Department of Health and Human Services


	Meeting of the
	NATIONAL HUMAN RESEARCH PROTECTIONS
	ADVISORY COMMITTEE (NHRPAC)

	Wednesday, July 31, 2002



	VOLUME II





	Four Points Sheraton Hotel
	Franklin Ballroom
	1201 K St., N.W.
	Washington, D.C.  20005




	A G E N D A

Wednesday, July 31, 2002

AM Session

8:30-8:45		RECAP
		     Mary Faith Marshall, Ph.D.
		     Chairperson, NHRPAC

8:45-9:45  	CHILDREN'S WORKGROUP: UPDATE
			Alan Fleischman, M.D.
			Chair, Children's Workgroup
			Senior Vice President     
			The New York Academy of Medicine

9:45-11:30	NATIONAL CHILDREN'S STUDY     
			Peter Scheidt, M.D., M.P.H.
			National Institute of Child Health
			And Human Development
			Joel Frader, M.D.
			Professor of Pediatrics
			Medical Ethics and Humanities
			Feinberg School of Medicine,
			Northwestern University

[10:15-10:30]	Break

11:30-12:30	SHOULD ALL DISCIPLINES BE SUBJECT TO THE COMMON RULE:  A REPORT FOR COMMITTEE DISCUSSION
			Moderator:  Mary Faith Marshall
		 	Discussants:
			Jonathan T. Church, Ph.D.
			Chair, Department of Sociology and
			Anthropology
			Assistant Professor of Anthropology
			Arcadia University
			Jonathan Knight, Ph.D.
			American Association of University
			Of Professors
			Linda Shopes, M.A.
			Pennsylvania Historical and Museum
			Commission

12:30-1:30	LUNCH

AGENDA - Continued

1:30-2:00		DISCUSSION/RECOMMENDATIONS CONTINUED

2:00-3:45		UPDATE AND DISCUSSION:  GENETICS WORKGROUP
			Mary Kay Pelias, J.D., Ph.D.
			Chair, Working Group
			Professor of Genetics
			Louisiana State University, HSC

[3:00-3:15]	BREAK

3:45-4:30		SOCIAL & BEHAVIORAL SCIENCES
			Felice Levine, Ph.D.
			Co-chair Working Group
			Executive Director
			American Educational Research 
			Association 

4:30	Adjourn

	ROSTER OF MEMBERS

MARY FAITH MARSHALL, Ph.D., Chairperson, Professor of Medicine and Bioethics, University of Kansas Medical Center

GREG KOSKI, Ph.D., M.D., Executive Secretary, Director, Office of Human Research Protections, Office of Public Health and Science, OS  (ABSENT THIS SESSION)

MARK BARNES, J.D., LL.M., Partner, Ropes & Gray

MS. MARGARET BORWHAT, President, Women's Cancer Advocacy Network  (ABSENT DAY 2)

SANFORD CHODOSH, M.D.

ELLIOT N. DORFF, Ph.D., Rector and Distinguished Professor of Philosophy, University of Judaism (ABSENT DAY 1)

ALAN R. FLEISCHMAN, M.D., Senior Vice President, The New York Academy of Medicine

JENNIE R. JOE, Ph.D., M.P.H., R.N.
Professor, Family and Community Medicine
Director, Native American Research and Training Center, University of Arizona

SUSAN Z. KORNETSKY, M.P.H., C.I.P., Director, Clinical Research Compliance, Department of Clinical Investigation

FELICE J. LEVINE, Ph.D., Executive Officer, American Sociological Association (ABSENT DAY 1)

ROBERT LEVINE, M.D., Professor of Medicine, Yale University School of Medicine

ABBEY S. MEYERS, President, National Organization for Rare Disorders

JONATHAN D. MORENO, Ph.D., Emily Davie and Joseph S. Kornfeld Professor of Biomedical Ethics, Director, Center for Biomedical Ethics, University of Virginia Health System

Roster of Members (Continued)

MARY KAY PELIAS, Ph.D., J.D., Professor, Department of Genetics, Louisiana State University Health Sciences Center

ROBERT R. RICH, M.D., Executive Associate Dean of Research, Emory University School of Medicine

ADIL E. SHAMOO, Ph.D., Professor, Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine

KATE-LOUISE GOTTFRIED, J.D., M.S.P.H.,
Executive Director, NHRPAC
Office of Human Research Protections, Office of Public Health and Science, OS

EX OFFICIO MEMBERS

Dr. James Shelton, USAID
Dr. Robert B. Ochsman, CPSC
Dr. Joseph Spence, USDA
Ms. Linda Beth Schilling, DOC
Ms. Patty Boll, DOD
Ms. Blanca Rosa Rodriguez, DOED
Dr. Susan L. Rose, DOE
Dr. Dixie Snider, CDCP, DHHS
Dr. David A. Lepay, FDA, DHHS
Dr. Belinda Seto, NIH
Dr. Alan Sandler, NIH
Dr. Francis D. Chesley, Jr., AHRQ
Dr. Paul Gatons, HUD
Dr. Donald Prosnitz, DOJ
Mr. Thomas G. Raslear, DOT
Dr. John H. Mather, DVA, VHA
Ms. Joan Porter, D.P.A., M.P.H., DVA, VHA
Mr. Roger S. Cortesi, EPA
Dr. Richard S. Williams, NASA
Dr. Philip Rubin, NSF
Mr. Howard L. Bradley, SSA


P R O C E E D I N G S
	[Time noted:  8:36 a.m.]
	CHAIRPERSON MARSHALL:  Good morning.  We had a wonderful day yesterday, I thought, a very productive day, very busy day for July in Washington, D.C.  I thought the turnout was great.  We had to bring in extra chairs, and I hope we have that same problem today.
	And the committee worked very hard.  They even worked after our meeting adjourned.  The Informed Consent Workgroups, I thank all of you.
	I wanted to do just a couple of brief housekeeping things this morning.  One is, I had a couple of questions about what happens to NHRPAC work products once they are finished and completed, and we have had several work products that are finished and completed.
	And generally the way the process works, it's really not that akin to sausage making.  It's much cleaner.  We exist to advise the Department of Health and Human Services, the Secretary and the Assistant Secretary for Health and the Director of the Office for Human Research Protections, and those who are in the federal agencies that either do or pay for human subjects research about research and protections of human subjects of research.
	So generally our products which are relatively short documents -- they are not 600 page documents, they're more like six-page documents -- will go directly through the Assistant Secretary for Health to the Secretary's office or through the Assistant Secretary for Health to the Director of the Office for Human Research Protections.  Or sometimes, depending on how we've been charged, they may go straight to the Director of the Office for Human Research Protections.
	And then the Secretary or the Assistant Secretary for Health or the director of OHRP certainly have the prerogative to take our advice or amend our advice or leave our advice.  I don't think any of it has been left yet.  Some of it is still in process at the department.
	But that's basically how we work.  So we give advice.  We do not issue guidance.  We certainly don't make regulations.  Advice is what we do.  So just to make sure that people understand the process.
	I also wanted to call on Dr. James Harris who gave us a wonderful presentation yesterday on research issues involving the mentally retarded and those with developmental disabilities.  He has a little bit more information for us today relative to what may be a charge from the Department of Health and Human Services.
	So I wanted to give Jim just a couple of moments to update us, and Jim, thank you so much for coming back and doing this.  And good morning, Felice. We missed you yesterday and we're so glad to see you.  I saw Elliot already, yes.
	Thank you, Jim.
	DR. HARRIS:  I didn't have this with me yesterday, but I thought I should mention it.  The last report that was issued by Surgeon General Satcher was issued in February of 2002 which was the month that he left office.  And because it was the end of his term, it got very little attention in the media.
	The report is called "Closing the Gap, A National Blueprint to Improve Health of Persons with Mental Retardation."  The pertinent part, I think, for your committee is this.  On page 5 under the title, "Increased Knowledge and Understanding of Health and Mental Retardation, Assuring That Knowledge is Made Practical and Easy to Use," there was a section on the research agenda, "Develop a national research agenda that identifies gaps in existing scientific knowledge related to health and mental retardation, including methodological challenges, priorities, feasibility and time tables for achieving priority research, potential strategies; develop specific agendas for basic clinical and translational research for studies of the efficacy of wellness and treatment services and service models for people with mental retardation; for legal and ethical issues, healthcare financing in relationship to outcomes and other matters identified by the community; implement the December 2001 research agenda of the workshop on emotional and behavioral health in persons with mental retardation in developmental disabilities; enhance research collaboration across multiple research agendas."
	The introduction was written by Tommy Thompson, the Secretary of HHS.  And I think that the issue about ethical issues aspect as well as implementing the research agenda that I presented yesterday in part is a charge that we were left by the previous Surgeon General and certainly we will be discussing with the next Surgeon General.
	But I think that this is very pertinent to your work, and I would hope that you might take a look at this.  I will give copies to Keisha to duplicate.
	CHAIRPERSON MARSHALL:  Thank you very much, Jim.  And we will get copies of both reports to the committee and the ex-officios, and I think this might very well occasion a welcome visit by Kate and myself to the new Surgeon General to follow up on this.  So thank you very much.  We appreciate that.
	Kate has also some housekeeping that she wanted to mention.
	MS. GOTTFRIED:  Just to expand for a minute on the process that Mary Faith was laying out, I just wanted to explain that the Office for Human Research Protections has developed an intradivisional policy-divisional workgroup.  So the recommendations that NHRPAC adopts and then forwards formally from Mary Faith to the Assistant Secretary for Health typically will get transferred by the Assistant Secretary for Health to the Director of the Office for Human Research Protections.  For example, in the case of third parties where that issue is being reviewed and considered and the policy group is determining what kind of input they want to provide and guidance.
	So the document that we worked on is feeding into that as well as the NIH document is feeding into that.  For example, with the conflicts-of-interest document that we put together and put forward to the Assistant Secretary, that's been elevated to the departmental level, and OHRP is just one of many divisions that's giving input to the department on conflicts of interest.
	So as things emerge, we will certainly keep you in the loop and let you know what the latest is, but that is the process that's ongoing at this point in time.
	CHAIRPERSON MARSHALL:  And the policy group within OHRP is headed by Dr. Stith Coleman.
	DR. MATHER:  Mary Faith, if you wouldn't mind, can I just follow up on Kate's point from an ex-officio standpoint?  One of the concerns that we have is that while we appreciate HHS's leadership, when something comes forth from HHS, like this is the world and this is how it's to be, I mean the impact on DOD, VA and all the other cosignatures to the Common Rule becomes kind of pertinent.  And I don't know, Kate, if there's some way in which we can work through at your level or at the secretary's level or at least something where in which we can get, quote, "a shot at it" through the Human Subjects Research Subcommittee or something like that before we get these excathedral declarations from HHS.
	I'm being a little florid, but I mean there's a real concern here I think that if something comes out and everybody sort of has to sort of stand in line, we will, but there needs to be some inputs coming from the other federal agencies.  So I would ask and make a plea that somehow or another that be made extant, explicit and not sort of implicit like, well, we'll make sure you know about things.  Let's make is explicit if we possibly can.  Thank you, Mary Faith.
	CHAIRPERSON MARSHALL:  I just want to clarify then what you're asking for.  We will be having discussions with Dr. Lawrence and others at HHS.  So you're obviously at this level of the process.  All of the ex-officios who are members of this committee have input as things are brewing up.
	But what you're saying is once they have been forwarded, it would be nice if there was a more concrete vehicle for communication as things are happening or perhaps before they're announced at large to the world?  
	DR. MATHER:  Well, maybe I need to clarify exactly what I'm saying. I would like to think it's an opportunity for looking at something that is not exactly decisional but is slightly predecisional.  And if the vehicle is the Human Subjects Research Subcommittee where all of the agencies sit, that's great.  But I'm not sure that HHS would necessarily want to put something through HSRS.  I'm just making a plea. 
	Let's find out a mechanism whereby HHS will work with its colleagues in this matter.
	CHAIRPERSON MARSHALL:  All right.  We will visit with Dr. Lawrence about this issue.  Thank you.
	Well, now that our housekeeping is done for the morning, I'm going to turn things over to Dr. Fleischman.  The Children's Workgroup has been very busy.
	DR. FLEISCHMAN:  Thank you, Mary Faith.
	Let me just give you the context of where we are in the Children's Workgroup work.  You will recall that one of the early pieces of work of the National Human Research Protections Advisory Committee was a review of subpart D of the Common Rule.
	We concluded and passed our comments onto the Office for Human Research Protections that the subpart D was in fact a sound part of the federal regulatory structure, but it required some clarification.  It required IRBs to be more accountable.
	And the workgroup has begun a process of developing brief, concise, what we hope carefully crafted and thoughtful clarifications-- documents that may be helpful to IRBs.  Our goal is to submit those through the process of OHRP with the hope that we will be able to educate IRBs and to get some more uniform standards of applicability of some of these definitions and to alleviate some of the concerns that people have about the way the regulations are being applied.
	So the workgroup has diligently set for itself a task of going through about nine different short tasks, and we bring to you today what we have as very close to a final.  I smile because before yesterday I thought it was final.
	[Laughter.]
	DR. FLEISCHMAN:  I'm sure it's not right.  You know, I opened my mouth yesterday for Jonathan.
	What we're attempting to do here with the materials you have in front of you are to clarify some simple concepts such as minimal risk and minor increase over minimal risk to add to our concerns about amelioration of risk.
	And then we have attempted with a great deal of effort and work, and it may be not useful, to develop two tables and four examples.  We are not in the tables or the examples attempting to be inclusive of all kinds of procedures or all kinds of research, but we were attempting to give some simple examples and simple ideas on these tables and examples.  And I'd like to go through this very briefly.
	You have seen the text before.  In fact, the committee has reviewed the text and we have integrated their comments.  We're open to other comments, but I just wanted to remind you that you have seen that text at the committee level before.
	What you've not seen is our attempt to develop tables and examples which has been very difficult.  It's been difficult because we were attempting to only put down on the tables things we could come to consensus on.  And I want to go through the tables and the examples with you.
	I'd like you to read carefully the paragraphs before the tables which basically argue that, "Levels of risk for specific research proposal must be evaluated based on the context of the research, the proposed procedures and interventions and the population study.  Levels of risk will also vary depending on the characteristics of individual subjects and the skill and experience of the investigators."
	Those two sentences are for every procedure, every project, and IRBs will need to use those in their considerations.
	In Table 1 we've listed procedures commonly included in research studies involving children that we could agree on in terms of categories of risk that we thought didn't need a lot of nuanced discussion at IRBs that seemed to fall into a category with the codicils in that upper paragraph.
	We have added to Table 1 two additional procedures that you don't have in front of you based on input from our social and behavioral colleagues.  We have added to Table 1 "Standard Psychological Test," and we've designated that as minimal in the category of risk.  And we've added to Table 1 "Classroom Observation," and we have added that as category of risk minimal.
	In Table 2 we have attempted to just describe how one would interpret the level of risk of these additional common procedures -- but they are more nuanced -- and what would be the criteria to think about what level of risk they might have.
	And in Table 2 we have given some kind of general guidance.  Now, whether this is helpful or not to IRBs is up for conversation and discussion.
	We'll get to the examples in a minute, but I present to you now the text and the two tables for conversation, if we can hold off on the examples which are even more difficult to reach consensus on.  So we're open for conversation about the text and the two tables.
	Elliot?
	DR. DORFF:  First of all, the fact that it's not a final draft is a good thing, Alan, because it means that life goes on.  Never mind.  I'm sorry.
	[Laughter.]
	DR. DORFF:  But it's frustrating I know.  On page 3 of the original document, especially given the example that you just added, it seems to me -- I'm on the second to the last paragraph. 
	"We interpret the concept or disorder or condition as relating to a specific characteristic, which describes a group of children, a physical or social condition affecting children."  What about a psychological condition?
	DR. FLEISCHMAN:  Certainly.
	DR. DORFF:  Because if psychological testing is going to be one of your examples, then it probably should be in the document.
	DR. FLEISCHMAN:  Sure.
	DR. DORFF:  The other thing I wanted to say was that this is wonderful.  I mean, I think it's the kind of concrete advice that IRBs really need to get, and it makes all of the principles very clear.  Congratulations on it.
	DR. FLEISCHMAN:  Thank you.
	Bob?
	DR. R. LEVINE:  I want to agree that this is a splendid document.  Thank you.  I have a couple of comments and a question.
	First, the comment.  On page 2 in the first paragraph, reference is made to probability and magnitude of risk.  I believe that you meant to say "probability and magnitude of harm."  It's in the fifth line.  Risk is of course an expression or probability.
	Now one topic that's come up that's not addressed directly here is whether or not the taking of a history, which is part of a routine physical or a psychological test or exam, would be considered minimal risk.  This has serious implications for, let's say, survey research or interview research.
	Many people talk about the risk of asking people, children and other people sensitive questions. But if you consider what goes on in the routine examination of any person who visits a physician, they ask all of those embarrassing questions.
	They ask about social or behavioral activities that might put them at risk for various diseases.  They ask about past history of abortion and so on.  And if that's considered part of a routine examination, that then allows us to classify or perhaps reclassify a lot of interview and survey research as minimal risk.
	I personally would be in favor of that, given the proviso that you have strong protections of confidentiality.  Measuring up to the protections of confidentiality that we have in medical practice should not at all be difficult.  I would hope for something better than that.
	My other comment is in Table 1, the last entry of the original presentation before you added the psychological stuff. I'm a little concerned about classifying bone marrow biopsies as more than a minor increase over minimal risk.
	I think that as I've read various descriptions or attempts by commentators in this field to suggest what is meant by "a minor increase over minimal risk," bone marrow aspirations and biopsies. I see aspirations are a minor increase. But bone marrow biopsies and lumbar puncture are the two procedures that are most common in the literature as exemplifying what's meant by a minor increase.
	So I would ask you to -- organ biopsy, liver biopsy, that's more than a minor increase, but bone marrow biopsy is associated with temporary discomfort. It can be serious discomfort.  And particularly given the regulatory context that this would have to be commensurate with what's going on in that child's life anyhow, the child can appreciate how did it feel last time I had a bone marrow biopsy and do I want to do this again when I don't really have to.
	So that's my little plea for reclassifying the bone marrow biopsy.  Thank you very much.
	DR. FLEISCHMAN:  Bob, in terms of your comments, we can certainly integrate the taking of a history and this protections of confidentiality easily. 
	The oncologists who we've consulted in the workgroup made a distinction, at least in pediatric work, between an aspirate and a biopsy.  They made that distinction quite explicitly, and they were comfortable with the aspirate like the spinal tap being at the minor increase over minimal.  And you'll see from example, we suggested that obviously we're talking about one of those.
	They see the biopsy as a different level of risk, different level of discomfort, so that's why we put those together.  So we can unpack it or even eliminate it if there's either confusion or disagreement, but that's how they can't do it.
	DR. R. LEVINE:  I'm not going to turn this into a big thing.  But from my experience in the distant past, it seems to me that with local anesthesia the discomfort of a bone marrow biopsy tends to be less than that of an aspiration because you can't really eradicate that bizarre sucking sensation that radiates out beyond the bounds of the local anesthesia.  Where with the biopsy it's probably not much more of a discomfort than having a tooth drilled.
	DR. SHAMOO:  Can you explain it to the audience?
	[Laughter.]
	DR. R. LEVINE:  With local anesthesia.
	DR. SHAMOO:  Alan, could you describe it to the audience so they'll know what we're talking about? Not everybody is familiar with it.
	DR. FLEISHMAN:  I think actually bone marrow aspirate or biopsy is basically a procedure done on the hip to look at bone marrow materials.  The biospy takes more.  The aspirate is a needle insertion.  The biopsy is a larger needle.
	DR. SHAMOO:  Where at?
	DR. FLEISCHMAN:  At the hip.  On the bone.  In the bone.
	DR. SHAMOO:  In the bone.  You drill through the bone?
	DR. FLEISCHMAN:  Well, you push.  You don't drill.  Some of my best dentists are friends, but we don't drill.
	DR. SHAMOO: You push through the bone.
	DR. FLEICHMAN:  What Bob is raising requires, I think, us to just eliminate the bone marrow biopsy category here and allow IRBs to think about that with their investigators.
	I think we have agreement on the bone marrow aspirate aspects.  Those are needle aspirations.  They're quite routinely done for children who have conditions and disorders and diseases that require those kinds of procedures serially, regularly as part of their clinical care.
	The biopsies are a little bit less frequently done and I have an opinion about this obviously, but I'm not sure we're going to reach consensus, so I'm not sure it's worth the level of kind of discussion.  We can allow IRBs to make those learned judgments there.  On point, Bob?
	DR. RICH:  Well, it's on the next --
	DR. FLEISCHMAN:  No, because I've got Jennie next and then I have you and then I have Adil.
	DR. JOE:  I also want to express my appreciation for the examples.  I think one of the things that would also be helpful for the IRBs to have -- I know you've footnoted that there is multiple procedures that are often done.  I think if we had two or three examples like that for IRB, that would be helpful.
	DR. FLEISCHMAN:  I agree. Bob?
	DR. RICH:  I think this is exceptionally useful.  I also think because of the fact that it's exceptionally useful, it's essential that we get as broad professional input into these because once this is codified as a recommendation, it will have a large impact on IRBs.
	I particularly would wonder whether it might be useful to discuss with our distinguished director of OHRP regarding the issue of general anesthesia in MRIs. I've had previous discussions with him about general anesthesia for normal volunteers, and he regards that as something perfectly acceptable and not a problem at all.
	Because of the language of what is imposed on increase over minimal risk, I don't know what his opinion would be, but it's obvious that question ought to be posed to an anesthesiologist I would think.
	DR. KORNETSKY:  Is that children?
	DR. RICH:  Well, the context of my discussion was not children.  I don't know what his answer would be if I had said rather than normal volunteers if I had said children.  He might be perfectly comfortable with this language.
	I only cite that as an example of a fairly specific recommendation that could have substantial impact beyond this committee once it's codified in one of these tables. And it's very particular to a technically demanding procedure in the hands of a real expert.
	DR. FLEISCHMAN:  Let me just ask Dr. Harris to comment because yesterday he told us about some very interesting and important work that was done that required general anesthesia or at least close to general anesthesia.  And it was, I assume, rather controversial in getting it approved and done because it was unusual.
	On this point?
	DR. HARRIS:  Yes, on this point, exactly.  The issue was also raised a moment ago about bone marrow biopsy.  The question of sedation in children is something that really requires careful consideration.  Most radiology departments in the country use Propophyl, some not cautiously enough I'd have to say because you can get apnea when you inject the Propophyl, so you have to be very careful in using it.
	So we have at Hopkins, it's a routine every Tuesday afternoon, we have a nurse anesthetist who uses Propophyl with good airway control generally using Laryngeo mask to do exams under anesthesia.
	Now, the word "general anesthesia" seems to be quite frightening to people.  But in fact when the sedation is critical in carrying out MRIs, we would be much safer in doing MRIs if we had much better airway control as it is in radiology suites because a child who's sedated without good control of the airway in an MRI is at considerable risk.
	So we have anesthesiologists and a nurse anesthetist who are specifically available to do that, and we do it for safety reasons.  In fact, the way this protocol was approved, and it wasn't only at Hopkins, we first did this work -- I'll give you two examples -- with Rhetts syndrome and Lesch-Nyhan disease.
	Neither of the neurochemical results could have been demonstrated in these disorders without exams under anesthesia.  We generally describe it as light anesthesia.  We can't specify one agent, but generally it's Propophyl that's used.
	So this basically would shut down NIH funded research on neurodevelopmental disorders if it were promulgated that general anesthesia cannot be used without clarifying what's meant by general anesthesia.
	Myron Yester [ph], who was the anesthesiologist who works with us, met with our JCCI and we talked in detail about what was necessary for safety for children to do imaging studies who had developmental disorders.  So I think that this could be a major problem.
	After we did our research on Lesch-Nyhan disease, the group at the NIH, actually we did primarily adults and we did one or two children who were twelve and older.  But the NIH then did much younger children using the same methodology that we had used.
	In fact they called us to ask about how we did this safely.  And the NIH then published another paper using a different ligand which documented in two different ways that there's a major neurochemical abnormality in this condition.
	So I would hope that there would be much more discussion about sedation.  And rather than a categorical rule that this a greater-than-minimum risk, it needs to be taken into account what would happen to research that could advance our knowledge.
	DR. FLEISCHMAN:  Let me just clarify both for Jim and Bob and the audience.  What the workgroup is suggesting is the concept of procedural sedation which is what you're describing which is not considered by anesthesiologists to be general anesthesia.
	Procedural sedation -- which is the careful monitoring of children without intubation with intravenous medications for sedation or oral medications for that matter, but the careful monitoring in order to perform certain kinds of studies like MRIs, PET Scans, et cetera -- is in our category of minor increase over minimal risk which would allow an IRB then to look at the condition or disorder, to look at the test and look at the context so it wouldn't just be in the outpatient department somewhere, but it would be with the appropriate anesthesia backup with the appropriate monitoring and the appropriate setting.
	Our understanding of this is that there is a distinction in the anesthesia world between no sedation, procedural sedation and general anesthesia, that those aren't just terms of art.  They actually have meaning.
	Now if they don't, then we will need some help.  I mean, I've got some colleagues in the audience here who may be helpful, but we asked.  And both the critical-care pediatricians, the pediatric anesthesia people were comfortable with those distinctions.
	What I believe you're describing is procedural sedation, not general anesthesia.  We non-anesthesiologists may use those terms without distinction or clarity.  And I think that's the difference.
	Now, for Bob, I think Susan's distinction was very important.  That is to say what adults, who are capacitated and autonomous and able to choose levels of risk, will allow themselves to undertake is in fact different and distinct from what children will be allowed to have done to them.
	But you're right.  Whatever we put here, IRBs will read and may generalize whether appropriately or inappropriately.
	DR. HARRIS:  Alan, I need to follow up with you about this.
	DR. RICH:  It seems to me that Dr. Harris is making a different point which is that in actual fact when one controls the airway, one has an increased margin of safety over simple sedation.  And if that's the case, I would submit that he might argue that there are cases where what you would call general anesthesia, which involves controlling of the airway too, is actually a safer process than simply because the patient goes into the MRI machine after all, and the airway is not readily accessible or may not be readily accessible at that point.
	So again, I think it's something that before it's codified, we need to be sure that we have checked with the technical experts who can advise us on this.
	DR. FLEISCHMAN:  This is one area where there is evidence actually.  There's not a lot of evidence in evaluating risk in children.  But this is an area where there is evidence.
	DR. HARRIS:  Alan, I just have to respond to this because yesterday we wrote a letter to RJCCI on this specific point.
	DR. FLEISCHMAN:  That's your IRB?
	DR. HARRIS:  Yeah, the IRB.  And the question that was raised was that, was this more than conscious sedation.  Now, it is more than conscious sedation because the patient's not conscious when they're sedated.
	But not only that, one needs sometimes in this routine procedure that's done every Tuesday afternoon to intubate or certainly to use the Laryngeo mask.  And I have to emphasize this because we've gone through it for fifteen years, this is a major issue in safety for children to be able to manage the airway.  And procedural sedation in many instances I don't believe is safe because there's not adequate control of the airway.  A Laryngeo mask is a way of avoiding conscious -- intubation.
	But I can't make this point strongly enough that this is not clear, and I've been dealing with it for a long time, to call it procedural sedation versus general anesthesia.
	DR. FLEISCHMAN:  Thank you.  Bob?
	DR. R. LEVINE:  Thank you.  Responding to Dr. Harris' comments, I'm a member of a group at NIH that reviewed a proposal to do exactly this, and it was decided that the procedural sedation came within the category of a minor increase over a minimal risk.
	On the specific point that you made, Alan, about "without intubation," part of our discussion was that although they planned no intubation, that on very unusual occasions intubation might become necessary not in order to perform the research, but in order to correct for some problem that came up in the course of doing the study.
	And it was agreed that it would be okay, even if you could foresee a possibility of endotrachial intubation in the interest of preserving the trial or making the trial safe.
	Let me also say that it's become increasingly clear to me as we talk that your definition of minimal risk is specifically designed to address the problems of children.  And that is sort of an echo of the National Commission which developed, I think, four separate definitions of minimal risk-- one for prisoners, one for children, and so on and so forth.  And the regulation writers then homogenized these so that they would have a one-definition-fits-all.
	One other point I do want to make, and that is that another procedure that's been very controversial is the use of either insulin or u-glycemic clamps.  In your example number one, it seems to me that part of that study might have been one of those clamp-type studies, but I don't think it's made explicit. 
	This was behind the problem doing a very similar study on obesity at NIH within the last couple of years, and I wonder if the group would want to address that explicitly.  Thank you.
	DR. FLEISCHMAN:  Let's come back to example one in a few minutes, and we'll deal with that because we have addressed it and this is the result of having addressed it.  But we'll come back to it.
	Abbey, I think.
	MS. MEYERS:  This doesn't address a major increase of risk.  You would never have developed bone marrow transplants from leukemia if there weren't some experiments with a major increase of risk.  There's no mention of that here.
	DR. FLEISCHMAN:  It is our hope that you will see from us, as our next report from the workgroup, the category of prospect of direct benefit, interventions and procedures with the prospect of direct benefit, 405, in which we will then talk about the levels of risk that are reasonable and acceptable with compensating benefit.
	MS. MEYERS:  I would suggest one word that really bothers me because I'm addressing this as a layperson who would come on an IRB.  And I would say that reading this definition "minor increase over minimal risk" that it says --
	DR. FLEISCHMAN:  Where are you?
	MS. MEYERS:  Page 2.
	DR. FLEISCHMAN:  In the italics or below it?
	MS. MEYERS:  Yes, in the italics.
	DR. FLEISCHMAN:  The italics or the quote from the Federal Regulations?
	MS. MYERS:  Okay.  But it says, "only if the IRB find that..."  So I would say after reading that, because of that word "only," that this is the beginning and the end of research.  You can't do research that has a major increase of risk because of that word "only."
	DR. FLEISCHMAN:  Well, look about two sentences up, and you will find the words "does not hold out the prospect of direct benefit for the individual subject."  If the research does not hold out the prospect of direct benefit for the individual subject, you're absolutely right.  You can't do more than a minor increase over minimal risk based in the present federal regulations.
	And unless as a committee we want to suggest that we change that, you're absolutely right.
	MS. MEYER:  I would suggest that somewhere in this narrative you say that the prospect of more risk will be addressed in another chapter.  Do something, so that the person who just sits down and reads this doesn't feel that anything with more than minimal risk shouldn't be approved.
	DR. FLEISCHMAN:  Bob, on point?
	DR. R. LEVINE:  Yes. For Abbey's consideration, it is the intent of the regulations to say that anything over a minor increase is a major increase, and that goes from just barely over a minor increase up to infinity, like 100 percent chance of that, probably rare to approve that.
	The other thing is, it's not strictly correct to say there is no way to do such research.  Another passage in the regulations says that for things that IRBs cannot approve according to Sections 404,5 6.  What you can do is forward the proposal to the secretary of HHS who will assemble a committee, et cetera, et cetera, et cetera, and they could make such a decision if things were sufficiently important and sufficiently justified ethically.
	MS. MEYERS:  I just feel that there should be some warning that it is possible, but it's addressed elsewhere.
	DR. FLEISCHMAN:  We've got it, Abbey.  We've got it.
	MR. MEYERS:  Otherwise, the word "only" means that if you just read that, you're going to go home and say there's no way I can approve anything with more than minimal risk.
	DR. FLEISCHMAN:  We got it.
	Sandy.
	DR. CHODOSH:  I want to change the subject just slightly in that I have some scientific concerns about when we get to the minor increase over minimal risk group in that one begins to wonder, are we going to have two levels of review if the study involves normal children as controls that are going to be going through the same business?  They clearly have no opportunity for benefit from the research.  And number two, it's not going to add to their information about their conditions since they don't have a condition.
	How will controls data be obtained?  Is this now the next level that's going to be considered in your next paper?  Because otherwise, we're now stepping back in scientific research to observational research of those who are sick without any means of comparing against what is expected to be normal.  Has that been addressed?
	DR. FLEISCHMAN:  Well, we think it has, and it may not, based on your question.  We have looked to the definition of disorder and condition as a way of looking toward predisposition, characteristics of groups.  We have defined condition to include such entities as adolescence, prematures, neonates, children in environments that might have toxic impact.
	So there are children who are otherwise healthy or normal who have conditions who could in fact have minor increase over minimal risk research based in their having conditions, based in our assessment of the definition of minimal risk, absolute index to the healthy normal child in the average environment.
	We could not do more than minimal risk research on a normal healthy average child unless that normal healthy average child had a condition or disorder as we have tried to define it within these paragraphs.
	Now, I'm trying to find out the paragraph.  The paragraph is full paragraph 3 and 4 on page 3 in which we talk about both the National Commission's use of the word "condition," and then our interpretation which agrees with their direction that a condition relates to specific characteristics which describe groups of children.
	DR. RICH:  Could condition be either maleness of femaleness?
	DR. FLEISCHMAN:  Theoretically it could.  If that were in fact about a disorder or condition impacting on males or females in a developmental sense, in my opinion it could.  Those are characteristics that describe groups of children.
	DR. CHODOSH:  I'm having trouble with the semantics here because if you're saying that you can use as a control for some purposes a child with one condition against another group of children with a different condition, well then you have not covered normals and you have no way of studying normals for comparison against a group.  This is the dark ages of science.
	CHAIRPERSON MARSHALL:  No.
	DR. FLEISCHMAN:  Susan?
	DR. KORNETSKY:  Sandy, I think you're hitting on a point that perhaps in pediatrics there are studies that you can't use normals as you would adults.  And I mean that's what I think the extra protections are.  I don't think that this is the dark ages of science at all.  I think that you need to look at what you're studying.  You have to look at the context.  You need to look at the condition.  There may be situations where you can use normals.
	But there may be situations where you can't use a normal child, I mean you can't use a normal child for a Phase I toxicity testing as we do in adults, nor do I think anyone would want to do that.  So I mean you're bringing up a point that the regulations were meant to address.
	DR. CHODOSH:  Let's take PET Scans because I'm sure it's going to come up, and you need to establish normals in normal children with PET Scans that requires sedation, perhaps incubation it sounds like if you're going to get a proper thing.
	Now, how do you base disease if you don't know normal?
	DR. FLEISCHMAN:  Sandy for 30 years we've been faced with this concern.
	DR. CODOSH:  Address it.
	MR. FLEISCHMAN:  Well, we are addressing it, although we have I think agreed as a workgroup, based in the regulations as Susan implies, is that there are certain kinds of physiologic experiments that we were not able to do in normal children and based in these recommendations would still not be able to do in normal children.
	That doesn't mean that there aren't some ways to do creative work to learn about normal physiology, also ways to do work with youngsters with various conditions that will allow us to understand a lot more about normal.  But there are things we based in these present regulations, and I would believe rightly so, can't do.
	Now, I can recall in 1976 an argument in an IRB with a very distinguished colleague in which he didn't think that was a good thing, and I'm sure there are IRB discussions that are similar in 2002.  But there are some limits to what we may do in normal children, and I think that there's at least one member of the children's workgroup who would increase those limits and has vocally argued in that direction that we are too allowing of looks at research.
	If that workgroup member were here, Dr. Harris, you would be hearing a vocal concern that the good work, the important work, the meaningful work that you have done, she would not agree was as important for children in general and would be concerned -- I don't want to speak for her really -- but would be concerned about whether that would lead us down a path to which children would be subject to increased risks and harms and would be concerned.
	I mean, there aren't a lot of people right now in the room with that view I would expect, although they would be welcome at the microphone if they have it.  I'd be please if they came to the microphone.
	Adil, please.
	But I just want each of us to know I want to voice that view because it's not in the room, but it's clearly a view that's in our society and voiced by some in their hope to protect the interests of children or some individual children, subject to research, versus the needs of all children to learn more about their diseases and disorders.
	I'm going to ask Jim for comment, and then come to Sandy.
	DR. HARRIS:  Well, I think I should respond to Sandy's remarks.  The way we started our research is with adults.  And it took me five years to find an adult with normal intelligence with Lesch-Nyhan disease who could give consent.
	It was only after we found this one adult and found this dramatic reduction that we looked for other adults.  I mean, this is a disorder that occurs 1 in 800,000, and we probably have studied 80 percent of the adults with this disorder.  But then we needed to work with children and it was not ethically appropriate to do PET Scans with young children.
	So what we did is we looked to see whether or not the deficits in adults were similar to those in children with the same disorder to get an idea about the developmental course.  And so we did it in that way, looking at the specific disorder.
	But I just wanted to make one quick point.  I don't want to emphasize too much.  But if this section sedation said "procedural sedation/anesthesia," it might make it somewhat clearer because we're certainly not the only people that would use this approach.  The NIH used groups that we never thought about using in their approach, but I think "sedation/anesthesia" might make it clear because there is procedural anesthesia that's different I think perhaps than general anesthesia.
	But I think there does need to be some sort of footnote, as Dr. Levine pointed out, about Lerengio mask airway control because airway control is safety.
	But the question I wanted to ask was this.  Do you see minimum risk in minor increment over minimal risk is two separate categories or do you see them as a continuum?
	DR. FLEISCHMAN:  Our approach is to see minimal risk as an absolute standard varying by age but not social consequences of the children.  Minor increase being a little more than minimal, which means it is on a continuum.
	But I have said recently that if this is minimal risk and this is significant risk, minor increase isn't at my nose; it's at my thumb.  That's how we've been thinking about it.  I think that's how the National Commission thought about it.  And that it isn't three-thirds of risk-- you know minimal over here, in the middle and significant.  It really is minimal.
	And because there is no prospect of direct benefit to the child, we allow just a little more because of the critical importance to children in general to learn about such problems as the ones you've raised.
	For the audience, I think it is important for you to tell us in your speculation, in your hope what is the hope for understanding of the kind of science that you're bringing to the table after so many years of work.  I mean, so what that you found some problem in the brain that has neurochemical input.  Now this isn't an hour's request.
	[Laughter.]
	But there is the need to make the case that what you're studying has that vital importance and generalizability to that condition that has some reason for us to want to do this.
	DR. HARRIS:  Well, the answer is simply this. In this instance, in this one rare condition, a disorder where compulsive self injury leads to great suffering for the patient, for staff members who are involved and for their family.
	There is a rat model of this disorder which proposed that dopamine depletion was the reason for self injury.  What we found by doing this by studying people who had the disorder and who have enzyme levels up to 20 percent is that it's not a sufficient reason, and so other lines of pharmocologic research are necessary to try to find a treatment for self injury.  So that's why it's important.
	And it's also important because it tells us about brain development and dopamine.
	DR. FLEISCHMAN:  Right.  So that we not only will be able help potentially those very rare sad cases, we will also learn a lot more about how the brain actually --
	DR. HARRIS:  How the brain develops.
	DR. FLEISCHMAN:  And develops.
	DR. HARRIS:  Right.
	DR. FLEISCHMAN:  And I think that's really the critical nature of why the National Commission in my opinion was quite brilliant in thinking about how to push that level of risk to my thumb without going so far as to jeopardize children, yet to allow children in general to have the kind of information that was needed.
	I'm going to go back to Sandy for a final comment on that issue and then to Dr. Joel Frader who is on this issue?
	DR. FRADER:  On this issue of minimal risk.
	DR. FLEISCHMAN:  Of minimal risk.
	Okay, Sandy.
	DR. CHODOSH:  Really, the reason I brought this up is I'm looking as an IRB member, and I see this protocol in front of me, and I don't see that there's any data on normals.  And it seems to me that we need to state in this document that in reviewing research  of certain natures of the concerned children, that controls may not be possible because of the risks involved, so that it's clear to an IRB that they should not be looking for that next step in science that insists on controls.
	I don't think that's in here, and if we can't do it, I don't disagree with that, believe me.  We need to make it clear to the IRB that it's not up to them to find a way to get it done.
	DR. FLEISCHMAN:  Thank you.  Dr. Frader?
	DR. FRADER:  Alan, I wanted to respond to your invitation to someone who would speak to the issue of whether the controls are adequate for protecting children.  And I guess what I really want to say is that even though you say in your first paragraph above the tables the level of risk will also vary depending on the characteristics of individual subjects and the skill and experience of investigators, I think you need to underscore a particular aspect of this.
	As you have this, it is procedurally oriented and doesn't address it from the child's point of view. And my concern is, even when there is prospect of benefit, the particular children may be so frightened by particular procedures that other children wouldn't be bothered by at all, whether it's insertion of an IV or doing a bone marrow or a lumbar puncture, that that must be considered seriously by both the IRB and the investigator, and I don't think this document emphasizes that adequately.
	DR. FLEISCHMAN:  Thank you.
	DR. KORNETSKY:  I think that's a very good point, and I think what you're talking to is the whole issue of the other part of the protections for children which is assent.  And I think maybe perhaps, Alan, there may be some way of putting in a sentence or two about that, but that's the whole other part of protection.
	DR. MATHER:  Alan.  I'm John Mather with the VA.  I want to pick up on two or three points very briefly.  First of all, I want to thank you for the heavy lifting your group has done.  This is a contribution so far, and with the continuing pulling of this together, I think this is going to be very helpful, notwithstanding Sandy's comments and a few others.
	Anyway, let me make it very clear though, since I'm with the Veterans Administration, I'm not discomforted with the fact that this might be published as a regulation, except that I would hope it would be a little more quicker than coming out as a regulation may be coming out as guidance.  I guess the British humor was missed there somewhere.
	[Laughter.]
	DR. MATHER:  I'm a pediatric laryngologist by training which may seem strange to be working with the VA, but I want to make the point though this issue of the airway is not an inconsequential matter.  Having done research involving children with Peeriban Syndrome which is a relative macrognathia through a small jaw and larger tongue, we're not quite sure which it is, and some serious airway problems.
	We have even children who don't really have full blown Peeriban Syndrome who have sort, we're not quite sure what it is, but we know in about sixty percent of them in about a year lose that, and they're not really therefore true macrognathia and Peeriban Syndrome.
	But this is a very serious issue in young children which I use as an example to segue into the points that you make at the top of this page, Alan, about, quote, "the following tables."  And it's sort of buried in here I point I want to make.
	You talk about the context of research.  You talk about population studied, and you talk about characteristics of individual subjects.  Buried in there is the concept that I think may need to be more explicit, and that is some reference to the severity of the medical impairment and/or disease process this is focusing on the particular child or adolescent, the level of severity of so-called disease process.
	To me, a child with florid leukemia and doing a biopsy or a bone marrow is a little different than a healthy child, so I would like to think that you can capture that thought in here somewhere, which I think is really buried.
	DR. FLEISCHMAN:  Thank you very much.  Adil?
	DR. SHAMOO:  Thank you, Alan, finally.  I think most of what I wanted to say has been said from my colleague, but I think unfortunately we're only -- and this is due to lack of some people in the audience or in the committee who are speaking other than the medical model.  We're really speaking only of the medical model.  This is good for science-- we have to do it because we need control, we need placebo.  Yes, that's true.
	The progress of science is not the only value system.  We have to move forward with and somehow we have to be very frank with ourselves.  How many in this room would let their 10-year-old, healthy with no condition -- despite the fact that that work condition is defined so broadly, you could pass anything through it, which I object to -- how many in this room would have their 10-year-old healthy child to have a very thick needle go through their butt flesh and then bore into their bone?  It has to be bone because you cannot just stick the needle.  It has to have rotating into the bone, and it's a thick bone, all the way to the bone marrow, and take out a sample of their bone?
	How many really in this room will let their healthy child, have no condition whatsoever, do this?  This is what will happen if we move this category to minor increase over minimal risk with no direct medical benefit. I don't think there are many parents, unless negligent parents, who will let that happen to their child.  So that is really the argument.  You've got to put it down into the reality.
	Now, if they have a condition, we could do it.  If there's direct medical benefit, we could do it.  These are healthy children.
	DR. FLEISCHMAN:  I think the workgroup shares your view.
	DR. SHAMOO:  That's not what we have been hearing.
	DR. FLEISCHMAN:  We've said that the bone marrow aspirate sits in the minor increase over minimal requiring condition.  We have brought to the table that bone marrow biopsy is more than a minor increase over minimal.  We have now eliminated that, and it will be up to the IRBs.  We remind everyone in the room that parental permission and in the category of minor increase or minimal risk, both parents if available, giving permission as well as the assent, the positive assent of the child is required.
	So one of the problems, Adil, with the argument about how many people in the room would, one of the problems is that if there were some.  This isn't a majority.  You don't need to have every family volunteering to do research.  So if there were some who would say yes, would that be okay?
	DR. SHAMOO:  That argument doesn't hold water. If you are above 18 years old and decisionally capable, yes.  We're talking about children. Parents have no right to volunteer their children for high-risk experiment.
	DR. FLEISCHMAN:  And we agree.
	DR. SHAMOO:  And the Maryland Supreme Court has stated that.
	DR. FLEISCHMAN:  We agree, Adil, and the workgroup agrees, and that's how we've come forward with these recommendations.
	DR. SHAMOO:  But you are eliminating it, making it our arbitrary for the IRB -- not arbitrary, sorry -- making it for the IRB to include it below, not above.  So you eliminate it.
	My support is leave it as is.  The discussion has been "remove it from there."  And I'm saying the workgroup decision was correct.
	DR. FLEISCHMAN:  On this point or a different point?  Different point.  Hold on a second.
	MS. MYERS:  Can I just say something?  It's usually the sisters and brothers of very sick kids who do this and serve as the controls in my experience because you have one kid with leukemia and Mom and Dad will say to a sister of brother, are you willing to take that PET Scan so that they can find out what a normal child looks like.
	DR. SHAMOO:  Abbey, usually in those cases there is the quote/unquote "condition."  It's a genetic disorder or whatever other disorder.  It's a condition and therefore that can happen, and there are own existing definitions.
	But we're talking about stranger, healthy, and we're asking them to do bone marrow biopsy.
	MS. MEYERS:  If you'll leave the sentence that way then --
	DR. R. LEVINE:  I think you've misinterpreted. 
	MS. MEYERS:  -- you can't allow the sisters and brothers to volunteer even though they're healthy.
	DR. FLEISCHMAN:  Let me see if I can help move the discussion toward the examples because I think the examples do help to clarify a little bit of this.  Let's look for a moment at Example 4.  Example 4 was placed there, perhaps not fully artfully but we tried hard, with the help of an oncology member of the workgroup.
	If you look at the last sentence which I think was critical piece to why we wanted Example 4, "Even if there might be some children who would be willing to assent and some families who would be willing to give permission for such a study, the IRB should not permit it to proceed as proposed."
	That example, and it may not be a perfect example.  You may want to help us change it or make it better, but that example was created in order to make the argument that Adil was making.
	DR. SHAMOO:  Well, I am supportive of whatever it is, but I just don't want to change it.
	DR. FLEISCHMAN:  I'm just trying to make clear that the workgroup does believe that both in level of risk and by adding procedures, one increases the potential risks and harms that an IRB ought not allow it, even if we could find parents who would, based on their belief about altruism or their belief about the disorder, would subject their youngster to that level. 
	Bob.
	DR. R. LEVINE:  I also want to add that the vivid imagery created by Dr. Shamoo has nothing whatever to do with reality.  If that imagery had to do with reality, I don't think there's anybody who would allow the child who had a condition to submit to this sort of thing.  Thank you.
	DR. FLEISCHMAN:  Comment?
	MS. MULLER:  Hi.  I'm Carol Muller from the Johns Hopkins Bioethics Institute.  My question is the sort of juxtaposition of page 1, in fact, the last full paragraph there, how you say specifically you want to index routine risk with that of a healthy normal child and so on even if some kids in there particular neighborhood or their particular life are exposed to more risks.
	But then on page 3, the last full paragraph there, you discuss how your notion of condition would include things like living in poverty for example.  And I'm just having a bit of a hard time reconciling those two kinds of goals especially, I hate to mention the Kennedy Krieger study but I feel like it's relevant-- the whole issue of whether children living in poverty who are exposed to lots of risk anyway, some researchers think it should make us more inclined to protect them particularly.  Whereas, others say, hey, they're already going through a lot of risks, so even if they're not going to benefit, they may contribute to the general knowledge of kids living in poverty.
	So will you just clarify why you make the notion of condition broad and are you concerned about that sort of risk?  Thanks.
	DR. FLEISCHMAN:  Let me just briefly go back to, our goal was to make a distinction between the two categories to work through the regulations which allow in 404 certain levels of risk called minimal, in 406 a minor increase over minimal.
	So it was our intention to make minor increase over minimal relative.  It was our intention to allow for the study of socially determined issues around health.  It was our intention, and I believe it was the National Commission's intention, to allow researchers to place children at some level of risk above minimal in order to learn things of vital importance that's generalizable about their conditions without getting into the specifics of the study which you mentioned, and I'd be happy to with you later if you'd like.
	But the point that you're making is precisely what we were trying to explain, that there is a difference, that we like the minimal risk standard to be interpreted quite strictly, clearly, indexed to the average normal child.
	That the IRB then might, based in minimal risk, have certain procedural approaches to research, streamlining the methods they use to review real minimal risk research, spending more time on research proposals that have a minor increase over minimal because they have standards they need to adhere to.
	This was our intent.  If we haven't done it, you need to help us to figure out how we can do it better, but it was our intent.
	Now, I'd like to go on to these examples because they're going to stop me at 10:00.  I've stolen a couple minutes from the National Children's Study, but I do want your comments if they're relevant to making us clear and clarify this because this is hopefully going to move forward soon.
	MR. PRITCHARD:  Iva Pritchard, U.S. Department of Education.  I'm not sure that I'm going to be able to make this anymore clear, but I have a difficulty that I think is pertinent and that has to do with what I see as still a double standard which is operant in the definition of minimal risk which I think I can illustrate by asking the following survey question which is, how many of the parents in this room allow their children to swim or to cross the street to visit a friend?  I'm guessing I'm not the only person whose hand is up without looking.
	DR. FLEISCHMAN:  Make your point.
	MR. PRITCHARD:  Both of these things seem to me to be risks that are substantially greater than the risk that are involved in the medical procedures that are being talked about as being above the minimal risk standard, and so it still seems to me that we're dealing with a difficulty that has to do with how you assign what counts as risk if we look at it in terms of something that's commensurate with the risks that parents will allow normal healthy children to incur.
	DR. FLEISCHMAN:  Well, I think the National Commission and our workgroup both agree that socially allowable risks which parents allows their children to undertake on a daily basis in the average communities. So crossing the street -- I always use to say Gunhill Road in the Bronx -- is a little more risky than crossing a small street in Scarsdale.
	So we're not indexing to crossing Route 287.  We're indexing to the average healthy normal child crossing a street after having been educated by his parents and being socially allowed because his parents have educated him to cross the street.  His parent also allow him to swim after he's been taught how to swim and after he's passed certain standards that his parent allow him to swim.
	Those are the daily lives of children in our society.  Now, you point out that those medical interventions which we do that are not part of the daily lives of children either in the normal routine physical exam or educational process or psychological exam or dental exam, anything more than those routine things are considered by these regulations more than minimal even though it's not intuitively obvious that the risks are so much greater.
	It's because our society through its parents have created certain allowable risks, which parents agree they don't keep their kids under a blanket all day, they've agreed that children will be in a society and therefore, we've indexed our level of minimal to that level.  It's not consistent necessarily, and it wasn't meant to be.  It was meant to be consistent with those routine risks that are socially allowable that parents allow their children to be subjected to.
	What we said in these regulations and in our workgroup, that we won't accept the social problem of a child living in an environment that on a daily basis creates greater risks.  We won't accept that as minimal.  We're indexing it to those average normal healthy children, and I'm looking for -- Elliot, thank you.
	DR. DORFF:   Another one of the examples.  The one example that you give on the behavioral and social science research is Example 3.  And it is a good example I think of minimal risk.  But I think there also, you want to give an example of something minor increase over minimal risk just so that IRBs have a sense because the whole point of these examples is to give people concrete examples of what constitutes minimal risk and what's a minor risk over minimal risk.
	So if you had a case that would do that, I think that would be good.  And then you want to differentiate it against significant risk.  So if you had a case -- and this is just frankly off the top of my head as I was reading this last night -- but living in a high-crime area and you're doing some kind of sociological research about interventions in trying to make sure that kids don't end up in gangs.  And if you were to do -- what kinds of interventions would be just minor increase over minimal risk?  I mean, is there something there?
	In contrast to something that might be significant risk, I was thinking of studying children who are the victims of abuse that are not yet extricated from the context of abuse.  In which case if they tell about what their parents have done, that might yet be the cause for further abuse.  So that would be significant risk.
	What I'm looking for is, and you don't have to use my examples, but what I'm looking for is an example in the social sciences of minor increase as against significant increase.
	DR. FLEISCHMAN:  Let's not try to unpack that here.  We'll go back to the table and see if we can unpack it.  It is very complex, and the more that we get into complex examples, the more difficulty we have of sorting it out, and some have argued we need whole-case studies in this guidance.  And in fact, there's a book that I think we're going to see soon coming from some pediatric ethicists that will give case examples and analyses which may be helpful, but we'll try.
	The problem is that when we've tried, we've gotten into such complexity that we've had to go through a whole explication and then it becomes questionably beneficial in my opinion, prior abuse.  But we'll give it a shot because I think you're right, it would be helpful.
	Yes, please.  Tell us who you are.
	MS. FLENSER:  Sally Flenser [ph].  I'm from the Children's Bureau, Department of Health and Human Services, and I came up to say in the social behavioral examples, let's think a little bit about abuse and neglect because it is quite complex, but it is an issue that IRBs struggle with quite frequently.  And there are some examples for abuse and neglect cases that are less complex than others.
	And I'm thinking of gynecological mapping so that you have a range of injury and normal physiology with very young children who are suspected of being sexually abused.  So there are some examples that would be easier to explain than others.
	DR. FLEISCHMAN:  We would be quite pleased if you'd send us some thought-through examples, and we can evaluate them and see if we could use them.  We would appreciate that.  This is tough work.
	All right.  Let's finish up with the examples.  Any other comments on the examples?
	[No response.]
	DR. FLEISCHMAN:  Dr. Harris.
	DR. HARRIS:  Very quickly.  Just to echo what Abbey Myers said.  Siblings commonly will be involved and these questions will come up, so it might be worthwhile just to keep that in mind in your consideration because the siblings, as I was saying yesterday, are often acting for altruistic purposes and it isn't necessarily the parent goes to the child and says, we want you to do this.  But it often happens the other way is, we want to do something for our sibling who we see suffering and afraid to bring our friends to the house.
	DR. FLEISCHMAN:  Madame Chairperson, our goal would be to try to integrate some of these issues.  I would hope that he could share with the committee a final draft for their fax approval, rather than wait for the next meeting.
	CHAIRPERSON MARSHALL:  I think that would be wonderful procedurally.
	DR. FLEISCHMAN:  And let me suggest that the workgroup will do in next three tasks -- oh god, Professor.
	DR. GELLER:  No, no, no.  It's a really quick question.
	DR. FLEICHMAN:  Have you ever been to Johns Hopkins?
	DR. GELLER:  Just a really quick question about where genetics research fits into this.  Is it a whole separate report?
	DR. FLEISCHMAN:  Yes.
	DR. GELLER:  Okay. My only concern that the venipuncture not be explicitly thought of in terms of its physical risk but the purpose for which the blood is taken.
	DR. FLEISCHMAN:  Thank you.  The workgroup will be moving into prospect of direct benefit, 406, and we'll be working on compensation and incentives, and we'll be working on assent/consent with a particular emphasis on adolescent consent.  Those are our goals over the next decade.
	[Laughter.]
	DR. FLEISCHMAN:  Months.
	CHAIRPERSON MARSHALL:  We've got you for life, Alan.
	Thank you so much.  And I want to say that I am very much encouraged by the wonderful reception that this document has gotten, and thank you all for your comment.
	Alan, you and the members of the workgroup have done superb work and it's very encouraging to hear a warm reception for that work, so thank you very much.
	I have one housekeeping detail before we move on to the next session.  But those of you who are our panel members, please come on up front.
	I would like at lunch today for the committee members and the ex-officios if we could all get together in the Corduroy Restaurant, we've reserved the front part of the restaurant.  I just have some housekeeping things, planning issues that I would like to talk to you all about that are not contentful in terms of our work.
	And what I'm going to do is, I'm going to send around two menus and ask you to write on here in an expeditious way, so that we can get these to the restaurant what you would like to have for lunch, and then I'll get those to Keisha.
	So all of the ex-officios, committee members, please within the next ten minutes, and then let me know when you're done, and then we'll get this to Keisha.
	Whenever the last ex-officio member finishes signing up for lunch, just raise your hand and I'll grab the list and take it out.
	So we will continue the discussion about children, and we have asked three folks to come and visit with us this morning to brief the committee and all of us in the room on the National Children's Study. You may have read from the description in the briefing books or the handouts, this is a tremendous endeavor, perhaps the largest longitudinal study that's even been done or proposed to be done, still in the proposal phase, on children.
	The Children's Health Act of 2000 authorized the National Institute on Child Health Development to create sort of this anaconsortium of agencies to conduct a national longitudinal study of environmental influences on children's health and development.  And this study is going to be very broad.  At least as currently described, it would investigate the interaction between biologic, genetic, social and environmental factors to better understand their role in disease etiology, and also to increase our understanding of health disparities in children.
	And so we've asked three folks who are associated in working on this proposal to join us and to describe the study.  First will be Dr. Peter Scheidt who is with NICHD.  Second will be Dr. Gail Geller.  Gail is an associate professor at the Johns Hopkins Medical Institution at the Department of Pediatrics, and well-known bioethicist in the field.  Welcome, Gail.  And Dr. Joel Frader, who is a pediatrician, who is at the Feinberg School of Medicine at Northwestern University and in their program in medical ethics and the humanities.
	So thanks to each of you for joining us this morning, and we really look forward to hearing about the work that you're doing on this proposed study.
	Dr. Scheidt.
	DR. SCHEIDT:  Thank you very much.  It's a pleasure to talk with you about what we now call rather immodestly "the National Children's Study."  And I'm here representing the Interagency Coordinating Committee of about 12 staff and scientists from each of the lead agencies who are supporting this planning phase of the National Children's Study from the Health and Human Services, NICHD, of the Centers for Disease Control and the National Institute of Environmental Health Sciences and then the U.S. Environmental Protection Agency.
	I'll just very briefly run through some of the background and process of this planning phase.  This project stems from the understanding that children do indeed have an increased vulnerability to influences from environmental exposures, and it stems from several aspects.
	First of all, there are critical windows in the development of various systems in the children where they're especially vulnerable and especially early in development during interuterine growth and infancy and early life.
	Their mechanisms for detoxifying and protecting themselves are often immature, their certain enzyme systems -- cytochome P450 enzymes and others -- that in young infancy simply do not protect them to the extent that older children and adults do.
	And there are differences in physiology and metabolism that place them at extra risk above adults, even in the same environmental circumstances.  The body surface area per kilogram is much greater in young children and infants than with adults.  The respiratory ventilation rate is significantly greater, leading to increased absorption through ventilation compared to adults.
	And they behave in ways that in the same environments place them at risk.  They crawl, they mouth, they swallow, they pour things on themselves as shown by this slide, and behave in ways that simply increase their risk compared to adults.
	We have a number of examples that are sort of case studies in this.  The effects of early-life exposure to lead is a good example.  Prenatal alcohol exposure in the fetal alcohol syndrome and mental disabilities that result from that, and a number of other examples illustrate for us this increased vulnerability.
	Given that, the president of the last administration formed a task force, the President's Task Force on Environment Health Risks and Safety Risks, and in 1998 charged this task force to develop strategies to reduce risks of environmental exposure to children.
	And this task force was chaired by Secretary Shalala and Administrator Browner of the EPA and HHS and staffed by seven other cabinet members, but staffed primarily by the scientific staff of the respective agencies.
	And this scientific staff of the task force very quickly recognized when attempting to answer the charge from the president, that clearly there was insufficient information to develop strategies for controlling the risks of environmental exposure to children and more information was needed for them to be able to understand what those risks actually were, and therefore that it would probably be necessary to undertake additional study to define and quantify the risks that would lead to strategies for prevention.
	They subsequently convened a consultation of experts from all of the current and recent very large longitudinal studies both in the U.S. and from around the world.  The ALSPAC, the Avon Study in England, the Framingham Study, the Old Collaborty Perinatal Study, the Women's Health Initiative, Kaiser, the Nurse's Study and the Birth Cohorts from Denmark and Norway and other studies.
	And the experts from these studies convened and advised the task force.  And on carefully considering the feasibility and advisability of the need for a large study that would address the concerns of the task force, they did conclude that such a large study would be feasible and should be done, but also stipulated that it should be large and bold in its planning, that it should involve the many agencies that have a vested interest in these issues, as well as various public/private partnerships in carrying out the study.
	And then they emphasized also that such a large and complex study, it was not feasible to undertake such a study with contributions from existing budgets of current agencies, and it would require new additional appropriated money to carry it out.
	The rationale, to just sort of re-emphasize is, the understanding that children do have an increased vulnerability to environmental exposures as evidenced by the experiences with lead, alcohol and other examples, that we know there are current exposures of relatively high prevalence experienced by our children such as pesticides, thiolates and other both chemical, infectious and physical exposures, and that no current studies exist that are capable of establishing the presence or, equally important, the absence of adverse affects from these exposures.
	And that clearly additional study is needed to identify the effects and to assure safety to our children and that the appropriate design to do this is a longitudinal study in order to link exposure to outcome and to be able to at least infer causality and to examine the multiple exposures that are of concern and to examine the multiple outcomes that could result.
	The lead agencies involved in this planning process then quickly got to work and brought some staff together and began the initial work of planning this study and formed the Interagency Coordinating Committee.
	Shortly after that, in the fall of 2002 Congress passed the Children's Health Act which Mary Faith has already alluded to, and this authorized NICHD to conduct a national longitudinal study of environmental influences on children's health and development and went on to define environment very broadly to encompass not only the chemical exposures that initiated the discussion, but physical, other biologic exposure, psychosocial and cultural exposures as well.	And that the lead agencies took as serious marching orders to carry on the planning of this study.
	The concepts of this study as defined by the Interagency Coordinating Committee are that it be a high quality, longitudinal study of children, not only children but their families and their environment; that it be national in scope; that environment be defined very broadly, not only chemical but physical, behavioral, social and cultural factors; that it be capable of studying and identifying low levels of but prevalent exposures, and relatively less common outcomes.
	And in order to do this would require about 100,000 children to be identified as early as possible in pregnancy and followed to adulthood.  So that's the scope at least on an order of magnitude of the sample that's being considered for this study.  It however will not be capable of studying rare outcomes as a result of rare exposures.
	That it include a study of how environmental factors influence genetic expression; that it embrace to the extent possible the state of our technologies applied to tracking, to measurement and to data management; that it involve a consortium of multiple agencies in the planning and carrying out of this study as well as extensive public/private partnerships; and that understanding that the study is and will be hypothesis driven.
	In addition to that, however, such a large and extensive study will also serve as a valuable national resource for future additional studies and hypotheses not yet part of the planning, and that the planners should plan and collect data in such a way as to optimize this opportunity.
	Who are we talking about for the population?  Well, as I mentioned, it is intended that this study and the sample be as generalizable as possible to the U.S. population, starting with sort of the gold standard as a pure national probability sample with the entire birth cohort of the U.S. as the sampling frame. And variations on that are being considered, but it should be as generalizable as possible.
	There are additional subpopulations that are of special concern.  The planners are considering, but not yet decided the extent to which this can look at how environmental influences affect fertility and development very early in pregnancy which would then require the identification of a sample of women who are not yet pregnant, and that's very problematic and not yet solved but that's being looked at.
	There are other high-risk populations that will need to be considered, such as agriculturally exposed populations, highly industrially-exposed populations and of course underserved and economically disadvantaged and minority populations.  And we anticipate some degree of oversampling of subpopulations to be able to look at those issues.
	This slide shows some of the implications of the sample and the kinds of things that can be included.  It portrays the sample sizes required to recognize a relative risk between 1.5 and 2 for various conditions, and in the first column aside the conditions are the assumed rates of those conditions.
	And one can see that for certain kinds of conditions such as serious head injuries at a rate of about 5 per 10,000 would require a sample of about 100,000 to even recognize a relative risk of 2 with a high exposure to half the population and low exposure of independent variable to the other half.
	Autism on the other hand -- well not on the other hand -- is well poised to be a condition included in this study with a relative risk of 2 per 1,000.  With a rate of 2 per 1,000 one would need about 80,000 sample to recognize a relative risk of 1.5.
	Cancer on the other hand, even combining all children's cancer as an incident outcome is too rare to be a prime incident outcome for this study, and yet the NCI is very interested in this study because of the ideal control group that it would provide for the 100 percent U.S. Cancer Registry to look at biologic and genetic markers for cancer.  There would be about 50 to 70 children in this cohort with childhood cancer just on the cusp of being statistically significant.
	There are other conditions such as birth defects, hypospadias and spina bifida that could be included in this study.
	As I mentioned it is the intent that this study be hypothesis driven, that if we're going to do things even of minimal risk to children and spend resources to collect measures, to include extra samples, the planners have stipulated that a plausible hypothesis be required in order to justify those inclusions. 
	However, we do recognize that there is no single hypothesis that's the driving force for this study, but a number of hypothesis in various areas that will serve to define the study design and the measures to be undertaken.
	Criteria for these hypothesis are that they be of public health significance with regard to prevalence, severity, mortality, morbidity, et cetera; that there be a need for longitudinal assessment in order to answer the hypothesis; that it be feasible; that it require a study of this size and it be answerable by a study of this size -- this is not a study for otitis media, for instance, a condition of very high prevalence in young children that doesn't require this kind of study; and that there be a plausible theoretical rational.
	Some sample hypothesis and these are only sample hypothesis, but these are the kinds of things that are emerging for consideration-- that exposure to endocrinactive compounds such as thiolates which are common in our every-day environment and especially hospital settings; during gestation increases the risk of hypospadias and cryptorchism; that placental compromises associated with later hypertension and insulin resistance; that household pesticide exposure is associated with delayed and abnormal neurodevelopment of infections and particulence on asthma depend on genotype; that socioeconomic disparities mediate and modulate environmental effects on child health and development; that chlamydial infection in infancy increases the risk of coronary artery disease in later life; that suboptimal fetal growth is associated with insulin resistance and heart disease; that repeat subclinical head injury is cumulative for poor neurocognitive development.  These are just a few examples, understanding that this is hypothesis driven.
	However, this very busy, complicated, sort of fun slide portrays what I think is the real strength of this study, and that is the opportunity to look at multiple exposures and multiple outcomes and the mechanisms and influences that affect those relationships in the same study.
	For example, one might look at how social environment results in effects on birth defects, development and behavior and growth all at the same time, or look at how infections, social environment and physical environment altogether interact and affect asthma as an outcome.
	And the opportunity to have the combination of these multiple exposures, multiple outcomes and then to be able to examine gene expression as a mechanism of how that occurs or to examine healthcare as a modifier for virtually all outcomes in the same study we think represents a unique strength of this undertaking.
	How do we go about planning such a complicated and extensive study?  We started with the Interagency Coordinating Committee from the lead agencies as I've mentioned.  And then in order to plan and develop the expertise at both the depth and breadth of expertise felt that we needed working groups under the auspices of a chartered advisory committee with sufficient expertise in enough areas to help and advise with regard to planning this study.
	And we've constituted 22 working groups that are comprised of both federal scientists and non-federal scientists from academic and other areas outside the federal government now totaling about 250 individuals to develop hypotheses with us and to help advise on design elements of the study and the measures needed.
	The organization looks something this.  These numbers of boxes in the middle are the 22 working groups, some of which are focused on methodologic issues, such as the Ethics Working Group of special interest to this committee; the Study Design Working Group that's task is to pull together this into a coherent study design; the Gene Environment Working Group that involves a number of specific areas.
	And many are hypothesis generated working groups such as asthma, birth defects, development and behavior particularly focused on outcome measurements, exposure to chemical agencies, fertility and early pregnancy, health services is a working group, injury. I won't read all of them, but you get the sense of early-life infections, medicine pharmaceuticals, and et cetera.
	All of these working groups with non-federal members are accountable to and under the auspices of the chartered Federal Advisory Committee of which Alan is a member who, in turn, consider the findings of the working groups and pass recommendations to the Interagency Coordinating Committee and especially to the director of NICHD who is accountable to Congress for this study.
	We have also constituted an entity called the Federal Consortium which is official representatives from the approximately 25 federal agencies that are involved in planning this, and that basically is intended to be a forum where the agencies can more or less have their day in court or duke it out over resource allocation and place and position in the study and the interests and their priorities.	And the infrastructure for this planning phase is provided by the program office at NICHD.
	At the very bottom is what we call the "study assembly" which is the simply the sum total of all of the individuals, organizations, agencies and whoever who express an interest in participating and being involved with or staying in touch with the study in any way.  And that list serve currently numbers a little over 1,200.
	The projected time line for this study, we are now two years into what we see as a five-year planning phase.  It is projected to begin the enrollment of the very first subjects in mid-2005.  Between now and then are finalizing the hypothesis and carrying out the any number of pilot studies necessary to develop the measures in the study design elements.
	And then we anticipate the very first preliminary results from pregnancy and early infancy to be available in approximately 2007 to 2008. And we plan continued waves of analysis and reports through the life of the study as the cohort ages. So we anticipate first results being available in approximately 2007-2008.  So you don't have to wait until 2030 for the first results of this study.
	Some of the pilot studies underway, there is a systematic review of core and potential hypothesis.  Most importantly is systematic review of and comparative analysis of the sampling strategies that need to be considered so that these decisions are made informed by some of the very best thought about the implications of different approaches to sampling, and a number of methodologic measurement development pilot studies that are underway.
	That pretty much covers a quick review of the nature of this study and how we're going about it.  We invite you to come visit us at the website that we have. The address is here at NationalChildrensStudy.gov and to communicate with us any questions or particularly desire to stay in touch with the study, our e-mail address is NCS@mailnih.gov.  Thank you.
	CHAIRPERSON MARSHALL:  Thank you very much, Peter.  I think this is what I would like to do procedurally.  I should have made a break in between the two morning sessions, and I didn't.  If you could just hold your questions until we come back, ten minutes, and I mean ten minutes. I'd like everybody in the room back in their seats at twenty minutes to 11:00, please, ten minutes.  Thank you, Peter.
	Can I ask if there are any ex-officio members in the room who haven't signed up for lunch?  Any ex-officio members who have not signed up for lunch?
[No response.]
	CHAIRPERSON MARSHALL:  No.  Okay, great.
	[Brief recess taken at 10:26.]
	CHAIRPERSON MARSHALL:  I think we're ready then.  So let's begin then with a couple of questions, back questions that we might have of Peter about the study in general and then we'll move on to Gail and Joel.
	DR. KORNETSKY:  This is obviously a very ambitious and a very important study, and you described it very, very well, and in the documentation that we got also alludes to the many ethical issues that are going to come forth.
	In your presentation you didn't talk about how you are building in either public advocacy, the public input, and also I'm bringing that up because I think some study like this is going to require a lot of public trust when you get to the point of recruiting subjects.
	And from my own experience, in dealing with the science and the hypothesis, is you're taking those things into consideration as you're building.  You may be better off.  And I'm just wondering where that falls into this.  Is there some advisory group or someone looking at that?
	DR. SCHEIDT:  The mechanisms thus far to sort of respond to the involvement of the public in this are that, first of all, we had projected, and already it's beginning to involve that there will be an ethics subcommittee of the advisory committee, the Ethics Working Group, and that's sort of at a fairly high level and fairly overarching level.  And Gail and Joel are both from the Ethics Working Group that deals with both overarching ethical concerns and specific methods development and pilot studies that need to be done to address ethical issues and so on.
	There is also a Community and Outreach Working Group that is planning how to interface with communities, and we anticipate the need for regional hearings.  But we wanted to get a little closer to what the sampling will look like so that we can identify the communities if it is community based.  And as soon as those decisions are made to work very directly with the communities that are involved, and that's as far as I can go.  I'm sure Gail and Joel will have more comments about that as well.
	DR. GELLER:  I just want to ask to defer possibly questions like that because I'm sure we'll come back to them in great detail after Joel's presentation.
	DR. KORNETSKY:  It was just that it was completely missing from his presentation.
	CHAIRPERSON MARSHALL:  Sandy?
	DR. CHODOSH:  Having been sort of involved from time to time with the VA Normative Aging Study and knowing what the drop-out rate was and that was actually very superior, is that 100,000 that your talking about really account for 100,000 at the end, or are you really counting on 80,000 at the end because of dropouts? I'm just curious.
	DR. SCHEIDT:  Yes.  And the answer is, in the absence of the final hypothesis, that's not yet determined.  And it depends on what power the hypotheses demand.  That's the order of magnitude that we're planning at the moment.
	DR. CHODOSH:  Thank you.
	CHAIRPERSON MARSHALL:  Felice.
	DR. F. LEVINE:  I just wanted to say before we get more specifically into the ethical issues that I have been so overwhelmingly impressed with the whole process and the openness under which this whole study is being designed.  I'm on a number of the list serves. I find the opportunity to contribute and share ideas are made very accessible.
	And in that sense, I think what I wanted to say before we got into the specifics of the ethical issues is that there's almost a very ethical process in place to be able to frame questions really quite broadly across the research community and well beyond, so I really applaud the study substantively, but also for the process in place.
	DR. SCHEIDT:  Thank you.
	CHAIRPERSON MARSHALL:  Anyone else, ex-officio members, laymembers in the audience have backed questions or questions?
	[No response.]
	CHAIRPERSON MARSHALL:  All right.  Dr. Geller.
	DR. GELLER:  Thank you.  I'm happy to be here.  As Dr. Scheidt mentioned, Joel Frader and I are both on the Ethics Working Group of the National Children's Study and so we decided to sort of split up the territory.  It probably won't be exactly purely divided.  There may be some overlap.
	But I'll spend a few minutes trying to put the National Children's Study in the broader context of population-based epidemiologic research.  And then Joel will talk more specifically about how the Ethics Working Group of the National Children's Study has been discussing some of these issues.
	I did hand out a one-page handout of a few of the slides that I'll be reviewing, and I also handed out a recent article that I came across written by someone named Mumford whom I assume is the PI of the Avon Children's Study that Peter Scheidt mentioned for your interest.  It's very much on point.
	And let me say I was trained in a school of public health, so public health research is near and dear to my heart, although I'm sure that some people in the audience are far more expert than I am on issues of epidemiologic study, design and some of the ethical issues raised by them, so please forgive me if my review is extremely oversimplified.
	Several years ago in 1978, Marvin Susser and his colleagues wrote a seminal paper on the ethics of epidemiologic research and they said, "The examination of ethics in epidemiology is in the examination of the ways, the values of the science and its potential benefits to public health are balanced against the values of individuals and communities."
	And there's been a lot of discussion in the literature and certainly lots of guidelines established about the ethics of epidemiologic research.  Some people would argue that the model of public health requires some sacrifice on the part of individual rights in favor of what we stand to gain or learn for the health of the public in general, coupled with the likelihood that a lot of this research involves fairly minimal risk, at least from a physical point of view.
	Some people argue that we may actually need to be a little bit less stringent in our human-subjects protections guidance about this kind of research.
	Other people like Larry Gostin [ph] argue that, no, in fact population-based epidemiologic research raises some additional ethical concerns that have to do with stigmatization of communities or groups.
	I want to put the National Children's Study in context of other broader population-based epidemiologic research.  The National Child Study is an example of a longitudinal study, and this is different from other kinds of population-based epidemiologic research like, good examples would be, HIV zero-prevalence studies or studies that involve secondary data analysis of anonymous data.
	So this study is different and longitudinal studies are different because by definition longitudinal studies require that identifiers be collected and maintained for the purposes of follow up.
	One of probably the most infamous longitudinal studies that involved the collection of new data on identifiable individuals is the Tuskeegee Study.  You all know about the ethical violations involved in the Tuskeegee Study including exploitation of an already underserved and stigmatized population, deception about the goals of the research, complete absence of any consent process or informed consent, complete absence of feedback of the results of the study to the participants, and in my view probably the most serious, the withholding of effective treatment once it had been established.
	The point I want to make here is that although these violations may be particularly egregious in the Tuskeegee Study, many of them, perhaps with the exception of the issue of informed consent, the violation of obtaining informed consent, many of them are concerns that are characteristic of all perspective longitudinal studies.  That is, we need to be concerned about potential targeting of already underserved or stigmatized populations.  We need to be concerned about providing benefit to the population once benefits are actually discovered.
	Dr. Scheidt mentioned a lot of the more current examples of perspective longitudinal studies-- the Framingham Study, the Nurse's Health Study, there's a Johns Hopkins Precursor Study which involves male medical students.  There are lots of examples.  He mentioned the Avon Children's Study.
	I want to call your attention to the term "observational" because this term is used in different contexts even within epidemiologic research, and I think the term in some ways generates a lot of the ethical challenges to conducting this kind of research. That is, sort of what make longitudinal observational research ethical and what makes it less ethical or perhaps unethical.
	Descriptive studies, the idea in epidemiology is that you should start out doing descriptive studies which are purely observational and the intention is to discover the distribution of health states in populations to determine what services may be needed, what changes have occurred and what control measures should be applied.
	The idea here is that you obtain this descriptive data and then you proceed to analytical studies.  And the purpose of the analytical studies are to generate and test hypothesis about the causes of particular health disorder.
	Analytic studies fall into two categories.  One is observational and one is experimental.  The observational studies can include case-control studies where you actually begin with cases of particular diseases.  And the other example of an observational study is a cohort or longitudinal study.
	And the National Children's Study in some ways has features of both of purely descriptive studies and longitudinal cohort studies.  It's certainly not purely a descriptive study because as Dr. Scheidt mentioned, it is based on the generation and testing of hypothesis.  So as a hypothesis-driven study, it's much more like a cohort longitudinal study, and some of the morally relevant differences between observational studies and experimental studies where there actually are interventions offered and potentially the prospect of benefit to participants.
	So with all kinds of research there's the prospect of benefit to society or the knowledge that we gain from doing the research.  But with observational studies, they're not intended to benefit individual participants. Whereas, often in experimental studies, most notably the randomized control trial, there is potentially a prospect of direct benefit to participants.
	And also in observational studies, not like the National Children's Study, the risks tend to be more social than physical.  Yes, there's a risk of venipuncture associated with blood drawing physical risks, but by and large the risks tend to be much more social than physical.  Whereas, in many experimental studies, the risks are often, they're sometimes fairly great risks at the physical level as well as social risks.
	Also the populations can be different.  In observational studies as is true in the National Children's Study, population is not being selected based on a particular known illness that the participants have.  They tend to be healthy children.  Some may be unhealthy, but that's not the basis on which they're being selected.  Often with experimental studies at least some of the participants are selected on unknown illness.
	There's a little bit of fuzziness here in the category of interventional epidemiology.  It's kind of a new term being applied.  And a good example of that would be an evaluation of a community-based hypertension control program for example.  So there's an experimental intervention, but it's done in a community on a population basis, and you're not selecting people based on unknown risk factor or disease.
	Let me just summarize very quickly what the general literature says about the ethical issues raised by population-based observational studies. One of them has already been mentioned.  I mean, there's a huge issue about the design and conduct of these studies, and the importance of involving communities in the development and the design of these studies.  I think Joel will talk much more about that.  I'm going to sort of defer that to Joel.
	I'm going to simply list some of the ethical issues that have to do with interaction with subjects and disclosure of the results -- so for example, subject recruitment and informed consent.
	This has sort of been alluded to that in order for a population-based study to be truly population based, all segments of the population need to be fairly well represented.  As Dr. Scheidt mentioned in this case, we may need to be oversampling some underserved populations or populations where we already know there are recruitment challenges.
	So in populations where there are recruitment challenges, and yet in order for the science to be valid, you really need to make sure there are sufficient numbers of those populations represented.  Oversampling is necessary and oversampling could in turn raise ethical concerns about targeting of populations that are already underprivileged playing into the fears that they already have about participation and research.
	There are concerns about privacy and confidentiality, concerns about interpretation of tests and study results, communication of individual test results to the participants themselves, and communication of overall study results, and that has to do with actually how you publish your findings and whether there's any risk of disclosure of identity of the participants depending on how the results are disclosed.
	There's a concern about how this data will be used by other research groups and whether the data that will be offered to other kinds of groups will actually be in an anonymized form or in a form that involves identifiers.
	One of my biggest concerns has to do with the provision of results back to individual participants when and if we discover certain benefits, certain interventions that may be beneficial to these participants.  And I think that's an issue that we really have a lot to figure out because if we don't do that right, it could look very much like the Tuskeegee Study or at least aspects of the Tuskeegee Study.
	Let me stop there.  There's a lot more that I have to say, but I think that maybe I can come back to some of these points when Joel speaks.
	CHAIRPERSON MARSHALL:  All right.  Thank you very much.  Do you have a fact question or something you'd rather hold?
	DR. DORFF:  Just on the slide.
	CHAIRPERSON MARSHALL:  Just on this slide.
	DR. DORFF:  There's a much broader ethical issue that's not on you list that I think you need to at least think about which is not, as far as I can tell, relevant to the Children's Study truthfully.  But one of the ethical issues in terms of these kinds of studies is for what.  In other words, what is its purpose?  Because I mean if you think about -- I think it was at Harvard in '60s where you had this guy who had done some studies on African Americans to try to show that they were less intelligent or some of the Nazi studies to try to figure out the eugenic stuff, to try to figure out who was a Jew and who wasn't.
	So I mean, the very purpose of the study has to be subjected to moral analysis.
	DR. GELLER:  I'm very glad you raised that point.  It's actually one of the points that I decided to skip before going on to Joel.  I mean, one of the sort of most painful aspects I think of the Tuskeegee Study is that it was funded by the federal government. And one of the things that we don't talk about very much is the fact that the very research questions we choose to fund have values attached to them.
	And I don't know if there's been sufficient discussion about the values that are actually driving this particular study and the interests that are driving this particular study.  The study is already underway.
	But I couldn't agree with you more that given that this is a huge, huge amount of federal resources being invested in a study and that we know that there are sort of moral elements to the research that we choose to invest in, I think it's a highly worthy issue to discuss.  So thank you.
	CHAIRPERSON MARSHALL:  Gail, let me ask you, do you want to have questions now, or should we just move ahead and then have general questions or do you have a preference?
	DR. GELLER:  Joel, do you want to --
	DR. FRADER:   Makes more sense to wait.
	DR. GELLER:  Yes, I think so.
	CHAIRPERSON MARSHALL:  Let's hold questions, please, until after Dr. Frader, and then we'll just open the floor up.
	DR. FRADER:  Well, what I'm going to do is to talk with you about what the Ethics Working Group has discussed with perhaps a little bit of editorial comments since I can't resist. So what you're going to hear is sort of a laundry list of the things that we have been considering.  And I apologize in advance if it's a little bit abstract, but you need to understand that since the study is still in its planning phase and there aren't specific hypotheses that have been chosen yet, it's pretty hard for us as the Ethics Working Group to comment specifically about things that don't yet exist.
	So having said that, the first thing I will say is something that both Gail and Peter have already mentioned which has to do with the general organization of the study.  And despite the fact that, yes, I think it is a very open process, it is nonetheless, at least to this point, very much a top-down versus bottom-up process.  And I think that's quite relevant to Susan's earlier question and to some of the concerns that the Ethics Working Group has had.
	That is to say, to the extent to which communities who may have subjects in the study are or are not part of the planning process, it seems to me we need to be concerned about the ability of those communities to both indicate things that they wish to be included as topics of the study, and also as least have an opportunity to comment on things that they might feel would be inappropriate subjects of the study, even if the professionals might very well like to know about it.
	Now, I'm not suggesting that either of the Ethics Working Group or I know what to do about that, but I do think it's an issue.  And I'd like to make a parallel here to the notion of informed consent.  That is to say that to the extent that we have evolved, if we have, to believe that a better model of patient or surrogate decision making or study subject surrogate decision making involves collaboration and partnership between the patient/subject and the healthcare professional/investigator, that that's something that is desirable; it eliminates some of the unfortunate power relationships between the professionals on the one hand and subjects or patients.
	On the other hand, we might very well see a parallel with respect to communities and that if we take seriously this notion, then we need to have communities involved from the beginning with respect to both choosing topics and indicating to us things that might not be acceptable for the study to consider.
Again, I'm not sure how one would resolve differences, but at least it needs to be something we're looking at.
	A related issue has to do with the degree to which the study is or isn't highly centralized in the control and organization of the study as it goes forward.  And you can think of two different models here.  There's the National Cancer Institute's Cooperative Group Model where everybody comes together in the beginning, they agree on a protocol, they even promulgate model consent forms which they highly encourage IRBs to use completely and not modify and so forth and so on.
	There's that model versus the model which I think, Peter, is the intended model here, which is to put out an RFA and expect people from around the country at various institutions and agencies and so forth to respond within broad parameters of what the goals are, in which case one would get very different kinds of protocols, some of which might be multi-institutional or multi-site studies or not.
	And it seems to me this has at least very important implications for specifying the content and the style of such things as consent forms, interactions with IRBs, what some IRBs would consider to be acceptable and what others wouldn't.
	And then of course we have to deal -- since this is a national study, remember -- with the extent to which state laws regarding consent, assent, reporting of observed illegal behavior, whether it's child abuse or elder abuse, should that be observed when people go into homes, or other illegal activity like drug trafficking that might be going on in the homes, to the extent to which those things might come up, and I think we need to acknowledge that they might, the study needs to have a plan for dealing with those, what's going to happen.
	And again state laws will differ about this. IRBs may well differ about this.  These things need to be taken into consideration.
	And then there is a related issue about the extent to which differing interpretations along the lines that we were talking earlier in the earlier session about federal regulations regarding research on children or in this case research that involves fetuses can or should alter the questions that the study will consider.  And remember here, it's important to point out what Gail already alluded to, which is as a general matter this is a study where there is no expected benefit to individual participants which certainly alters the way things fall with regard to both the regulations on children and the regulations regarding fetuses.
	And that might or might not have an effect on the kinds of questions that one is simply allowed to ask and to try to answer or how one goes about it.  For instance, whether you need permission from two parents or not is a concrete example of how that might be an issue.
	Now, moving along, to get back to this issue that I alluded to in a procedural sense before, the question about involvement of community, that of course presupposes that we know what a community is.  The study at the very least needs to come up with a definition of what constitutes a community.  We want to talk about it in terms of geography, ethnicity, socioademographic factors, et cetera.
	And then when we talk about planning for including communities, are we talking about including leadership in the community?  Well, who is that leadership?  Are we talking about elected officials?  Are we talking about clergy?  Are we talking about voluntary associations?  Are we talking about healthcare professionals or public health authorities in localities?  These are all very important questions that the study design will need to take into account.
	And then we have to deal with the fact that once there is some better definition than we have now of what specific hypotheses are, what the goals of the study are as defined by federal organizers and people like Gail and myself and so forth and so on.
And then with respect to community buy-in, what do we do at a level beyond that when there are specific individuals or groups who we may very well be interested in looking at in particular, say no, no, we're not going to participate because of mistrust of the health-related research in general, ala the Tuskeegee Study, what do we do about cultural influences on such things as privacy and modesty that would prevent us from getting answers to questions that we might want to ask people who are Islamic or Orthodox Jews or so forth and so on.
	What do we do in a similar line along questions about the role of particular individuals and their decision-making or the authorization for participation?  There may very well be communities where the men are expected to make the decisions for the women.  Is that acceptable to IRBs?  Is it acceptable to the study?  How are we going to deal with that?  Going to have to deal with matters of gender identity, sexual preference, sexual behavior that will be topics of investigation but may be culturally sensitive, and we have to be thinking about that.
	So there are a whole host of these things at a level of I think quite significant detail as well as generalization that the study has yet to really come to grips with.
	Then there are sort of more obvious, more mundane things about what do we do about the limits of understanding of proposed study participation that are based on culture or based on literacy or based on language difficulties.
	For instance, as I'm sure many of the people in the room know, the federal regulations will allow for short form agreement to participate in consent which basically says that if you present somebody with a piece of paper in their native language, assuming they can read of course, that says, yeah, somebody really has talked to me about this study, that's sort of good enough and raises some interesting questions about equity, it seems to me, with respect to those people who get consent forms that are fully articulated versus people who get the so-called short form.  And personally I think short form is crazy-- personal editorial comment.
	As recruitment and retention in the study is going to be the key to success, we then have to think about what incentives, both to participate and to stay in the study are on the one hand practical and significant, but on the other hand not so great as to border on or maybe even cross the border to undue influence or coercion.
	And then I think I'll just end with respect to questions about two things.  One is along the lines of the coercive business.  Remember, we're not talking about benefits to individuals by and large, but we need to be concerned about a kind of therapeutic misconception here, which is the misinterpretation on the basis of individuals who may become subjects, that there will be benefit when they're won't.
	And Gail pointed out to me in a conversation we had on the phone the other day, a particularly important one where women who may be recruited to participate because they are pregnant or likely to become pregnant may want to participate based upon some misconception that either the study will help prevent a teratogenic exposure to their fetus to become baby or will somehow help them with respect to identifying a health concern later on, that we might be able to do something about.  It's actually quite unlikely that we would be able to do that through this study, but I think we need to pay attention to the fact that some people might believe that's what's happening in the study and we need to try to prevent that.
	And then the last thing I want to comment on has to do with the role of the children who are going to be subjects in all of this clearly in the beginning. They're not going to be able to participate personally in some meaningful way, but at some point they will be capable of giving assent and at some further point down the line they will be capable of giving full consent.  What do we need to do to ensure their continued or ongoing buy-in and participation in the research? 
	And then what are we going to do if they say when they're adolescents, which many of them might likely do, sorry, I don't really feel like participating anymore and we're getting to they're being 14 or 15 and we really want to know what's going to happen when they're 17 or 18 or 21?  How are we going to respond to that?  Are we going then offer inducements?  How big are the inducements going to be?  Those are issues that I think the study really needs to think through very carefully, and I think I'll stop with that.
	CHAIRPERSON MARSHALL:  Thank you, Joel.  Let's just open things up for question.  I'm going to move over here in the center just so I can make sure I see everyone.  Let's start with Elliot.
	DR. DORFF:  Just a question of the study design.  I was in college in the '60s when virtually every group that came in year after year was like a new generation.  And what I'm wondering is that if you're going to start with infants and follow that group through, are you going to be really studying only one generation as opposed to starting to study teenagers now in addition to infants and children of elementary school age?
	DR. SCHEIDT:  The intent is to follow a cohort so that the plan is to enroll that cohort in the early pregnancy if not before, over a period of about three years, could be as long as five years, and follow that cohort to adulthood.  We do not plan to have staggered cohorts at different ages starting at the same time because in that event it would not be possible to look at the effects of early life exposure on events in adolescence, for instance.
	DR. DORFF:  You're the expert on this.  I'm really not.  I'm a philosopher.  But what you'll end up with is the study of one generation.
	DR. SCHEIDT:  That's correct.
	DR. DORFF:  But couldn't you also get -- I mean you were talking to the teenagers now.  Couldn't you get at least through some questioning, if nothing more, right, some aspects of their early childhood?  I mean if you have a hypothesis that disease X or condition X is a function of something that happened in earlier childhood, you can ask about those things.
	DR. SCHEIDT:  As a retrospective design.  That's true, but that would only be by report or by some retrospective mechanism, but not by observational or biological or actual environmental samples.
	DR. DORFF:  What if you got their medical records?
	DR. SCHEIDT:  As inconsistent and incomplete as it is, yes, that's possible.
	CHAIRPERSON MARSHALL:  I've got Adil, and I then I have Felice, Abbey, Alan and Jenny.  Sandy.
	DR. SHAMOO:  Thank you, Mary Faith.  I have a comment and then a two-point question.
	CHAIRPERSON MARSHALL:  We only have fifteen minutes, so I'm going to allow one question per person.  Let's refrain from editorializing and give everyone a chance to ask the questions he or she would like to.
	DR. SHAMOO:  I'll jump and then I'll come back.  I'll ask Dr. Scheidt, even though I think my first question to me was more important, but anyway.
	I didn't see in this huge multibillion dollar project, you didn't imbed in it methods of prevention of fraud and misconduct because there will be a lot of pressure to produce fast data and keep up with everybody in this project.  You have bioethicists, that's okay, et cetera, et cetera.  The data management and its integrity is very important here.
	CHAIRPERSON MARSHALL:  Thank you, Adil.
	DR. SCHEIDT:  That's a level of detail we've not gotten to yet.  I'd be very interested in examples of the kinds of risks we face with regard to fraud and misinterpretation.  I guess I have to confess to naivet on that respect. But to the extent we need to be informed about that, please share your information with us.
	CHAIRPERSON MARSHALL:  I would note that this September the IOM will be forthcoming with a report on promoting integrity in research.  That was chartered by the Office of Research, integrity, so we all look forward to that.
	Felice.
	DR. F. LEVINE:  I am wondering whether your committee has begun wrestling with, or might wrestle with the challenging problem when there isn't a commonality of interest between the community and the child and the family, especially in a national study where there may not even be commonality of interests between and among communities.
	And I think when all of this is on the same page and if somebody has done community studies, you know, it fits beautifully.  But it is not always the case that was in the best ethical practices and protection of the individual subject may be at odds with the communities in which they reside.
	DR. GELLER:  Joel could probably say something about this too, but I think we're not even there yet where we totally recognize that as a major concern.  Because of the structure of the study, there's another working group on community outreach.  So we're at the level of actually figuring out what our communication and interactions will be among different working groups that have overlapping concerns.
	CHAIRPERSON MARSHALL:  Alan.
	DR. FLEISCHMAN:  I'd just like to thank all three of you for presenting so well.  And I'd like to say, having thought about this study for two years now, having seen the beginning of the thinking, I think it's bold and exciting and incredibly important for the children, not only of America, but of the world potentially.  It is a unique opportunity, but it has no new ethical problems, except maybe the serial measurement of the human genome as the children grow.  Since we've never done that before, we don't know what we're going to find, but it's incredibly important.
	But even that may not be a new ethical problem.  It's just a new thing that we need to think about in terms of its ethical implications.
	This study also gives us, though, almost all of the ethical concerns of human subjects research with children because ultimately we'll have intervention studies, ultimately we'll be doing various kinds of public health work and various kinds of individual work, and we will also have all the problems -- Gail raised the problem of what are we going to do when we find something that we know has a relationship.
	I think that's easy.  The harder one's going to be, what if we find something and we haven't got a clue whether it has a relationship, how much ought we to tell families, individuals, communities about those things in which there is total uncertainty.
	Those issues again aren't new, but they are incredibly important.  What I would argue as one of the reasons why I hope Mary Faith thought about bringing you here, is that we also have an incredible opportunity to study the process of informed consent, assent, consent, as children evolve, the issues that you're raising.
	This study allows for a careful study of everything about the federal regulatory structure with children and their parents.  So my hope would be -- not today as we're planning this critically hypothesis-drive study because I don't have a hypothesis to test at the level of importance of the hypotheses you're raising.
	But I hope that we are creative enough to remember like the human genome project that sought to think about the ethical, legal and social implications of what they were doing, that this study has the potential to study the ethical, legal and social implications of research in children as we go forward, to mine a very critically important thing and to help us to develop the empirical database which we don't have as a committee which we're trying to make recommendations.
	CHAIRPERSON MARSHALL:  Thank you, Alan.  Really super important to Joel.
	DR. SCHEIDT:  I agree completely.  We've already begun thinking about a step prior to that actually which is to examine what happens when similar things are submitted simultaneously to IRBs across the country and what's going to transpire in that.  So there are some medi-questions that the Ethics Working Group has begun to consider.
	DR. GELLER:  Can I just sort of invite you all to actually submit hypotheses or proposals to us because one of the things that is not completely clear to me is whether informed consent, Ethics Working Group members can actually conduct the studies themselves.  My understanding is that it's nonmembers that have to be doing this sort of research which means that we invite you to submit hypothesis and proposals that you would want to --
	DR. FLEISCHMAN:  Then we only want bad people on the working group.
	[Laughter.]
	CHAIRPERSON MARSHALL:  And I'd invite anyone, ex-officio, public members, please come up to the mike and join the conversation.  Abbey, I'm sorry.  I'm sorry.
	DR. SCHEIDT:  I have a question actually, stimulated by the presentations and Alan's comment which is actually a proposal for a pilot study from the Ethics Working Group.
	What are the markers of reasoning that are markers for the ability to assent and consent?  You might say that you can assent at eight years of age or consent at eighteen, but that's an arbitrary chronological age, and it's only a proxy for what really the abilities to reason.  And are there not better tests for ability to reason that we could define and pilot? Or are they out there that we don't know? I'm not an expert in this area, and I don't know those, but if they're not, we have two years to define them as a pilot.
	DR. FLEISCHMAN:  We have four or five.
	CHAIRPERSON MARSHALL:  Anyone on the committee would like to -- Jonathan?
	DR. MORENO:  Actually your question dovetails very nicely with some things that I'm thinking about in terms of the implications of neuroscience for whether we're learning about reasoning and memory which suggests that the systems in the brain that have to do with attaching a quantum of emotion to a reasoning process turned out to be very important in terms of making the jump from knowing something is the case logically to identifying with is sufficiently to act on it.
	So as children develop, they develop this capacity to integrate these two systems, the reasoning and judging system and the emotional determination system, and this is an opportunity within the neuroscience to dovetail some interesting new work in terms of assent and consent with what you guys are doing now.
	CHAIRPERSON MARSHALL:  Abbey.
	MS. MEYERS:  Okay.  We just had a presentation from a gentleman from NICHD about Lesch-Nyhan Syndrome which is, believe me, the worst disease in the world.  There is nothing worse than Lesch-Nyhan, when he mentioned it.
	CHAIRPERSON MARSHALL:  He's from Johns Hopkins, just to clarify.
	MS. MEYERS:  Oh, Johns Hopkins, okay.  And we were saying that he really can't study healthy children because you can't do it under these regulations.  But now they're talking about studying tens of thousands of healthy children, some of whom will be put at minor increase over risk with PET Scans or MRIs or CAT Scans or blood tests or whatever.
	I mean, I just don't understand it.
	CHAIRPERSON MARSHALL:  Let's clarify the facts.  Let me just ask.
	DR. SCHEIDT:  We do not anticipate doing those kinds of imagings on that scale.  It is not inconceivable that for a specific issue or question that a small sample might be, there might be some proposals to image neurodevelopment in ways --
	MS. MEYERS:  Yeah, but you're talking blood tests, right, from all of these children?
	DR. SCHEIDT:  We do anticipate blood tests.  Now we have not determined that there will be venipunctures done strictly for the purpose of this study.  We do anticipate biologic samples that may infer no risk at all -- hair, buckle smear, cord blood, placenta, breast milk, et cetera.
	It may be that we'll seek to do venipuncture specifically for the purpose of this study, but that's not yet been determined and not assumed.
	DR. FADOR:  Peter, let me just comment that we do need to remember that there's a distinction to be made between physical risk and other risk, so that even hair samples, et cetera, may involve social and psychological risks.
	MS. MEYERS:  So there is some risk for everybody who goes into the study I assume, whether it's just emotional or whether it's physical.  And if they can't study healthy children for the Lesch-Nyhan, how can you study healthy children here?
	DR. FADOR:  But the issue isn't whether one can or can't.  The issue is how one designs the study to afford adequate protections so that the risk is in fact minimal.
	MS. MEYERS:  But there is no disease or disorder here.  Their condition is childhood.
	DR. GOTTFRIED:  Abbey, it's minimal risk research.  We're talking about a large study dealing with kids who are coming in or being born, et cetera, and they're doing very mundane standard operating type procedure data collection.  I think you've really misconstrued what the study is about.
	CHAIRPERSON MARSHALL:  We are at time, so I'm going to give Gail the final response to this, and then we'll have to move on the next session.
	DR. GELLER:  I think one of the concerns has to do with additional studies that will be done on specific subgroups of participants in the study for which I assume additional consent would be sought.  So I think what we need to think about is what is it that the pregnant women are consenting to at the time that they're enrolled and what they're consenting to as I understand it, is a lot of survey data.
	MS. MEYERS:  And if one of these women, pray that women enroll and you happen to find out that they're HIV carriers, are you going to tell them?
	DR. SCHEIDT:  It is our expectation that when we identify risks that are known to be risks, that we are obligated in a timely way to inform any subjects about those risks.
	A good example, this study is not about lead. We know enough about lead to not have to mount this kind of study to study it.  We will measure lead because it's an important confounder of the outcomes that we will want to look at.  And if we identify an elevated lead level in a child, we would view that it's incumbent on us in a timely way to let that family know that there's an elevated lead level so that they can do something about it.  That's the most ready example I can think of, that would be any number of other outcomes that we would anticipate measuring and finding out and sharing with subject in the study.
	CHAIRPERSON MARSHALL:  We're at time, and we need to move on.  I would like to thank Peter and Gail and Joel for coming this morning.
	[Applause.]
	CHAIRPERSON MARSHALL:  A wonderful job they've done, a hugely important study and I think that the invitation was extended to each of us in the room to communicate with you during the design process, to perhaps submit requests for proposals in the future when that stage is entered.  So I think they look forward to hearing from all of us.  Thank you very much. 
	And let me ask our panelists for the next session to please head on up to the table.
	CHAIRPERSON MARSHALL:  This really is housekeeping work getting settled.  Give us a moment.
	[Pause.]
	CHAIRPERSON MARSHALL:  All right.  Well, we're going to change focus, I think, and dramatically go from one extreme to the other in terms of our thinking.  I'd like to welcome back to the table our good colleagues, Jonathan Knight who is the president or chief?
	DR. KNIGHT:  Actually Associate Secretary.
	CHAIRPERSON MARSHALL:  Associate Secretary of the American Association of University Professors; Jonathan Church, who is chair of the Department of Sociology and Anthropology at Arcadia University; Linda Shopes at the Pennsylvania Historical and Museum Commission.
	You've heard from these folks before and we have been asked and they are helping us to address a very important question, very broad question that gets into real fundamental issues-- should all disciplines be subject to the Common Rule.
	And I think we are looking perhaps more specifically here at disciplines within the humanities. We have, as you know, a standing workgroup on the social and the behavioral sciences which Felice Levine most ably chairs and productively chairs.  She's one of our hardest working members on this committee.
	We were charged with this issue by Rick Koski, the Director of the Office of Human Research Protections and I think it is certainly, in terms of its potential impact on the research community, on the academic community, one of the biggest questions that we might consider, and we want to make sure that we give it ample time for consideration and certainly a fair hearing and a thoughtful hearing in terms of our process and our outcome. 
	So I just want to make a couple of remarks at the beginning of this session -- we will stay on time 
-- and that is to remind us that when we were charged by the Secretary for Health and Human Services as a committee, that part of her remarks were that no priority in research is more important than the protection of human subjects and that our system of protection must be exemplary.
	And that is certainly what this committee is all about.  We have a very simple mandate from our government and our people, and it is the safety and protection of human subjects.
	So I think to that end we have to be mindful of our social contract between the scientific and the research enterprise, the academic enterprise and the public, and that if we are to have exceptional outcomes in terms of our deliberations as a committee in our final workgroup products, then they depend on the integrity of our work process.
	So I want to just remind us of the ground rules by which each of us in this room functions as a member of this committee as a discussant and that is that we are fair, that we hear all voices who should be heard, that we are creative and flexible in our thinking, that we have and demonstrate respect for our guests, for our panel committee members, that we are collegial, that we are civil in our deliberations, and I think finally and perhaps most importantly, that we engage in real critical thinking.  And by that, I mean that we are able to suspend judgment when we come to the table and think about new ideas or even ideas that are not necessarily new, but that may be a new approach.
	So I will be heavy handed if I need to in exercising sort of the chair to make sure that we maintain civility in our discussions.  We are going to, for purposes of arriving at a concrete endpoint today, going to proceed along these lines.
	My goal at the end of this session from the committee is to have you consider and I hope give approval for the creation of a, we will call it a working group, to look at the issue of whether all of the disciplines, most especially the humanities or let's say perhaps nonbehavioral social science disciplines or biomedical disciplines, whether they come under the Common Rule, how subjects in research are best protected within those disciplines, recognizing that some of the fundamental issues that need to be addressed are, how we construe research among these disciplines, how we construe the methodology within and between disciplines, what a research subject is or isn't.  We're going to have to get at some very basic fundamentals.
	And so the point of this session is not to hash out these issues.  The point of this session is to identify the issues with which we would like to charge a working group that in the next, let's say, six months would work on this and report back to us at our early spring meeting in January or February.
	So that's the goal.  Does each of you have a list in front of you of the issues?   Kate.
	We've distributed the list to each of the members.  All right.
	These guys don't have a list.
	There we go.  Excellent.  So let me ask Professor Knight, how would you like to proceed?  Do you have remarks that you'd like to --
	PROFESSOR KNIGHT:  I was saying Bob Levine --
	CHAIRPERSON MARSHALL:  Yeah.  But anything that you wanted to say before we move forward?
	PROFESSOR KNIGHT:  No.
	CHAIRPERSON MARSHALL:  No.
	PROFESSOR KNIGHT:  Can you hear me?  Yes, you can.
	Well, my colleagues and I are very pleased to be here again.  We think that the issues presented under the question of "should all disciplines be subject to the Common Rule" are not only very important issues, but they're also very vexing ones.  They have been issues which in one fashion or another have been discussed and debated going back probably to the late 1960s.  I see that Bob Levine in his remarks refers to Athele Disola Pool [ph] who in the early '70s and indeed in '80s was raising questions about the application of the Common Rule to areas outside of the biomedical and behavioral framework.
	Our perspective here I think, that is to say the perspective of myself and my three colleagues, is one of wanting to see how the Common Rule and IRBs with implementing the Common Rule can be made to work more effectively, more fairly, more efficiently when they come to focus on areas of research which historically have not been the major focus of campus IRBs and still today are not the major focus of campus IRBs.  That is to say, most campus IRBs if we look at the totality of the research they review, it's principally in the biomedical and behavioral realm.
	But of course they do take in typically within the jurisdiction all research carried out by faculty on their campuses involving human subjects.
	There are, as I've indicated or suggested, very serious difficulties in these realms in terms of applying the Common Rule to these very different kinds of academic disciplines which have very different conceptions of how research is done, what it means to do research, what indeed is a subject of research.
	But speaking for myself, I'm confident that working with the committee we can make serious progress in trying to resolve some of these very thorny problems of both implementation and indeed understanding.
	A final point in the work that I've been pursuing in this area, one of the things that's clear to me is that the problems are not that we have local IRBs who are dismissive in some fashion of the other disciplines.  Rather, we have IRBs which are terribly overtaxed, overworked, find themselves having to do a great deal and in fact perhaps too much in some respects, and the issue with trying to both explain, not simply only to researchers but to members of IRBs, what it means to do research if you're a historian or a political scientist or you're a journalist or even, believe it or not, a professor of English.
	We've already been hearing situations of professors of English coming under review by IRBs.  So thank you again to the committee.  We look forward to a productive dialogue.
	CHAIRPERSON MARSHALL:  Thank you very much for being here, for coming back.  And I think perhaps you were a little too kind to some IRBS, because I think at least in my own experience I think sometimes things that are nonbiomedical have gotten short-tripped and do get short tripped.  And that's a problem that we need to look squarely at and eradicate if we can.
	My husband often tells me that I put the emphasis on the wrong syllable, so I just want to remind all of us that it's Adil and not Adeel, and that's it's Felice Levine and not Levine, and that it is Robert Levine and not Leveen.  And my mother is sitting in the audience, and if you call me Mary instead of Mary Faith, then I promise you she will hurt you, all 98 pounds of her.
	[Laughter.]
	CHAIRMAN MARSHALL:  So we have asked in terms of being historically accurate, Bob Levine, and he's graciously agreed to, give us an historical account of what the commissioners, the national commissioners were thinking relative to the humanities and other disciplines when they wrote the Belmont Report and brought the Common Rule into being just so that we have some grounding in where we came from, and that will guide us in terms of where we're going.
	So, Bob, thank you so much.
	DR. R. LEVINE:  Thank you.  First, I want to say that since we agreed that I was to give a presentation this morning, I have not been in a place where I had access to proper copying equipment.  What I did though is, I typed out my remarks yesterday evening and enough copies were made to distribute to the people seated at this table.  And I hope somehow they'll be made available to the rest of the people in the group.
	CHAIRPERSON MARSHALL:  They will, Bob.  We'll have made copies for everyone so that they can get them at lunch or during the break.
	DR. R. LEVINE:  Thanks.  In the course of our discussion, our planning for this meeting, the question arose as to whether the National Commission considered carefully what types of activities ought to be covered by the regulations, the regulations that came to be known as the Common Rule, and what types of activities ought to be left out.  I was asked to think about this question and present my reflections at this meeting.
	The answer that I'm going to give you is that the National Commission was aware of the full range of activities that could be considered research involving human subjects.  This is, as I'm going to try to show you, this is not the same as saying that they considered carefully which of these activities ought to be covered by the regulations.
	The National Commission was named by the U.S. Congress.  Implicit in its name is that the charge was to cover both biomedical and behavioral research.  It had no problem understanding what was meant by biomedical research.
	But by contrast the behavioral part seemed rather ill-defined.  One interpretation of the congressional mandate to the National Commission is that by behavioral, Congress meant a body of science that contributed to the development of behavioral therapies.  This could have been read as implicit in the first of the general conceptual charges Congress presented to the Commission.
	In this charge, the commission was directed to consider the boundaries between biomedical or behavioral research and the routine or accepted practice of medicine.
	Well, adopting this narrow concept of the congressional mandate would have left out sociology and the other social sciences completely.  This idea was rejected early in the game by the National Commission. It was decided to include such fields as sociology, political science and other similar fields.
	This decision annoyed many social scientists.  They pointed out quite correctly that there was nothing in the legislative history of the National Research Act that suggested that Congress had any interest in regulating social sciences.
	As an aside, as I read the legislative history, most of the historical incidents that troubled Congress and caused them to create this commission were examples of malpractice.  The problem really was that no research had been done to substantiate or validate the sorts of malpractices that troubled the Congress, but that's beside the point.
	The social scientists at the time protested that all they ever did was talk with people, and in their view this was rather a harmless enterprise. They complained that regulation of social sciences was an unconstitutional prior restraint on freedom on speech.
	This idea was championed primarily by the man that Dr. Knight mentioned, Athele Disola Pool,  a political scientist.  This argument could not get very far with the National Commission.  However they lobbied energetically in having Congress intervene.  Congress didn't intervene but the regulation writers did respond by creating the first five of the exemptions that now may be found in the Common Rule.
	The National Commission had not recommended that any research be considered exempt from coverage by the regulations.  Now, I want to consider evidence that the National Commission thought about extending the bounds of their recommendations for regulation beyond the social sciences, particularly into the humanities, and for example into such activities as oral history.
	I'm also going to mention as a borderline case the field of anthropology, including ethnography. There was quite a bit of discussion in the 1970s about activities that had features in common with biomedical and behavioral research.
	As I recall, the most commonly discussed field was journalism.  It was asked repeatedly, why is it that the National Commission's recommendations were not understood to cover the activities of journalists.  What they did seemed almost identical to what many social and behavioral scientists do.  They ask questions, they collected answers and attempted to synthesize their answers into generalizable new knowledge.
	Why should they not be regulated just the same as social and behavioral scientists who did more or less the same thing?
	The National Commission never offered any response to these questions.  They listened to these questions and then by their actions, or perhaps I should say inactions, seemed to imply, "well, that's just the way it is."  They were presented with examples of history including oral history and silently let these pass.
	Implicitly they were saying, that's not our problem.  They were very clearly aware of the problems presented by anthropology and ethnography.  It's not at all clear whether their statements, for example, on conditions under which one might waive or alter some of the elements of informed consent were meant to be responsive to the problems of anthropologists and ethnographers.
	One constant reminder they had of this field was that they themselves were the subject of a study by a participant observer who was supposed to sit in on all of the meetings of the National Commission and then write a report, sort of an ethnography of the National Commission.  I, for one, was very disappointed that she abandoned this project and we never did get a conclusion.  I understand she even left the field of study.
	[Laughter.]
	DR. R. LEVINE:  But I don't think it was because of this assignment which would have been the subject of her Ph.D. dissertation.
	The National Commission contemplated developing separate sets of recommendations for regulations, one for biomedical research and one for social and behavioral research.  They had me write a paper on how to distinguish the two enterprises in a way that would permit the development of separate sets of regulations.  The paper I wrote at their request demonstrated to their satisfaction that there was no satisfactory way to separate these two enterprises for purposes of regulation.
	Now, this story I just told about the National Commission, about my role in persuading them not to attempt to develop separate sets of regulations will serve as a segue into some other general remarks I want to make.
	These remarks are concerned with the question posed in the agenda, should all disciplines be subject to a Common Rule?  I am not going to argue today about whether any particular fields of study should or should not be covered.  Rather, I am going to comment on some criteria for distinction that have been proposed.  A proper title for my remarks would be, "If we are going to recommend that some types of research should not be covered by the Common Rule, how should we distinguish these from others that should not be covered?"
	First, I would not develop separate rules or exemption for specific fields of study.  Rather, I would focus on specific methodologies as the distinguishing criteria.  Survey research presents the same mythical problems, whether the research is carried out by a sociologist, an epidemiologist or a geneticist.
	Differences in research regulations should be directed at the particular problems presented by the methods employed by the researcher, rather than the field or departmental affiliation of the researcher.
	Another criteria that has been offered is the source of funding or the nature of the sponsorship of the research.  As far as I'm concerned, the source of funding is immaterial.  Ethical problems either are or are not presented by specific research proposals, no matter whether they are funded by the government, the pharmaceutical industry or a private foundation.
	This point notwithstanding, as of today the reach of federal regulations extends only to three categories-- (1) research funded by the federal government; (2) research on test articles subject to regulation by the Food and Drug Administration; and (3) other research conducted at institutions that have promised in their federal-wide assurances to apply the requirements of federal regulations to all research carried out at those institutions.
	In the past, several national deliberative bodies, such as the National Commission and the President's Commission have proposed extending the coverage of the regulations to all research involving human subjects.  Such proposals have been resisted successfully by those who claim that the government does not have constitutional authority to regulate all research.
	The Common Rules' authority is grounded in the conditional spending clause of the Constitution, and FDA regulations are grounded in the constitutional authority to regulate interstate commerce.  I don't know if you're going to need a congressional amendment in order to extend the scope of coverage of the regulations.
	Finally, some have proposed to be exempt from coverage by the Common Rule of research carried out by students.  I think this would be a mistake.  I agree that the great majority of research carried out by students, particularly students in the professional schools, does not need the full application of all of the requirements of the Common Rule.  Many of these projects are exercises in education in which the students actually perform one small component of their supervisor's research program.
	However, some research projects carried out by students must be considered independent and original research in the full sense of these terms.  This is, or at least it ought to be, characteristic of most research done by Ph.D. candidates.  Thank you very much.
	CHAIRPERSON MARSHALL:  Bob, thank you.  That was just superb.  I don't know how late you stayed up, but we appreciate it.
	DR. R. LEVINE:  You know what the antecedent was.
	CHAIRPERSON MARSHALL:  Fabulous dinner, yes.
	So we have half an hour, and again I would like to focus our discussion so that we can be the most efficient and effective and productive that we can on issues with which we would like to charge a working group and so we're not here to resolve any of the issues on the table, but to identify them and to think about the process through which we would like to address this question with which we have been charged.
	I've got Jonathan, Sandy, Abbey and, please panel members, any time you would like to join in the discussion, just turn your mike on or raise your hand.
	Jonathan.
	DR. MORENO:  In light of your qualification that we need to think about the agenda, the ongoing agenda, I'm going to rephrase my question.  It's actually based on a question that I think I raised the first time our colleagues were with us, and also response I made in e-mail circulating about the response to that report.
	I don't understand why, and maybe I'm missing something here, I don't understand why people in humanities and social science fields don't constitute their own IRBs, would deal with the problems of expertise and to a very great extent the workload issue.
	For example, the American Historical Association could constitute an IRB.  I gather the AHA is in an excellent position to have plenty of historic expertise and certainly has the intellectual qualifications to learn the rules and be as confused about them as we are.
	I just don't get it.  I hear the same complaint at my own university.  I hear it elsewhere.  I don't understand what the obstacle is.  And so the question, Mary Faith, for the agenda is, what are the obstacles creating appropriately staffed personnelled person IRBs for this purpose?
	CHAIRPERSON MARSHALL:  Let me respond to that.  Please refer to the list in front of you for the purposes of discussion.  I think that's available to everyone in the room as well.  There is an issue that's currently listed as "system of review and approval," so are you asking Jonathan that we need to rephrase this or suggesting that?  Because it seems to me that your question would come under the issue of "system for review and approval."  That would seem to me to look at both what is currently out there, and we know that there are all sorts of different approaches out there, and then look at the question of what should, any "system for review and approval" look like.
	Is it on point?
	DR. RICH: To Jonathan's point.  I think there's nothing in principal that impedes the development of such IRBs whatsoever.  I can you tell that at our university, Emory University, one of our five IRBs is specifically constituted for research in the humanities and it works very effectively.  It's under our same administrative structure as all the other IRBs, but it has the expertise and understanding of the special issues that these represent.
	DR. MORENO:  Ours does as well.
	CHAIRPERSON MARSHALL:  Okay.  Again, I do not want to waste time on content.  That's what we're going to ask this group to do.
	[Laughter.]
	CHAIRPERSON MARSHALL: I don't mean "waste time," but I want us to focus our time on charging a workgroup, so that's your job.  I've got Sandy, then Abbey, Felice, Adil.
	DR. CHODOSH:  I would just like to make a very strong plea that many of the comments that came from the NRHPAC members had to do with the orientation of the whole approach to this, namely that it should be the approach of how we should best protect human subjects, and that that focus should prevail in looking at all of these issues.  Otherwise, I think we get bogged down again. 
	If that is the prevailing interest, then it doesn't really appear in here, but it should be the content of how it's done.  I don't know how everyone else feels.
	CHAIRPERSON MARSHALL:  I agree with you, Sandy.  That's the framework under which we're operating, and I'll agree.
	Chime in any time, folks.
	Abbey.
	MS. MEYERS:  Yes, Bob, that was just an excellent overview except for one thing and that is the FDA is not a signatory to the Common Rule which is the most mind-boggling thing that I read in all the information that you sent us before we had our first meeting.
	DR. R. LEVINE:  That's correct, Abbey, and as a matter of fact, when the National Commission was making recommendations, there was no such thing as the Common Rule.  It had as one of its recommendations that all federal agencies should speak with one voice.  Well some of the voices developed footnotes and FDA developed a set of regulations that's almost identical, but not exactly.
	MS. MEYERS:  Almost.
	DR. R. LEVINE:  Thank you.
	MS. MEYERS:  That's the problem.
	CHAIRPERSON MARSHALL:  Let's focus on the task at hand, please.
	MS. MEYERS:  I think this has to be human focused.  That the question is, are human beings involved in the research, and if so, are they going to be exposed to any risks whether physical, psychological, sociological or whatever.
	CHAIRPERSON MARSHALL:  So on our list, and I'm going to keep you focused here, folks, on our list nature of risk, evaluating risk.  So I want this conversation to specifically refer to issues that are on the list for consideration, things that need to be added to the list, okay.
	So Abbey, I'm hearing you say that you endorse nature of risk, evaluating risk.  Do we need to amend the way that's written in any way?
	MS. MEYERS:  No, I think it's a matter of how we think about this problem.  We can't think about it as lightening the burden of students and academics.  We have to think of it in terms of protecting humans from harm, period.
	CHAIRPERSON MARSHALL:  Correct.  Absolutely.  That's our driving assumption, and again, that's the framework through which we're operating.  So, well said, Abbey.
	Yes sir.
	MR. ROLD:  I wanted to mention --
	CHAIRPERSON MARSHALL:  Please tell us who you are and you might need to come up to the front.
	MR. ROLD:  Bill Rold.  I was on the committee yesterday on prisoners, and I wanted to say that I think what you're doing on the Common Rule in terms of your charge, you should keep in mind it's going to impact subpart C, and that a lot of this is going to deal with research in prison.
	CHAIRPERSON MARSHALL:  Which he means research with prisoners for those who aren't familiar with that part of the reg.
	MR. ROLD:  Right. It's going to deal with research beyond biomedical which we focused on a lot yesterday.  But Dr. Anno talked about the dirth of research on behavioral and social issues in prison.
	A typical example would be, does getting a GED decrease recidivism.  Those are very important issues and I would hope that you would keep that kind of thing in mind in looking at this.
	CHAIRPERSON MARSHALL:  Thank you very much.  We most certainly will.
	Abbey, thank you.  Felice.
	DR. F. LEVINE:  I would like to try to generate some discussion and maybe some feedback from our panelist, is taking the view that Bob set forth which is the view that I support that we should be examining this from a methodological point of view in terms of the ethical practices from various modes of inquiry.
	I'm trying to ferret out in the context of these bullets in the areas of disciplines that have had either less exposure or perceived of themselves to be outside of the umbrella of the Common Rule, what are some of -- I can think of one that Linda and I have talked about at length -- but what are some of the perhaps unique challenges from let's say the humanities?  One, for example, has been biographical anonymity. 
	CHAIRPERSON MARSHALL:  Felice, I'm going to focus this.  You're speaking to the issue that's currently stated as disciplinary discussion versus methodology-based discussion.  Is that where you're --
	DR. F. LEVINE:  Yes.
	CHAIRPERSON MARSHALL:  That's the way it's currently phrased, so does it need to be amended in any way?  I want us to focus here.  I don't want to get into a discussion about content here.  I want to focus on the issues that we're going to charge the working group.
	DR. F. LEVINE:   Well, what I think in charging the working group, yes, the working group should try to flesh out those issues that are somewhat unique that we are not currently addressing under many of the bulleted issues we're currently addressing.
	CHAIRPERSON MARSHALL:  Perhaps what we need is to add, maybe perhaps as a sort of subheading under this issue is, what are we leaving out, what discipline or field or methodology are we leaving out, so what's not at the table.  Thank you, Felice.
	Jeff.
	MR. COHEN:  Jeff Cohen from OHRP.  I'm just sort of building on what Felice said, and it may be getting at, I think we're probably of the same mind because we're on the same working group. I'm not clear how the boundary between the charge for this working group and the existing working group for the social and behavioral sciences.  And that's the part that I'm not sure-- what goes in which.
	CHAIRPERSON MARSHALL:  Thank you, and I really didn't slip him $5 under the table to ask that question, but I wish I -- and I'm glad I didn't; you saved me $5.
	What we're envisioning is a sort of overlapping circles if you think of each working group as a circle, and that certainly there has to be hand holding with the working group that Felice and Jeff co-chair.  There will need to be I think overlap in terms of representation on both groups.  And also, you know, whether we need to think of this sort of new workgroup as borrowing members from your group, thank you, Jeff. We need to figure that out.  So there's obviously overlap.  How we approach that is something that we should discuss within the next half an hour.
	MR. CHESLEY:  Hi.  Francis Chesley from AHRQ, Agency for Healthcare Research and Quality.  One of the things that we've been trying to do is develop a partnership with our colleagues that the National Endowment for the Humanities.  And we're looking specifically at health services research at the intersection between -- we're looking rather at research at the intersection between health services research and the humanities.
	One of the things that we discovered is that we're not necessarily using the same language.  And so my comment is specifically related to the last bullet on the list.  I don't think that the question "what's research" at this point should be limited to student work.  I think our definition of research, their definition of research and scholarship need to be ferreted out a little bit.
	CHAIRPERSON MARSHALL:  Absolutely, you're right.
	MR. CHESLEY:  And just one recommendation.  As you put the workgroup together, that we might invite our colleagues from the National Endowment.  They happen to be one of the groups that's not signatory to the Common Rule, and yet their processes, while they overlap with research perspectives, they also have nuances that I think would be enlightening to this group.
	CHAIRPERSON MARSHALL:  Thank you very much, and you're right on target with your first observation. I think we do.  I think this group will have to get at fundamental definitions, for example, not only what is research but who is a research subject within their context.  So they're going to have to do some very hard foundational work, so we will add that to the list.  Thank you so much.
	DR. MATHER:  Mary Faith, John Mather with VA. I was trying to line up what I wanted to comment on with each of your bullets, and since they're not numbered, I'm having trouble lining them up.  So if you wouldn't mind me just asking questions because I think they may tuck in somewhere.
	I have trouble first of all with the title, "Should all Disciplines be Subject to the Common Rule." First of all, I'd really like to say, "should all brands or varieties of research."  I do not think that a survey researcher is necessarily limited to a particular discipline.
	Secondly, we've focused on the Common Rule which is actually Part A.  Why don't Parts B, C, and D apply?  We've already had reference to prisoners.  Well, what about children and what about others.  So I would like it somehow changed and not just be limited to the Common Rule.
	CHAIRPERSON MARSHALL:  Right on target, yes.
	DR. MATHER:  The definition in the, quote, "Common Rule" of what is research, I've heard that mentioned many times.  It's very unclear what is subsumed under that definition.  So the question I have is, is it clear to everybody concerned what is really subsumed under that definition?
	My next question is, do all of the now "disciplines" subscribe to the principles of the Belmont Report.  There are three-- respect for the individual, beneficence and justice.  If we talk about respect for the individual, do we really understand what confidentiality and privacy means, especially in light of what HIPAA means?  And is HIPAA going to be a part of what these other disciplines are going to have to handle and therefore it will apply to all brands of research?
	I mean one of the things I've heard, and maybe even Abbey wants to mention more about this, is who owns this ultimately, this data and this information that is gleaned in research?
	I mean, we've seen many instances of "embarrassment," quote/unquote, in all brands of research, not medical research, not clinical research, but in sociobiobehavioral research, and my god, even journalists is embarrassed sometimes.
	And where does this reflect respect for the individual?  We've talked about exemptions, so in a sense we take them off the table. And then we have expedited after that because somehow it's low risk.  I'm nearly finished.
	The other part is the concern I have in terms of brands of research, and not being a discipline issue, we need to also boil in here government does intramural research, and Jonathan will be the first to talk about intramural research.  Does this mean we cover program evaluations as is required by the Government Performance Act, GPRA?  Does it include operations research to a certain extent?  That's a brand of research.
	Should we also include varieties of quality assurance and quality improvement research?  What about 46 CFR 46 111 where it says, an agency can say we will declare this as somehow not research, we'll tell OHRP and we'll publish it in the federal register?
	Well supposing that determination by the department is in fact incorrect?  
	CHAIRPERSON MARSHALL:  Thank you.  I think we're going to have to add, what is the meaning of life to the list.
	[Laughter.]
	CHAIRPERSON MARSHALL:  You are right on target.  Well, we've well noted it.
	MR. PRITCHARD:  With regard to the fourth bullet --
	CHAIRPERSON MARSHALL:  If you could tell us for the record.
	MR. PRITCHARD:  Iva Pritchard, Department of Education.  With regard to the fourth bullet from the bottom, and related to several of the comments made already.  I think it's going to be necessary to talk about the purposes of research in the various disciplines as well as methodology in order to make this thing meaningful.
	And I have particularly in mind first the charge to this committee which is to protect subjects, and just putting in mind the disciplines, if you will, of law, journalism and business.  They characteristically carry out what they would call research with the deliberate intent of harming some of the subjects of their research so long as those people get what's due to them.
	And so it seems for those kinds of activities, the notion of protecting subjects from harm just doesn't make sense.
	MS. MEYERS:  [Off mike.]
	CHAIRPERSON MARSHALL:  Thank you.  Great.  Thank you, Iva.
	Mark.
	MR. BARNES:   Yeah, I would put on the list the issue of whether -- in these disciplines that you want to carve out, to what extent are their professional ethics different than what the Common Rule would require?  I mean, what is the gulf?  What's really at stake?  I think we should ask that question the gentlemen just asked about journalism which is one thing.  But I mean, in sociology, anthropology or anything else what do professional ethics say that are different than the Common Rule?
	MS. SHOPES:  I agree with you.  As I was reading the comments of the committee to our report, it did become very clear to me as perhaps it should have sooner that we were talking past each other, the language as this gentlemen said that we're using does not refer to the same things, and there are ethical narratives within my discipline of history that is simply not congruent with the ethical narrative that informs the Common Rule.
	I'm not prepared to say that either is wrong. They are just very different narratives which they are real points of conflict.  Individual harm is something different from issues of social justice for example.
	CHAIRPERSON MARSHALL:  Thank you, Linda.  We've got that on the list.
	Thanks, Mark.  That's an excellent question.
	Please.
	MS. MINOR:  Hi.  Caroline Minor, Bureau of Prisons, and I would just like to suggest that also there be some consideration of whether there are alternative mechanisms already in place that might serve the purposes that Common Rule serves for the types of the research that's reviewed now.
	This came up when we were talking about public used data files.  Public used data files aren't considered human subject's research.  There's already appropriate mechanisms in place for the most part to review those, to make sure they're done correctly and they're not harming individuals.  It may be possible that in some of these --
	CHAIRPERSON MARSHALL:  Excellent, yes.  Thank you.  Certainly one of the things that we have on the list, and this might be a subheading under that, is at least within the academic world, what level of scrutiny occurs at the level of the department, departmental review, those sorts of things.
	So you're asking a much bigger question, but thank you.  We definitely need that on the list.
	Elliot.
	DR. DORFF:  Under the nature of risk and evaluating risk, I think that the committee should pay attention to the list of things on page 10 of the paper that our colleagues have prepared.
	CHAIRPERSON MARSHALL:  No, sorry.  We're not -- I'm sorry Elliot.  That was a draft.  It's not something that we've made available to the folks.  We're not working off of that.  We're working off of the list in front of us.
	DR. DORFF:  Let me just say that the criteria for expedited procedure that the Common Rule gives, they suggest it should be exempted from coverage altogether.  So under evaluating risks, I think one of the things that the committee needs to talk about is whether those who formed the regulations to expedite procedures had a greater sense of risk about these things than our colleagues who want to exempt them.
	So the question then is, should they be exempt or should they just be expedited?
	CHAIRPERSON MARSHALL:  Thank you.  So we'll fold that in, under sisamer review and approval.  All right.  Thank you very much.
	Susan.
	MS. KORNETSKY:  I wanted to just suggest, maybe it was just the way that it hit me that the first thing on the list be deleted.  And I don't know a researcher who does not think that they are burdened, and I think part of the problems of feeling burdened is because there has been a misinterpretation that the IRBs are not educated on how to appropriately review these things.
	And my sense is that the charge of this committee is protecting human subjects.  And burden on researcher, I think if we solve some of these other problems, that should go away.  I don't think that should be a driving force to be considered.
	MS. MEYERS:  I'll second that.
	CHAIRPERSON MARSHALL:  I understand where you're coming from, and I think that we've said that in the sense that the framework is protecting subjects of research.  But I think we need to think outside of the box here.  Certainly our job is not lightening the load of researchers. 
	But I think we need to be attuned to things that are not effective in terms of providing human subjects the protections that they are owed from a moral perspective.
	And if there is perceived burden out there, if there are obstacles that we need to be cognizant of as we're thinking through this process, then I think that's important.
	And this is not something that's not unique.  Obviously in the humanities we hear it from biomedical researchers all the time.  So maybe we need to frame it differently.
	DR. MORENO:  How about responsibilities of the researcher?
	CHAIRPERSON MARSHALL:  How about "responsibilities of the researcher?"  But is that going to get at the question of --
	DR. MORENO:  It's a different statement.
	CHAIRPERSON MARSHALL:  It's a different issue.
	MS. MEYERS:  Can I say [off mike] research expeditiously.
	CHAIRPERSON MARSHALL:  Undue burden?  Undue burden, would that be --
	MS. MEYERS:  No.  No.  It's institutional.  It's not the Common Rule.  It's each institution and how they make the --
	DR. F. LEVINE: Perhaps no more inelegantly phrased than some of the other bullets, but I think what we're talking about and have been, as part of what we're all about as a committee, is advancing ethical research expeditiously.  We're trying to have best ethical practices in the advancement of the production of knowledge on the same page, and not --
	CHAIRPERSON MARSHALL:  We will work on it because this list is going to come back to the committee.  So Susan, can we work on it and committee members find something that has the right moral tone?
	DR. KORNETSKY:  Yes.
	CHAIRPERSON MARSHALL:  Okay.  Bob.
	DR. R. LEVINE:  I think one of the most difficult issues that we face and I anticipated coming up again, it may be an amendment or a subsection under the third bullet, "system of review and approval," is basically the "who decides" question with respect to who makes the decision as to whether or not a proposed piece of research actually first comes to an IRB or having made that decision, can be either expedited or waived.
	I mean, the vexing issue for the investigator is, am I as an investigator able to make some sort of a decision with regard to the proposed protocol that I'm going to do, or do I need to have somebody else make that decision for me.
	CHAIRPERSON MARSHALL:  Thanks, Bob.  So we will fold that in the system of review, but it's really a very basic preliminary question-- what even comes, how does it get there.
	Okay, Adil and then Kate.
	DR. SHAMOO:  Thank you.  I was hoping the philosophers in this group would have brought what I'm about to bring, so if I'm on shaky grounds, you know.  And the working group should I think address the issue of conflict of values, and let me explain very briefly. We have philosophy.  We have ethics.  We have bioethics.  We have protection of human subjects.  We have philosophy.  We have rights.  We have Bill of Rights and First Amendment basically.
	And I think there's a conflict of values, and I think the committee should address that directly.  Not everything alive in the United States is only one value, protection of human subjects overriding all other values.  And the committee, let them address that.
	How much of our Bill of Rights we want to give away in order to protect the human subject and vice versa and where that tension and conflict are to be?  That's really the fundamentals, supersede all these other questions.  These other questions in my view they're methodological and they could mire with much more conflict.
	CHAIRPERSON MARSHALL:  I'm sorry, Kate was next.  Elliot after.
	DR. GOTTFRIED:  I think with respect to burden on the researcher, I think what we were trying to get at is the efficiency of the process, and that that's really the issue and we have some built-in mechanisms already in the Common Rule.  The question is the adequacy, and that's what we need to sort of assess, and I think you're going to have to take into consideration to some extent the risk involved in the particular protocols, et cetera, et cetera.  So that's I think where we're heading.
	The other point I just wanted to make about your other comment earlier, Mary Faith, with respect to the committee -- I'm sorry, the evolving workgroup, in our time frame is that one proposal we had that we were going to put out here for discussion is, an expansion of the group that worked on the paper, plus members of the social and behavioral sciences workgroup, plus people from the external community who somehow bridge some of our gap area -- say, a person who is both conversant with social science and biomedical and humanity research, or people who are administrators of IRBs but also have expertise with social science, et cetera.
	And we may have some of that already in the SBS group, but we were looking to supplement it with a caveat that we don't want a huge group because we have a time frame put forth as well, which is, we're hoping to get this on track and a proposal made to the committee by January of 2003.
	CHAIRPERSON MARSHALL:  Thank you, Kate, for clarifying all of that.
	Elliot.
	DR. DORFF:  Just a brief point.  I think the conflict of values that Adil's after is that the conflict of values that applies not only to these disciplines but to medical ethics as well, namely the conflict between advancing research that's ultimately going to help us and on the other hand protecting human subjects in the process where they could be harmed by the very research.
	So that's what I understood burden on researcher to be about, namely, how do you protect human subjects while you are, as Felice said, advancing ethical research expeditiously?
	CHAIRPERSON MARSHALL:  Thank you Elliot.
	I don't have anybody else on my list.  Have I missed someone, ex-officio folks, how about members, panelists?
	[No response.]
	CHAIRPERSON MARSHALL:  Do we have everything on the list that should be there, at least that we can recognize at the moment?  I'm sure others will come out.
	Kate.
	DR. GOTTFRIED:  I'm just curious in terms of our process here.  If we think that we have a fairly exhaustive list --
	CHAIRPERSON MARSHALL:  Yes.
	DR. GOTTFRIED:  -- are we going to somehow prioritize or pear down the list so that it realistic? Because I'm thinking from a practical perspective about how we're going to approach this and whether we can come up with something.
	CHAIRPERSON MARSHALL:  Here's what I would like to do because we only have I think about three minutes left.  I would like to ask the committee's permission for us to convene this new working group beginning as you just said, with the members of the panel, with some of the members of Felice and Jeff's workgroup.
	I would ask that we have from panelists, committee members, ex-officios, public members, suggestions for those whom you think should also be members of this group, understanding that we want to keep it a reasonable size so that it can work effectively and efficiently.  And then we will circulate to the committee, as is our process rule, a final list for its approval, both of the issues and of the members.
	That the first charge perhaps to this new group would be assigning priority to the items on the list and reporting back to the committee.  And these discussions I think can be had via e-mail and so forth, and then at our next meeting in October, we would have an update from the workgroup.
	So that's my thinking.  Please, in the next two minutes let me know whether you agree, disagree, how we should proceed.
	Any disagreement committee members, ex-officios?
	[No response.]
	CHAIRPERSON MARSHALL:  All right.  Then I'm going to take that as permission for us to move ahead with this endeavor.  And I want to thank especially our panel members who have come back to the table with us for yet another round in this process and giving up their summertime to do so, and we do really appreciate your being here, all of the hard work that has led up to this.  But more importantly thank you in advance for all of the hard work that is forthcoming.
	DR. GOTTFRIED:  Mary Faith?
	CHAIRPERSON MARSHALL:  Are you coming back?  We have an half an hour I forgot.
	DR. GOTTFRIED:  We have a half an hour after lunch.
	CHAIRPERSON MARSHALL:  Do we need another half an hour?
	DR. GOTTFRIED:  If we need it.
	CHAIRPERSON MARSHALL:  Well, I mean, do we need another half an hour, let me ask you?
	DR. GOTTFRIED:  Well, if you wanted to do a sort of --
	CHAIRPERSON MARSHALL:  I don't think that we do.
	DR. GOTTFRIED:  I don't know if you want to raise any substantive --
	CHAIRPERSON MARSHALL:  Before you leave, guys, I don't think that we do. 
	Ex officio and committee members, I'll see you upstairs for lunch.  We have some housekeeping to do, so upstairs at Corduroys for lunch, but I think we're good to go, Kate, unless you think otherwise. 
	All right.  We'll see you all back here in an hour.
	[Whereupon at 12:30 p.m., the meeting was recessed to reconvene this same day at 1:30 p.m.]








	A F T E R N O O N   S E S S I O N
	[Time noted:  1:40 p.m.]
	CHAIRPERSON MARSHALL:  We are going to resume.  If everyone in the room could take your seats, especially committee members, that would be a good thing.  We could finish on time or even early.  Let's be expeditious.  Could someone in the back of the room close the door for us so that there's not lobby noise distracting us?  Thank you.
	Some of our committee members are standing in line trying to pay for their lunch.  They're not being remiss, but we are going to go ahead and start.
	Mary Kay and her working group on genetics have also been working very hard in the interim since we last met, and there are a lot of words on paper in our briefing book that have been put down.
	DR. PELIAS:  Yes, there are.
	CHAIRPERSON MARSHALL:  So, Mary Kay, the floor is yours.
	DR. PELIAS:  Okay.  I would like to go to page 1 of the briefing book just for a moment and note the message that Kate sent out to all of us.  This is just before tab 1 in which Kate referred to tab 11 which is the "genetics information."  
	And Kate mercifully noted that when we review this chapter on genetics, it's important to remember that this is aimed for inclusion in the IRB Guidebook and that the target audience are IRB administrators, staff members and so on.  So that we need to, as we go through this, we need to make sure that it's written in a manner that can be understood by people who do not have expertise in genetics and genetics research.
	So we're talking to what I call real people in the IRBs, and we're not aiming at immensely scholarly language or thoroughness as well, either as well.  Okay.
	Yes, of course.
	DR. R. LEVINE:  Which IRB Guidebook are you referring to?
	DR. PELIAS:  I have a copy of the chapter in the IRB Guidebook that we have used.  We sent this out I think last time.  OPRR.
	CHAIRPERSON MARSHALL:  OHRP.
	DR. PELIAS:  OPRR 1993.
	DR. R. LEVINE:  Thank you.
	DR. PELIAS:  So that's where we started, and I'd like to bring you up to date on more or less what we've done already before we get into the content of this emerging chapter for the next IRB Guidebook.  We have worked by a couple of conference calls, and at the end of our meeting in April, we spent a whole day -- the working group spent a whole day trying to put together an outline or a plan for writing this particular chapter.
	Our members were asked to sort of pick a topic and send in written submissions on the topics that they had chosen, and then I became a supersecretary and compiled all of the submissions which, once they were compiled, were sent out for review and then were revised again and sent back to me. And they were finally edited in June and up to early July, May/June and to early July, into this single document that you have now for your review.
	The model, as we just mentioned, the model for this chapter was the chapter on human genetics research that appeared in the 1993 IRB guidebook.  This was suggested as something to work from with the knowledge that we have a lot of updating to do because the world of genetics and genetics research has changed immensely over the last few years.
	So at our April meeting you may recall that we started out with an outline of the chapter on human genetics research in the old IRB book and began modifying that with all sorts of suggestions to try to bring it up to date, and I think we are on the way --well on the way, I might say -- to achieving meeting this goal.
	Once again, the audience for this document is going to be the average IRB member who has little knowledge of the science and social issues in genetics. And particularly as I was typing all of this in and editing it, I kept in mind some of the members of my own IRB at the LSU Medical School in New Orleans and I tried to write for them.  So that's the way it was aimed when we were writing it.
	The content of this document you will find in this document some repetition and some redundancy.  And the reason why I have done this, not only because it's going to be edited by people that I will never see, but also because I imagine that people on our IRBs who are not geneticists and who are asked to review proposals in genetics research, may not have the patience to be flipping back and forth through a document that is at least this thick to find everything.
	So I'm trying to put all of the genetics, the pertinent stuff in genetics together with a little bit of redundancy of what appears elsewhere in the guidebook but not to make it an impossible task to get information out of the whole guidebook.  So we are aiming at a self-contained chapter on genetics as far as possible.
	I would also like to introduce to you the consultants who have come in to the working group from outside on this particular project.  Some of these individuals you may know, some you may not.  Dr. Rodney Howell who is a pediatrician geneticist at the University of Miami and was particularly interested in contributing to our discussions of newborn screening and carrier testing; Dr. Wayne Grodey [ph} who is at UCLA and who is very knowledgeable in the world of metabolic diseases, orphan diseases and regulations having to do with CLIA and the role of the College of American Pathologists in all of our work in genetics.
	We also would thank Dr. Steve Warren who is at Emory University and who is our authority on bioinformatics, data protection and data management, Dr. Findley Austin who is at Hoffman La Roche and is consulting with us on issues of pharmacogenetics, and Sarah Carr who is here in Washington working at NIH and who is, I believe, the executive director of the Secretary's Advisory Committee on Genetic Testing. 
So these are the folks who are outside of our committee and who have contributed to these efforts.
	In addition to the outsiders, the members of our committee who have worked on this document in alphabetical order are Margaret Borwhat, Sandy Chodosh, Abbey Meyers and Bob Rich.  I hope I haven't left anybody out, have I?  Bob Rich I said.  That was the alphabetical order.
	So we have put together this document, and my own role in it is to cut and paste and then try to go through it and create something that reads consistently and to kind of even out the writing styles that we all have and to edit the substantive information so that people who are not geneticists will understand it and do it without too much repetition.
	And now, I invite your input, all of you, for helping smooth out any further rough spots.  And with that, we'll go to page 1 of the document.  This is tab 11 in you materials and go through very briefly the outline that we created at the end of April and in the weeks shortly thereafter from which we have compiled this whole document.
	We started out with the old outline that was in the old IRB guidebook and right away made some major changes to it.  We have included sort of a generic introduction about the advances in genetics and went on to a section on general considerations for IRBs.
	Going back up a couple of lines, we have key concepts in genetics.  This is our definition section which we have expanded from the last edition of the guidebook, and we've tried to keep these definitions absolutely as simple as possible, knowing that in the world of genetics we can get into amazingly convoluted definitions of things.  We've tried to keep this as simple as possible so that the people who read it will understand it, people who read it who are not geneticists will understand it.
	Section 2 has general considerations for IRBs. This is pretty much the outline that came out of the old IRB Guidebook and is a series of topics that should be familiar to all of us who have been dealing with IRBs, anyway all of us in this room I suppose.
	The next section, Section 3, we'll go through in some detail.  This is a new section, and these are all of the topics that came up in May after our last meeting having to do specifically with genetics research. And you'll see that we devote a section to family studies, monogenic traits, multigenic traits, complex traits and so on and so forth.
	There's a new section on applied research on newborn screening on bioinformatics and we'll go down these as we go through the document over the next hour or so.
	As a question of logistics, should I ask for comments as we go along here?
	CHAIRPERSON MARSHALL:  Sure.
	DR. PELIAS:  I would welcome interruptions so that we can resolve any questions as we go along.  We're just going to do this page by page.
	Moving on to page 3, we have introductions, and introduction with our definitions.  And the first four paragraphs sort of, I think, outline where we are at so to speak in the world of genetics and how genetics is touching our lives in many, many ways.
	The major concept here is mentioned in the third paragraph, and that is the therapeutic gap.  And I know from my own experience doing research with families and talking to families, that it occurs very, very frequently that people who come in, families who come in to our genetics research projects very often have unrealistic expectations of what they're going to get out of the research.
	And so we have this thing called the therapeutic gap that we have to talk to our families about, and this is mentioned again later on because this is a very important thing.  We don't want to mislead people about what they can expect if they participate as subjects in genetics research.  It may be really in the long run an altruistic act on the part of these families because it may be that they gain nothing out of it.  Maybe somebody in the next generation will, but we have to be very honest with them.
	Yes.
	CHAIRPERSON MARSHALL:  I have a question.  I have a question just about content in that third paragraph.  I guess Jesse Gelsinger is known to all of us, and I'm assuming that's who you're referring to here.
	DR. PELIAS:  Yes, I was.
	CHAIRPERSON MARSHALL:  Why not name him?  I mean, it's in the public domain.  I think he -- I guess my sense is, he would be better being named.
	DR. PELIAS:  I did have him named when we were running through one of the drafts, and then if you notice, we have declined to talk about gene therapy in this chapter.
	CHAIRPERSON MARSHALL:  But it is gene transfer research and I wouldn't use therapy word either, but I would say Jesse Gelsinger who did a gene transfer trial.
	DR. PELIAS:  Okay.
	CHAIRPERSON MARSHALL:  I think you killed a couple of birds with one stone there.  Just a suggestion.
	MS. MEYERS:  What section?
	DR. PELIAS:  We're on page 3.
	CHAIRPERSON MARSHALL:  Page 3, section 11.  Tab 11, page 3.
	DR. PELIAS:  Tab 11, page 3, third paragraph.
	DR. RICH: Mary Faith, I'm inclined to disagree with that suggestion just in the sense that we go to great lengths to talk about confidentiality, and even though this is clearly in the public record, and there's no question about that.  I think just the general respect for -- it communicates a message to IRB members that sometimes what is after all private information, in this case in the public record, my recommendation would be that we keep it as it is, that we keep this entirely third party and not personalize it.  I think there is a down side in recognizing that everybody knows who we're talking about.
	DR. PELIAS:  Do we have other opinions, please?
	Alan.
	DR. FLEISCHMAN:  I agree with Bob.
	DR. CHODOSH:  I agree with Bob.
	DR. PELIAS:  In that case, we'll leave Jesse's name out. 
	CHAIRPERSON MARSHALL:  Okay.  All right.
	DR. PELIAS:  Okay. Thank you.  Scratch that out.
	Alan, yes.
	DR. FLEISCHMAN:  Just a question or a suggestion on these introductory comments, and I really like your concept of therapeutic gap.  The other one that I thought might be appropriate here is genetic determinism, the myth of genetic determinism, and the understanding that we need to share with our subjects and their families that genes aren't everything even though it's a lot.
	DR. PELIAS:  I can add that, and it'll be in the next edition for your approval.
	Yes, Elliot?
	DR. DORFF:  First of all, I want to say this is wonderful.  It really is a terrific product.
	DR. PELIAS:  Thank you very much.
	DR. DORFF:  And the committee members are, you in particular, are really to be congratulated for it. 
	Along the lines that Alan was just talking about, the other thing that I thought may want to come in the introductory comments is the fact that a lot of the genetic research raises moral and religious issues for some in our society, and that I don't think you have to talk about them.  I think you just have to note the fact that part of the reason why some of us are very excited about it and some of us are very much afraid of it is because it raises all kinds of questions about who is a person and when does life begin and what is a life and all of those kinds of questions.
	DR. PELIAS:  I'm not inclined to delineate all of those issues just to say that they're there.
	DR. DORFF:  Just refer to moral and religious questions.
	DR. PELIAS: Okay.  I'll probably put that up in the second paragraph on the pervasive nature of genetics and that it'll go in there somewhere, okay.
	And the last paragraph says that you got to make sure that your IRBs can read all of this stuff and understand it.  So I would then, the issue of gene therapy we have dispensed with because there's supposed to be a chapter in this new guidebook on gene therapy, and we're not going to do that here.
	I have a bunch of definitions down here.  Does anybody have questions about the definitions? 
	Yes, Elliot.
	DR. DORFF:  First of all it's great that you put in the definitions.  On page 14, you mentioned two other things that probably need to be defined here.  You talk about as a haplotype and single nucleotide polymorphisms.
	CHAIRPERSON MARSHALL:  Elliot, you don't know what that means?
	DR. DORFF:  So you use the terms on page 14 about eight or nine lines from the bottom. 
	CHAIRPERSON MARSHALL:  A-plus, Dr. Dorff.
	DR. PELIAS:  I would be inclined, since that's so specialized in this discussion on page 14 to define them there when I use it, rather than put them in the front end for the definitions for everybody.
	Is that okay?  All right.
	DR. RICH:  Or just delete the words there on page 14.  I think you can actually -- that truly is genetic jargon in a sense.
	DR. PELIAS:  It is.  I know that.
	DR. RICH:  And one could get the meaning of that paragraph on page 14 without actually using those words.
	DR. PELIAS:  Thank you.  So I have delete on page 14 now.  That will take care of that issue, won't it.  Sometimes you can't get away from the jargon, you know.
	DR. SHAMOO:  I have a simple question.
	CHAIRPERSON MARSHALL:  We have one from Bob, then Adil.
	DR. SHAMOO:  No.  Bob goes first.  Beauty before age.
	DR. R. LEVINE:  You have here, Mary Kay, you have a definition of pharmacogenetics.  I think the terms that's being used much more is pharmacogenomics, and it may be that you want to define both.
	DR. PELIAS:  Well, then let me run this by you.  Pharmacogenetics I think is being used in the context of medical treatment.  And pharmacogenomics I believe is being used in the context of population studies and how we all share our DNA.  If you want me to include both of them, I will.  But most of what this is about since it's IRB stuff is pharmacogenetics.
	DR. R. LEVINE:  Let me say that the reason that IRBs repeatedly get introduced to the term "pharmacogenomics" is that it's an add-on to virtually every control clinical trial that they review, that they're setting side a little blood for pharmacogenonmic purposes.  What is the feedback?
	CHAIRPERSON MARSHALL:  Would it help if we just differentiated between the two so that even if you're only using one, people will know that they're terms of art that mean different things?
	DR. R. LEVINE:  I just want to see both words presented to the anticipated readership.
	DR. PELIAS:  I do have this in the text as a footnote, both of those terms, but I'll put it up front as well.
	DR. SHAMOO:  Just for my own understanding this, you have the multigenetic, multigenic trait, two genes and more, but the complex diseases you say is influenced by gene/gene interaction, gene environment interaction or other confounding factors.  But it also could be multigenetic loci and the interaction, so this is like as if eliminates.  I'm not an expert, so it doesn't have to be gene-gene interaction only.  It could be just multi-loci, comma, gene-gene interaction, all these kind of interact with the environment.  Correct me if I'm wrong.
	DR. PELIAS:  When I said "gene-gene interactions," I didn't specify how many.  When we talk about multigenic traits, it has to be two or more loci.
	DR. SHAMOO:  Well, I understand that.  But I'm talking about the complex diseases.  To me, at my first glance at what it will mean, it's not about the loci because it doesn't mention it.  It only mentions gene-gene interaction and their environment.  That's all.
	DR. F. LEVINE:  I thought this was terrific. I had just a few things, one of which is probably maybe a difference in the use of a term of art.  These are, socioeconomic factors would actually have a narrower meaning than you intend, and so you may want to define it as social factors, and then outline social, legal, economic because "socioeconomic" sort of implies that one narrow band as it were within a broader range, and you actually don't in your paragraph mention economic and legal which might -- you mention it in you narrative in the front. That's on page 7 under socioeconomics.
	DR. PELIAS:  Thank you.  I will take note of that, but I'd like to go through this page by page now and not be jumping around because sooner or later we'll get all the way through it, all the way to the end.
	DR. F. LEVINE:  All right.  Okay.
	DR. PELIAS:  All right.  Are there any other comments about the definitions?
	[No response.]
	DR. PELIAS:  Okay.  Let's move on to general considerations.  Now we're on page 6, "General Considerations for IRBs."  This is largely couched in the language that we are familiar with in the world of informed consent and IRB activities.  It is modeled after the existing CFR positions, but we have rewritten sections of it so that it is now slanted specifically towards genetics research
	The first section has undergone a considerable metamorphosis since it started out because we had parties in genetics research, and then if you remember the document that we went through on defining human subjects and third parties, I had paraphrased or taken a lot of that and stuck it in here.  And then in one of our conference calls, one of our members said this needs to be generic.  So now you have something generic that does not quote the product of our other older working committee that is still under consideration.
	I appreciate, by the way, your pointing out language problems and typos.  I've tried to get all of them but after I read this thing fifteen times, I can't even see it anymore, so I'm not recognizing little errors that Elliot is helping me with, for example.
	CHAIRPERSON MARSHALL:  Mary Kay, just let me interject for a moment if we're going to ask questions and ask for clarification as we go along.  Those of you guys who are facing this direction, please feel free to step up to the mike and let us hear from you.
	DR. PELIAS:  I guess now I'll entertain any comments that you might have on "Subject recruitment and retention," noting that the idea that family studies in genetics research are extremely important and that we do acknowledge that in family studies, members of families put pressure on each other to go into these studies.  I don't know how we'll ever avoid that, but we can discourage it.  We can't get rid of it entirely.
	Comments, please?  Yes, Felice.
	DR. F. LEVINE:  Okay.  It comes up in A, and it's sort of a theme throughout that when we're referring to the fact that this emphasis on family studies and genetics research fits into a larger hull, I'd like that larger hull to use biomedical, social and behavioral research so that we cue that -- the larger hull is the whole arena and we start sending the right signals in our language.  So that's on A.
	DR. PELIAS:  Okay.
	DR. F. LEVINE:  On B, it might be useful, that as I think about this in some of our conversations over an extended period, that the subset of genetics research is part of a larger class of work on families and family studies more generally that may or may not include measurement of genetic issues, and I think these same issues pertain.  You just might want to send a little signal to that, that some of these issues aren't involved in research on families generally.
	DR. PELIAS:  Okay.
	DR. F. LEVINE:  And I didn't know whether these are examples 1, 2 and 3, but whether there is ever recruitment by actual postings in newspapers, you know, college newspapers, et cetera that says we're going this study on X.  I mean, you know, I get them in the mail all the time, and other kinds of outreach that are sort of almost like random digit dialing and whether your want to at least account for that mechanism of recruiting.
	DR. PELIAS:  You raise a very interesting question because in my own experience, I have never  been familiar with recruiting people for genetic studies by public advertising.  We have had notices published in newspapers for example of tentative results of genetic studies saying you might want to come back for further testing if you participated in this study.  But recruitment from newspapers, I don't think I've ever experienced it.
	DR. RICH:  I think there is, for multigenic diseases.  I mean for complex diseases there may very well be recruitment efforts for women at risk, who think they may be at risk for breast cancer, for example, for families with breast cancer.
	DR. PELIAS:  Okay.
	DR. KORNETKSY:  Mary Kay, the other area that is somewhat related is there may be sort of those types of recruitment notices in like patient articles or patient advocacy types of supports groups.
	It's a little bit different, but that I've seen the support group distributions.
	DR. PELIAS:  I'm familiar with recruitment in the newsletters of support groups.  Yes, that's something that's been around for quite a while.
	MS. MEYERS:  [Off mike.]
	DR. PELIAS:  I would like to say that the point here of delineating 1, 2 and 3 as methods of bringing people into genetic studies, I think, is to say what we in the recruitment business have found acceptable and how we are adamantly opposed to direct recruitment in which we call up someone and say we met your cousin last week and now we want to meet you and we're doing a study on whatever.  And that is by and large regarded as an invasion of privacy, and we don't condone it at all.
	Any further questions?  We can move on to defining risks and benefits.  I note Felice's language suggestions about social, psychological, economic, et cetera separate these things out and I will be happy to do that. 
	Any other comments?  I'm defining risks and benefits.
	One of the things that we're going to run into that I see here, I've noted here, and that we'll run into again is a question of genetic counseling, and this is something that I think at least in my own experience with IRBs is that folks don't realize how valuable genetic counseling is.  So we've mentioned it a few times throughout this and as we get further on back, I talk a little bit more about the profession of genetic counseling, and we'll go into this.
	I'll give you this as food for thought while we move along, and that is that when I wrote the section further back on genetic counseling, I did have comments from Rod Howell who was brought in on this issue about using a couple of paragraphs to describe the profession of genetic counseling.  My reason for doing that is, I don't think that people in other medical specialties have much of an appreciation for what genetic counselors do, for how they're trained and how critical they are for operating a thorough genetics unit or genetics clinic.
	So just think about that because I know Rod has written to me saying this has no place in this document at all, all this stuff about genetic counselors.  And I tend to disagree with him, but I'm looking to you all for guidance on this as we go on through.
	MS. MEYERS:  I think it's really important that you do have it.  It's crucial.  I don't think anybody realizes.  I understand there's only 3,000 certified genetic counselors in the country.  There are not very many, and one of the reasons is there are very few medical professionals who recognize the importance of not just the test, but how you present the results of the test, how you've handled the family, and it's only genetic counselors who understand that.
	CHAIRPERSON MARSHALL:  Here, here.  I think it's critically important.  I've seen too many protocols come through lacking that exact planning, and not just in genetic studies but other studies that have genetic application to the possibility of it.
	DR. PELIAS:  We have a critical shortage of genetic counselors in this country, and the ones who are good are very, very good, and they get to be very, very specialized.  A lot of them, for example, spend their lives talking only about cancer and not about storage diseases or whatever, and they are very, very valuable people.  So thank you for your support on how important they really are.
	Felice.
	DR. F. LEVINE:  In that regard, which I share the sentiment of our group on that, that I think that one of the very useful ways NHRPAC has made a contribution in a number of the working group areas is sort of the discussion of when there's a risk factor, there's a vehicle for the amelioration of risk, and it seems to me you might want to say that explicitly because that is something that comes from our risk and harm paper that's penetrating the Children's Working Group, and I think that's really a very central kind of contribution that's being integrated into a lot of the work that we're doing.
	DR. PELIAS:  Thank you.  On this section.  As we move right along. Really we're on page 7.  We're going to be on page 26 before you known it, folks, if we're lucky.
	So we've made a recommendation that IRBs should consider the business about genetic counseling and make sure that if it is appropriate, it should be provided.
	Moving onto page 8, "Privacy and confidentiality."  I tend to come down.  I've been corrected by several members of the working group because I tend to come down very hard on confidentiality.  And one reason why is because when we do genetic studies, we need information about families, and we gather information that is extremely sensitive, and I tend to use all these adjectives like extremely and thoroughly and don't ever open your mouth -- no, that's kind of -- about this stuff.
	The information that we get is private and sensitive.  Sometimes we learn things in families about paternities or adoptions and we have to keep this information protected.  I was recently at a conference on confidentiality in Rochester, and I heard a talk by one of my lawyer colleagues on this particular issue, and she related the experience she had in helping set up a confidential system in Marshfield, Wisconsin.
	And in her slides she showed a diagram of the access, the protection and the kind of access to computers that had patient information in it.  And she said, we have created a purple room, so when you hear of a purple room, this is a room that's almost like a safe, and very few people have access to it.  And I think this is going to be developed as we go on because we need the information on the one hand, we have to protect it very, very carefully on the other.
	So when you hear me refer to the purple room, it's sort of like keeping three people locked in a safe and only they can get into the computer that's got the really sensitive information about patients or subjects and their families.
	So if you've got any comments on this section on privacy and confidentiality?
	Yes, Alan.
	DR. FLEISCHMAN:  I want to say in general, this is marvelous and extremely well written.
	DR. PELIAS:  Thank you.
	DR. FLEISCHMAN:  The thing that struck me as I read "Privacy and confidentiality," I was looking for management and secondary use of tissue samples.  Now, in my head those were linked.  I see back on page 20 you've got it.  So if I were reading this as an IRB member, for me, the privacy of the storage sample issues and the confidentiality and the delinking and anonymizing of all that stuff is linked to this.  So somehow I think you ought to flag that if they've got a question about that, you've covered it down the road.
	And that struck me just now, as I'm not exactly sure of the distinction between general considerations for IRBs and approaches in genetics research, there's a lot of stuff that is both.  It's just how you parse that out.  But you know, I don't think it's really important, but there are a lot of things in the approaches in genetics research that should be considered by IRBs.
	DR. MATHER:  Can I amplify Alan's thought because I was holding back until you got to page 22.  If you could look at page 22 and through to the top of page 23 --
	DR. PELIAS:  Do you want to have this in right now or could we wait until we get to the back end of the table?
	DR. MATHER:  Well, I'd like to consider it now because I think Alan's made the point these are linked concepts or thoughts. And right here in the last paragraph on 22 you talk about the IRB should consider the most optimal methods.  Well, to me conceptually that's the same as the general paragraph in "General Considerations for IRBs."  
	So to me, I think I'd like it teased out a little bit now if you don't mind, just the discussion on 22 and 23.  I was left comforted and discomforted at the same time.
	I think the middle paragraph on 23 if eloquent and well written and yet at the same time, I can just imagine this notion of consent for future use is going to be troublesome for a lot of people.
	Then you start working on down, Mary Kay, and you get to the issue on the bottom of the page, and that is all of these tissues that have existed for 20, 30 years, these brain banks, these, that and the other banks, and I'm sorry to put it in that context because what I see a lot of what is written here is a subset of the generic issue of tissue repositories.
	So when you get down there, the bottom of page 22, I'm going "wow."  And then you say, "IRBs should consider appropriate measures to allow such research," blah, blah, blah.  I feel like I'm left hanging because isn't this something that if you had done a little bit more to give some guidance to IRBs, how to think this through because I can tell you, within the VA we have a lot of biological repositories, let alone data depositories.
	And how do you reach back to that stuff which 20 years ago we never got informed consent for?  They sit there, they have identified -- some of the veterans are dead, but a lot of the veterans are still alive.  And even those that are dead, what happens when you go and access that and somebody who is their now widow or next of kin says, wait a minute, we don't need to worry about that, this is dead material.  And they say, no, I'm sorry, confidentially, you're learning now stuff that you never knew before.  You never were able to do DNA runs on this stuff before and now you are, and this wonderful, beautiful frozen set of materials.
	So I raise it because I think the point is to be made here.  This is serious IRB stuff when you talk about on page 22 and 23, and I'd like it moved up to the front which I think is what Alan was alluding to.
	DR. PELIAS:  Thank you very much for those comments.  I will make a confession, now that we're on page 22 and 23, a personal confession, and that is this consent for future use is something that I have been extremely concerned about by myself in a very lonely area for the last few years.  And I will also say with regard to your general comments that there have been studies done in the world of genetics having to do with retrospective studies on collections of samples that have been collected in the past and current and prospective studies that will be done and how we should conduct ourselves with regard to new collections of samples and questions of informed consent and future use, consent for future use. 
	So there is information available.  My question to you then to follow up is, would you want a discussion of the distinction between historical, retrospective collections and current and future collections that might well be governed by new rules?
	DR. MATHER:  I think my simple answer is yes, but I think I'd make the distinction that there is stuff that's hanging around for which there is no informed consent for the use of in subsequent research, but in fact exists as a repository/depository. That are those where in fact in the past somebody sort of gave some quasi permission for this to be used.  But even there they may be some concerns because of an entirely new research process that produces information, that now the person didn't realize ten years ago would be incredibly embarrassing, then that's another ethical dilemma there.
	And this issue of confidentiality and privacy is part and parcel of this, and I think your allusion to HIPAA is entirely appropriate.  I think the future-use issue is relatively simple in the sense that if you've got a new set of materials you're collecting today, you can say, look, it's for this particular research project and would you mind also signing down the bottom here where it says, and you allow it to be used in the future ad naseum.  That's different.
	The past stuff is a very difficult and troublesome area to get at.
	DR. PELIAS:  I think we'll come back to this area in a little while, but I have included a discussion on questions about ownership of samples and what happened in the past and how in the past the donors attachment to the sample was severed when the sample was collected.  This is all in here, and I do think we need to examine this question of possession and ownership with regard to historical collections and what we're doing now and in the future and there's a bit of consideration of this here.  I got on another one of my soapboxes about possession and elements of ownership and stuff.
	Yes.  Excuse me.
	DR. HARRIS:  I wanted to bring this up because it did come up at the workshop at NIH, I discussed yesterday.  And although it may seem very unreasonable that this would actually be considered for a physician taking a history.  There was the question raised at the workshop about taking a genetic history and having permission to give information about other family members simply in getting the history itself.
	So is that something that you've discussed within your group because I gather this was an issue at one university.
	MS. MEYERS:  [Off mike].
	DR. HARRIS:  Third party.
	DR. PELIAS:  This is the third-party issue.  It hasn't been completely resolved.  We're trying to get a document out, but this is no longer at our level.  It has been taken up higher about defining who are human subjects and who are third parties who may become human subjects and who are third parties who don't become human subjects, but this is at another level right now.
	DR. HARRIS:  Well, the reason I raised it is, this is written in a way that it seems to me assumes that the information can be collected.  But the third-party issue, it seems to me, is assumed in this document.  Maybe I misunderstood.
	DR. PELIAS:  Go ahead, Kate.
	DR. GOTTFRIED:  I think that might be right. I'm not 100 percent certain.  I have to look it over more closely, but one issue was that because we don't have a departmental determination on guidance on how to deal with this particular issue, we were sort of just leaving it for the time being. 
	This was an issue -- you wouldn't have necessarily any reason to know this -- but that predates you with respect to this committee that worked for over a year on making recommendations to the assistant secretary for health about the third-party issue.  And that issue now has formally been transmitted to the Assistant Secretary for Health and then referred back to the director of OHRP for consideration, and so the Office for Human Research Protections is looking at this issue.
	MS. MEYERS:  The first paragraph under (d), and it basically says that while all individuals are entitled to confidentiality of their personal, medical or health information, probands who offer family history information, convey information that is often common knowledge in the family, information that adheres both to the proband and the other family members.
	And so it's accepted that whether you're just giving a person a physical or taking a case history, everybody's going to tell you about their relatives.  And the question is, are you going to keep it confidential.  And that's I think the key.
	DR. PELIAS:  Jennie, I have you on the list right here.
	DR. JOE:  This is related to this, I guess, is that maybe somewhere in this area talk about the new initiative on data sharing.
	DR. PELIAS:  That point is well taken, and I haven't gotten into data sharing.  So okay.  Thank you.
	Mary Faith.
	CHAIRPERSON MARSHALL:  I'm back on page 8, under, "Privacy and confidentiality protections."  And I wondered whether you might want to be more concrete rather than being sort of courtatory that an investigator should not contact a remote family, "data should be stored in a manner..."  If you might want to say "must" if you mean must.  Just throwing that in for your consideration.
	DR. PELIAS:  As I recall, we had a discussion about using the word "should" and "must" when we were on one of our long conference calls, and I will go back to my notes on that conference call and think this all over and then bring the issue back to you.  Is that okay?
	CHAIRPERSON MARSHALL:  Sure.
	DR. PELIAS:  Felice.
	DR. F. LEVINE:  I want to second what Abbey said.  I would have said it first, and that is, I thought one of the strongest parts was how effectively you avoided the false dichotomy of the controversy and handled this in a way that was sustaining irrespective of what's done.  I think it's very clear what you meant and how that operates and how subjects of study can indeed provide family history in a way that reflects their knowledge and understanding without, and with the researchers obligations to protect it.
	DR. PELIAS:  Thank you, Felice. 
	Do we have any other comments on this section, now?
	[No response.]
	DR. PELIAS:  We can move on to, "Informed consent."  Oh, we have one.  Yes.
	MS. BOOTH:  Christina Booth, University of Southern Maine.  Our university does a lot of rural health research and the one issue that I don't see really covered in "Privacy and confidentiality protections," is provisions for de facto identification that very small communities who might be carriers for certain traits.
	And literally in Maine we have some communities in which there's 50 people in the population and they could potentially all be carriers.
	DR. PELIAS:  That's a very well-made point, and one well taken.  The HIPAA regulations if fact are addressing that.  I believe that they have not been, I don't think, finally promulgated.  Is that right?
	DR. F. LEVINE:  But our privacy and confidentiality statement does address it explicitly as does the public use statement.
	DR. PELIAS:  I would also say that we have a section in this document on communities and on communicating with communities.  And I think that a very important aspect of working in especially small communities is that people understand that while you'll do everything you can to protect their privacy and confidentiality, there is always an outside chance that something is going to leak out.  The most important aspect of this is being honest about that possibility.
	However, I have a note here about de facto identification and so we'll put that into the thinker and come up with more on it next time.
	How about moving on to the bottom of page 8, "Informed Consent," and something you've heard me comment about from time to time and that is that we'll set out in the first paragraph that it is the investigator or the investigator's agent who does the informing, and it is the subject who consents to whatever he or she is being asked to do.
	One of the things that has come out in the last few years and you've heard me railing about this already is the idea of saying "to consent a person," I will consent a patient.  That doesn't work, and so that's why that little statement is here.
	And then we have on page 9, all of these possible things that should be included in -- not all in all consents, but a list of things which should be considered in going through an informed consent process.  This is a complicated process.  It's complex, and it requires a great deal of patience in talking to people who don't have backgrounds perhaps in genetics and ethics and law and so on and so forth.  So this is a long list of things that might be included in the consent process according to what the project is about and what would be appropriate.
	Susan.
	DR. KORNETSKY:  Mary Kay, I just wanted clarification whether this list is just the risks or anything in the informed consent because you talk on the bottom of 8 a detailed discussion of informed consent is included, and then you say, "specific risks to the informed consent process in genetics research includes the specific issues below."
	And then I looked at number 1 which didn't look like necessarily your risks, so I didn't know what you were focusing on.  If you are focusing on risks, I would ask the risk of possible incidental findings, such as paternity which is not listed here.  Number 7, who will have access to the medical records, I think you also probably want samples there as well, the genetic samples.
	And then it again it depends.  If you want everything that should be in a genetics consent, I can come up with some other types of things.  If you're just limiting it to the risks type things, I think that's my only comment.  The other thing is, I think what we're seeing a lot of, and I don't know where to put this in, is sort of repositories for sort of unknown or vaguely specified purposes such as repositories of samples from subjects with cystic fibrosis or whatever types of thing.
	And so I don't know sort of how -- there are specific other risks with that, or you're talking about specific issues that need to be included in informed consent, so I think you need to clarify what the purpose of the list is.
	DR. PELIAS:  That point is well taken.  I think that we are not confining ourselves to risks, and for that reason, I would suggest changing the language there to specific issues related to or topics related to informed consent, kind of grab-bag for people to go down and check off, is this pertinent to this particular project.
	DR. KORNETSKY:  I would add also then to that who has access and just what -- the first one is the kind of information that can be expected and from when, but I think also what it's going to be used for, and that's where maybe I get into this repository issue where it's maybe a little bit more vaguer.
	And I think also number 8, their rights to respect to their tissue samples, are you talking about the issue about their ability to withdraw?  So you may want to put in parenthesis "withdraw" and also commercialization.  You may want to list those two things in there as well.
	DR. PELIAS:  Thank you very much.  Yes, we need to make this as complete as possible I think.  Mary Faith?
	CHAIRPERSON MARSHALL:  I wondered in the first sentence there on page 8 under "E. Informed Consent," whether we might not try and reflect our evolving concept of informed consent as an ongoing process of decision-making, communication so that we would say, provides the framework for an ongoing process of communication and decision making that protects the interests, et cetera, that were consistent to cross our workgroups.
	DR. PELIAS:  Thank you, Mary Faith.  I have Bob Rich and Alan.
	DR. RICH:  I'd like to speak to something that Susan just said, and I know we discussed it, and I'm not sure, I can't remember whether it's in the document or not, but there are certain kinds of risks that it's the responsibility of the investigator to prevent, and in particular I would like to not see the risk of paternity as one of the risks.  It's the responsibility -- there are some kinds of information that are gained in the course of genetics research, and paternity is the classic example where it is a profound risk of the investigator to hold that information from the participant.
	I think that most genetic researchers, because we know that in approximately ten percent of random populations one will gain, one will discover nonpaternity at least in the United States.  One will discover nonpaternity that one will not as a genetic researcher disclose that information and will protect it to a maximal extent.
	DR. PELIAS:  My own experience in genetics is that when a nonpaternity is discovered, it's unusually the mom who's informed and it ends right there.
	DR. KORNETSKY:  It really depends, and I think this is something that IRBs talk a lot about.  We will say an informed consent that it's possible but it won't be disclosed.  So I don't know what the right or wrong answer is, but somehow in the informed consent, I think it needs to somehow address it.
	DR. PELIAS:  Thank you, Bob.
	Alan.
	DR. FLEISCHMAN:  I share your disdain for the use of the word "to consent," or the wrong use of that word, but there is a problem with the way you've written this.  In this process, the investigator informs the subject.  Sometimes the investigator herself doesn't interact at all with the person who's going to give a blood sample, you know maybe a distant healthcare professional who's just obtaining a sample and sending it to the investigator.
	So I don't think we should imply in the document that an investigator must, here, and that's kind of implied.  So I think we need to have some kind of wiggle room.
	DR. PELIAS:  Okay, I'm noting "wiggle room." The investigator or the investigator's agent whoever is carrying out that study.  Yes, but agent is such a legal term.
	CHAIRPERSON MARSHALL:  Designee.
	DR. PELIAS:  Or his designee.  A designee?
	DR. FLEISCHMAN:  Yes.
	DR. PELIAS:  There we go.
	Jennie, you were next.
	DR. JOE:  Yes.  I think one of the things that we, in our IRB committee meetings we discuss more and more is what's going to happen to the tissue and how long is it going to be kept, and if it's going to be destroyed, when should that happen.  And that's been part of our process in forming the participants into genetic studies.
	The other one has to do with if you are going to provide genetic counseling, that it should be some mention here as a benefit that it will be available to them should they need it.
	DR. PELIAS:  Thank you, Jennie.  Next on the list is Felice.
	DR. F. LEVINE:  As an extension of what Mary Faith was saying about kind of triggering to how we're trying to cue IRBs and researchers to think about the consent as being a process and a continuing process, I think that we might want to make reference to the fact that just having -- and that it should be presented in a way appropriate to comprehension by the participant, meaning that a lengthy document may not necessarily cut it, so that I think you'll want to give a sense that that's not necessarily a form
	And that I don't know in this area, but it seems to be one where there also may be some inhibition to sign a consent form and how you address the circumstance where persons may not want to have a written record, but yet be depending upon what their situation is, may be otherwise willing and interested in participating.
	As so there's both the kind of this is sort of a consent process that you may want to make reference to and then get into the risk issue that kind of merged into one section.
	DR. PELIAS:  Yes, Sandy.
	DR. CHODOSH:  I think that one of the problems that we were faced with, that this part of an IRB guidebook, and we don't know what the chapter on informed consent is going to say right now.  So that we sort of have to wait until an editorial system gets in place to make sure that it is and does say things that we want, or otherwise we need to state something different. 
	But until we know that, it's sort of like a process that's not going anywhere.
	DR. F. LEVINE:  Thank you.  I agree.  I actually think though, that Mary Kay, and the way you did it on page 8 that you'll be able -- because these are all allowable in the process, that you could write just a few sentences that gives a sense of the richness of how IRBs can go about approaching these situations.
	DR. GOTTFRIED:  Felice, can I just ask though when you were just talking, were you talking particularly in the genetics context?
	DR. F. LEVINE:  I was because I thought it probably came into play quite a bit. Maybe not, you know.
	DR. PELIAS:  If I can comment briefly.  When we do consent forms, when we talk to people about projects, and we give them consent forms, which I admit are all too often much too complicated, one of the things that we do do is send them home with a copy of the consent form so that they can sit down at home and read the thing if they wish, that they get a copy of the complete thing.  And there is a move afoot now to give people the consent forms, ask them to take it home and then not ask them to sign it until the next time they come back.  They might have more questions and a better understanding of what's going on.
	Elliot.
	DR. DORFF:  I just wanted to say that along the lines that Sandy and others have just been talking about, it's important, and as you probably heard yesterday, the informed-consent group is trying to work out what the kind of dialogue would be that would be a good process for informed consent. And I think the list of things that you have down here is a very helpful list because it would say that in an informed consent process on genetics, these are the things that have to get into the dialogues.
	And similarly in other areas of medicine or in other areas of social and social scientific work, if there were specific issues that have to get into the dialogues, it would be helpful to have a list of those kinds of issues.
	And so the only thing that I would suggest, I mean it's a very minor suggestion here, is that you italicize the word "process" in the second line of page 9 to indicate the fact that that to which you're talking about is not simply signing a form, but that you're talking about an entire process, the nature of which we're now trying to work out in this other group.
	DR. GOTTFRIED:  Just with respect to Felice's earlier comment and what Sandy was saying, we were clearly trying to avoid duplication because this guidebook is going to be very large, and we don't have a clue as to how that chapter will evolve.  So we might look at adding a few more sentences here, but pretty much we're trying to minimize any references because of the chapter that's anticipated.
	DR. PELIAS:  Thank you, Kate.
	Mary Faith.
	CHAIRPERSON MARSHALL:  This is just another brief point but in this same first paragraph under the informed consent section.  If it would be possible -- I understand what you're trying to do here is get away from this consenting notion and that the investigator is responsible for disclosing adequately all the information that the person would need, and that it's the prospective subject who gives consent.
	But I wonder if you might be able to just throw a phrase in there because the subject is also going to be communicating and informing the investigator or staff about things that may be pertinent just to convey the idea that the communication is bilateral.  It's the subject who consents, and certainly it's the investigator who has to disclose adequately.
	But communication's going both ways we hope all the way throughout the process as well as decision making.
	DR. GOTTFRIED:  We talked about that and I think you're right.  We can make it clear that it's an interactive process.  I also was just going to say that I think comprehensive and when we have detailed, you might want to talk about a comprehensive discussion in the informed consent so that it's clear that it's going to be an in-depth.
	DR. PELIAS:  Have we done our job with informed consent for the moment?  I'm sure we'll come back to it later on.
	Moving on to the issues of, "Withdraw from participation."
	Yes, Adil.
	DR. GOTTFRIED:  For the record.
	DR. SHAMOO:  I share my colleague's compliment, how good and thorough really the job the working group did and your leadership, and we thank you.
	Yes, I have a couple comments on that, and especially on page 10 on the top, the first sentence says, "The issues include.."
	I have problems number 1 and 2, and number (1), "whether withdraw releases the subject."  Release means there is an obligation, and I have trouble seeing that the subject after he withdrew, he has an obligation to provide human tissue samples.  How are we going to force him to give tissue samples, biopsies, whatever.  So that, I think we need to rework it, and even providing further, may we could beg them and talk to them maybe.
	And item number (2), "whether the subject's identity will be removed from the research record," I think if the subject asks for it, in my view should be honored.  The rest of it, I think the use of data I can see that you don't want to -- you know the tissue's already given, the data already given, the identified should be used of course, otherwise the whole research project may be disrupted.  But those are the two items I have some questions about.
	DR. PELIAS:  Thank you very much for those comments.  I think I have raised these three issues as subjects of discussion when we're talking to people, but I admit the language needs to be reworked so it doesn't seem to be so rough or stiff.  Thank you very much.
	Alan.
	DR. FLEISCHMAN:  As just a simple IRB member, I have a big "oye" for the next sentence, "Indeed investigators may remove information although regulations are not consistent about whether removal of information is required or prohibited."
	DR. PELIAS:  [Off mike].
	DR. FLEISCHMAN:  I don't know, but it's not very nourishing, that paragraph.  I think we're going to have to consider best practices as well as just describing the craziness that exists.  You know, what is it that we think is a process by which we will get the best outcome?  I mean somehow.
	DR. PELIAS:  Thank you.  I try to work on nourishing language, but sometimes I really don't quite get there. 
	Susan and then Findley.
	DR. KORNETSKY:  The last sentence it looks like we've torn apart every sentence here, so I'll tear apart the last one.  I guess my question is, you're referencing that in FDA regulated clinical trials that it prohibits destruction of the data, and I think this is almost in some way biasing it.  And think that the reasons that people would withdraw genetic samples or data versus in an FDA regulated study are very, very different.
	So I was concerned about that sentence.
	DR. PELIAS:  Shall we -- is your suggestion to leave this sentence out?
	MS. MEYERS:  I think it's important to leave it in because people don't realize that if the FDA does govern it, if you're developing some device or a drug, and if FDA ever gets to regulate genetic tests, that they need -- FDA requires that you keep the information about anybody who dropped out of the trial and why they dropped out.
	DR. PELIAS:  Abbey, I agree with that if it's FDA regulated, but I think the majority of genetic research that's done in this country right now has no correlation with FDA.  And I think this is almost saying to individuals, FDA doesn't permit it so you shouldn't permit it either.
	MS. MEYERS:  But if they ever -- there's a move afoot to have them regulate genetic tests.  That's what that Secretary's Committee on Genetic Testing is probably going to conclude in their report.  And so it's extremely important that it's left in because you're not going to revise this booklet every year.
	DR. RICH:  Not only that, but as we move into an era of pharmacogenomics or pharmacogenetics, we can be sure that FDA regulated products that are designed for people with certain genetic profiles will in fact be a part of the FDA regulated process.  I mean I think the pharmaceutical industry is moving in a direction in which this sentence becomes very much germane.
	DR. KORNETSKY:  Then I would clarify it that it's regarding genetic research that is under some auspices of FDA regulation.
	No, it doesn't.  It says, "While some subjects will permit removal or destruction of the data, the subjects you trust in clinical trials that are governed by FDA regulations, investigators are required to include information about all subjects."  I don't think that was meant to talk about genetic research.  I thought it was just meant to put -- this is including genetic research?  That's why it was said?
	DR. PELIAS:  I would like to recognize Findley Austin now, please.	
	DR. AUSTIN:  Thank you.  I think we need to work on this, I mean, obviously.  As a workgroup member, I'm kind of embarrassed by number 1.  When you do go back and read it, I know that's not what we meant.
	But I think I wanted to kind of clarify and obviously maybe we need to expand this because I think what we were trying to do was capture all types of situations.  For example, currently with some clinical trials we'll run a study as a subprotocol where there's a hint of a possibility that genetics may be involved in the efficacy of a drug, but there's certainly not enough clinically valid data to include that as an inclusion or exclusion criteria part of the trial.
	So we do a separate study under separate IRB review where the trial participants are allowed to volunteer different time and all that point.  And in doing that, because we're only interested in the aggregate data, in order to maximize privacy and confidentiality, we anonymize everything at a certain point after the trial's ended.  Six months later we literally delete the key from the database.
	So at that point, it's absolute impossible to trace a sample back to an individual, but the sample and the clinical outcome still exist.  So it's possible to analyze new loci in the sample, but when we consent individuals in this study, we have to let them know, you've got up until six months after the trial ends to withdraw if you want to withdraw.  After that point, it's impossible to withdraw.
	CHAIRPERSON MARSHALL:  You just made an F-minus remark, you do know?
	DR. AUSTIN:  Huh?
	CHAIRPERSON MARSHALL:  When you said, "When we consent individuals who are in this study."  Findley.
	DR. AUSTIN:  Oh, I'm sorry.  During the informed consent process, we let the subjects know that they have.  And so I think and our discussions of these various strategies of using coded, double-coded, anonymized, the various strategies, we were trying to capture that in some instances you can't withdraw after a certain point.  But by definition you're no longer a human subject at that point because there's no personally identifiable information left with that sample.
	DR. PELIAS:  Thank you, Findley.  You and I will work on this paragraph for the next edition of this document.
	DR. FINDLEY:  And maybe what we need to do is to put in the different definitions and the outcomes.
	DR. PELIAS:  We will get to and we'll undergo another metamorphosis, so we'll see what happens.
	How are we doing for time?
	CHAIRPERSON MARSHALL:  It's just about three minutes to 3:00 and you have 45 minutes left.
	DR. PELIAS:  Okay.  Let's move on with that. "Vulnerable populations," I think this is a rather generic statement.  This is on page 10, a couple of paragraphs about vulnerable populations and I have a note to myself to say to you, remember, this is general information for IRB folks.  We don't have to go into a tremendous of detail in this.
	Yes, Adil.
	DR. SHAMOO:  Is the language used in the section, you're trying to keep the same language in the regs or this is your own language?  Then I have a follow-up obviously.  This is your own language?
	DR. PELIAS:  Pretty much, yes.
	DR. SHAMOO:  Then there is a confusion here because we want to keep the same language we've been using throughout NHRPAC proceedings and even the federal regs, and that is, there is the vulnerable populations are defined by the federal reg-- the prisoner's children or pregnant women.
	And the other part is the decisional capacity, that's the language we use to encompass mental illness, mental retardation, Alzheimer-type patient, et cetera.  And I think this whole section needs to be cleaned up to have two different paragraphs basically addressing the two issues, otherwise they are in mesh together, and I think they will be more confusing to IRBs rather than helpful.  That's one.
	Second is, I don't like the, "whose capacity for self determination is limited or even lost," and that's really decisional capacity will take care of that.
	The other thing in the second paragraph, the third sentence you use the word "persons with diminished mental capacities or competence."  Competence is a legal language and we don't deal with it.  We're only talking about decisional capacity.  If the person is incompetent legally, then you can't have them participate in research unless there is legally authorized person, et cetera, et cetera. 
	And of course, I'll bring the last issue because Mark Barnes is not here whom I don't favor to spend and waste time on it, and that is, "legally authorized representative."  Guess what?  We can do nothing about it.  That's a state issue beyond really our ability.  Maybe we could give example or two.  I thank you.
	DR. PELIAS:  Thank you, Adil.
	DR. FLEISCHMAN:  On that same sentence.  The only words Adil didn't dislike, I meant to dislike.  I don't understand what the words mean, "must be carefully protected in communications between their legally-authorized representatives, the researchers, investigators."  I don't know what that means.
	DR. PELIAS:  I will put a box around that and I will think about it, and then I will figure out what it means.  Thank you.
	Dr. Harris.
	DR. HARRIS:  Well, since we discussed this yesterday, first the term "legally authorized representative" I think is a term, it was discussed yesterday, it needs a little bit more clarification because in some instances it's a guardian and so on.
	I assume that mental retardation is covered under the category in the earlier paragraph, "persons with some types of cognitive disorders."  I assume that's why that's there because when you say "mental capacities," you're referring to all three of these previous designations, right?
	DR. PELIAS:  Yes, and if I need to clarify it, I will.
	DR. HARRIS:  Mental retardation is a developmental cognitive disorder.  I mean, there's been a lot of debate about dropping the term "mental retardation," and there's kind of an ongoing search at the Association of Mental Retardation about what else to call it.  Most of the rest of world, it's called intellectual disability.  In fact, the scientific association that meets every four years is called the International Association for the Scientific Study of Intellectual Disability.
	But I think that you're safe in calling it cognitive disability.  But I think that the term "cognitive disorder," or "cognitive disability" actually might be better than cognitive disorder because it emphasizes the vulnerability in that regard.
	DR. PELIAS:  Thank you very much.  It's well taken.
	CHAIRPERSON MARSHALL:  Jim, we've really benefited from your participation in the meeting yesterday and today, and come back anytime.
	DR. PELIAS:  Shall we conclude this with the discussion of named populations and community?  This may need to be expanded and worked on, and then finally publication practices and we'll have a short break.
	So any comments on named populations and community?  I know that this is something that's very important in the world of genetics right now, and it's going to review a lot of attention in the next couple of years.  Named populations and community?
	[No response.]
	DR. PELIAS:  I might add that you can address your questions to Elliot since he contributed this paragraph.
	[Laughter.]
	DR. SHAMOO:  One less thing for me to do.
	DR. PELIAS:  Are there questions or comments, and "Publication practices," then?
	So we're about halfway through, folks, and it's time for -- Felice, yes.
	DR. F. LEVINE:  It seems only some reference to, you say not naming subjects or revealing the identity of subjects or any other named persons.
	DR. FLEISCHMAN:  Mary Kay, one other question here.  In terms of publication practices, the IRB may not be involved in this until after the research.  So there are some obligations for the IRB to inform the investigator at the time of the initiation of the research that when they consider publication, that they may have to come back to discuss some of these issues.
	Now if they know about it prospectively, that's fine.  But you know, sometimes they don't figure it out until later on.  Since there's no place else to go in the institution to suggest that these ethical deliberations occur, the IRB is probably the right place.
	DR. PELIAS:  Thank you.  That will be included right away.
	Bob.
	DR. R. LEVINE:  Some people have advocated entering some of the information that's published with such things as pedigrees.  Is this document going to address that sort of thing?
	DR. PELIAS:  I know that people do alter pedigrees.  I know that people have become more and more reticent about publishing pedigrees.  One of the issues is the ability to replicate these studies and also to keep the families that are represented in pedigree charts, protect their privacy.
	My response to you is, that rather than spelling it out here, I think this is an issue for IRBs on an individual case-by-case, project-by-project judgment.
	DR. R. LEVINE:  Would you plan to go that far and to say those who think that it's okay alter information in pedigrees, and even more than pedigrees and that the IRB should evaluate these on a case-by-case basis?
	DR. KORNETSKY:  Mary Kay, on page 17 you talk about it.  I don't know whether it's -- it says, "alteration" on the very first part under "Bioinformatics and data sharing."  It says, "Alteration of such data, by changing birth order, adding false siblings is sometimes advocated as a means of filtering out identifying information."  And then it goes on to say, "because such data alteration may fake usefulness."
	DR. PELIAS:  What paragraph is this?
	DR. KORNETSKY:  17.
	DR. DORF:  Very top of the page.
	DR. KORNETSKY:  Very top of the page. It's like the second sentence.  Now, I don't know if that's in reference to publication specifically, but there is reference to changing things.
	DR. RICH:  We actually discussed this very specifically, and in fact this is the language that Steven Warren, who is the editor for the "American Journal for Human Genetics," said that if that is done, it's important that the publication explicitly state that that has been done and then anybody who reads the information will be forewarned that you can't rely upon this pedigree or upon this birth order or whatever in this particular publication because we've changed it.
	I mean, they basically discourage the practice when at all possible.  But if it's felt that it needs to be addressed, then it should be addressed with a codicil in the manuscript itself that says don't rely on the specifics of this pedigree or this birth order.
	DR. PELIAS:  Thank you Bob and Bob. 
	And we have another comment.
	MR. PALATUCCI:  I'm Chris Palatucci.  I'm with Athena Diagnostics.  Before we move on to Section 3, I just had one general comment on the first part of the document.
	First of all, I'd like to say thank you on the wonderful effort that's been put forth here.  But my comment is, someone at the very beginning of this session we started, and I don't remember exactly who said it, but someone introduced the concept of genetic determinism.  I think another concept that the document might benefit from is that sort of goes along with that is genetic exceptionalism.  That is, that most of what's in the beginning of the document applies to all medical research, and I think you could almost take out the word "genetics" throughout the whole first two sections, and it would equally apply to virtually any IRB doing any medical research.
	And in fact, it's not only until you get into Section 3 where the specific genetic issues I think are really raised.  And I think it's very dangerous to contribute to the notion that there's somehow some difference about genetic disease -- I'll have to be careful about how I say that.
	And certainly there are issues with genetic testing and genetic diseases that one wants to be very careful about.  On the other hand, you don't want to contribute to the stigmatization of hereditary disorders.
	DR. PELIAS:  Thank you very much.  Are we now done up through page 11?  Can we have a break?
	CHAIRPERSON MARSHALL:  Let's do this.  I can't remember who this person was, but someone informed that when one has breaks in meetings, that they can be divided into subcategories of one function, two function and three function breaks depending on the time allotted.  One can grab a coffee, visit the lew, make a telephone call.  This will officially be a three-function break, and we'll see you back at twenty-five after.
	[Brief recess was taken at 3:05.]
	CHAIRPERSON MARSHALL:  It's time folks. 
	DR. PELIAS:  Jeff, would you all mind closing the door for us?  We're going to get started again.  Thank you.
	I can turn on the microphone and talk very loud if necessary.  It sounds like a pneumatic drill upstairs, a dentist.
	We're going to give it our best shot, folks. We are now on page 12 at Roman 3, "Approaches and Considerations,"  I goofed on that, "in Genetics Research."  
	With regard to the time frame, I've been allotted until 4:00, and we will go as far as we can in this, and then we will return to it next time with an updated and reedited first part, and then we will continue with whatever we don't finish today. Is that okay with everybody?
	[No response.]
	DR. PELIAS:  Okay.  All right.
	CHAIRPERSON MARSHALL:  Let's try and finish it today.
	DR. PELIAS:  Yeah, let's try to finish it today.  I won't tell you how highly I think of Part 3. I'll let you have a go at it.	  But at any rate, we separated out the issues, the general IRB issues which we've spent all the time up until now talking about, and we created this section, Roman No. 3, that should set out a little bit of information specifically about genetic studies and what they are and how they're done.
	Once again, this is not supposed to be a genetics textbook.  It's supposed to be an introduction for other folks on our IRB.
	So let's start with Section 1 on "Family studies."  Do you have any comments about -- I mean Section A on "Family studies."  I have a couple of comments, but I'd like to hear yours first.
	DR. GOTTFRIED:  We're working on getting that shut off.
	DR. PELIAS:  If I don't have any immediate volunteers, I will ask you opinion on including descriptions of twin studies and the description of effected sib-pair analysis.  I am not convinced, although some of my colleagues are, that these two sections on twin studies and effected sib-pair analysis are necessary for this discussion.
	On the other hand, we can leave them and maybe some IRB members will be interested in the description.
	Yes, Susan.
	DR. KORNETSKY:  I probably agree with you.  I mean, I've been working with IRBs for a while and have not really at the IRB level gotten involved here.  I would say if there were specific issues that these studies presented for IRBs, that they should be educated.  But I don't have a problem leaving it in.  It's educational, but I think the day-to-day work of an RIB, an IRB member usually does not refer to this.
	DR. PELIAS:  May I ask you, then, do you think it would be useful if we had two footnotes with this information in it, that people could just read on by and not bother with if they weren't specifically interested?  
	DR. KORNETSKY:  It's going to cause no harm.
	DR. PELIAS:  Cause no harm, okay.  Thank you.
	How about the discussion of monogenic traits, and I have a question here specifically from members of the committee, and that is in paragraph 2 we mentioned these are contributions by Dr. Howell in Miami.  He has brought in the questions of preimplantation diagnosis and prenatal testing.  And my question to you derives I suppose from the world of politics, and that is, should we mention this because when we talk about this, we may not find a favorable reception outside of the world of genetics.
	Elliot.
	DR. DORFF:  I think we should.  But what you have may want to do is have another paragraph in which you talk about the fact that the status of preimplantation diagnosis in testing is a moral issue, a moral and religious issue for some, in both directions.  And by the way, my earlier comment in the introduction should go in both directions.  There are moral and religious reasons for people to oppose genetic research and testing and the like, and they're equally strong, moral and religious reasons for those who want to carry it out.
	I mean, take me for example.  Right, I think we should do it aggressively, okay.  So the thing is, and similarly here, I think what you could do is describe these tests -- that's what you're doing -- for the IRB, and then you just simply need to include a paragraph saying that some people object to this and some people very much embrace this.
	I mean, in the Jewish community Tay-Sachs testing is de rigueur, right.  And so I mean I think you can have that kind of a paragraph.
	And Susan and I were having a discussion, and she pointed to me that there's another paragraph that you may want to put into this which has to do with families or individuals for that matter that don't want to be tested because they don't want to know.
	This occurred in the BRCA-1/BRCA-2 thing, but it occurs in regard to other things as well because they may not want to know because (a) they can't do anything about it anyway; (b) because even if they're living with this as -- especially if it's a recessive gene -- they're living with this as a possibility during the course of their lifetime, they don't want to face it now, or they don't want to think about their children having to face this or about the question of whether they should have children given that they have this.
	In other words, there are a series of reasons why people may not want to be tested that are not moral or religious but are simply based upon their own personal lives and their hopes for the future.
	DR. SHAMOO:  Could we add Huntington Disease, another one, because that's the most clear monogenic as well as manifestation and so dramatic, Huntington Disease, and the age of onset is so sharp?
	DR. PELIAS:  Thank you.  I'll put that down in the next paragraph with dominant genes, unexpressed dominant genes.
	Yes, Bob.
	DR. R. LEVINE:  I may be mistaken, but I think I remember seeing a passage in this on the right not to know.
	DR. PELIAS:  It is in here.
	DR. R. LEVINE:  That might be elaborated a little bit to incorporate Elliot's concern.
	I think also that I would be inclined to retain the preimplantation diagnosis.  And I might even be tempted to go beyond and to discuss, add a sentence on how this is often done by blastomere biopsy or even -- I don't know if anyone's doing polar body analysis now.  But that's where the ethical tension, I think that's where the greatest ethical tension has come up, is over the meaning of blastomere biopsy.
	DR. PELIAS:  I think we call that the baby technique, blastomere analysis, before implantation, spelling baby wrong but nevertheless.
	Yes, please.  Would you identify yourself?
	MS. RADCLIFFE:  Sara Radcliffe with the Pharmaceutical Research and Manufacturers of America.  I'm a little confused about the inclusion of paragraphs 2, 3 and 4 on page 13.  It seems to me that these relate really to issues of clinical practice and not issues of research.  And therefore, if they're going to be retained in the document, I think that the relevance to research has to be made clear.
	DR. PELIAS:  That point is well taken, and we will make it clear.  I believe these topics should be included in this discussion, so we'll make it clear.
	DR. F. LEVINE:  It is a simple question if I said could you say quickly why, why you want to retain them?
	DR. PELIAS:  I believe, and this is something that I need to get in here somewhere, that this business of prenatal diagnosis of this carrier testing, this represents an area where there's an overlap of research and clinical practice.  And one of the things that we cannot do in genetics research is divorce the research from perhaps present or future clinical practice.
	This is an area of overlap, and I've heard a lot of people who speak vehemently about I'm doing research as if it has no implications for people who might become sick or who are sick or are coming in to see doctors because of genetic problems.  And so I have to think about this and make this fit together a little bit better.
	DR. F. LEVINE:  Might that be the handle though?  Meaning, there are a bundling of human subjects issues at the borderline of research that intersects with clinical practice so that these are illustrations of that broader point.
	DR. PELIAS:  Exactly.  Thank you.
	Should we move on to multigenic traits?  Any comments on this section?
	Adil.
	DR. SHAMOO:  Simple one and trivial one.  Remember I said about complex diseases, definition?  If you take the second paragraph, the first two sentences, you define it exactly the way I -- maybe subconsciously that's where I got it from.  That gives you -- this is a particular type of multigenic and multifactorial, blah, blah.  These diseases are complex because they are and then you go on.  So you have both of both worlds definition there.
	DR. PELIAS:  So you would like me to take that wording and put it in the definitions up front?
	DR. SHAMOO:  Exactly.
	DR. PELIAS:  Gotcha. 
	DR. SHAMOO:  It would be more complete I think.
	DR. PELIAS:  Sure enough.  Okay.
	If there are no further comments on that section, we'll move on to the section on "Applied research."  That's on page 15.
	Elliot.
	DR. DORFF:  It's a very simple thing, but I didn't know what CLIA meant until I got to page 20 where you spelled it all out.  So you may want to just spell it all out here and then put in parenthesis "CLIA" and then you can use the acronym afterwards.
	DR. PELIAS:  Thank you for that.  I was thinking I don't know was CLIA is either.
	All right.  That will be taken care of.  We're not at the top of 16 on newborn screening. 
	Yes, Alan.
	DR. FLEISCHMAN:  This one I do have some substantive issues with.  My understanding for about twenty years since Ruth Faden's initial work in this area is that we've had some agreement about the ethics of newborn screening as the criteria that would be used by a state to determine what types of diseases would be tested for, okay.  That those diseases would be serious diseases that had consequences in childhood for which there were tests that were reliable and valid and there were effective interventions that could be instituted. 
	And therefore, we could argue as you do, that overwhelming the autonomous right in the family to make that choice was in the child's interest and perhaps society's interest as well.
	Having said that, which is how I would start this, we now have the ability on simple chips to do, you say, fifty -- you know, whatever number -- hundreds, thousands of tests.  I would consider all of that research unless it reached the criteria that had been kind of agreed to as the ethical standards for newborn screening, then everything else is research.  And if it is research, and I'm willing to argue this one or have disagreement, but if it then is research, then IRBs ought to worry about it, and there ought to be a process of getting approval and consent and dah, dah, dah, dah, dah.
	But I don't think we have that concept here.
	DR. PELIAS:  My understanding is that the folks who are active in the world of tandem aspectometry are pushing this so that they can get lots and lots of genotypes done in one fell swoop on one infant.  Whether or not there is treatment pending or treatment may be generated in the future, it was my impression of newborn screening is that it was always contingent on available treatment and benefit to the child.
	And this paragraph, I'll have to work it over, but this paragraph represents the confusion in the world of genetics now because people are being pushed with this new multiple testing technology to generate genotypes for things that they can't do any -- I'll work on that.  I acknowledge your concerns.
	DR. FLEISCHMAN:  I have a second concern, but we can talk about this one if Bob -- yes, I have a second concern on the newborn screening.
	DR. R. LEVINE:  I would have to disagree that this is per se research.  In the language of the Belmont Report, if anything it would be innovative practice, and in the language of the Belmont Report, that ordinarily innovative practices should be made the object of research to evaluate whether they're safe and effective, which has the effect of bringing it under the purview of the IRB.
	But the screening itself is not research any more than an investigational drug would be.
	DR. FLEISCHMAN:  I'm going to have to think that one through, Bob.  I mean, I need to learn more about that.  It's not obvious to me that that's in fact the case.
	DR. R. LEVINE:   An intervention or procedure per se can't be research, research being defined as a class of activities designed to develop or contribute to a development of generalizable knowledge.
	This procedure which is purported by some to have diagnostic value has apparently not been evaluated to your satisfaction so that you can say here are certain things we ordinarily say about diagnostic tests that are out there available for you, such as here's the specificity, here's the sensitivity, et cetera.
	That would make it an innovative practice, and then the commission said, now when you have certain types of innovative practices, and I believe it would include this, then you have an obligation to do research to see whether or not it's all you think it is or all you hope it is.
	So the bottom line is the same.
	DR. RICH:  I disagree with that, Bob.
	DR. R. LEVINE:  You can't disagree with that. That's what's in the Belmont Report.  You can say you don't like what's in the Belmont Report.
	DR. RICH:  What I disagree with is that it's innovative practice at the outset.  I do think that with the technologies that are emerging now, both with respect to genotyping and with respect to tandem aspectometry, the analysis of gene products at a molecular level one can formulate a hypothesis in advance of generating this kind of data and then can use the newborn screening as the way of validating the hypothesis. 
	So I tend to agree that it's research from the get-go if it doesn't satisfy the criteria that Alan enunciated.
	DR. SHAMOO:  Can I add something on the point?
	DR. PELIAS:  Excuse me, Adil.  Alan said he had a second point to make.
	DR. SHAMOO:  It's on the same point.
	DR. PELIAS:   All right.
	DR. SHAMOO:  I think NBAC addressed this issue and is in agreement with you, Bob -- innovative therapy versus research.  And they sort of more weighed into -- those kind of things should be considered, some of them research.  So National Commission is a quarter of a century old and NBAC is only a few years.
	DR. PELIAS:  Sandy.
	DR. CHODOSH:  I just want to pipe in and agree with Bob Rich on this.
	DR. R. LEVINE:  In that case, what you're doing is saying we have to rewrite the definition of research because certainly having an intervention or a procedure is not an activity designed to contribute to generalizable new knowledge.
	DR. RICH:  That's not correct in this case.  For newborn screening, what you have is a sample of blood presumably from a baby.  And you can formulate a hypothesis that it would be efficient to screen hundreds of thousands of samples to pick out those two or three that might be able to demonstrate a particular either genetic or protein profile.
	So you can formulate that hypothesis in advance of -- and it's not innovative therapy at that point.  It is truly research.
	DR. R. LEVINE:  Innovative practices.
	DR. RICH:  Innovative practice.
	DR. R. LEVINE:  It's not every therapy.
	DR. RICH:  I'm sorry, innovative practice.  I misspoke.
	DR. R. LEVINE:  But doing the things you have to do to test that hypothesis, that would be research. The particular device that you have to evaluate is not in and of itself research.
	DR. RICH:  I beg to differ.  The technology is well established, so the technology of the phenotype being of the aspectrometry is known.  You don't have to validate the technology.  What you have to do is pose the --
	We may be getting beyond where we want to go in this discussion.
	CHAIRPERSON MARSHALL:  I think we are at the moment.  That's why Mary Kay said that this is an unsettled issue.  It's something that if you wanted her group to look at, we could do that, but you're not going to settle it here. 
	DR. PELIAS:  And is why I also say at the end of some of these paragraphs, this is something that's not settled yet and it's open for further discussion.  I don't know that we can solve this particular issue in this group.
	CHAIRPERSON MARSHALL:  But maybe we should address it.  I think we should, but both Bobs, I think that we should if things have changed, then maybe we do need to revisit.
	DR. FLEISCHMAN:  But both Bobs agree that when you get beyond those known newborn screening diseased issues, you're into something that requires IRB involvement.  Whether you call it innovative or research, IRBs should understand that they have some obligations around that area.
	Is that right?
	DR. RICH:  I agree with that.
	DR. FLEISCHMAN:  That's where I was going.  I learned something in this discussion.
	DR. RICH:  And I think specifically enunciating those four points actually would be a helpful addition to this section.
	DR. FLEISCHMAN:  New York State Task Force and Life in the Law monograph on that, on genetic issues, I think does a reasonable job of that.
	DR. CHODOSH:  I think it's really important to stress that different states have different rules about this, that every IRB has to look at where they are sitting in terms of looking at all the implications because it's quite different from state to state.
	DR. FLEISCHMAN:  The diseases that are tested are different, but the criteria are not.  I mean, the criteria have been agreed on nationally.  It's just a matter of how much money and where the line is that they're willing to -- how many diseases they're willing test.
	CHAIRPERSON MARSHALL:  Alan, could you get Mary Kay a copy of the monograph?
	DR. FLEISCHMAN:  Indeed.
	CHAIRPERSON MARSHALL:  Thank you very much.
	DR. FLEISCHMAN:  My second issue has to do with, and it may be covered in the banking area, but one of the really interesting ethical dilemmas in the last few years concerning newborn screening has been the use of discarded blood samples that have either been anonymized or not.
	And in the HIV testing world that was a really quite, let's say, controversial issue used initially as a surveillance technique with so-called anonymized samples.  It was then criticized when  potential diagnoses were made or risks for diagnosis were made.  And IRBs got involved in that question as to what was required, what was ethical.  There was a whole lots of conversations and discussions.
	And at least in there somewhere we ought to reference the concern that IRBs may deal with or may be asked to deal with when people begin to look at those stored samples, whether they are anonymized, where there is linkage, and they ought to be reminded of those issues.
	DR. PELIAS:  Thank you very much, Alan.  Do we have more comments on this section on newborn screening?  
	Shall we go on to "Bioinformatics and datasharing?"  Do we have comments on that that you would be willing to address to Dr. Rich?
	[Laughter.]
	DR. CHODOSH:  I guess I came away from this without a good understanding of, is there any way to protect computer information, because it states here that even when you think you have a firewall up on your own computer, that the institution still has access to that.
	Is there in fact any way that we can tell an IRB that this is what you should be looking for, or is it totally hopeless?
	DR. PELIAS:  That's a question that I will have to inquire about, and my consultant on that will be Ellen Clayton who helped them set up the purple room in Marshfield, Wisconsin.  She seems to feel that the computers that store patient data and very sensitive information, that the computer stuff that's in the purple room is completely safe and even separated from institutional computer facilities.
	DR. CHODOSH:  I think it's really worthwhile information for people to know about because right now we promise confidentiality and we don't even know how to do it.
	DR. PELIAS:  Okay.  I will inquire.  Do you want me to include a paragraph on this about whatever exists?  All right.
	DR. RICH:  These are very rapidly moving areas as you can imagine.
	DR. PELIAS:  Yes, yes.
	DR. RICH:  And I'd be a little cautious about being too specific here, other than to simply, to state that the IRB needs to remain cognizant of this issue.  Obviously, it's going to be very much controlled by the impending HIPAA regulations which will define just how hard it is to get behind a firewall and things like that.
	I think that the IRB handbook may not be the place for a great deal of specificity.
	DR. PELIAS:  Felice.
	DR. F. LEVINE:  You and I talked about a little bit at the break.  It would seem that this section might be constructed in terms of data access and data sharing with information, computer technology or information technology, just being a subparagraph part of this because there are several generic issues with respect to obviously subjects providing access to their information in a dataset triggering back to the earlier portion of consent.  There are public-use files, limited-use files, files that may be accessible electronically and not.
	And it seems to me that one of those issues have kind of gotten merged into this, and it's not that it needs to be a lot longer, but I just think that an IRB would be informed by knowing what the topics are and it could be unraveled a little bit better and unpacked and probably simplified.
	DR. CHODOSH:  Kate, is it possible for us to find out from the people who put an IRB book together whether there's going to be something about this, a chapter?  Because they may in fact deal with it quite extensively, and for us to try to figure it out, wouldn't make sense.
	DR. RICH:  These are not --
	DR. GOTTFRIED:  No, I'll definitely check on that.
	Susan Rose is overseeing that whole effort, so I'll talk with Susan about it, from the Department of Energy.
	DR. R. LEVINE:  I even say quickly that I think that's an important enough topic that has penetrated a number of our other prior discussions that we might want to schedule that as a discussion point on the agenda so that we know what's happening there, we can put input to that, and that then it makes this task easier.  This could in a way just trigger to that and only clarify what may be unique.
	DR. PELIAS:  Thank you, Felice.
	Do we have any further comments on bioinformatics at the moment?
	[No response.]
	DR. PELIAS:  Moving on to genetic counseling, psychosocial issues.  You will recall that my colleague, Dr. Howell, said he didn't think that this kind of discussion is appropriate here, and I am disagreeing with him, and some of you agree with me, so I'll leave it there, and we'll see what happens next time around when I tell Dr. Howell that he was kind of voted down.  Is that okay?
	[Laughter.]
	DR. PELIAS:  If you have no further comments or do you have further comments?
	Yes, Felice.
	DR. R. LEVINE:  The only thing I wondered in that conversation, and I'm not an expert at all on this, but I recognize that you have to have some level of expertise to provide counseling.  But it seemed to be very specific to a particular form of training and expertise of which you say it's a relatively small number -- now of course I will show my pedigree.  I imagine that there could be any number of clinical psychologists-- for example, appropriately, all right, well or MSW.
	And it seemed a bit oriented to this specialty and it may be that it could be broadened a bit.
	DR. PELIAS:  I can do that and make sure that -- I have some of these groups included in here, the nondoctoral-level types, but I'll work on them.
	DR. GOTTFRIED:  It says, "Individuals and other ancillary professions are valuable contributors to the counseling and education process," and then we could expand it a little bit I think.
	DR. PELIAS:  Can do.
	Elliot.
	DR. DORFF:  Did you ask for questions on any of the rest of the document?  Is that what I just heard?
	DR. PELIAS:  No, we're on genetic counseling.
	DR. DORFF:  Okay.
	DR. PELIAS:  Kate reminds me that we're now on children and adolescents.  I think we're going to try to finish this up today.
	Yes, Susan.
	DR. KORNETSKY:  I don't know how to deal with this, but it's something that often comes up.  Children grow to be adults, and samples stay around a long time, and like I said, I'm not sure how to deal with it, but there are issues of assent turning into consent.
	I think if this is just being discussed, I don't think there are any clear guidelines about what should or shouldn't be done, but maybe that should be acknowledged.
	DR. FLEISCHMAN:  I think we've talked, Mary Kay, about the issue of the sexually active adolescent, and the implications of not doing certain testing, and I'm not sure I see that here.  You basically argue that -- I'm not sure that's a medical benefit.  So there are some social benefits of testing potentially in adolescents that --
	Do geneticists have such a consensus among geneticists that no child should ever be the subjects of genetic testing even in the potential for them to pass a gene in pregnancy?
	DR. PELIAS:  There is a dichotomy in the world of human genetics and medical genetics about this business of testing, and you're raising a question that I think maybe we should include in this discussion somewhere, that there may be gray areas where the testing is appropriate, but I need to think about this, and I will do it, and work on it.
	Any further questions?  
	This is a subject that's been near and dear to me for a long, long time, and I was rather amazed yesterday when we talked about children with mental retardation and developmental disabilities.  And in the whole discussion very little was said about the role of parents in these children's lives as the decision makers for their own kids.
	But that's just an editorial comment.  Let's move on.
	We'll go to "Race and ethnicity," and I'm picking up typos.  I appreciate your pointing them out to me if you have any, but I'm picking up on them.
	DR. R. LEVINE:  Mary Kay, could you summarize what the basic guidance is here with respect to the measurement of race and ethnicity?  You're kind of giving a nice overview of the background of it, and the different views, but in the end I wasn't sure what it was an IRB should be thinking and doing.
	DR. PELIAS:  I'm not sure that geneticists are certain about these ideas right now.  I know there's a tremendous amount of discussion in the world of genetics about how much emphasis we should put on classifying people according to race or ethnic groups and what is the meaning of race now that things are, at least in this country, quite mixed up.
	What I'm trying to do is say that this is a topic of discussion without any real guidelines generated at this point.
	DR. F. LEVINE:  My concern is IRBs coming away perhaps with the view, not just in this area, more broadly that than they should be assessing whether or not the collection of data on race and ethnicity is important when it is as you pointed out with respect to federal agencies, but it really is for a whole wide spectrum of research including family studies and genetics and in the social and behavioral science parts of those and epidemiology. It's just fundamentally important for understanding the nature of our society, so I would hate to have what might be looked at as human subjects issue convoluted with the scientific issues.
	I'm a little bit concerned about leaving it open-ended.  I'd almost rather leave it out than leave it open-ended.
	DR. PELIAS:  Well, I think where the world of genetics research stands right now is that if you are going to include race or ethnic group as a quatahearing, you better have a sound scientific reason for doing so.  And maybe I need to say that.
	DR. F. LEVINE:  Yes, but not --
	DR. PELIAS:  I did say it, but I could probably say it a little more strongly.
	DR. RICH:  I tend to disagree with that statement in the sense that at least the NIH now mandates the inclusion of racial disparities as part of how one designed the study.  And it doesn't matter whether or not you believe as an investigator that there's a scientific question at issue or not.  I can cite for you a good number examples where it was very clear there was not a scientific question at issue, other than the fact that it was mandated by the National Institutes of Health.
	DR. PELIAS:  Thank you, Bob.
	Yes.
	MR. RABER:  Yes.  Carter Raber, anthropologist for consulting firm, LTG Associates.  I think the last paragraph -- I think the discussion that we just had here actually raises part of the problem in always grouping the term "race" and "ethnic group" together at the same time.
	Ethnic group was in anthropology at least developed precisely as a response to the use of the term "race" which clearly add a biologic connotation.  Ethnic group was a social construction and is seen as that.
	Now there are various proxies and various ways of identifying membership in ethnic groups as in skin color and et cetera, et cetera.  So the first sentence on the last paragraph somehow I think gets away from that and raises some problems as the boundaries of biological race become less distinct.
	You know, it sort of sounds a little bit like, dare I say miscegenation of something like that, and that that's the root of the problem.  When in fact, it's really a question of the construct or the notion of race is contested as opposed to the question biological race less distinct.
	DR. PELIAS:  Okay.
	MR. RABER:  I think there's some other issue surrounding that as well, but I think in the NIH literature, the notion of ethnic group and healthcare disparity is really defined.  They emphasize the social construction of race in that body of literature, and they're trying to sort out the fact that we're trying to come up with new labels for particular populations. We just haven't figured out how to do it yet.
	DR. PELIAS:  Thank you.
	Do we have other comments on this section of the document?
	[No response.]
	DR. PELIAS:  I've noted a couple of redundancies.  I'll take care of them.
	On page 20, we have "Subject access to research data."  Comments on this, please?
	[No response.]
	DR. PELIAS:  And finally management and secondary use of tissue samples.  This is a real problem for us these days.
	[No response.]
	DR. PELIAS:  Or shall we table these last few sections for a lot of argument next time?
	CHAIRPERSON MARSHALL:  No, no, no.
	DR. PELIAS:  All right.  I have a note to myself here that on page 22 in the paragraph on "Consent for future use," I've noted to myself that this is my own view.  This is not necessarily a view that's widely shared, but it's something that I think it's important for us to think about, so in my role as the person who types all this in, I included it and it can be eliminated if you wish.
	DR. R. LEVINE:  Mary Kay, on the access issues, subjects potentially at the interim data level, but certainly after data are gathered, although in certain respects we could end up being ongoing, that subjects have the option of having access to their own data?  Is that the quest of this?
	I'm feeling very well briefed, but then I don't know what the thrust is from an IRB's point of view.
	DR. PELIAS:  Yeah.  Sometimes these things are not settled, and they're going to have to be issues that will have to be dealt with at the local level by the IRB there.  At present, there are many, many genetics researchers who do not want to release any kind of provisional data to research subjects.  And yet there are other geneticists who are saying maybe we better not be so absolute about this and we should allow for the possibility that a research subject may want that information, understanding that it's provisional information because he or she may want to pursue testing elsewhere to see if he or she's got a really bad gene.
	Well, what would you like me to do with this?
	DR. F. LEVINE:  Well, it seems as if we're seeking here to give IRBs some sense of whether humans subjects have the capacity to make those requests and if that's sort of a built-in part of the process or is this something that an investigator only has a responsibility to inform a subject that if you participate in this study, you will have access and then IRB, just the IRBs would need to --
	It seems to me it's part of that consent process.  I felt more comfortable about what you were saying at the front end than here because then, okay, it's something that, like anonymity, it either comes up in the consent process and the agreement that's struck or it isn't.  And if a researcher has --
	Researchers may have very valid reasons for wanting it.  It can often identify other subjects.  If one subject has information of it in there in small samples, and that's done disproportionately, it can unknowingly reveal information about other subjects.
	DR. PELIAS:  Sandy.
	DR. CHODOSH:  I guess the dilemma that we were faced with was that it's clear that in some studies that discussion is going to be made anonymous, everything is going to be anonymous.  It's almost easier when it's not that case where there is an opportunity to maintain identifiers to tell or ask a subject do you not want to know about the results.  That's sort of clear, okay.
	So it has to come up in some way, but only if there are going to be identifiers left around.  Now, if they're told that there are no identifiers, the subject may say, well, I'm going to want to know the data, I'm not going to go on this study.  If you're going to wipe it away, I don't want to be in it.
	So that there are so many variabilities to all this that as I said, the only clear cases seem to be when the subject does not want to know.  If they do want to know, then the problem arises, is the data going to be made so anonymous that it's not possible to retrieve it?  Or will it be an exception to maintain identifiers so that they can retrieve that data.  It creates a lot of problems.
	Bob, I'm sure is aware of what that would mean if you had a mix of that coin or anonymous data mixed in with identifier data, so that sometimes you can offer to subjects and sometimes you can't.  And I think that that's up to the IRB and up to the particular protocol.
	DR. PELIAS:  I think we'll let Bob Levine have the last comment today.
	DR. R. LEVINE:  I think that there are certain -- I think it's fairly common that the IRB and the investigators have to reach an agreement that certainly in the early stages of development of either a diagnostic test of a genetic linkage that they will not turn over the information to the research subjects, and also as part of that, it's usually stipulated that that means you also don't turn it over to any treating physicians or put it in the medical records.
	There comes then another point along the way that you might consider making such information available to the research subject who want to know it. I think geneticists have published criteria for -- in fact, I think some of the earliest criteria were published by Philip Reilly about how serious is it, how confident you are in the meaning of the result, is there something you can do about it and so on.
	And also at that point, you would have to take into account whether or not the clear approved laboratory criteria would apply to this particular research, and then later on down the road when you're pretty confident and you know what's going on, you would offer all of the individuals the option of learning what the result is.
	I think it would be helpful to layer some of these things out here.  Thank you.
	DR. PELIAS:  Thank you very much.  Do we have any further comments from our guests and from the consultants?
	[No response.]
	MS. LEGGETT:  Hi.  I'm Wendy Leggett from Merck and Company.  I just have two brief logistical questions.  Has the OHRP indicated when they intend to revise the entire IRB Guidebook?  And when can we expect the revised draft from the workgroup here?
	These are two questions that I know the person to call about that, but I don't know the answers to your question, so we'll work on that for next time, okay.
	MS. LEGGETT: When can we expect the revision from this group, from the workgroup?
	DR. PELIAS:  From this group?
	MS. LEGGETT:  From the workgroup, right.
	DR. PELIAS:  The revision from this, I hope though it will be out by the end of October for sure when we have our next meeting, a revision.
	DR. GOTTFRIED:  And the OHRP Guidebook, there's a process underway to create all the different chapters, revisions to the preexisting chapters, and I'm thinking that -- I don't know if Jeff is still here, but sometime next winter, is that right, like 2003 winter as opposed to December 2002.
	MS. LEGGETT:  Thank you.
	DR. GOTTFRIED:  I think that's it for this particular session.  I just want to strongly echo the sentiments expressed both yesterday and today by the committee and others for the really extraordinary work completed by the workgroups, the workgroup on decisional impairment on children and genetics by Jonathan Moreno, Alan Fleischman and Mary Kay.
	They have really done exceptional work with respect to providing guidance and leadership to very large workgroups with often complicated and controversial issues, and I personally appreciate all the effort that you all have put in.
	DR. PELIAS:  And I would like to extend my thanks to the members of my working group, too.  It was a very satisfying team effort. Thanks a lot.
	Sandy.
	DR. CHODOSH:  I have to speak up because without Mary Kay, this would not have happened.  She put in one fantastic amount of work and knowledge.
	[Applause.]
	DR. CHODOSH:  And we appreciate that effort.
	DR. JOE:  I just have a question.  Since this was in response to the guidebook, are any of these things going to go forward as separate recommendations like we normally do?  Is this where the focus is going to be primarily, it's just on this particular work?
	DR. GOTTFRIED:  We hadn't really explored that to date, but certainly the focus right now is for a contribution to the guidebook.  But as a committee, we can certainly make a recommendation that this be put forward in a different context as well.
	CHAIRPERSON MARSHALL:  And this workgroup is not going anywhere.
	[Laughter.]
	CHAIRPERSON MARSHALL:  Bob, you may leave momentarily, but just don't get any big ideas of divorcing or disassociating yourself.
	Thank you so much.  Thank you, Mary Kay.  Fabulous work that you should be proud of.  I hope you are.
	Felice, we do have fifteen minutes.  Would you like those fifteen minutes?  You may elect not to use them if you so choose.
	DR. F. LEVINE:  Are you still here, Jeff?
	JEFF:  I'll wait.
	DR. F. LEVINE:  All right.  Well, let me just say briefly where I think we are collectively on a number of issues, including the social and behavioral science working group.
	As my NHRPAC colleagues are hardy here, recall we completed work also on the NHRPAC with one voice and unanimity, completed work on the confidentiality and privacy document in April, at the end of April.  Those of you who are as preoccupied with e-mail as I sometimes are, know that I made a transition to a new job on May 6, so the fine tuning of the few footnotes I didn't pass along until about two weeks ago to Mary Kay and Kate Louise, but it was ready to now advance to the assistant secretary.  That really is work that started with the working group, but really has gone through NHRPAC, and so as soon as that gets advanced, it'll be circulated.
	I didn't bring copies for a good reason.  If I made a typo or anything that looked out of place and that hadn't been read, I would have preferred not to distribute it until it's been really read by the chair of the committee.
	I have a similar task to complete for NHRPAC with respect to risk and harm, and I could only kind of hit one of those, and I will do risk and harm.  Although I think risk and harm needed one final review by this group, so it will come back in October, but was in principle approved by this group.
	We talked about the fact that the social and behavioral science working group has, predating the informed consent working groups, had been working on this issue and had a couple of meetings -- well, more than one meeting -- that focused on that with Bob Levine who's a member of the Informed Consent Working Group, and Joan Siebert [ph] taking the lead.
	We now have a draft that I want to send to our working group that will then be finalized and really transmitted to the other two working groups to give them some additional background on some of the thinking of the social and behavioral science group on that.  It isn't going through NHRPAC.  It's really going to the working groups, and that will happen soon enough so that it has some impact on the thinking and work of those working groups for October.
	I think assuming the chassis that is logical, I will share that with NHRPAC just so that they know what's being passed along, but it doesn't have any formal status in any sense from us giving it to NHRPAC until it's been massaged and essentially given some additional input by this committee.
	The area that we have been taking to a next step further was the discussion of student research, and that was really based on what I thought was a terrific conversation we had in April.  This is a revised outline of the thinking now of the subgroup of the social and behavioral science working group working in this area which is essentially Jeff Cohen and I and Dick Campbell and Paula Sketchfold [ph], but reflects both the discussions of the working group and -- I'll leave a stack here -- that reflect both the discussions of the working group and a discussion at the NHRPAC meeting in April.
	It's long in introduction because it's goal it to really orient you to our thinking, but it's really thinking that it really was very effectively shaped by the NHRPAC meeting in April.  And that is, which if I can digress for one moment, I think, something that when we think about how other disciplines who have been less culturated to operating within the human subjects protection system, as we think about their integration, I think one of the most refreshing parts about being a part of the social and behavioral science community and NHRPAC is how frequently we recognize, which of course most of us have, that we're talking about generic issues and generic issues that don't divide by either wear-one/got-one degree, what field one got it in or what one labels oneself as.
	And so readily it became apparent that of course while because perhaps the earlier training and involvement in student research in the social and behavioral sciences, that these issues we want to take up generically for the good of all fields just as ultimately we did with confidentiality and privacy and just as we did with risk and harm, and even with public-use files.
	One of the transformations is to make that more generic, even though we may drop on the experiences of the social and behavioral science community that this is something that hopefully will enrich the thinking and training in all fields.
	We recognize that there is difference in view about the meaning of and perhaps the generalizable knowledge with respect to issues of student research, but at least from our point of view, we think student education and training and ethical practice and some forms of review of projects, whether they fall under the federal regulations or not, is important.
	So the introduction kind of gives you an orientation to how we want to approach it.  And then the flip side, which in a sense would be the opening part of the report, gives you an overview of the topics we hope to cover.
	So my hope, given the hour and given the lack of quorum, is that everyone feels comfortable within NHRPAC, giving us advice and guidance so that we can have your ongoing input as we bring something to the group in October.  And those of you who stayed and hung in here, probably for the moment, the easiest thing would be to directly e-mail me.
	Paula, we can still use the "human subjects" box, I guess, right.  Okay.  And what's the --
	PAULA:  HumanSubjects@asanet.org.
	DR R. LEVINE:  So we have part of a home page from the American Sociological Association that's just for the social and behavioral science working group.  And we would love feedback and input because we really think this is a very important topic in something that would enrich all aspects of not only the quality of the ethics of research in general, but student development and training and preparation in doing so.  Even for those who don't go into research careers, we may make a more informed citizenry. 
	The other issue that I want to just touch upon really briefly is that we are hoping in our working group to have the resources.  We did have some resources last year from the Office of Behavioral and Social Science Research at NIH, and were some additional resources to be forthcoming.
	We are hoping in February-- we had a very good initial meeting discussing that -- Jeff and I and Paula -- last Friday, to convene a small workshop.  Chairs of IRBs that are either specializing in the social and behavioral science and, slash, sometimes humanities or sometimes just the nonbiomedical, but also social and behavioral sciences who are chairing mixed committees, to talk about how they view the process, how do they look at these issues as they come in the door so that we have a better understanding both how an IRB group who disproportionately see these protocols address these issues and that also can produce some really good guidance in terms of best practices for researchers, not just in the preparation of protocols, but understanding what those points of tension and challenge are as IRBs who are not neophytes are looking at these documents.
	So we're hoping that that really provides something that will avert what we often say are the fault lines between what our intellectual capacity leads us to know is possible and conceivable within the regulations, but then there's a kind of mismatch between that and what often happens in the daily lives of investigators preparing protocols or IRBs evaluating them.
	So we're hoping that that will help to bridge some of that chasm.  I think it's a very exciting possibility and will be a small working group where we, if we can meet in February where we then hope to have a report of that meeting at the end of April meeting.  So that's how we're staging that.
	The other area that was on our agenda, original outline, that I think is one of those areas of confusion, I think, in terms of best practices, best ethical practice in terms of research as well as how the work is reviewed, and I think we need to get into that methodological cut of ethnographic and qualitative research.
	And it was on our list.  It wasn't as much of a priority in terms of key issues that we wanted to chip away at initially, although many of the topics related to that, but I think now we need to take that methodological cut and provide some guidance to NHRPAC, working recommendations that NHRPAC can chew on and offer through the process.
	So we are viewing the 1992/1993 year and each of the meetings that follow to be opportunities to I think continue to engage in important issues as well as work across working groups to give the kind of input that I think NHRPAC in general seeks.
	CHAIRPERSON MARSHALL:  Thank you, Felice.
	Alan, briefly.
	DR. FLEISCHMAN:  Having just had the opportunity to skim this student research outline, it's very impressive work, and I think it's really a tremendous move forward.  The one thing that I would think would help is an acceptance that people who are students can do harm to human subjects even if it's breaching confidentiality issues or causing discomforts or whatever the level.
	And I think that flavor isn't here.  That if we're going to create streamlined or other approaches, there has to be an acceptance that there has to be a culture of protection, and that even students can do harm.
	DR. F. LEVINE:  I'm going to say I agree, but I think that that was philosophically why we believe there needs to be review as opposed to the general knowledge standard, but we should make it explicit.
	DR. SHAMOO:  Felice, I think you've had a lot of innovative ideas on that sheet, and I want to commend you with it, especially the student IRBs and the other things.  The department chairmen, the connections are wonderful.
	CHAIRPERSON MARSHALL:  Yes, absolutely. Thank you, Felice.  I think that our business day is at a close, or our two days are at a close, and just a couple of remarks before you walk out the door.  It's been a very gratifying two days.  We had a heavy agenda.  We did a lot of work, and I think we saw the product, the tip of the iceberg of even more work, all the work that has gone on between our last meeting and now.
	So it's felt a little bit like an incestuous lovefest because there have been so many kudos flying around the room and there's so much work that overlaps, but I want to thank you all-- our committee members and workgroup chairs, our ex-officios for being here and being actively involved, our public members.  We can't thank you enough and we look forward to seeing you in October, very close to Halloween.
	And e-ail us.  We've heard from you about wanting to be on our working groups and participating more actively, so don't fade away and let us hear from you and we'll put you to work.
	Thank you all.
	[Whereupon, at 4:30 p.m., the proceedings were adjourned.]
	- - -

	CERTIFICATE OF OFFICIAL REPORTER


	This is to certify that the foregoing proceedings before the National Human Research Protections Advisory Committee held Wednesday, July 31, 2002, was held as herein appears, and that this is the original verbatim transcript thereof, and is a full correct transcription of the proceedings.


		                      
		Cynthia D. Thomas
		Official Reporter
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