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FRIDAY, APRIL 21, 2006

Session 6: Children and Clinical Research

Council Discussion led by Robert Levine, M.D., Professor of Internal Medicine, Yale University

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.


  - The President's Council on Bioethics -  
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