you're going to do some good for your brother or sister."  I mean, that would be — the common sense around IRB people is that that would be considered an undue influence, and I agree with it.

PROF. GEORGE:  But having said that, obviously, this is beyond your control, it would seem to me to be not unreasonable for the parents in explaining to the siblings why they would like the siblings to participate and would approve to say, "Your brother or your sister is afflicted with this terrible disease.  We're hoping that the work that is being done by these investigators will benefit possibly him — that child himself or herself and also other children now and in the future who may be afflicted by this disease."  

You couldn't stop that if you wanted to stop that, but my sense is you probably wouldn't — I wouldn't want to stop that.  That seems to me a reasonable statement for parents to make and a reasonable consideration for the parents to have in their own minds. 

DR. LEVINE:  I think it's reasonable. However, other pediatricians here, the way kids are brought into the metabolic unit in a university hospital, before they're brought in, before there's any discussion of assent or permission or anything, there's a conference which includes the parent or both parents and the child.  It also includes the investigator, usually a research nurse and invariably a social worker.  And the purpose of this is to give a full account of what to expect, what are we doing here, why do we want to do it?   And in case the parent comes on strong saying, "Look, kid, you know, you've got to do this for Johnny," the social worker and the investigator will generally say, "Whoa, wait a minute, let's put a little brakes on here." 

PROF. GEORGE:  And that strikes me as exactly right.  That strikes me as something they should be doing and I think that's consistent with you know, the parents reasonably saying what I said a moment ago, it would be reasonable to say.

DR. LEVINE:  Yes, but then after this, they go home and we can't go home with them.

PROF. GEORGE:  Absolutely. 

PROF. MEILAENDER: There are people who think that Robby and I think alike on a lot of things and I want to dispel that notion.

PROF. GEORGE:  We are siblings after all.

PROF. MEILAENDER: Right.  I think this question is more complicated than you seem to hear, Robby.  I mean, on the one hand, particularly with the children on the younger end of this spectrum, I mean, I can conceive of thinking of encouraging their participation on the grounds that it might at some point help their brother or sister.  I can conceive of encouraging them to do that, precisely as part of my carrying out my responsibility for their moral education and to try to foster in them certain kinds of attitudes and so forth.

But I can also conceive of it as placing a certain kind of pressure on the child that wouldn't — you know, if this were — I mean, that's why I wasn't sure what I thought about recruiting siblings here as opposed to just a random group of people, because if it's just a random stranger, we'll get a clearer sense of whether "I'm just prepared to do this or I feel a certain kind of pressure." 

So, I mean, on the one hand, it may conduce to a certain kind of moral training and rearing that the parent is interested in.  On the other hand, I'm not sure it's fair to the child.  It makes it much harder to say, "No, this isn't really something that I want to do."

PROF. GEORGE:  I agree that that's an important worry.  I don't think that this is an easy case and I think that it's something that does need to be taken into account.  You're right to take it into account in evaluating it.  On the other hand, I guess I'm enough of a familialist and anti-individualist, perhaps, to think that when diabetes strikes the child, because of the relationship of the child to the family, the diabetes strikes the family and that, too, has got to be factored into the equation here. 

I'm not saying that it's definitive, that it resolves every —

PROF. MEILAENDER: You push that too hard and the research begins to look like it's a direct benefit not just to the child who has diabetes but to the one who doesn't and you surely don't want to say that.

PROF. GEORGE:  Well, what do you mean?  A benefit to the child who has diabetes is not a benefit to the family of the child who has diabetes?

PROF. MEILAENDER: Well, we have to talk about how broadly or narrowly we wish to construe the language of benefit here.  You're right about that, but at least — it's a very different sort of benefit from the kind of benefit to the child who has — possible benefit to the child who has diabetes.

PROF. GEORGE:  Well, I think this raises a really important issue that people who share as much as you and I share by way of background ethical conviction really need to talk about.  I mean, what does it — how — what does it mean to have the special connections that people have by virtue of being members of the same family?

We know, for example, that parents have certain obligations to their children, unchosen obligations to their children just by virtue of being the parents of those children.  You have taught us better than anyone that children have certain obligations to their parents, despite the fact that they did not ask to be born by virtue of being the children of those parents.  I think it's fair to say that siblings have certain obligations to each other.                Now, I'm not trying to force this case into a case of sibling obligation, so I'm making the points that I'm making in terms of obligation not because I think that this is a question of sibling obligation but because I want to highlight the implications, that the implications can be very strong of natural relationships.

DR. PELLEGRINO:   Dr. Gomez-Lobo?

DR.GÓMEZ-LOBO:  On this same topic, of course, the flip side of recruiting a sibling of the child with diabetes is that as the presentation of the case indicates, you can provide a much better atmosphere for the child and if really the physical harms are negligible, as I understand it, and the real worry is the fact that there can be emotional effects, the fact that, you know, the child comes in with the whole family, it to me makes a lot of sense. 

I think it's a form of respecting the child and inviting the child to a form of solidarity, I would say.

DR. LEVINE:  I'm going to ask that we — the point you're pursuing here I think is fascinating and what was left out of yesterday's discussion in the McCormick-Ramsey debate is that McCormick said part of the parent's responsibility is to try to bring the child up to be the right sort of person.  And he interpreted this as having a general obligation to contribute to the well-being of the community when you could do this with little or no risk. 

The standard he specified was no discernible risk.  Ramsey almost bought it but he said he would insist on it being discernibly no risk, right?  No discernible risk means there's unknowns out there.  Ramsey wanted to say not fair, you've got to know what you're doing.  And then all of their followers, Friedman, Ackerman, all that wrote about research involving children afterward, focused on bringing the child up to be the right sort of person.

DR. PELLEGRINO:   Peter Lawler?

DR. LAWLER:  Well, I think that's right, exactly.  So in order to justify this, the benefit to the kid with diabetes in the family is questionable.  The benefit to the kid in the family without diabetes is not there or negligible minus.  So how would I justify this if I had a kid in my family that had diabetes and another kid of the appropriate age?  It would be something like this; there are a lot of diseases in the world and as charitable as people are, we can't take an interest in them all.  If someone in my family has this terrible disease, I'll take a special interest in this one.  So I would give money to this one.  I would participate in walks and such for this one, but would I go the extra mile and participate in research in this way in this one? And the answer is, well, I would, but I would as an adult.  I would consent to as an adult.  As an adult I would do this, sure.

But the pressure put on the kid here to look at it in this kind of way becomes a question, especially to an eight-year-old kid.  This disease is now our family project.  We're all making sacrifices for it.  And this — we are very interested in this disease because your brother has it and so we want to get this disease cured or done away with because of the terrible things it does but don't be deceived that this experiment will likely benefit your brother at all or very little but we, as a family, have taken an interest in this and as part of our interest in this, we want to participate in experiments such as this.  Will you consent or would you agree with this?  This is a real burden to place — I think with a 17-year-old there's no problem here.  With a eight-yea-old, this is quite a question, quite an abstract issue.

DR. PELLEGRINO:   Dr. Bloom?

DR. BLOOM: Well, when I said before it would increase my benefits to risk ratio if we knew what the hormonal profile that it was going to be measured with, I was talking about benefits to the future management of pre-pubertal Type 1 diabetics.  So if we take ourselves back to 1984, the two axis that would most concern me are not the other gluco-regulatory hormones, but the stress access and the gonadal access.  And unless we knew where they were in their progress towards puberty, we wouldn't be able to ask the main question that they're asking.  Unless we knew what their reaction was to the hospital environment, we wouldn't be able to assess the orthogonal influence of the stress access on glucose metabolism.

So my suggestion to these PI's would be to use same gender siblings who are already post-pubertal as the control for the diabetic.  And that, to me, would increase the generalizable knowledge to be derived from the study to the point where the relatively modest risk becomes much more reduced in a relative basis.

DR. LEVINE:  Let me say that — let's stipulate one more thing.  In case this group decides to approve the protocol, let's say it would be contingent upon developing a satisfactory response to Floyd's proposals — to Floyd's questions, but now let me move you towards some things we must address in order to decide whether we want to approve this.  The first question is, can we call this "minimal risk," recalling that minimal risk is risk that one expects to encounter in a regular medical examination and it's supposed to be somehow related to the risks of everyday life.  Would you call this minimal risk?

DR. EBERSTADT: I would say this is minimal risk.  It's a lost weekend.  It's an inconvenience.  It's a pain in the neck, perhaps.  It is possibly an emotional stress for the child but that emotional stress, it seems to me, by this design, may be dramatically if not entirely mitigated by involvement of the parents.

DR. HURLBUT:  This idea of encountering risk in daily life is an interesting one because you're talking about all people and the risk that everybody takes or the — I mean, you look at adolescents, they actually subject themselves to risk and they flirt with risk, they experiment with risk.

DR. LEVINE:  The risk can be very different in different areas of the country and of the world, but what I think most of the people who have addressed this issue say, "We ought to be thinking about what is the risk that's out there in the routine experience of people in comfortable situations, not the risk of living" — I was going to refer to some borough of New York but — well, I gave a lecture on research involving children in German South Africa and the day before the lecture, I was on a free range, which means that in the next block a leopard had come and eaten one of their neighbor's dogs, and it struck me that saying to the children, "Go out and play" —

DR. PELLEGRINO:   Leon and then Gil.

DR. HURLBUT:  Can I add just a little comment to that?  I don't know quite how to put this into the equation but it does strike me that our civilization has sanitized quite a few of what you might call basic human realities.  Among them, for example, is the fact that we have no — very little consciousness where our meat comes from.  We don't that — we don't relate very quickly to the fact that animals die for us to eat their meat.  That takes us out of the realm of what you might call the order of sacrificial existence and takes us out of the realm of the sense that there's a hierarchy of beings subservient one another's needs by some people's analysis. 

And it strikes me that medical realities are one of the primary areas we've distanced people from fundamental knowledge of reality and even though my father was a physician and even though I saw his medical books all over our house, including some very graphic things, when I got to medical school, I had to go through the same experience that I think several of us have of encountering medical realities and having to realign my overall life philosophy in relationship to those realities. 

I think when you start to add that into the equation of consideration here, even though we've been talking about direct benefits to the individual, there is something to be said here about the value of  knowing how serious the issues we're dealing with are generalizing them, I like to get my undergraduates to go over and see medical realities at Stanford Medical Center when I can because I think it informs their ethical reflections and their personal increase in overall understanding of life.

Now, that's not to shift the equation of consideration here entirely to philosophical goods or whatever you want to call that, but it does strike me that there's something pretty important going on here, not just for the development of the individual, but for the reality of what Leon eluded to earlier if the real question is, "What are our obligations to others where we have no direct benefits?"Then we should at least know the context of the realities we're evaluating that situation against.

DR. LEVINE:  Again, I think that's a very important set of concerns you've presented us with but I would like to ask you to decide whether you think within the confines of the admittedly fuzzy definition presented to us by the regulations, would you be willing to call this minimal risk?  Would anyone not be willing to call it minimal risk?  Gil?

PROF. MEILAENDER: We're a recalcitrant bunch, hard to channel, and I just wanted to say, you introduced this question.  I do not want to derail — I'll say this and I'll shut up because I don't want to derail the direction that you want to get us to go.  But when you introduced the question about getting us to think about minimal risk by saying, this is the first question that has to be asked.  See, I do not think it is the first question.

I think the first question, at least for the younger children in this spectrum is whether anyone ought to be able to consent to their use as research subjects, the children in the control group at least.  So I would just put that on the record and that will make a difference in — I mean, to the degree that I give a no answer to that question, I don't actually have to answer the question about minimal risk.

DR. KASS:  Yeah, I'll also — I'll answer because it seems to me when asked a question, one should not hide, but I wonder — well, let me ask you a question.  If this really were the IRB sitting, would this be — would we be obliged by law or is it in your view the way to proceed that we somehow go through these checklists and answer the question minimal risk?   Or would one say, "Dr. Foster, Dr. Bloom, Dr. McHugh, Dr. Kass, other people, yes or no, and then why do you say yes or no?"

I mean, I'm going to wonder at the end having sort of answered this checklist of questions, what a conclusion necessarily falls out of that or whether we're still left with some kind intuitive judgment for which we then have to give an explanation.

DR. LEVINE:  No matter what your answer, you're also going to be — it will be necessary for you to respond to your intuitive judgment.

DR. KASS:  Okay, well —

DR. LEVINE:  But let me say this: that if you were really an IRB and part of the purpose of this exercise is to give you an experience of the IRB interpreting current policy, you would be required not only to say minimal risk, yes or no, but you would be required to document that the IRB raised that question and answered it.  Then if you say no, then there's a whole series of additional questions.

DR. KASS:  Okay, well, I'm a law abiding fellow.  I think this is minimal risk.

DR. LEVINE:  I hear no dissent from this being minimal risk.  Well, that settles that.  I don't have to ask you all those other questions. 

PROF. GEORGE:  On minimal risk, is it fair to say that when one judges that it's a minimal risk, one is judging the entirety of the circumstances in which the child would be brought into the scheme and supervised and so forth.  So I want to hold out the possibility that there may be a child for whom this would not be a minimal risk but that there are protections that have been put in place, and you've described them to us, for that child even late in the day if it becomes apparent that this child has high anxiety, as you've described the procedures, there is a very, very strong likelihood that that child is going to be removed from the — removed from the system.       

And bearing all that in mind, I would agree with Leon, this is minimal risk.

DR. PELLEGRINO:   Dr. Gómez-Lobo?

DR.GÓMEZ-LOBO:  I think I'm going to take a seat on the IRB finally.   I'm — what I'm trying to think about is what are the relevant moral norms that should be taken into consideration in this case and in my mind, I've discarded a couple of them.  Clearly, there's no intention to produce harm.  There's no intent on evil, to put it in general terms.  There is a pursuit of the good, it seems to me, the better knowledge of physiology.  Whether it is conducive to therapies, short-term or not, it still seems to me of value.

The chief concern is the one that Gil mentioned is whether a child is being manipulated, used, used simply as a means.  My inclination, I don't use the word "intuition" actually, goes something like this:  From my familiarity with children at the age of eight, nine, 10, I think that many of them are able to give assent.  I mean, if you explain to them what's going to go on along the lines Peter suggested, of course I would not force a child, but I think a child could be easily persuaded.

And the fact that there are all of these safe-guards in the sense of the protected environment, the presence of the family, the fact that the child can be withdrawn at any point inclines me to say this is a morally permissible form of research.  That would be my first reaction unless I hear very strong arguments against that.

DR. LAWLER:  Let me just agree on both those points.   It is no more minimal risk for the reason Bill described.  It's less than minimal risk because many of these teenagers, again, in this heavily regulated environment, this is going to be the least risky weekend they have all year, probably.  But I think that question is not so important.  I agree with Gil on the question of the appropriateness of thinking eight- and nine-year-olds could consent to this or even realize what's at stake and what's not at stake. 

What's not at stake is the health of your sibling.  What's at stake is carrying this horrible disease.  That's a pretty abstract thought.  I'm not an expert in child psychology, but I wonder.  You might be right, Gil might be right, but that's the tough question. 


DR. McHUGH:   Well, I also have been on IRBs and so I know how it will come out on this, but there were a couple of things that have not perhaps been sufficiently emphasized in relationship to the context in which we're asking these kids to do it.  We are working with diabetically unstable children and if they live in a family, they have seen the effects of diabetic instability in their siblings.  They have seen the distress that's come over them and even at the age of eight, I know a lot about kids age eight because I've got several grandchildren that are flourishing around there.  They appreciate the suffering of each other and so I think that they would, given that they're being told that they're going to be guinea pigs in this way, that they would begin by wanting in some way, I think most of them.

The problems for me with this case and this experiment are several though.  The first one is  that the importance of this subject is clear but we're talking about unstable hormones and we're taking new — taking kids and putting them into a very distressing environment, kids, by the way that we have not evaluated psychologically in any way.  We have a research social worker there, but, you know, kids are not like collie dogs.  They aren't all the same.  And some of them would be much more vulnerable and a reasonable assessment of them for their psychological vulnerability should be there. 

The second thing is, why does this have to be done in a hospital?  Now, maybe in 1985 and in metabolic units that's the best and easiest way, but fundamentally we're just talking about an indwelling catheter for which these kids can run around and sleep in their own beds and do things like that.  And I would ask on the IRB, "Why aren't you doing this at home and then four hours in the ambulatory outpatient clinic?  What better (information) are you going to get and how much more do you worsen the problem of studying the hormones?"  I've done 24-hour hormone things under distressing circumstances.  How do you complicate the issue of studying instability when you're putting kids into unstable situations?

So my response would be to say this is minimal risk, but whether the research is really done in a proper way and whether the subjects have been properly selected before they suffer the distress, I don't know.  But I wouldn't — I would appreciate that the kids cared about their siblings and they had seen them suffering and we could explain to them even at the age of eight, that this is due to the instability that comes from their hormone imbalance.

DR. FOSTER:  Let me just make one — I don't think you can do glucose clamps at home because you'd have to have the pumps, and in addition to that, you're constantly measuring every minute or so the blood glucose and the hormone.  So it's not possible to do that — so they always have to be done — yeah, and they have to be done in a general clinical research unit to do that, just because it's not like just drawing blood out.  You could do — the 24-hour that you're talking about you could do at home but this is —

DR. McHUGH:  Okay, that is an important point.

PROF. MEILAENDER: A couple of things; I mean, I do think that I'd probably call it minimal risk if I'm going to come around to answer the question you actually asked, but I have — I mean, I have a clearer idea about what I really thought about that.  If we complicated the research protocol in such a way that that parents didn't just accompany the children but that the parents wore an IV — had an IV line for the 48 hours and had their arm tied down to a board for periods of time and had some hormone sensitivity test done, you know, it may just be a weekend and a pain in the neck but I'd bet most of us wouldn't do it under many circumstances.  So I just have a clearer idea of what minimal risk for someone who is really in a position to say, "No, I don't want to do this," meant if we included that.  That's the one comment.

The other is that I mean, I think that — I mean, I am worried about the younger children, at least, in this.  And I think that if I were to — because I think one could wrong them by simply using them this way.  I think if I were going to justify is, as I might try to, it would be precisely on the grounds of trying to initiate one's child into a moral understanding of helping others and so forth.

I just think we shouldn't over-estimate our ability to do that and if I may, just a brief story.  I don't think I told this one here before.  I forget where I told it, but when I moved to the University of Virginia to teach, our oldest son — he wasn't quite eight yet, he was, I think he was six, but we moved there in the middle of the summer and we were very — it was very sad.  You know how you are with your children.  The little groups of boys in the neighborhood were already set and everything and our poor kid was out there kind of looking at them and nobody was playing with him and so forth.  And you just feel sad for your child but you know there's nothing you can do.  Time will solve it and by the end of the summer he had a group of about three other little boys that he played with and so forth.

And at that point, another family moved in, a new faculty family moved in next door to us with two little boys and I watched my son and his three friends, you know, studiously ignore these and exclude these little boys and so forth.  And so the ethicist swung into action and I took him aside and I said, "Peter, remember when we moved here a while back and nobody played with you, how you were kind of sad."  And he said, "Yes."  And I said, "And now you have some friends to play with you and that's good."  Yes," you know, and so forth.  "Well, how do you think Johnny and Tommy here feel when you guys don't play with them?" — simplest form of Golden Rule reasoning. 

And he said, "But we don't want to play with them."

And I always think of that when I think about this notion, you know, which I'm willing to buy in this case.  I mean, I'm willing to buy the argument that, in fact, I ought to try to initiate my child into a world of moral concern, but we should be a little careful about our confidence in our ability to do that, that's all.

DR. LEVINE:  Do you know what I would like to do, I would like to pause at this point and let you know what the IRB decided, what the outcome was and then have you continue your very interesting discussion.  The IRB decided that it was more than minimal risk.  It said, putting children in the hospital overnight, they considered that in and of itself as more than minimal risk, but also lashing the arm down to a board for four hours, they thought would be traumatizing.  So they called it more than minimal risk. 

They then had to reach a determination as to whether or not it would fall under the rubric of a minor increment above minimal risk and they agreed that it did.  They then said, "We are concerned that not all children from eight to 18 can be treated similarly," so they insisted that the first cohort be limited to 14 to 18 and the next cohort could be, I think it was 10 to 13.  And then the youngest children came last. 

Then if they detected any problem in the older children, they would call it off and not go any further.  Since it was a minor increase over minimal risk, they had to reach a determination in the language of the regulations that the information being pursued was of vital importance to understanding the child's condition.  This was easy for the diabetic group.  And this is what lies behind the agreement to use siblings of diabetics rather than normal children at large.

They were able to persuade themselves that siblings had a condition that needed understanding, too.  So they reached that.  The next hurdle was the regulations say that the procedures that present more than minimal risk must be commensurate with what these children would experience in their actual or anticipated medical circumstances.  This is not by way of saying, look the kids already had one spinal tap, what's another one.  This is by way of getting a more knowledgeable assent.  They know what they're doing.  They've seen it.  And some of your discussion of witnessing what their siblings went through during their periods of diabetic instability figured into this but also this is why they wanted the sibling in the hospital at the same time as the diabetic, so they could see what was being done, and so they can say, "I'm looking at that and I don't want that."

Let me give you the outcome.  We interviewed Dr. Emil at the end of the whole thing even after the — we interviewed her several times along the way.  But she said that the chief problem she encountered with the children was that they were bored.  They said, "I am bored," not "This hurts," or, "I'm frightened."  "I'm bored." So she decided she was going to show them all a video tape and she showed them two movies, one of which was "Raiders of the Lost Ark." The kids were delighted with it.

The only complaint she got was from one mother who said, "You know, I really wish you'd have shown them a Disney movie," she thought "Raiders of the Lost Ark" was a bit advanced for an eight-year-old.

PROF. GEORGE:  I mean, if they weren't traumatized by the snake pit scene in Raiders, these kids are tough kids and we don't have to worry about them.

DR. LEVINE:  Snakes, what about the spiders?  So there you are.  This is what happened.  I want to give an epilogue, too.  About ten years later the Office of Protection — we were so proud of this study, that's why we invited publication.  About 10 years later, the Office for Protection from Research Risks closed down the research operation at the National Institute of Child Health and Development because they were doing a protocol that is almost precisely the same thing except that instead of diabetes it was obesity.

I mean, we were so proud of our thing, but OPRR, when they noticed it going on in Bethesda, closed it down.  So there can be very differing judgments about all of this.  And that's all I wanted to say.  I would love to hear the rest of your conversation.

DR. PELLEGRINO:   Any further conversation?

PROF. GEORGE:   I want to say that I do share Gil's worries.  I think they're legitimate, especially the worry about possible undue family pressures on a small child and for understandable reasons, where you have a family that has suffered this terrible affliction of a child in the family and who might themselves be tempted to exaggerate the potential benefit for their own children of the research.

Gil made one point that I think is — might shift me across the line to really thinking this shouldn't be approved, if I thought Gil was right about it, and this was the question, I think it's the right question: Would the parents themselves be willing, if it would have been useful in the research, to subject themselves to having the arm lashed for several hours to the board and so forth?  And I think Gil was suggesting that probably a substantial percentage would not. 

That's not my sense.  Now this is not a normative judgment.  This is our impression of what people are like or what parents are like.  I think most parents, if they thought that it would possibly benefit the children and certainly benefit lots of children who are afflicted with what their child has been afflicted with, probably would agree to do that, and I'm wondering, Gil, why you're skeptical.  It might be this Lutheran side of things with the original sin very strongly —

PROF. MEILAENDER: Well, you have actually, perhaps, hit upon part of it.  No, I think it's two-fold.  One is you're obviously just a better person than I and that's part of it, but I don't actually presume a whole lot of altruism even in well-formed adults.  I just don't anticipate a lot of it necessarily.  And so I think a certain skepticism is in order.

PROF. GEORGE:  Let me try to ameliorate some of the skepticism in you.  I notice that in my own experience, people who have afflictions in the family will put themselves out — often put themselves out in ways that require physical exertion and doing boring things, like stuffing envelopes and things like that, and really giving their time to fund-raising, for example, for research on breast cancer or another affliction that might happen to be in the family, which leads me to think that, gosh, if those people are willing to exert themselves and inconvenience themselves in those ways, even for fund-raising, they probably would be willing to subject themselves to this level of inconvenience where they're actually involved in the research, they're not just raising money for somebody else to do the research and, you know, pedaling 20 miles on a bicycle or running 10 miles to do it.

They're actually involved in the research. Don't you think so?

DR. LEVINE:  Let me offer something here.  As the Chair of an IRB, I reviewed no fewer than 50 protocols which involved doing hyperglycemic or insulin clamps on adults.  We had as one of our faculty in those days a man named Ralph DeFronzo, who did these clamp studies in almost every possible condition.  So I, myself, have — you're from Stanford.  I don't know if you knew Gene Robbin, but when he was — when I was an intern at Brigham or what used to be called "the Brigham," and he was on the faculty there, he did sleep studies on all of my intern cohort.  I mean, we spent eight — oh, you too. Then you know, he not only had our arms on a board but he passive tilted us and gave us radioactive iodine and —

DR. PELLEGRINO:   Final comment, Paul.

DR. McHUGH:  Yeah, I just think that it was splendid, Dr. Levine, that you showed us the second step, namely, the things that happen in real IRBs, namely the interactions between the IRB and the investigator, where the investigator shows a responsiveness to the IRB's concerns and comes up with solutions and suggestions that will permit the process to go forward and yet has, as well, trip lines along the way. 

I think that was a demonstration of why when the — back in 1985, IRBs were interesting programs to be on in a way that they aren't in 2005.  Let me tell you, this is the kind of interactions with investigators that made the — that brought great pleasure to lots of us who were on IRBs at that time and maybe we can get back to that.


DR. HURLBUT:  Maybe this is already obvious from what's been said, but it does seem to me worth pointing out for our broader reflections both on human dignity and the use of children in — as human subjects, the significant factor of actual life context in which the individual subject is having their life experience, reflecting on this specific case, I think if I imagine putting it in the context of my own family, I think I would favor my children being involved in such a study, not just feel neutral about it.  And for the very reason that I know personally the value of siblings understanding the afflictions of their unfortunate brothers or sisters, but I don't think I would say to my children, "Hey, there are people out there that have these problems.  I'm taking you down to the medical center to participate in a study." 

And the reason is because I think that we should acknowledge that this somewhat mysterious and wonderful quality of altruism or in its extreme form, actual sacrifice of self in some way that depletes something or gives up something — I noticed in — let me finish that sentence.  That it does have a very personal context and we should, in our methodical thinking acknowledge that.

I very, very much liked Leon's essay on the organ donation, but I did come to one point where I wished instead of — I can't remember what the word was that was used but it had to do with — it was a word that had to do with giving and I wish that the word giving up had been part of the sentence because I think — I'm sorry, I can't just generate this but it just strikes me that one of the things we have not put into the equation of our ethical thinking adequately in our civilization is the very personal context in which the best things of human beings are  brought out.

I often reflect on the fact that there's an AIDS epidemic going on in KwaZulu-Natal and there are circumstances where relatively small amounts of money could help people extraordinarily, and yet we feel perfectly justified using that same amount of money going out for a fancy meal or something like that and I think we need to come into better balance on that. 

But I also think there is a kind of concentric circle of giving in life that we need to acknowledge, that when you're closer and there's a more personal context to things, that changes the equation a little bit and we should wrap that into some of our thinking.

DR. PELLEGRINO:   Thank you.

DR. LEVINE:  One more thing I neglected to say from our exit interview with Dr. Emil, she reported to us that the siblings were thrilled to have this opportunity.  The way they described it to her was that their brother or sister had access to this mysterious place where they did things and the kids felt left out and many of them said, "Look, I'd like to be in there, too.  I want to be kind of an insider," which I found astonishing, but —

DR. PELLEGRINO:   Thank you very much.  Thank you very much, Bob, for providing the case and discussion and thank all of you participating.



I just didn't press hard enough.  Wendy Wright, is she here?


DR. PELLEGRINO:   Of Concerned Women of America.

MS. WRIGHT: Thank you for this opportunity (inaudible) but I am speaking to you today on organ procurement as a donor.  Four years ago I donated a kidney to a young man from Ethiopia.  I knew him from — I knew his sister actually, didn't actually know him.  Yesterday in listening to the discussions I felt like there were two groups of people that were being overlooked and these two groups are represented by myself and by Sora. 

Sora comes from a low income family.  If payments were allowed for organ procurement, he would not be able to afford — he'd always be at the bottom of the list because he would never be able to afford paying for an organ.  And so there was much discussion yesterday about how payments would affect the poor, but that attention was all on potential donors, not on recipients. 

The second group of people are those like myself, who donate altruistically and one comment that was made yesterday is that there is no moral impact of allowing payments on those that are of a middle or higher income.  I very much disagree.  One week before my surgery, there was an editorial in the Wall Street Journal that advocated allowing payment for organ harvesting.  Well, I, one week away from doing this, was incredibly offended, incredibly insulted, it actually caused me to think twice about what I was doing.  That if payment was allowed for this gift that my gift would be tainted and I'd be ashamed to tell people in the future that I had done this because it would appear as if I did it in order to get paid.

So, yes, there is a moral impact and unintended consequence on the group of people that everyone wants to have more of, those are the altruistic donors.  Yesterday, Professor Epstein, who, by the way, I think he authored that article in the Wall Street Journal that so offended me, he stated that transplantation is the only place that is regulated where compensation is treated as coercion.

That's not true.  Adoption, adoption is an area that is regulated that we certainly don't want to allow any perception of buying of babies.  So I have two recommendations for the Council.  One is, find out about altruistic people.  Learn about us, what motivates us, where are we.  There was a study that was done, written into a book called "The Altruistic Personality."  It's a study of people who had rescued Jews in Nazi occupied areas.  And they found that there are three types of people.  Fifty-two percent, the largest group, were those people who belonged to  a group in which this is what you did.   This was the right thing to do. 

The second group, 37 percent were those who had empathy for the victim and the smallest group, 11 percent, were those who were principled, they had very strong core beliefs that this was the right thing to do.

So I believe that the first priority that ought to be when you're looking at organ procurement, is to grow the pool of altruistic givers and in order to do that, first find out about them.  And also find out how to make the opportunities available, more known.  I've been willing to donate for years.  I've been on bone marrow registry for over 15 years but had never gotten a call.  It wasn't until there was someone I knew of that needed a kidney that gave me then an opportunity to come forward and to do this.

My second recommendation is "do no harm."  Please do not recommend anything that will have the unintended consequence of reducing the pool of altruistic givers or that would create more harm to the most poor patients who would not be able to afford to pay for organs.  Thank you.


DR. PELLEGRINO:   Thank you very much.

PROF. GEORGE:  Dr. Pellegrino, could I invite Wendy back to the microphone just to ask a question?

DR. PELLEGRINO:   Yes, surely.

PROF. GEORGE:  Wendy, if there were to be permitted a regulated market in organs, would something about that have precluded your making an altruistic private donation of the kidney to Sora or could there have been a market in which those transactions, if I can use that inappropriate word in these context, would be permissible anyway?  I mean, why would it preclude — why would a market preclude your doing for Sora the generous thing you did?

MS. WRIGHT: That's a good question.  All I can really go back to is that one week time, when — the one week before the surgery when I read about this and to me it would have been a huge hurdle.  It would have been — I would have felt like this decision was now tainted.  It would not be perceived as altruistic. And that's even if you have these — they say two areas.  You could have one which people could go into this arena and be paid or you could choose this other route of altruistic.  The average person out there wouldn't be able to make the distinction and that was something that concerned me. 

Now, I still would have gone through with it but I enjoy telling people what I've done because I want to encourage them to do the same thing.  And one friend of mine is willing now to donate a kidney if the opportunity arises.  I would not feel as willing to tell people if there was this concept of doing it for payment.

PROF. GEORGE:  Not to press you too hard or to subject you, Wendy, to a cross examination, but if you have a physician who is willing to, because he's already made quite a lot of money and he's got enough to retire on and take care of his family responsibilities and so forth, and is now going to dedicate himself to providing free medical services to the poor, can do that without his generosity being tainted by virtue of the fact that most other doctors are providing their services to people for money and he, himself, did that. 

Why couldn't it be the same with organ donors?  We would still praise the altruistic people who did it without financial incentives and people would know that some people do that and that's terrific and it wouldn't detract from our sense of their virtue that other people are — I'm not doing this —

MS. WRIGHT: No, no.

PROF. GEORGE:  — to promote the idea of a market, but it seems to me these are obvious possible lines of objection to the point you're making.

MS. WRIGHT: Right, I think it's the same kind of difference we have between those that are paid for their labor and prostitution.  Giving up an organ, it's a part of yourself that I believe we don't really have the right to sell.  And so I think there is a distinction, a distinction between labor and selling of human beings and their parts.

PROF. GEORGE:  But that makes me thing that it's not really so much a perception that other people won't understand the virtue of what you've done, rather that the foundation of it is this view that —


PROF. GEORGE:  — which Dr. Kass articulated so well, that there's something about the organ and its relationship to the person that makes it, perhaps, just inappropriate to be in commerce.

MS. WRIGHT: I completely agree with that.


DR. PELLEGRINO:   Thank you very much.  Meeting adjourned, thank you.

(Whereupon, at 12:01 p.m. the above-entitled matter concluded.)

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