Department of Health and Human Services

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

	Tuesday, July 30, 2002

	VOLUME I

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

	A G E N D A

Tuesday, July 30, 2002

AM Session

8:30-8:45		WELCOME:  OVERVIEW OF MEETING
		     Mary Faith Marshall, Ph.D.
		     Chairperson, NHRPAC

8:45-9:30  	PUBLIC BIOETHICS
			James F. Childress, Ph.D.
			Kyle Professor of Religious Studies and Professor of Medical Education
			University of Virginia

9:30-10:15	WORKGROUP ON DECISIONAL INCAPACITY
			Jonathan Moreno, Ph.D.
			Director, Center for Biomedical Ethics
			University of Virginia Health System

[10:15-10:30]	Break

10:30-11:30	RESEARCH ISSUES:  MENTAL RETARDATION AND DEVELOPMENTAL DISABILITIES
			James C. Harris, M.D.
			Professor of Psychiatry and Behavioral Sciences, Pediatrics and Mental Hygiene
			Director, Developmental Neuropsychiatry
			Johns Hopkins University, School of Medicine

11:30-12:30	FULL DISCLOSURE IN THE RESEARCH CONTEXT OF OFF-LABEL AVAILABILITY
			Jerry Menikoff, M.D., J.D.
			Department of History and Philosophy of Medicine University of Kansas Medical Center

12:30-1:30	LUNCH

AGENDA - Continued

PM Session
1:30-1:45		INFORMED CONSENT:  A BRIEF UPDATE
			Elliot Dorff, Ph.D.
			Co-Chair Workgroup
			Professor of Philosophy, Georgetown University of Judaism
			Nancy Dubler, LL.B.
			Co-Chair Workgroup 
			Montefiore Medical Center
			Professor of Epidemiology and Social Medicine
			The Albert Einstein College of Medicine

1:45-3:00		RESEARCH WITH INCARCERATED PERSONS - PANEL PRESENTATION & DISCUSSION

			Moderator:  Nancy Dubler
			B. Jayne Anno, Ph.D., C.C.H.P-A
			Senior Partner
			Consultants in Correctional Care, LLC
			Stanley Richards
			Deputy Executive Director
			Fortune Society
			William J. Rold, J.D., C.C.H.P-A
			Attorney
			Brady, Klein and Weissman, LLP
			Anne C. Spaulding, M.D.
			Medical Officer and Team Leader of the Corrections and Substance Abuse Unit
			The Center for Disease Control
			The National Center for HIV, STD and TB Prevention

[3:00-3:15]	BREAK

3:15-4:00		Prisoners Continued

4:00-5:00		Maryland Health Care Act
			Jack Schwartz, J.D.
			Chief Counsel, Health Policy
			Attorney General's Office of Maryland

5:00		ADJOURN

5:00-6:00		Informed Consent Workgroup Meeting

	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

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

Roster of Members (Continued)

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 not noted a.m.]
	CHAIRPERSON MARSHALL:  Welcome all of you to our summer NHRPAC meeting.
	I do apologize for the delay.  Our transcriber/ recorder, apparently had some confusion about the dates and should be here by 10 o'clock.  But we wanted to wait until we could get a tape recorder set up because we don't want to miss a word of what Jim Childress has to say.
	So I would like to welcome all of you, and our ex officio members to thank you for being here and sitting up front.  And I think perhaps it would be nice if you all could just stand up and introduce yourselves to all of us.  And those public members in the room who many not know who everyone is.  Can we start with you Phil?  Would you be willing?
	DR. RUBIN:  Philip Rubin, National Science Foundation. 
	MR. BRADLEY:  Howard Bradley, Social Security Administration.
	MR. CORTESI:  Roger Cortesi, Environmental Protection Agency. 
	DR. MATHER:  John Mather with the Veterans Administration.
	MS. DeCOE:  Patty DeCoe with the Department of Defense.
	DR. LEPAY:  David Lepay with the Food and Drug Administration.
	DR. SPENCE:  Joe Spence from the Department of Agriculture.
	DR. OCHSMAN:  Good morning. I'm Bob Ochsman, Consumer Product Safety Commission.
	DR. CHESLEY:  Good morning.  I'm Francis Chesley from the Agency for Healthcare Research and Quality.
	CHAIRPERSON MARSHALL:  Wonderful.  Well, thank you all so much.  And I hope more of our ex officio members will be arriving today and we're taking the names of those folks who aren't here.
	[Laughter.] 
	CHAIRPERSON MARSHALL:  Send them a more ardent invitation.
	So it's always a distinct pleasure to be around one's mentor especially when one's mentor is as wonderful as Jim Childress is.  I think probably to this room of folks he doesn't need an introduction.  Those of you who followed the National Bioethics Advisory Committee, for it's seven-year tenure -- six to seven-year tenure, it just seems like a decade -- know Professor Childress.  He served on the NBAC and currently serves on the Recombinant DNA Advisory Committee.
	Jim Childress is the Kyle Professor of Religious Studies and Professor of Medical Education at the University of Virginia.  And I received my Ph.D. studying under Jim.
	He, as you all know, along with Tom Beauchamp who co-chairs our informed consent working group is the author of "Principles of Biomedical Ethics" which is in its fifth edition -- fifth edition now.  I got a signed copy of it.  But he is a fabulous scholar as you all know, a very thoughtful person, has been advising the government on many things for many years.  He's a member of the Institute of Medicine at the National Academies of Science. 
	I guess I want to say coming into the field of bioethics as a neophyte, a burned out critical care nurse many years ago, the first class I ever took with Jim Childress was a wonderful class entitled, "The Human Body, Its Parts as Property."  And there were several of us from the hospital who took that course.
	Jim is a wonderful teacher, he's received the Governor's Award in the State of Virginia for being the best teacher in the State.  And he was always very kind to those of us who were making our foreway into the world of philosophy and moral theology and didn't have much grounding in that area as undergraduates.  He's also a tough teacher, and you don't ever want to misspell a word or put forth a shaky idea, he'll pin you.  But you don't know you've been hurt until you hit the ground, I don't think. 
	[Laughter.] 
	CHAIRPERSON MARSHALL:  But we're just delighted, Jim, to have you here.  And I've asked Jim to talk to us about engaging in public bioethics and doing public bioethics, the importance of bringing people to the table who should be there.  It's, I don't think, quite the same as doing lunch as doing bioethics, but we'll find out.
	Jim, thank you very much, we're delighted to have you.
	DR. CHILDRESS:  Mary Faith, thanks for that generous introduction, and also thanks for the opportunity to share some reflections with NHRPAC in its very important deliberations.
	My reflections grow out of my experience on two national bioethics commissions; one notoriously unsuccessful, the Biomedical Ethics Advisory Committee, BEAC, I'm sure a number in the room have never heard of it, and rightly so.  It had a very short existence and accomplished virtually nothing. 
	The other Commission was the National Advice Advisory Commission which I believe was more successful.  But later in these comments I will come back and raise some questions about criteria for success and the work of any Commission such as this in relation to bioethical issues.
	I will also draw on some experience with other governmentally established bodies that address directly or indirectly issues connected with bioethics.  These include standing bodies such as the Recombinant DNA Advisory Committee, but also one-shot, single-issue, ad hoc committees such as the Federal Task Force on Organ Transplantation in the mid-80s, or the Human Fetal Tissue Transplantation Research Panel.
	I will concentrate these remarks on issues related to research involving human subjects or participants since NHRPAC's mandate focuses on that particular area.  But I will refer to some other issues in bioethics when they might cast some light on what it means to do public bioethics.  And I will play my own views off against some of the literature.
	After a few of you had come in I did put out a handout on "Doing Public Bioethics" which gives an outline of these remarks, but also on the back, about six items on public bioethics that you might want to pursue.
	Public bioethics, the ambiguity of both terms in this phrase can create a lot of problems.  Let's start with ethics or bioethics.  Ethics or bioethics is a reflective activity.  But "reflective activity" has narrow and broad meanings.  In a narrow sense it refers to the academic discipline of ethics of what moral philosophers and moral theologians primarily do.  In a broader sense though it refers to what any of us can do when we step back from our first order of moral judgments and reflect on the meaning and justification for those judgments.  And we can do this individually or in a group.
	Al Jonsen and Louis Butler are responsible to a great extent for the popularity of the phrase "public ethics."  They developed this in a 1975 article in the Pasting Center Report on Public Ethics and Policymaking.
	Now, they drew this phrase from a historian's description of moral philosophers who participated in the debate about slavery in the years prior to the Civil War.  These moral philosophers remained in their pulpits or classrooms, but they saw their arguments as primarily aimed at influencing legislation and policies.  Hence the phrase "public ethics" as a characterization of their work.
	Now, Jonsen and Butler concentrated primarily on the professional ethicist, the moral philosopher and moral theologian.  But, as I suggested, reflective activity we'll call "ethics" is not limited to those professional ethicists.  Indeed, I sometimes say that public bioethics is too important to be left to professional ethicists.  And in my own experience we cannot expect greater moral wisdom from ethicists than from others who participate in the debate.  Moral wisdom is fairly evenly distributed, at least in my experience on these commissions.
	Nevertheless, I think professional ethicists can make a couple of important contributions.  They can bring to the table familiarity with traditions and patterns of moral reasoning and that is sometimes useful in a committee's deliberations.  And they can bring us skills in the logic or analysis of the logic of moral discourse.
	In a somewhat similar vein, Leon Cast distinguished two senses of bioethics in his role as Chair of the President's Council on Bioethics.  He distinguished a domain of inquiry from a specialized academic discipline with specialized methodological approaches.  He emphasized that the President's Council on Bioethics includes -- is a council on bioethics, not a council of bioethicists.  And its members, he insists, come to the table as thoughtful human beings engaged with these issues.
	Now, I think that general distinction is an appropriate one, but I believe that Leon Cast neglects the potential contribution of professional ethicists in the modest ways I indicated, and that his approach can sometimes be elitist depending on how you define "thoughtful" and "wise" that can lead then to a certain interpretation of the kinds of persons who contribute to the work of a commission.
	Well, those are some of the ambiguities in ethics or bioethics.  What about the ambiguities in public -- in public bioethics.  Because public is ambiguous as we know not only in terms of public bioethics, but even for example in something as common as public health.  And I think we can explore this ambiguity by noting several different prepositions that can be used to explicate public bioethics.
	Years ago, John Fletcher, another of Mary Faith's teachers reported that a distinguished colleague at NIH, upon retirement, observed that the biggest change during his tenure was a change in prepositions.  When he arrived at NIH researchers conducted research on subjects.  When he left they conducted research with subjects.
	Well, consider several prepositions that might be used with public in public bioethics.  Public bioethics might be bioethics for the public.  And this meaning is primarily in public health and I think it's important in public bioethics too.  The public is the primary stakeholder even if the commission or committee or panel is accountable to a particular part of the government.
	And bioethics for the public can occur and often does occur through the formulation or recommendation of public policy including legislation and regulation.  But it can also include efforts to shape public culture or to shape professional culture.  And this is a direction, particularly in public culture, that the President's Council on Bioethics is emphasizing.
	Public bioethics is also bioethics in public.  Open as in transparency are indispensable.  And public bioethics involves public justification; justification to the public of particular proposals for policy.  But it is not only in public it is -- going back to the preposition that Fletcher's colleague emphasized -- it's "with the public."
	Because public participation is crucial, I think, as an ethical matter as a requirement of justice and a requirement of respect for public citizens.  But in addition there are some consequentialist reasons for having public participation, reasons that have to do with creating and maintaining public trust.
	For example, the Federal Task Force on Organ Transplantation recommended that there be public members on bodies establishing the criteria for organ allocation.  And one of the arguments it offered for this requirement was that public trust is essential for public donation of organs.  And it seems to me something similar applies in the area of research involving human subjects. 
	In NBAC's report on Research on Persons with Mental Disorders that May Affect Decision-making Capacity, NBAC emphasized you don't have to choose between protecting vulnerable populations such as the one described in that report, and promoting research, but, indeed, you need to protect those populations in order to promote research and the connecting link is public trust and confidence.
	It's not only bioethics with the public, but also in a sense, by the public.  And this includes, in part, a public body and it includes public participation.  Well, one could go on with prepositions that help us understand different ways to think about public bioethics.
	But let me turn to the third point on the outline and ask how we might distinguish public bioethics from some other areas of ethics.  And Jonsen and Butler do this in several different ways.  I want to focus on one of their themes.  And that is the relation between distinction and relation between social ethics and public ethics including public bioethics. 
	Public ethics in contrast to social ethics and social ethics being concerned with long-term, general, and fundamental aspects of society's life understood in terms of ethical categories.  Public ethics deals with a more precise problem, they argue.  It deals with an issue which is pressing and about which some determination must soon be made.
	And it usually doesn't try to affect structural changes or at least profound ones in the social order, rather it's usually concerned with more minor modifications.  And I think generally speaking, the way they characterize public ethics over against social ethics is important and useful.
	But then they go on to -- following this line of argument -- identify three tasks of public ethics and this would include public bioethics.  And let me -- these are on the outline, but for those who don't have it, let me just note these three tasks and then spend a little time talking about one of them.
	They argue that in public ethics including public bioethics, the first task is to articulate relevant moral principles in the policy problem.  And then they suggest there's a need to elucidate proposed policy options in light of the relevant moral principles and then to display a ranked order to moral options for policy choice.  Sometimes that rank order will obviously include a very precise recommendation and an argument for that, or it may simply be a rank order that then policymakers can use in making their own judgments.
	Now, I think those are three of the main tasks of public bioethics.  But there are some persistent issues and let me just focus on the issues that come out of the first of these tasks.  Identifying relevant moral principles is by no means an unproblemmatic task.  And identifying and framing the policy problem is also more complicated than is often thought to be the case.  So I might paraphrase, Allistair McIntyre [ph], Which Principles, Whose Problem?  It seems to me those questions arise when we engage in public ethics including public bioethics.
	So which principles?  Well, in research involving human subjects we tend to refer to the Belmont Report and the three principles of beneficence respect for person's and injustice.  And, yet at the first meeting of NBAC, Ezekiel Emanual [ph] who was then a commissioner before he went to NIH, argued that the Belmont principles and the guidelines associated with those principals do not adequately address community.  And that we really needed to attend to community as an important moral concern.
	Now, does that mean we should elevate it to the level of a general principle, or does that mean we should interpret the Belmont Principles perhaps in a less individualistic way than they've often been interpreted, attending, perhaps, to their implications for community or even interpreting through the lens of community.  And one could think about beneficence, for example, not only in terms of society's welfare, but also in terms of harms to community as is becoming increasingly important in research involving human subjects.  Or talk about respect for persons as respecting persons in their communities with communal values and traditions and the like and so forth.
	One could add to just as important the participation of communities in the design of research.
	So there are ways one could interpret the Belmont principles in a more communitarian way or through the lens of community that perhaps would address some of the issues that Emanuel raised.
	Or, one might argue that we could do this best by elevating community to the level of a principle.
	Well, those examples from the research area suggest why it's important for in-public bioethics to revisit the principles again and again to make sure that their formulation and interpretation encompass the full range of moral concerns.  And this ongoing reflective process of looking at particular cases and types of cases, for example in research involving children, an area that I know NHRPAC is looking into, this may lead to significant changes in the formulation and the interpretation of the principles.  So there's a kind of dialectical process between these -- the way we think about broad general principles and the kinds of problem areas that you're addressing.
	So, that's one point to be made under the heading of "Interpreting or Identifying and Interpreting Principles."
	A second point would be that sometimes when principles are functioning in our deliberations even when we do not explicitly identify them as such.  After NBAC had prepared its report on cloning humans, one commissioner contended that principles played no role in NBAC's deliberations about cloning and recommendations for cloning when NBAC recommended a ban of three to five years on human cloning and the process of ongoing public dialogue.
	But I think if one looks closely at NBAC's report, one can argue that it is shot through with principles, that the reason for proposing the ban had to do with concerns about, in the first instance, safety for the "clone," if I might use that term.  And that clearly reflects some of the concerns that are captured in a principle of beneficence.
	Furthermore, NBAC couldn't identify benefits from human cloning that would outweigh those risks or that would outweigh the -- couldn't identify benefits that would outweigh those risks and it couldn't identify claims to autonomy in reproduction or in scientific research that would outweigh those risks.  And respect for persons entered into our concerns about commodifying and objectifying children and so forth.
	Now, perhaps our report would have been clear in this regard had we more clearly articulated the principals.  But I'm not sure that we always need to do that as long as we're aware that they may well be functioning in our arguments.
	However, when we're unclear or whenever there's considerable debate, then it's often important to move our moral considerations to the level of a principal so that people can really understand and evaluate the argument.
	On the President's Council on Bioethics Leon Cast has suggested that both sides of the argument on stem cell research, particularly on the creation embryos for research purposes that both sides tend to invoke the life principle, just different interpretations of life principle.  And yet he goes on to argue that that alone, even with those different interpretations won't capture all the relevant moral concerns.
	So in contrast to what appears to be relatively simple in the Jonsen and Butler approach articulation of relevant moral principles in the policy problem.  This is, again, a much more complicated matter and requires ongoing attention and deliberation.
	A second concern raised by their first task has to do with the selecting and framing the policy problem.  This is often a central and neglected issues in public bioethics -- about policy problems as given as clear and all we need to do is bring in the appropriate moral principles for addressing them.  But I actually think this is a central issue that can arise both in terms of the constraints placed on the public bioethics body by the way in which the issues get framed by those who are requesting that bioethical issues be addressed, or if there's greater latitude by the way in which the public bioethics body chooses to select and frame the issues.
	The human fetal tissue transplantation research panel in the late 1980s had to address ten questions and these questions were very specific in terms of the relation between human fetal tissue transplantation research and abortion.  So the way in which this panel could address the issues was really shaped by the questions they received.  So there wasn't a lot of latitude.  Some who participate in that panel have argued that we probably would have been better had we simply said those questions the wrong way to think about the issues instead of the alternative and then to open it up.  But at least we have that constraint and we have the address.
	By contrast NHRPAC has within the range of research involving human participants a fairly open-ended mandate for selecting and framing problems within that area just as the bioethics advisory commission did in its mandate to focus on research and protections of the rights and welfare of research subjects and the use and management of genetic information as the two primary tasks.
	Now, NBAC's charter said that we are to look at a variety of bioethical issues arising from research on human biology and behavior including the clinical applications of that research and then listed as the first the two I've just mentioned.  But then we could identify and pursue other topics depending on the urgency of the issue, the absence of another body that could deal with it, the extent of interest and the issue of cost to the government and so forth.  So there were certain criteria we could use.
	Within limits then we had considerable discretion, just as you do, about which specific topics to examine.  But since human subjects or participants research already falls under important federal regulations, professional norms, and institutional structures, we decided to try to identify any gaps in current protections, especially for vulnerable populations.  And we determined, rightly or wrongly that in contrast to some other vulnerable populations, persons with mental disorders that may affect decision-making capacity do not receive special protections or benefit from specific guidance for IRBs and investigators.  So we identified that as a gap and then thought we should pursue that to see if there are ways we could close that gap.
	Now, I'm not going to focus on the content of our recommendations here, and I know you have discussed some of those issues with Eric Cassel [ph] and others in earlier sessions.  I only want to consider the question of how one selects and frames a policy problem for attention. 
	We didn't identify a perceived crisis in this area.  Rather, we identified considerable confusion about the principles and procedures that should govern such research and we found this confusion to be evident in legal cases and public discussions and the like.  So we focused on the confusion.  We also focused on a critical mass of thoughtful analysis and proposals by various individuals, private organizations, and public bodies whose work greatly aided our deliberations.  Putting those two together, we decided that this topic was ripe for attention and then tried to provide that.
	Now, another point pertains to the selection and framing of policy problems, particularly the scope of the problem.  We chose to focus on this particular vulnerable population and then to build up or build out to others who may have cognitive or decisional impairments.  That's a judgment that many disputed.  And for quite understandable reasons about this stigmatizing a particular vulnerable population when as a matter of fact they have characteristics that are quite similar to those in other populations.  And we recognize that many of the issues and concerns in that report could be applied to, as we put it, "all persons with questionable or diminished capacity."  And we encouraged such an extension noting that the additional protections could and should be extended that way.
	Now, that was a judgment call, and, again, one that many would dispute as to whether it's better to start with something smaller and then build up knowing that there are risks with that approach or to start with the broader approach and then build down or into the particular population.
	Let me turn to criteria for evaluating public bioethics.  You have on the -- this is a difficult matter because it's difficult to set up the criteria in part because of the wide range of activities that fall under public bioethics.  And certainly it's necessary to avoid what the Institute of Medicine calls in their list on your handout that Ruth Bulger and others edited, any sort of perfunctory checklist.
	Well, the Fletcher and Miller article which you've seen in your readings earlier identifies four main perils to public bioethics:  political co-optation, obviously there's not -- there are ways in which any particular public bioethics body can resist that, but that's obviously dependent, to a great deal, on a particular political context; bioethics orthodoxy, diversative views obviously is important among members, but also in the way a commission or task force or committee interacts with the public; neglect, obviously that can happen again on the part of a body politic in relation to a public bioethics group.  And poor performance which is obviously an internal matter to a commissioner or a committee. 
	Now, the IOM report states this in a more positive way, not so much the perils, but looks at several criteria for evaluating public bioethics bodies and those are on your handout and I won't elaborate them here, I just want to say a word particularly about effectiveness.  And I want to consider the debate about NBAC and its relative success or failure noting that I'm not in a position to evaluate the work, according to these or other criteria because I'm not a disinterested observer, and I think the evaluation may depend on in part a specific topic addressed whether we're looking at a report and recommendations impact on public policy or on public culture or on professional culture; whether we're considering short-term or long-term effects, so there are a lot of nuanced matters that have to be considered in evaluation.
	So I'm not going to try to evaluate NBAC's work.  What I want to do is simply note the kinds of evaluations that some others have offered, both positive and negative.  Because they begin to invoke these sorts of criteria and particularly relating to how we can think about effectiveness.  But clearly intellectual integrity, logic, scholarship, and sound judgment are important in any report by a committee or panel of this sort.  Clearly it's necessary -- democratic values is very important all the points I emphasized about involvement of the public and public participation and transparency enter in there.
	But effectiveness -- some of the valuations that appeal to different criteria can be seen in the following comments on NBAC's work.  Rick Weiss of the Washington Post says, "The NBAC Commissioners rarely resolve the issues that burden them.  And none of their . . ." -- this was written last fall as we came to an end -- ". . .none of their recommendations has yet been translated into law or regulation.  But their analysis of why they regard as among the most thoughtful and scholarly on the topics they addressed . . ." and he particularly stressed the report on human cloning
". . . and some of their ideas have become informally integrated in the way U.S. science is conducted today. In that regard observers said the group provided important if largely unheralded service during a period of dizzying biomedical achievement."  Well, you hear in that the implication of different criteria.  That is, emphasizing, well, the lack of effectiveness in terms of public policy and legislation, some informally influenced and yet for some of their reports, at any rate, satisfying the standards of intellectual integrity and the like.
	The ineffectiveness in the recommendation of public policy is something that a number of commentators emphasized, for example, Jeffrey Brainard of the Chronicle of Higher Education said that, "while NBAC's recommendations have prompted plenty of debate, they've been almost in all cases been virtually ignored by policymakers and legislators."  He went on to say that, "his discussion with others indicated that the reasons are complex, some had to do with lack of support from the Clinton Administration, the commission wasn't given power to enact its suggestions."  But then, and this is what I wanted to focus on, because it seems to me this is a critical issue for any commission or panel, the panel most of whose members came from academia hoveled itself by proposing politically unrealistic recommendations. 
	Now, I think this is an important question for any particular public bioethics group, and there are differences of opinion about NBAC's recommendation on this spectrum of idealism and realism.  Some emphasize that we could have been more effective had our recommendations been more realistic and politically viable.  Ron Green, for example, argues that we try to move beyond where there was a viable consensus offering comprehensive reports.  We should have made recommendations only when the ground to receive them was already fairly prepared.
	And former secretary -- HHS Secretary, Donna Shalala, in thinking about NBAC's work and the future of bioethics commissions said that such commissions should attend more carefully to formulating recommendations that can influence public practice and even included lobbying Congress and administration as appropriate.
	And that, I think, is a dominant theme in the criticism of NBAC's recommendations, but some took the other side.  George Annos [ph] said that our reports were well reasoned, but our recommendations were milquetoast. 
	How do you, in any particular committee or commission, move along this spectrum from the idealistic to the realistic? 
	Now, another distinction of importance is between process and product.  And I think that sometimes the process of public deliberation may be as important or even more important than final product.  And I think that was certainly the case with our capacity report, the report I mentioned earlier, that if it had an impact it wasn't in terms of so much of what was adopted though some changes may well have occurred as a result of NIMH actions of following our process, not our report.
	Because a dialogue occurred with the public and with professionals and administrators as we developed this report over a long period of time.  We developed it so long that I think it lost a lot of its impact by the end.  But the process may have been useful in highlighting the issues even if the final report and his recommendations were not fully adopted.  And they certainly weren't, rarely adopted.
	In bringing this to a close, let me just say that concern for effectiveness narrowly understood can often damage the work of a committee or panel especially if there's a restricted conception of feasibility.
	When NBAC prepared its report on stem cell research, and it was arguing for -- developing an argument for federal funds for both the derivation and use of human embryonic stem cells from leftover embryos, the White House made it very clear that it would not welcome or act on that recommendation.  So, it was politically unrealistic.
	We decided to pursue it anyhow because we thought it was the right one to make.  And as it turned out that may have actually helped position the administration politically speaking because it had those who opposed federal funds for both derivation and use and then the crazies at NBAC who proposed federal funds for both of those.  So one who opposed federal funds for either of those and NBAC proposing federal funds for both.  And then in between could develop a position that federal funds might be used for use or research on stem cells, but not for their derivation.
	Furthermore, a recommendation that is currently politically unrealistic may shift the debate, the center of the focus.  And I think that happened some in the stem cell debate.
	Furthermore, the fetal tissue transplantation research panel, it took several years and two administrations before those recommendations were adopted. 
	The last point has to do with consensus.  And I think that in its own internal deliberations a panel or committee has to be very cautious about seeking the consensus.  I hesitate to address consensus since my colleague, John Moreno, is the acknowledged expert on that, but I think that achieving consensus, while important, may have a serious cost.  And we have to be very cautious and not, for example, to over simplify, not to attend to the range of positions, to fail to note important differences and the like when we're moving toward that consensus.
	And perhaps NBAC erred in seeking consensus as much as it did, referring that to taking votes and developing majority/minority reports on particular topics, but that's something other can address.  I just think it's an important matter because it's going to determine in part the specificity, the meaningfulness and the sharpness of the kinds of recommendations that are offered.
	Thank you very much for your attention and I'll be glad to address any questions or comments or concerns that people have.
	CHAIRPERSON MARSHALL:  Wonderful.  Thank you so much, Jim.
	I asked him to give this talk.  I heard an early version of it at research ethics grand rounds at my institution, the University of Kansas, and it seemed to me that we certainly, all of us, as committee members, ex officios and our public members had a lot to learn from what Jim had to say in terms of his experience and a thoughtful analysis of what we're about and how we should go about doing our work.
	One of the first duties that I had after assuming the chair of this committee was to go before the then NBAC which was still extant.  And the question that was on the table was, what will you all do that is different than what we do?  Or I think it was phrased, "Do you exist in a sense to make sure that our recommendations are implemented to a certain degree?"  And I think the answer to at least the second question was, no, although obviously a lot of our work has been directly informed by the work of NBAC and certainly as in our work with the decisionally impaired and others, we are addressing NBAC's recommendations directly.
	But, Jim, I want to thank you because even though we don't think that we are NBAC, we have a lot to learn from them, and I think some work to carry forward.
	So let's have some time for questions and I see Bob Levine's hand, and then Jonathan and then Alan.  Bob. 
	DR. R. LEVINE:  First I want to say thanks to Jim for a talk that's typical of his talks, very thoughtful and thought provoking.  I have one comment and one question.  First the comment.
	I would add to the list of references an essay written by Richard McCormick in the early 80's, and it had to do with how could a member of a story tradition address public bioethics.  And one of the key features of this, by story community or story tradition he meant principally people who spoke from a or were members of a religious tradition that made statements about moral philosophy.  He said one of the key criterias of doing it right was to make the ultimate groundings of your arguments available to people who were not members of the same story tradition.
	So it would be not very helpful to appeal to a revealed truth unless you made your arguments also accessible to those who didn't share your commitment to following that set of revealed truths. 
	My question, Jim, comes from one of the first things you said.  And that is that ethicists or moral philosophers can bring to the discussion a familiarity with the traditions of moral reasoning.  I have a problem then with so many people including prominent people in the world of bioethics show great disdain for tradition.  Some have actually gone so far as to say that anthropologists and sociologists have no place in discussions about public policies that relates to ethics because they never say what's right and wrong.  I disagree with that.  I would not reject these.
	I think, in fact, a person is more successful or productive as an ethicist speaking to public policy if they are sufficiently familiar with the traditions of the community in which they're operating so that they can anticipate the reception and the responses that whatever recommendations they have might elicit.
	I think this was implicit in the critique of NBAC when they said that there was -- some of their recommendations were politically unrealistic.
	I think one final point on this is that all too often when people are writing guidelines to guide the conduct of all sorts of activities, but in our case research involving human subjects they get involved in idealism.  They write documents that are aspirational rather than documents that say, here is what we expect you to do today and perhaps a footnote or commentary to say here is how we hope we will do it better in the future.
	I think the tendency to aspirational guidelines is what underlies much of the fact that even the Declaration of Helsinki is so widely disregarded.
	Thank you. 
	DR. CHILDRESS:  Let me just say very quickly I appreciate all the points you raised and I would just note, I did at the end on public reasoning, because I had gone on too long, leave out discussion of religious traditions which played a very important role in our discussions of stem cell research and cloning.  But not so much our discussion of research involving human subjects, though obviously McCormick and Ramsey and others were often focused on, say the recent use of children in research from a religious standpoint.
	I think an important question to public reasoning arises in a liberal prolistic democracy about how we attend to religious perspectives and listen to religious voices.  We came to the conclusion it was important to include such voices and such perspectives in part because of the insight they might offer, and in part because the way they might stimulate our imagination as well as needing to address the whole spectrum of views.  So there are a lot of different reasons that could be offered for doing just that.
	How one does it and how then after the process of listening to such traditions, how one then formulates public policy still remains an important matter since it's important not to impose from a single religious perspective, but rather to have adequate secular reasons for whatever is recommended.  But I appreciate your point.
	CHAIRPERSON MARSHALL:  Jonathan.
	DR. MORENO:  Jim, I enjoyed that.  I hadn't heard you give that talk before because we don't have a chance to listen to each other when we're in Charlottesville.  Clearly one wants to distinguish between governmental and nongovernmental public bioethics.
	In governmental bioethics there's always a problem of deciding for whom the members of the committee or commission speak.  I know you're very interested in this problem.  In what sense do we represent whom, other than our own particular groups from which we come or the fields which we represent.
	And so I wondered if you would say something about the problem of what we might loosely call representation?  And also say something about what kinds of side constraints there are on the distortion of discourse within a commission that is supposed to be doing public bioethics?  This applies not only to bioethics commissions, of course, but any public advisory committee.
	One constraint, I guess -- one protection against distortion, once we have a theory of representation, which we really don't, but one protection, I guess, would be that it be open and transparent, the proceedings be open and transparent, as you mentioned.  Another might be, I guess, that as Toolman and Jonsen suggest, we should concentrate on specific issues and cases rather than dig deep to sort of whip out our foundational moral views which could only divide us and make agreement on specific cases and policies more difficult.
	DR. CHILDRESS:  On that theory of representation, I actually tried to state this for a public bioethics body in terms of representation to the public.  Because it does seem to me that that orientation has to be primary, though obviously there are issues of accountability to the appointing body as well as a recognition that people are invited to participate in commissions and panels and that in itself raises a number of issues as to how people get selected.  But they're often, because they come from a particular professional or other background, so in a sense they're chosen because they can bring something to the table.  But what I would hope they bring to the table is not a representative -- as I'm moving away from an interest group liberalism model of this, not that they're representing a particular interest group where the research is something else, but rather from the perspective that they have given their professional or disciplinary or other background, they're able to offer certain kind of interpretation of the public interest.
	So I would tend to press it, but that is moving me in the idealistic strain going back to the ideals in realism distinction to be short.
	And I don't think I have anything else to add.  I'll have to think further about it, maybe we can have a conversation about that -- of the side constraints.  And I do agree with the ones that you've mentioned as important, but I'm not sure I have anything else to add at this point.
	CHAIRPERSON MARSHALL:  I have Alan and then Adil.  And then ex officios, please feel free to jump in.
	DR. FLEISCHMAN:  Jim, thank you, terrific.  I was reflecting on an experience that I've had and I wanted to ask you a little bit more explication on the concern about fundamental disagreements among members in such a public bioethics discourse. 
	At the New York State task force on life and the law, who have for over 17 years been doing public bioethics, and from some measures of effectiveness, at least historical measures of effectiveness, one could argue that they have been effective, have had some reasoned reports and some effective legislative and regulatory outputs.  One of the things we chose to do early and one of the philosophers on the group who is no longer on the group, argued against it, we chose to have private sessions and we did -- 
	[Laughter.] 
	DR. FLEISCHMAN:  -- and we did in fact with those private sessions overcome some of the attorneys who thought that was both illegal and unethical.  But we were able, I believe -- this is my own personal opinion -- with people with fundamental differences -- fundamental differences, to allow them to roll up their sleeves and try to compromise, you know, taking some of Jonathan's book as background, in ways that I don't believe we could have done in the public.  These same people could not have been as open about what was possible.  And I think that really, at least from my experience, helped us deal with fundamental differences and helped us to have greater respect for one another's strongly held beliefs.  Some comment, if you would. 
	DR. CHILDRESS:  That's a very important example and obviously the work of that group has really been quite influential.  Reports are read in other states and nationally because of their quality of satisfying the IOM report standards and obviously the effectiveness that you mentioned.
	I think that building relationships among members of a committee or commission or task force is very important, and that obviously includes sharing some informal conversations somewhere.  I guess I am so committed to the requirement of the sort of public context for deliberations that I still would want to hold on to that even while recognizing in some cases individuals might be able to move along better if they could have some of those fundamental discussions outside that arena.  Clearly with the emergence of e-mail a lot of that does go on.  But, for NBAC, and that may be true for NHRPAC too, e-mail is considered pertinent in the public domain as well so people could get access to that.  So it wasn't quite as private as what you're discussing.
	So I guess I still would come down on the public side and say that building relationships is obviously critical, but not for the deliberations actually to occur in problem.  No.  What I would emphasize is that fundamental disagreements can often be overcome or resolved through that process of deliberation by hearing a variety of views.
	The best example I can think of from the work of NBAC had to do with one particular commissioner who in the discussion of human embryonic stem cell research was very strongly committed to the protection of the embryo and felt that there were real dangers in going the direction we were going, but who, finally, as a result of public hearings in which he heard the variety of views about the moral status of the embryo actually said that he could not legislate his own views, but rather had to work in terms of what he understood to be the evolving diversity in the public debate. 
	So sometimes that can happen as well.
	CHAIRPERSON MARSHALL:  Thank you.  I have Adil and then, please, those of you ex officios or our public members, feel free to come up to the mike and join in the conversation.
	DR. SHAMOO:  Thank you.  My question was asked by Jonathan Moreno.  Not knowing what other questions were about the appointing authority and the limitations and the agenda they have in mind already.  But, as you know, dean of any school can effectively know what the outcome is by putting the right faculty members in that group or adding and subtracting as he goes along sometimes even though faculty independently can still convince the dean once in a great while in the opposite direction.
	Having said that and I really am not asking the question again since you and Jonathan dealt with it, I wouldn't be as hard as some are on NBAC.  I think NBAC's reports are going to become a beacon to us all.  And I think time is too short, historically, to evaluate the effectiveness of the NBAC report.  Let's wait 10 to 20 years and see their effectiveness.  I am one of those who will predict that they'll have much more impact on our discourse in these areas than some others.
	I thought the whole process was fair and inclusive and good.  And the credit goes, of course, to you and Dr. Shapiro. 
	DR. CHILDRESS:  Could I just add one point?  I think that even in selecting a committee or commission there are limitations to what one can predict.  And I think the report of the President's Council on Bioethics that came out a couple weeks ago is a good example of that.  That in the process of dealing with the issues that few may end up in different positions than what the appointers might have predicted.
	CHAIRPERSON MARSHALL:  Ex officio folks, please.  Those of you from the public, please join us.
	DR. MATHER:  I'm John Mather with the VA.  Jim, I appreciate your remarks.  I've been reflecting here though on several years of government service on various commissions that have been around and the impact that some have and have not had.  And so I would focus a question for you about NBAC because it strikes me in the realm of politics timing is crucial.  And when I say "timing" I don't just mean timing in a practical sense.  I mean also in an ideological sense.
	So I wonder the extent to which you might feel that NBAC got caught in a little bit of both the practical and an ideological time warp that maybe Adil's point is well taken, you know, it's going to come back again.  But talking about the precise point in time when we had a change of administration and so forth, the extent to which not just practical politics, but ideological politics influenced the situation.
	DR. CHILDRESS:  I think you've identified an important part of the context that is absolutely crucial.  I'm not sure I can add any insight to it.  But I would also note that the timing relative to media attention, for instance, there are a whole host of factors that will play into how a particular report and its recommendations might be received.  And so I very much agree with the ones you emphasized and would just also note that the attentions directed towards some at a particular time may also have an impact so that the role of the media in this is imported as well.
	CHAIRPERSON MARSHALL:  Anyone else for the good of the order?
	[No response.] 
	CHAIRPERSON MARSHALL:  Jim, thank you very much.  It was a delight having you here and we will, as we progress through our conversations in the next two days and our future meetings, bear what you had to say in mind. 
	[Applause.] 
	CHAIRPERSON MARSHALL:  So we are going to move on with our agenda actually into some of the work that the NBAC did.  So we are making things practical, I think. 
	And we will take a break after this session, I think.  Somewhere around 9:15 or so.  We've cut a little bit into Jonathan's time.  So Jonathan is going to bring us up to date on the workgroup on decisional incapacity or those who are -- who lack decisional capacity.  There are lots of different ways of posing that problem with the National Commission. 
	There is a handout for those of you who may not have one, committee members, in your notebooks, and out on the desk for anyone who doesn't have one in front of him or her.  
	Jonathan, the floor is yours.
	DR. MORENO:  Thank you, Mary Faith.
	I would like to provide just two sets of brief points to set the stage for what I believe and dearly hope will be the final draft of a report on this matter from the workgroup on decisional incapacity.
	The debate about the appropriate involvement of persons who lack decision-making capacity in research is by my estimate 102 plus years old and probably begins in the sense of public bioethics although it wasn't called that in those days with the determination by the Prussian government in 1900 to issue a directive on the appropriate role of certain persons in research following a scandal in the 1890 concerning research and the identification of the mentally ill as among those who were -- not to use the language of the directive, but to use our contemporary language entitled to special protections. 
	About 30 years later the YMAR German ministry of the Interior issued a set of guidelines on the participation of persons in research and included again persons who were mentally ill as those who were entitled to special protections.  The background to the exchanges in the Nuremberg so-called, "Nazi Doctors Trial" included conversation apparently between the judges and the medical experts about whether any particular population should be included as among those requiring special protections.  And there was a very interesting exchange concerning the mentally ill and again a decision was made in the case of the Nuremberg Code not to specify any particular population.  Apparently because that population was not at issue in the trial.
	In the late 1970s, of course, the National Commission took up the issue again and delivered a report on those persons who were, "institutionalized as mentally infirm," recommendations that closely resembled the recommendations that have become Subpart D concerning pediatric research.  Unlike the other National Commission recommendations, these recommendations concerning the institutionalized -- those institutionalized and mentally infirm did not see their way into regulation. 
	Then in 1990s there were, of course a number of cases, perhaps the UCLA schizophrenia washout being the most famous of these and the most visible of these that seemed to bring this issue back to public attention.
	I will also say that apart from the historical background that I find fascinating about this debate, I have -- I bring a significant personal interest to this issue having had family members who suffered from schizophrenia and depression and also because my father was a psychiatrist who ran a small mental hospital, as many of my friends and colleagues in the room know, in the Hudson Valley, and I basically grew up in that hospital in the days in which a single person could own a hospital which seems absolutely unbelievable to us today.  And so I saw the transition from what you might call milieu therapy and action therapy to drug therapy up close and I also saw the ravages of mental illness up close and became aware very early of how hard it is to know at what point a person has moved from the patient role to the subject role.
	In candor, we also operate today in an environment in which there are unprecedented commercial opportunities that create some pressure for research involving persons who lack decision-making capacity.
	But, at the same time we also have humanitarian concerns that co-exist with those commercial opportunities for improving the treatment of people who lack decision-making capacity, whether it's a mental illness or whether it's a physical -- another kind of disorder that is complicated by their lack of decision-making capacity.
	And, finally, today we have a remarkable potential, some people would say, unprecedented potential for growth in the knowledge of the human brain and nervous system.  And some people with whom I speak believe that we're on the verge of the decade or perhaps two decades of neuroscience in much the way in which we experience in the last two decades growth in the knowledge of genetics.  That being the case, there is going to be continued interest and pressure and arguably humanitarian need to engage people in research who lack decision-making capacity. 
	Now, when we started this effort with the workgroup I articulated several principles that I hoped would move us on our way and principles that I believe that we can glean from previous experience, including the experience of NBAC for which I worked as a consultant.  First of all, that we couldn't do everything.  I think that arguably -- and Jim kind of alluded to this -- arguably the NBAC report in trying to embrace all of the issues, concerning at least persons with mental disorders in research try to do too much.  And so I argued that we tried to set a rather lower threshold for any document that we produced recognizing that there would be lots of other opportunities to refine it.  Lots of opportunities for public criticism that whatever implication of any recommendations we issued would be interpreted by IRBs and by human research protection programs and by administrators and by lawyers and by investigators and by advocates so that what we could do, at best perhaps, was create a framework that would be broadly acceptable.
	Secondly, I also suggested that we needed to learn from the NBAC experience and accept the importance of addressing in whatever recommendations we made, all persons who lacked decision-making capacity who may be involved in research regardless of the origins of that impairment.
	Thirdly, we did have an opportunity and we have chosen to exploit it, to build on a number of NBAC recommendations that had been accepted by the Department of Health and Human Services workgroup.  So we, in fact, already NBAC has, as Adil Shamoo pointed out, laid a foundation of some sound principles that we can build on for this purpose. 
	Finally, I want to point out that our workgroup was meeting at least some of the criteria for sound public bioethics in that we were, I think, open and transparent and that we certainly were composed of individuals who if they did not, strictly speaking, represent various stakeholders brought the perspectives of various stakeholders to the table, working scientists and other investigators, administrators, people who had a person interest in this issue, ethicists, historians, and others.  We had a rather large, and I would say, vigorous workgroup that had many exciting exchanges over the telephone and in our meetings.
	Having said that, we do seem to have arrived at some agreement and, of course, I presented a previous draft at out last meeting.  I am not going to rehearse the DHHS workgroup report on the NBAC recommendations.  A number of those recommendations we are simply saying in our report we would presuppose in order for our own recommendations to be adopted.
	So that our recommendations actually begin on page 3, further recommendations by the NHRPAC workgroup. 
	Mary Faith, do you want me to read these?
	CHAIRPERSON MARSHALL:  Please do, Jonathan.
	DR. MORENO:  Reading is one of the best things I do -- says my kids -- out loud.
	"In addition to the NBAC recommendations cited above, we conclude that the following considerations should apply to all persons who lack decision-making capacity for purposes of research participation.  Concerning persons who meet this description:
	1.  We believe that research involving persons who lack decision-making capacity may be conducted or funded if it does not involve greater than minimal risk and if the subjects legally authorized representative has given permission."
	Now, I think that at the previous meeting there was essential assent to this first recommendation. 
	"2.  The workgroup also concludes that research may be conducted or funded that involves greater than minimal risk but includes interventions or procedures that present the prospect of direct benefit to the subjects if:
		a.  The risk is justified by the intended benefit to the subjects and;
		b.  The relation of the anticipated benefit to the risk is at least as favorable to the subjects as that presented by available alternative approaches; and
		c.  A legally authorized representative gives permission."
	Now, you will note that there is a footnote under 2 that refers to NBAC recommendation 8 and I'm not going to read that.  It provides reinforcement, we think, for the conditions according to which this recommendation has been made.
	So should I wait for any comments or questions about -- Bob.
	CHAIRPERSON MARSHALL:  Why don't we take them one by one. 
	DR. R. LEVINE:  All right.  Recommendation 2, and when we get to 3 I'll make a similar comment, is a part way correction of the conceptual problem we identified the last time we discussed this.  Whether you have done here is -- what do I mean by "part way"?  You say that it's the research that presents greater than minimal risk.  Yet the anticipated benefit cannot come from all the research.  It can only come from those interventions or procedures that hold out the prospect of direct benefit.
	What should be done here is that the number two statement should say, research that includes interventions or procedures that present greater than minimal risk and then proceed with the rest.
	Mary Faith, if you don't mind, I would continue to make the same correction on number 3, or I can start all over again later.  But once again, in number 3, it's the research that presents a minor increase and it should instead by -- we have to justify each intervention and procedure separately.  Just for emphasis, for people here who have not sat in on all of this discussion, when you say that the research which presents greater than minimal risk can be approved if there is some therapeutic component, it opens up what I have called the fallacy of the package deal.
	One example of this was a study of a new treatment for myocardial infarction where the treatment was supposed to have a good effect, and yet they justify the insertion of plastic catheters into the coronary arteries for purposes of administering a placebo.
	I'm not saying you can't justify that, I'm just saying that the recommendation here, and at all other documents that permit this lumping everything together doesn't give us a vocabulary for assessing the particular risks presented by that particular route of administration for placebo.  At the end of the day you would probably come out approving it, but I'm warning against this packaged deal.  Thank you.
	DR. MORENO:  That's a cogent criticism recommendation I'm sure that -- I don't see anybody in the advisory committee having a lot of trouble with that clarification. 
	Abbey.
	MS. MEYERS:  I think the way it's stated I'm troubled because we've discussed in so many statements that there's a therapeutic misconception.  When it comes to research there really can't be this promise of a therapeutic benefit because you just don't know.  So if you look at 2. b. "the relation of the anticipated benefit of to the risk is at least as favorable to the subject as that presented by available alternative approaches."  So if you're talking about an antipsychotic medication and the risk may be tardive dyskinesia [ph], how do you know that this isn't going to cause damage to the liver?  You don't know until the research is finished.  And so we are caught in this web here that is so difficult.  If I was on an IRB and had to look at that sentence in anything below phase three, I would vote no.  I would not allow the research to go on, because there really can't be a promise of a therapeutic benefit.
	DR. MORENO:  Can I just respond to that?  I am very interested in the problem of so-called "therapeutic misconception" and in fact worried sometimes that it's intractable, as you do.
	But, nonetheless, it seems to me that if we can approach that problem the approach is going to be at the level of the communication between the researchers and the potential subjects.  And this document is not intended to reach to that communication.  That communication needs to be clear that this is research and not therapy.  But this document is intended, as any regulatory guidance is, to set out the framework to inform the responsible parties of their obligations for assessment.  So I don't think we can in fact hope to escape from this circle that you identify, I think, accurately in a document like this.  I think we have to work at a different level of the human research protection system to do that if we can; my view.
	DR. SHAMOO:  I think the key word is "anticipated."  We are not saying the relation of the benefit to the risk, the anticipated.  In all research there is some kind of anticipation.  If there is no anticipation from animal study, from other data, you will not be doing that research.  So the key word is "anticipate."
	CHAIRPERSON MARSHALL:  Bob.
	DR. R. LEVINE:  Thank you.  The key word actually is "holds out the prospect."  It's not that you -- I mean, with all therapy you can never promise success, even with the therapies, the remedies that have been around dating back to the eight specifics, you know, opium digitalis and so on, you can never promise that it will be successful in any particular patient.  But holding out the prospect means that you have sufficient previous studies to allow a group like an IRB to say it's a reasonable judgment to say that this thing holds out the prospect of direct benefit. 
	A consequence of your formulation, Abbey, is you would not approve anything until you got to phase three.  That means there would never be a phase one or two.  Phase one never holds out the prospect of direct benefit.  It must always be approved according to recommendation three because you're using healthy volunteers who don't have any problem to fix.
	Thank you. 
	CHAIRPERSON MARSHALL:  Jonathan, would it be possible to -- instead of using the word "anticipated" to use prospective?  Is that more accurate? 
	Abbey, would that make you feel more comfortable or does it matter?
	DR. MORENO:  I don't think it matters.
	CHAIRPERSON MARSHALL:  It doesn't matter.
	MS. MEYERS:  I think there's a problem with the wording the way it is.  I mean, our role -- 
	CHAIRPERSON MARSHALL:  Do you have a suggestion for a change?
	MS. MEYERS:  This goes back to the question you asked Dr. Childress which is, "What is the difference between us and NBAC?"  And that is that we are really writing the recommendations, we're writing the training manuals for people on these IRBs.  And so we have to translate this into something that they can use every day.  And so the language, I don't know how to change the language.  But, I like what Bob just said about "holding out the prospect" of being at least as beneficial. 
	CHAIRPERSON MARSHALL:  Abbey, if we look under number two there, the sentence says, and if we go with Bob's language, "research that includes interventions or procedures that present the prospect of direct benefit" and then under b. the language is "anticipated benefit" would "prospective" help you?  But I'm asking Abbey. 
	MS. MEYERS:  No.
	CHAIRPERSON MARSHALL:  No?
	MS. MEYERS:  I don't know how you can tell that unless you're a soothsayer.  How can you tell whether it's going to be -- how many people have been injured and died in clinical trials thinking that it held out the prospect of being beneficial and it wasn't.
	DR. MORENO:  Again, Abbey, I think the problem is that we often feel tempted to try to load into a document and a set of statements like this, all of the corrections for a very difficult problem.  And I don't think we can do that.  I think we have here the basis for further elaborations that will be undertaken by the IRBs and by others who are responsible for individuals who are in research. 
	I would also say that -- I mean, we do in fact have an inherent tension research that no sort of language can resolve.  And that is the fact that, you know, somebody has got to be among the first.
	CHAIRPERSON MARSHALL:  And I think sort of definitionally to get back to what Bob was saying, we are agreed that at least, you know, in a phase three trial that there is the possibility of benefit extant in the universe here.
	DR. R. LEVINE:  Let me also -- Abbey raises the point that's raised so often these days.  Look at all those people who enrolled in clinical trials thinking they're going to get benefit who then died.  Well, most of them die because they have diseases that are lethal. 
	The empirical research on this shows that if you have a disease that could be lethal and if you enroll in clinical research including clinical trials, that you're probability of either death or disability is considerably less than it would be with the same disease in the same institution as part of regular medical practice.
	So, you know, you have a clinical trial of people with cancer, a lot of them are going to die.  What we are hoping is that fewer die getting the new treatment than getting the old treatment.
	MS. MEYERS:  Well, except that we're talking about mentally disabled people here.  We're talking about not just the mentally ill, but mentally retarded people, et cetera.  And these are people who have disorders that are not lethal.  And yet, I mean, I remember an experiment down here at NIH with people who their symptoms of the disease was fine, but they ended up needing -- a few of them died and several of them needed liver transplants because it destroyed their liver.  And NIH didn't even mark it down as a side effect at that point.  I guess it was about give years ago.
	DR. R. LEVINE:  Yes, the drug in question was phialuradine [ph] and the patients had no mental incapacity.  They had hepatitis.  And, in fact, NIH didn't record anything at the moment because the NIH investigators identified the problem immediately upon the second case.  The first case had been falsely attributed to anesthesia.  But it wasn't a case that occurred at NIH, so they didn't have direct observation.
	That is a case that was reviewed by three public bodies, two of which came out saying that it was ethically conducted and reported.
	CHAIRPERSON MARSHALL:  Okay.  I think I want to recognize Shawn and then I think we need to move -- Alan.  Okay.  We need to move forward because we're a little behind schedule.  But we need to get through this document.  So, go ahead. 
	Just tell us who you are first. 
	DR. MATHER:  John Mather with the VA.  I hesitate to engage in wordsmithing.  That's always a committee problem.  But I am sympathetic -- 
	DR. MORENO:  So that means you're going to sit down now, John? 
	DR. MATHER:  Yes, I'm going to sit down and forego my comment.
	But I'm very sympathetic to Abbey's point in the sense that the way 2.b. is written it's sort of like, okay, it will happen.  I wonder if we can strike a little by putting a few words in which make it much more a volitional thing?  I mean, something -- somebody is going to have to make this determination and I would suggest maybe putting in a few words between the risk is and then adding the words, "specifically determined to be at least"; "specifically determined to be."
	The notion here is that somebody is actually making a particular judgment or determination.  It's not just sort of sitting there.  I'm trying to avoid the word, "prospectively" and all this.  But somebody specifically -- it is specifically determined to be.  So that's my contribution of wordsmithing.
	CHAIRPERSON MARSHALL:  Thank you. 
	DR. MORENO:  Mark, I think is next on the list.
	MR. BARNES:  Yes, I have a couple of questions.  The workgroup has endorsed the NBAC or at least some of the NBAC principles, but the NBAC principles specifically relate to people with mental disorders, not people who lacked -- not the larger category of people who lacked decision capacity.  And as I understand it in the history of NBAC, that was somewhat of a controversial decision made in regard to those particular NBAC proposals.  And so I guess my question is, you know, what group are you really trying to get at?  And I would ask, sort of in addition to that, that my concern is really perhaps less people who actually lack decisional capacity who perhaps in an in-patient setting at least have patient advocates or psychiatrists who have a vested interest in their welfare.
	I'm actually more concerned about people who have diminished capacity who are receiving -- for studies regarding stroke drugs, regarding cardiology devices, regarding -- thing that were -- where the intake, the recruitment for research occurs in the emergency room setting or in other urgent circumstances.  So I wonder sort of where that fits, where that category of people fits within what you're doing.  
	And let me just ask the other question, if I may, and then you can -- or the other one is perhaps less a question than it is a comment which is that in all of your recommendations you talk about legally authorized representatives.  And I just want to point out that, you know, that you really are punting on that.  OHRP recently has issued two letter rulings, one against or regarding, I should say, Case Western and the other regarding Mount Sinai -- no, I'm sorry, that's not right.  It's one regarding a California medical center and one regarding Mount Sinai in New York regarding what their policies have been about who is a legally authorized representative.  And to get to it, of course, you have to go back to state law because there really is no federal law in it.  But in most states the law on who is a legally authorized representative outside of the guardian or the healthcare proxy is completely amorphous.  And I just want to point out and sort of using that term, you know, you are -- you may not have a choice, but you really are punting on what is an essential concept around which there is a debate raging in IRBs every day about what we're supposed to do with people who have diminished capacity, not no capacity, but diminished capacity who have family members around them.
	DR. MORENO:  All well taken, as usual.  You're right, we are punting.  Because, as you point out, there is no federal authority on this matter.
	NBAC did make some recommendations to state legislatures, which, so far as I know have not been taken up by any state legislatures.  And I think what we propose for one of the next pieces of business for the workgroup is to go back to those recommendations and try to push that issue a little bit more, maybe even develop a model statute that we might draft you to help us with.
	As to your point about the NBAC recommendations, yes, we are interested in bringing those forward.  I think I speak for the workgroup.  Although they do speak to a narrower population than the one that we have chosen to address.  But we don't want them to be lost in the mists of history, because we think they still do address some important problems with persons who have mental disorders and maybe in research.
	As to precisely whom these recommendations would apply, again, I think we have to be careful not to try to do everything in a single document.  The human research protections process is going to have to make a determination about whether in specific cases individuals lack decision-making capacity on functional grounds.  And so they might be, indeed, in the emergency room, but not subject to the FDA waiver.  They might be elsewhere in the institution, they might be outside the institution in a clinic, that is going to be, again, a determination that is going to have to be made by people who are responsible in the process and they're going to have to be held accountable.
	But I think Mark is helping us note again that one of the major historic problems with this issue has been that it's so hard to get one's arms around the population we're talking about which is one of the reasons that NBAC made its strategic choice albeit one that's gotten criticism about focusing on persons with mental disorders.
	I think Alan is next -- I'm sorry, Sandy is next on the list and then Alan and then Robert.
	DR. CHODOSH:  A lot of what I have to say has been said, but I just want to reemphasize the dilemma that the IRB is still going to be in with this set of rules.  And particularly if you go back to the NBAC recommendation number one in which we're talking about having a certain number of expert people on a committee depending on whether they see a lot of this or not a lot of it and it interrelates to all this in that you may have two "people" who are know about it but not knowledgeable about the particular thing that's come out of the protocol.  And in NBAC it does not say, well, once you've got -- it suggests that once you have those two people you don't need anyone else, but in truth there should be some comment in that about using specific consultants for special problems.
	It is covered in the situation where the IRB does not head many.  It gets back to this how it's going to be interpreted by the IRB, and I can see IRBs who will interpret to say, well, you know, we don't know the results, therefore we cannot allow such research to go on.  And there are others who are going to interpret it very loosely and say that, well, there might be possibly a benefit down the road and we'll approve everything.  So that I know that we don't want to be too specific, so I sort of like John Mather's idea of saying, specifically determined, that specifically sort of going back to having proper kinds of consultants to make a judgment because I can assure you that the PI is going to anticipate great benefits from everything that they want to do.  And that -- and often that's all the IRB sees.
	DR. MORENO:  Two quick responses to those cogent comments.  First, I think that may be an agenda item for the workgroup to continue to look at this issue of people who are represented of or can speak for individuals who have this sort of question on IRBs.
	Secondly, my guess is that as the IRB accreditation process unfolds in the next few years there will be more and more of an interest in the functional ability of IRBs to call on people who are familiar with the specific kinds of disorders.
	Alan.
	DR. FLEISCHMAN:  Three quick comments.  The  first has to do with your second introductory paragraph in which you use the words, "nor gravely ill neonates for whom research protections are specified in subpart (b)."  I think that's an inaccurate interpretation of what subpart (b) relates to and I wouldn't use the word "gravely ill."  I would reflect the language of that subpart.
	DR. MORENO:  Of uncertain viability?
	DR. FLEISCHMAN:  Yes, please.
	DR. MORENO:  Okay.  That's no problem.  That's an editorial change we can do. 
	DR. FLEISCHMAN:  Yes, the second -- the other two are more substantive.  I would like to go on record as arguing that NBAC's recommendation eight is not an appropriate one for us to endorse.  I believe, and I've said this publicly that the presumption of incapacity is stigmatizing that we ought to be more careful in how we use that recommendation.
	I would argue that for those research projects in which interventions or procedures do hold out the prospect of direct benefit that we ought not presume incapacity.  If we are going to use the recommendation and argue that it's softened by its last sentence that is that the IRB may allow investigators to make the case that they can do these assessments in a less formal manner.  I think we ought to flip it on its ear and make the argument that there needs to be some reason to believe a subject is incapacitated before they are presumed to be and require assessment.
	You know, I do think that that has been argued in some of the criticisms of the NBAC report and I would like at least my view of it on the record.
	The third point, I want to really strongly urge the committee to take Mark's concerns about the legally authorized representative to heart.  I don't believe that merely, merely writing a legislative or a suggestion either for state or federal legislation is sufficient.  I think we ought to make recommendations based on our best judgments as to how those terms ought be interpreted in states that do not have clarity about those words.  I think this is extremely hurtful, both to research and to human subjects protection and I think the committee should forthwith consider doing that task.
	CHAIRPERSON MARSHALL:  Thank you and Mark for volunteering to assist with that endeavor.
	DR. FLEISCHMAN:  Our pleasure.
	DR. MORENO:  Robert.
	DR. RICH:  Actually, I'll continue this last discussion because the first point that I wanted to make also related to the legally authorized representative.  I think that's in fact a hazardous term to be using right now when we don't know what we're talking about.  And I think even as we go forward in the immediate future, until we have actually gotten to the position of understanding what we mean by "legally authorized," we may need to think about some other language that carries less specific import in the law which is "duly recognized" or something like that, that basically says we don't know what we mean.  When we say "legally authorized" we're implying that we know what we mean, and I think that that is a real difficulty.
	So I would urge that we try to stay away from "legally authorized" until we have some sense as to what that language means.
	The other minor issue that I would like to raise comes back to something that Sandy was talking about I think having to do with basically the words "populations" in this particular -- as recommendation one.  Concern that we should have two representatives on the IRB who understand the populations that are being studied.  And one begins to ask the question, what is a population?  Is a population any individual with mental diseases, or is it just from the population of patients with schizophrenia.  Or does having one person from the population of patients with schizophrenia then carry over to being an expert in a population with mental retardation or does that represent a different population for which you have to have another two representatives? 
	And in the final analysis, I think as we go through this exercise globally, not just with this particular thing, it would be worth at least counting up how many mandated kinds of experts we really believe an IRB needs to have if they're a general IRB for an academic medical center.  I mean, how many different kinds of people do we think need to be sitting at a table to be able to do the work of an IRB that we are prescribing?
	DR. MORENO:  Just two brief reactions.  The term "legally authorized representative" is, of course, used in the current regulations.  The current regulations also don't know what they're talking about, so I grant you that.  And they didn't when they were first written, they don't now, I take the point that a number of members of the advisory committee want us to look more closely at perhaps some set of recommendations on that question as integral to this report.
	As to the term "population" and the role of IRB members who are expert, Bob, I'd just say that I think the point is not in the historic discussions of this that they necessarily needed to be members of the IRB, but they need to be available to the IRB to consult on specific protocols.  And that, again, goes to the problem of trying to build everything into a single set of recommendations.  At some point the process has to take over -- 
	[Simultaneous conversation.] 
	DR. RICH:  The NBAC language is a little different from what you just suggested which is to say it calls for two members of the IRB except in those circumstances where the IRB only rarely sees such an individual.  But if you're in a busy academic health center -- 
	DR. MORENO:  You're going to see everything. 
	DR. RICH:  -- you see protocols from psychiatry coming regularly. 
	DR. MORENO:  Right. 
	DR. RICH:  But in fact from the whole spectrum of psychiatric diseases from patients who have Alzheimer's disease to schizophrenia to Parkinson's, you know, they all have cognitive impairment of one sort or another, but they have very many different kinds of problems. 
	DR. MORENO:  I'm going to give Susan the last word and then I understand we have to move on in the agenda.  I'm going to presume, Mary Faith, that my job is to incorporate, as best I can, what's been said this morning and then at the next meeting we revisit some of these specific issues.  I think we have made progress and are really digging in now into the meat of some of the problems in these recommendations.  So I thank you.
	Susan. 
	MS. KORNETSKY:  Jonathan, the only thing I want to add is that a lot of this parallels a lot of the thinking and categorization that we use in pediatric research and from years of experience of sitting with an IRB trying to pull apart the words of minimal risk, greater than minimal risk and all those things, I guess my sense is we now have spent time in the pediatric working group thinking about the definition of minimal risk and I can see IRBs now having to make this determination.  And there may be reasons to accept some of the rational and reasoning we've used and that will be discussed at a later point or there may be reasons otherwise.
	But I think either guidance-wise later or part of this you're going to be dealing with the same things and there should be some thought given to that and some guidance given up front as opposed to where we are now in pediatrics trying to get -- 
	DR. MORENO:  So perhaps to incorporate some of the reflections of -- 
	MS. KORNETSKY:  If it's pertinent.  I mean, I'm not suggesting that it is or it isn't, but I think that you should be thinking about that. 
	DR. MORENO:  Yes.  Thank you very much.
	CHAIRPERSON MARSHALL:  We are going to see how our time goes right before lunch and we can, we hope, come back and revisit 3 and just sort of finalize where we are on this.  But I would like for us to take a break. 
	I know that Dr. Harris is on a tight schedule so we don't want to -- ten minutes on the break, please.  We will resume at 10:30.  Thank you all.
	[Brief recess taken at 10:20 a.m.]
	CHAIRPERSON MARSHALL:  We are going to resume again.  We want to make sure we have adequate time.  Committee members, if you all would please take your seats.
	NHRPAC members, folks who are standing, please be seated. 
	[Pause.] 
	CHAIRPERSON MARSHALL:  Well, we're moving right along and we have invited to join us today, and we're delighted he's here, Dr. Jim Harris.  Jim is the Director of Developmental Neuropsychiatry, Professor of Psychiatry and Pediatrics at the Johns Hopkins University School of Medicine.  And he also was the chair of the conference organizing committee of a workshop that was held last year, November 29 through December 1st of 2001 at the NIH.  The workshop was entitled, "Emotional and Behavioral Health in Persons with Mental Retardation, Developmental Disabilities, Research Challenges and Opportunities."   And it was a, I think, Blue Ribbon workshop in the sense of the faculty, and I think, those who attended it, it was a very well done workshop. 
	The executive summary is available, I think, to all of you all on the table.  Committee members, it's in your briefing book.  And I have to say especially if you look under the recommendations that were made that are listed in the executive summary on page 5 of our report, I am delighted to see, and I hope that those of you on the committee join me in being delighted, Dr. Levine -- Dr. Levine, that you all join me at being delighted at having our committee mentioned in terms of someone who should take some action relative to the endeavors that were done at the meeting.  So, thank you very much for recognizing us and giving us some work.
	Dr. Harris, we're delighted to have you. 
	DR. HARRIS:  Perhaps I should start by describing what developmental neuropsychiatry is.  This is a specialty focus within psychiatry, but deals with neuro development and neuro genetic disorders, head trauma.  But any disorder that affects the brain in behavior resulting in adaptive difficulties is the purview of developmental neuropsychiatry.  The reason I'm mentioning this is there has been an absence of focus for many years within psychiatry in dealing with developmental disabilities specifically and that is now the focus of this specialty area. 
	I would like to start by making a very quick comment on the last presentation.  The NBAC report did not include or focus on people with mental retardation and developmental disabilities.  Before our NIH meeting I talked to Eric Meslin and William Raub about this because as a result of that absence of discussion and the fact that mental retardation organizations were not contacted in terms of the issue about mental disorder.
	You know, I would raise a question about whether your previous discussion can be specifically applied to adults with mental retardation.  And I raise this at the beginning because when you talk about, as Dr. Fleischman did, legally authorized representatives, this is an issue that is one that requires considerable discussion when you deal with adult retarded people.
	There are many people who are in group homes around the country whose parents don't have adult guardianship and decisions need to be made about their treatment and it's very difficult to do that.  In fact, one IRB, when faced with this problem, told the investigator that she should get assent from the adult retarded person for the research project and provide a fact sheet to the families because the families didn't have information, but they couldn't give consent.  She felt very uncomfortable about this.
	So I wanted to bring this up at the beginning because it's an issue that wasn't dealt with by NHRPAC.  And the implication is that anyone who has decisional incapacities involved there hasn't been an adequate discussion about mental retardation.  And I think that's one reason that Mary Faith invited me to come today.
	Now, the next point is the reason this meeting was held.  And this is the first time the NIH has ever addressed behavioral, emotional, and psychiatric problems in people with mental retardation and developmental disabilities.  In most states we continue to have separate administrations for mental health and for mental retardation and developmental disabilities.  Often there's not adequate communication among them.
	So in order for this to be accomplished three institutes came together, NINDS, the Neurological Disease Institute, Child Health and NIMH. 
	The reason for having the conference was to talk about inclusion of mentally retarded persons in federally funded research because mentally retarded people are often excluded.
	It's very common, particularly in psychiatric research for there to be an automatic exclusion for anyone with an IQ under 70.  Despite the fact decisions can be made to participate and not carrying out research often leads to off-label use of drugs with people who are mentally retarded where there actually have been no specific trials or even sometimes consideration about the metabolic variability among mental retardation syndromes.
	Now, the idea also in having this meeting is that, as you all know, with the infamous Willow Brook case back in the '60s there was a real effort to not involve people who were mentally retarded in research because they may be taken advantage of as they were in that instance and in some instances this went to extreme.  For example, the first research project I was ever involved in was in drawing blood from people with mental retardation at the Rosewood Hospital outside of Baltimore using a new assay to determine whether or not the neurologic drugs that they were using that might put them at risk were helpful and if we found that they weren't measurable in terms of measuring blood level, then perhaps they could be discontinued.
	Well, it was extremely difficult for me to get permission to do something at that time that was simply intended to try to actually take people off of medication that might be inappropriately used.  So, I mean, I think we've come a long way since then.  We've certainly come a long way in terms of the warehousing that took place of mentally retarded people with community living.  But now we are faced with new issues about the use and treatment and judgment in their care in the community.
	But what research advances are we talking about?  You know, we're considering genetic issues, we're considering advances in neuroscience and neuroimaging issues and assessment that are involved in developmental neuropsychiatry, various intervention psycho-social treatments, so the idea just to emphasize this was that we were looking for ways to include people in mental retardation and therefore the ethical considerations are the first considerations.  If we are going to have inclusion we need to have guidelines that work.
	Now, who was at the meeting?  There were representatives from the academic fields from universities, government agencies, service providers, consumer advocacy groups, parents; we tried to get the full spectrum of people at this meeting to talk about these issues because we really felt it was crucial.
	And I'm going to now move on to talk very briefly, as you see in your handout about several mental retardation syndromes.  First to point out that it's somewhat misleading to keep focusing on capacity when capacity is often situational and it depends to some extent on life experience.  When you're conducting research, you know, often the best research is the best medical practice.  And if the decisions are continuous and ongoing, and there's a process of consent -- consent, after all, you know, has to do with talking with, but specifically with deciding with.  And so we are making decisions in terms of trying to judge both the intellectual understanding and the emotional understanding of the individual.
	But the focus is too specifically on capacity and Michael Rudder actually brought this up and we have some guidelines from the U.K. about this.  The issue is not only the capacity of the person, to participate, but what happens next, and how are they going to be informed as you move along through each step of the research process and to make certain that their rights are fully respected as you proceed.
	Now, the first slide is to demonstrate, you know, how far we've come in community life.  This is John.  He's a young man with Down Syndrome.  He lives with his family and he is employed as an office helper.  You see him in panel B helping a customer -- panel A, rather, helping a customer; you see him in panel B operating a copying machine; in panel C on the way to the bank and then depositing his paycheck.  As you may know many people with mental retardation have identity cards now that they get at age 18 instead of driver's licenses.  So we want to make certain that we appreciate how much can be done.
	Now, there's another example that I can give you of a young man with Down Syndrome who was part of an inclusion community supported employment program in Richmond who was working in a restaurant peeling potatoes and taking out garbage and helping in general ways who was severely mentally retarded by IQ, but in fact was productive and with Down Syndrome, given his personality he actually cheered other people up in the kitchen.  So, I mean, I think we need to think about how much individuals may do and how we need to think about their involvement in making decisions.
	Now, on the left there's a girl with Down Syndrome.  On the right a young adult male with Fragile X syndrome.  Fragile X syndrome is a disorder that was among the first to be shown to be the result of an unstable trinucleotide repeat that's passed from one generation to the next genetically, so the disorder may become worse as one moves from one generation to the next.  But it's a disorder with a very unique finding in terms of cellular metabolism and denduretic branching and brain development.
	Now, this research in understanding the mechanisms that are involved in Fragile X syndrome where neurons don't prune out in the proper way, is probably a simple way of describing it, could not have come about without participation of individuals with this disorder who function in the mentally retarded range.
	This is the most preventable common form of mental retardation.  This is fetal alcohol syndrome.  Fetal alcohol syndrome is a major issue particularly in certain parts of the country.  The physical features change with age.  The young girl on the right in panel B has more typically the facial features with the broad-based nasal bridge and the lack of the filtrum of the face on the upper part of the lip.  The young man doesn't look as severely involved.  Individuals with fetal alcohol syndrome have a syndrome that requires considerable intervention because behavioral problems are really quite common; 92 percent of individuals as they reach adulthood with fetal alcohol syndrome and fetal alcohol spectrum disorders come to the attention of psychiatrists or mental health professionals.
	This is Rhett's disorder or Rhett's syndrome.  Rhett's syndrome was described first in 1966 by Andrius Rhett when his nurse noticed three girls with this type of hand movement in this clinic and thought that was interesting and brought it to his attention.
	Subsequently Rhett's syndrome has become a disorder that's extremely important to understand neurobiologically.  It results in profound mental retardation occurring almost entirely in girls involving an abnormality on the X chromosome that has a major affect on brain development.
	In the final slide this is Lesch-Nyhan disease, a syndrome that I do research on.  And there are two boys shown wheelchairs at the entrance to the Hopkins Hospital with their sister standing on the edge of the wheelchair waving to us.  Their sister is not a carrier, although this was a major concern of the family because this is a disorder that's an excellent recessive disorder.  And in some ways it's one of the most difficult neuropsychiatric problems we see because these individuals compulsively self-injure, may have to -- generally have to have their teeth removed in many instances.  The self injury occurs throughout life although it may lessen somewhat as adults, and involves restraint.  Both of these boys have their arms restrained to keep them from biting their hands. 
	It's a disorder where pre-implantation and genetic diagnosis has been considered because of its severity.  It's a disorder that involves the purging pathway that leads to hyperuricemia, increased uric acid and potentially stones, renal stones.  But it is particularly interesting to us in terms of research because we were able to get permission to do PET scans on these young men and to demonstrate for the first time that there is an abnormality in dominion function and 80 percent reduction in the brain that may be the cause of their movement disorder and related to their self injury which now has led us to look more carefully at how a metabolic disorder of the purine system affects neurotransmitter systems in the brain.
	Now, that research couldn't have been conducted had we not been able to get permission to do PET scans with these individuals and to use general anesthesia in order for them to participate in the study.
	Now, this required considerable discussion because if someone has a severe movement disorder, how can you do an MRI or a PET scan.  They need to be sedated.  And if there's conscious sedation, how can you control the airway with someone who has a movement disorder in these sort of circumstances.
	So this raises an issue about, you know, what do we mean by minor increment over minimal risk when we are thinking about sedation?  And how does this relate to what the everyday life of someone with a disorder?  Because if you look at the everyday treatment of these individuals, they would have light anesthesia, propythol [ph] is generally the drug that's used, previously.  So this wouldn't be something that was novel or new to them to have an imaging study, but it does involve a procedure.
	Now, it is also the case in all the major medical centers, there are slots in the radiology department for examination with light general anesthesia in order to do MRI studies for children who need them who can't cooperate.
	So I raise these issues at the beginning to stimulate discussion, but also to try to give you a feel of who the people are with mental retardation syndromes and how they may contribute.
	Now, there's one theme that I often am told I'm naive to bring up, but that's the issue of a principle that I think is an ethical principle of altruism.  Now, if you think about this -- I thought I would read you the ethical conduct section on research of mental incapacitation from the Medical Research Council in London.  And this is what is said:
	"We have however argued on ethical grounds that a mentally incapacitated person should not be excluded from the opportunity to contribute to the welfare of other mentally incapacitated people and possibly his own welfare provided no more than minimum risk of harms involved in research."
	Now, this often comes up and I'm bringing it up and this is a very difficult point because now we're suggesting that you can actually talk about someone making an altruistic choice who had difficulty making other types of choices.  But it comes up in a different way with adolescents who are normal volunteers who have family members, for example, that they would like to be of some benefit to and volunteer for procedures.  And, as you know, it's often more difficult to carry out research with normal volunteers than it is with individuals who have some of these mental retardation syndromes which makes it difficult also to have control groups when you do certain types of studies.
	Now, let me move to the recommendations of the workgroup.  These are in your handout, I believe, and I thought I would mention first is what we dealt with at the meeting.  We dealt with the following issues, epidemiology, not only prevalence, but outcomes research in mental retardation syndromes, diagnosis and assessment and the need for specific instruments to diagnose mental disorders and behavioral disorders because the DSM-4 categories often are not sufficient in terms of making diagnoses.
	For example, in the past there's an increased prevalence of depression in Down Syndrome, often misdiagnosed as Alzheimer's Disease in adults with Down Syndrome.  And it was assumed for a long time that you couldn't be depressed if you had Down Syndrome because you didn't have the capacity to have the sense of guilt that was required in the definition.  Rather than simply looking at the behavior and the social withdrawal.
	I mean, one of my patients who was a 17-year-old who was misdiagnosed with Alzheimer's disease who was depressed I treated with an antidepressant.  Her favorite activity was to come home and write and her writing some people might describe as scribbling, but she would come home from her workgroup workshop every day and she would do her writing before she did other sorts of things.
	Well, that was the indicator we had looked at because she now was returning to her usual activities after becoming socially withdrawn.  So the criteria need to be considered carefully.
	Research design becomes an interesting theme and I've incorporated two slides from the research design group as I move along and then research training needs are important because we need to train more researchers in order to do the research that we feel is necessary and to begin to include mentally retarded persons in research.
	Now, the first recommendation from the research group was that it's the normal expectation that persons with mental retardation will be included in federally funded research.  To the extent that we ask the question whether or not there should be a check box when federal research is carried out for both physical and mental disorders to see whether or not you have considered an individual with mental retardation for this particular protocol.  I mean, as you know leukemia has an increased risk in Down Syndrome for example.
	The investigator assumes a responsibility for justification of any exclusion roles including or not including people with mental retardation.  Exclusion should not -- should be based upon function and safety features of the experiments under study and not based on sweeping generalizations such as IQ less than 70.
	Designs that emphasize the understanding of for whom and under what circumstances should be emphasized in mental retardation research.  These designs in general are to be preferred to designs that result only in estimates of group means.
	Now, this is the point that I think we need to also consider as we think about this and you look at the guidelines that are being recommended.  Multi-site, multi-collaborator designs need to be thought of as normative in dealing with these populations.  Many of these disorders are quite rare.  Because they're quite rare, you know, one needs to work with more than one site.  And this becomes an issue particularly in how do you have protocols that can be carried out in more than one site.  This became an issue the year before last with the study on normal adolescents who were depressed when one of the sites the local IRB didn't approve the  protocol.  All the other sites did, the other 13, so the research was conducted there.  The protocol was sent to OHRP and after a year and a half when they hadn't gotten a response, they finally dropped out of that particular protocol.
	Now, let's move on.  You talked earlier about terminology.  Individuals with MRDD refers to individuals with mental retardation and developmental disabilities.  The reason we use both terms is that there are people with syndromes where there's a range of IQ level.  So, for example, in autism the majority of people with autism over two-thirds have IQs that are under 70 and that holds even though we are looking at nonverbal intelligence to make that characterization.  But somewhere between 10 to 20 percent may test in the normal range.  And so they still have a developmental disability.  And so a normally intelligent person with a developmental disability, high functioning autism, Asperger Syndrome, for example, may have different needs in terms of research protection as you begin to speak with them.
	For purposes of this report, I just talked about that, MRDD does not, but perhaps should include individuals with acquired brain injury or cognitive deficits.  By definition, if you have a head injury, for example, before age 18, and subsequent mental retardation one is referred to as being mentally retarded after 18 and that's not the case.  But we need to take into account, as I talk about mental retardation and developmental disabilities, I'm also talking about acquired head injury.
	Now, the next issue has to do with the legally authorized representative that was brought up earlier.  I mentioned at the beginning this is an issue as you deal with adult mentally retarded individuals who are in group facilities particularly.
	Now, the preamble to the -- and this is the ethics group now I'm describing and this is all in the handout.  It's not in the interest of individuals with MRDD to be excluded from nontherapeutic research they may offer important information to understand or ameliorate conditions affecting them.  This includes placebo research.  Now, you know, you may not normally think about it like this, but if someone has a condition and they would like to be involved in research that will be helpful to them, and placebo trials are necessary, then individuals with mental retardation shouldn't be excluded.  This is in the part of the final recommendation that you have in the handout.
	By the way, I mean, I know there's a lot of discussion about placebo effects, but placebo is a treatment, it's not nothing.  So, I mean, I think a lot of people don't understand that.  Any determination about decisional capacity should be based on functional criteria and not on simple label of MRDD or IQ.
	Social understanding is something that comes with time and experience.  Individuals with certain syndromes have a lifetime of experience with their disorder and one has to take into account what their special circumstances are.
	Persons with MRDD who have the capacity to consent, like any person with the capacity to consent should be given the widest latitude to consent or refuse to participate in research. 
	Now, is the Common Rule adequate for research involving individuals with MRDD?  Subpart (a) does not address the inclusion of individuals with MRDD in research.  Existing reports, NBAC, as I mentioned earlier, do not address the issue of individuals with MRDD.  Whether a separate subpart is needed and to whom it should apply is a complex issue.  It should apply to people with MRDD, persons with mental illness, persons with impaired decisional capacity in general.
	Now, the recommendation of the NIH group was the IOM should convene a group of all stakeholders with necessary expertise to address this issue.
	Two, does minimum risk -- the minimum risk rule need to be reconsidered as a guideline for nontherapeutic research involving individuals with mental retardation. 
	The definition of "minimal risk" is ambiguous as you have discussed here.  It's being interpreted in widely different ways resulting in wide variations among IRB.  Is minimal risk, risk of ordinary life?  Norman Faus was a part of this group and the reason it says Kabul vs. Madison, what's ordinary life in Kabul, Afghanistan compared to Madison, Wisconsin, for example?  You know, what's the situation of ordinary life.
	What about routine tests?  A routine test for a nephrologist is a kidney biopsy.  A routine test generally is a vena puncture.  What do we mean by "a routine test"?  A routine test for someone with some forms of leukemia might be a lumbar puncture.
	Now, is minor increment over minimum a different category?  This is something that Skip Nelson from CHOP raised.  Is this a continuum to go from minimum risk to minor increment over minimum risk, or are we talking about a completely separate category when we consider this?  Do we index to the healthy person or the ill person?  And do we index to procedures commonly used for a person with a specific disorder? 
	And to continue, the minimum risk rule needs further specification and application to research involving individuals with MRDD who lack decisional capacity.  A national workshop should be convened to make recommendations on this issue.  
	Now, to move on to a third point, how should consent/assent be applied to research involving individuals particularly nontherapeutic?  The group indicated that their understanding of informed consent and assent needs to take into consideration the very capacities of individuals with MRDD to make decisions.  We need a better understanding of specific vulnerabilities in MRDD.
	Suggestibility is a major concern, witness mentally retarded people volunteering that they were involved in criminal activities when they were not.  But suggestibility and the effort to please is something we see in children.  It's a feature that needs to be considered for mentally retarded people.  And this needs to be placed in the context of a specific research.
	Now, if an individual with MRDD appears unwilling to participate should that be respected, even for procedures with minimal risk?  After all, the guideline that we talk about for capacity is age seven, but children who are five make certain contributions.  Children who are three and four can be involved in undue standing because if you think about doing research you also need to think about what happens in the everyday practice of medicine where you give consent to be examined and you give consent to treatment.  The research is another form of that, but it takes into account the understanding of the individual.
	Dissent should be honored.  I think we all should keep that in mind. 
	The issue is, what evidence would be considered sufficient to establish dissent?
	Quivering lip, you know, refers to the fact that a procedure is beginning and the child becomes anxious.  Should one automatically stop?  Or help the child to calm down to understand further what's involved?  You know, these are things that we need always to take into account.  But if this is evidence of dissent, then one shouldn't proceed.
	Investigators need sufficient expertise with this population as the IRBs and this is a question that came earlier.  You know, how does the IRB get the guidelines?  As I understand it, the group at Children's Hospital in Philadelphia there's something called IRBIV where you can go on line to talk to people in other IRBs around the country to see how they're handling this particular type of situation.
	Further analysis is needed about issues of assent and dissent in this population. 
	Four, what should be the role of the surrogate consent for research involving adults with MR?  Now, this becomes an issue not only in mentally retardation, certainly, but in general.  But decisional capacity often seems to be global and ignoring evidence to the contrary one needs to take into account decisional capacity for what because decisional capacity is situational.  A global appointment of a surrogate for an adult with MR would be inappropriate.  And that I think goes along with some of the earlier discussion. 
	Today when you talk about legally authorized representative, legally authorized to do what?  What is the specific reason that that person is being assigned.
	Absent state law to the contrary, legally authorized representatives may authorize research that has the prospect of direct benefit.  But further discussion is needed for legal authority of a surrogate to authorize research that doesn't offer the prospect of direct benefit.  The discussion here also looked at the without common ways of looking at this, the best interest and substituted judgment and came down more in favor of looking at best interests, but the question still remains in how to determine that.
	Five, should there be different guidelines for research involving individuals with MRDD in institutional, group or home settings?  
	Individuals with MRDD may be more or less vulnerable depending on the residential setting, including the possibility of undue influence or coercion in the absence of an appropriate advocate.  Does the staff enthusiastically want the individual to participate in research or is more commonly the issue, do they have the general philosophy that mentally retarded people shouldn't be involved?  And yet in the same group home an individual might be taking five psychotropic drugs.  You know, one of the big issues that we have these days.
	So to conclude, further reflection and discussion is needed on the role of residential settings and associated factors in research protections, issues of home ownership and control, contracting for services within the residential setting are part of this discussion.
	Six, what are the legal and regulatory barriers to research involving individuals with MRDD?  Well, one of the issues that comes up with IRBs is fears of sanctions from OHRP in approved research.  This may be exacerbated when there's research involving vulnerable populations.  IRB members and investigators have a growing concern about lawsuits.  And this concern can affect approval of research on vulnerable populations. 
	There is considerable variation from state to state.  It's who can serve as surrogate?  And this is something that Dr. Fleischman raised and I think it needs to be part of the continuing discussion, particularly when you deal with these populations.
	The jurisdictional state or local variability in interpretation and informed consent by surrogates and individuals by MRDD may hamper research. 
	Now, to continue this there needs to be greater clarity in the legal and regulatory framework particularly in regard to surrogate consent.  The appropriateness of punitive sanctions for noncompliance with regulatory requirements needs to be reviewed.  The process of approving research proposals that fall outside the local IRB authority needs to be conducted in a timely manner.  And I mentioned this earlier, if there is a central referral when there's a question about research that takes place with minor increment over minimum risk, how long will it take for that review to take place?
	Because certainly this project in Texas that simply didn't participate because they didn't hear, I think is an example.  Hopefully that's an exception.
	Now, the other issue has to do with genetic research.  And, you know, I believe you're talking about this in a different context.  But, for the mental retardation development disability community there is ongoing discussion about procedures such as pre-implantation genetic diagnosis.
	In the disorder that I mentioned, Lesch-Nyhan Disease, this is often an issue for families about whether to tell their teenage daughters that they are carriers or whether to test them as carriers, and if they are carriers whether or not going through a pregnancy and then having to make a decision about abortion is the thing to do or whether pre-implantation and genetic diagnosis should be discussed.
	In Lesch-Nyhan Disease, it may be possible to do this without -- with essentially only looking at the ovum rather than looking at a fertilized egg.
	Questions have arisen as to whether family members should be treated as research subjects if the involvement is limited to being identified in the family history.  So when the physician takes a family history and asks, do you have a family history of this particular condition, do you need the consent of each individual family member to be notified that they have a particular -- have a problem.  The authority of surrogates to consent for nontherapeutic genetic testing for research is unclear.
	And to go on with these conclusions, federal guidelines need to clarify whether taking a genetic family history necessarily makes a family member a research subject.  And this, as I understand it, one IRB was closed down over this issue.
	Identify the conditions under which genetic testing for research is permissible.  And then eight, what considerations should be given to risk, benefits and burdens to third parties?  Because when you carry out research with someone who has a mental retardation it does affect the schedule, the life and other who are engaged.
	Third parties can be affected by research.  The individual may need to be taken out, may need more increased -- need supervision.  One may need much more careful monitoring during that time.
	Conclusion.  The effects on caregivers, family members and others need to be considered in the evaluation of risk and benefits.  The discussion of these issues should include potential conflicts of interest between individuals and affected caregivers in terms of carrying out the research.  And these issues also need to be considered by IRBs, investigators, and institutional people.
	Now, should an NIH application form be required in terms -- when you apply to NIH should you have to state whether or not -- why you're not including people who are mentally retarded.  As a general principle individuals should not be excluded from research based on mental retardation and developmental disabilities.  This is especially important for research focused on mental illness in the context of mental retardation.
	Such a requirement, this group felt, may have symbolic importance, but may be unlikely to result in an increase in research.  Now, this was something that was debated because we felt it was something that should be brought to investigators' attention.  But one of the members of the panel pointed out that having this requirement for inclusion of children hasn't necessarily led to more research involving children.
	More funding is needed for research focused on the issues that are particularly salient to MRDD.
	And then, finally, should an IRB be required to include members with expertise?  The need for sufficient expertise applies to all research and not only to mental retardation.  They are two separate issues.  Research focused on conditions with MR and research that may include individuals with mental retardation among others. 
	An IRB should have sufficient expertise to evaluate research primarily involving individuals with MRDD.  The expertise could be obtained through consultation.  Other protocols should be evaluated on a case-by-case basis.
	Now, finally, just to wrap up, appropriate tools for the assessment of decisional capacity in individuals with MRDD need to be developed.  There is one request for proposals at NIH that would fund research to look into these areas in a more general way and it might be applied specifically to this group.  Further research is needed on enhancement and decisionmaking capacity.
	Now, this is important because if you do an IQ test you get a number that applies in general.  But if you then talk to the individual and prompt them, they actually may know the information.  And so it's not sufficient simply to go on an IQ test.  One really needs to look functionally at the individual to see what they understand.
	A workshop to develop federal guideline and research involving individuals with MRDD that addresses all of the above concerns should be convened.  Perhaps this group might consider participating.
	And then let me just -- the members of this particular workgroup are listed here.  Just quickly to point out a few, the first person, Carlos Caban was from the extramural program at NIH.
	Douglas is at the University of Washington.
	Bob Dinerstein is with the American University.  He's an attorney who wrote a book on consent for mental retardation.
	Steve Eidelman is the executive director of the ARC, the Association for Retarded Citizens.
	Norm Faus is a pediatrician and ethicist at the University of Wisconsin and the chair of the IRB.
	Robert Nelson is the chair of the IRB at the Children's Hospital in Philadelphia.
	Sieg Pueschel is a pediatrician and also a parent of a child with Down Syndrome.
	Lainie Ross is at the pediatrics department at the University of Chicago.
	Nicollette is government affairs representative for the Epilepsy Foundation.
	Marcia VanRiper is the school nursing U&C and has been quite involved in ethical issues.
	So I'll stop there. 
	CHAIRPERSON MARSHALL:  Wonderful.  Thank you very much.
	So new things to think about relative to the work that we're doing both in terms of our workgroup on decisional incapacity and I think there is some overlap with our informed consent workgroup and perhaps others as well.
	So thank you very much, Jim, appreciate that.
	So let's open things up for some discussion and questions.  I have Bob Rich and Mark.  Other hands?  Go ahead, Bob.
	DR. RICH:  First of all, I would like to thank you for that discussion too.  I think it was a real contribution to our thinking about these issues and the workgroup should be commended.  I would like to sharpen one particular issue.  I think I know what the response is, but I would like to hear it more explicitly.
	Let's take as a hypothetical a study involving an MRDD patient who happens to present with leukemia to a physician who has no expertise particularly in dealing with MRDD patients but is now confronted with the issue of, should he or she offer enrollment of this patient into the study.  The study has nothing to do with the patient's other disease, that is to say, MRDD, but it's obviously germane to the patient's now life-threatening disease, leukemia.  It would be more convenient to the investigator to simply exclude this patient.  Because there are plenty of patients coming into his or her practice and this patient could be excluded because of the "inconvenience" -- and I put that in quote -- of dealing with this patient for whom special considerations with regard to consent must be considered.
	What would your view be about the either correctness or non-correctness of offering participation in this study into a patient who has cognitive impairment in this sense?
	DR. HARRIS:  Well, I think first there's a caveat because leukemia and Down Syndrome may not necessarily have exactly the same presentation as some of the other treatments, but in terms of a general question about inclusion, it's critical that they have the option to be included.
	The way we all got started at Hopkins as pediatric residents with this was with a child with Down Syndrome who had intestinal atresia and this could be corrected by a simple surgical procedure.  But the parents denied consent and so the hospital became in loco parentis.  I mean, it stimulated Norm Faus who was the chair -- was the chief resident at that time and Bob Cook who was the chair of a department at the Kennedy Foundation and many others to begin to look at this issue.  But denying care to someone because of a category of being mentally retarded doesn't acknowledge the value of that person.
	In fact, if you'll notice, we always refer to persons with mental retardation.  We try not to just say mental retardation because people often forget that categorically, you know, these are individuals who deserve treatment.  And so, certainly, I mean, the inclusion for leukemia or routine surgical procedures, surgical procedures sometimes come up or for the more complicated cardiac abnormalities that occur with Down Syndrome, but these are all questioned.  But it would have to be addressed directly by the investigator.
	DR. RICH:  To clarify, I'm not talking about offering the best possible care to the patient.
	DR. HARRIS:  Right.
	DR. RICH:  I'm talking about offering them participation in a trial.  So, I mean, I think no one would argue with the idea that they're entitled to the best possible care for whatever disease they present with.  The question is, is there a responsibility of the investigator to engage them just as any other patient in some clinical trial which may or may not offer them any advance in the quality of care? 
	DR. HARRIS:  Well, I'd say yes.
	CHAIRPERSON MARSHALL:  Bob, can I push that question just one step further?  I mean, you alluded to this, Jim, in your remarks.  Should the default position or assumption be that person's -- that MRDD -- persons with MRDD be included in trials unless a cogent argument can be made for their exclusion just as we've done with women and children recently.  Is that a fair question? 
	DR. HARRIS:  Right.  And that's exactly the issue we raised with NIH about including -- having basically a box to check off about why these individuals weren't included.
	Now, there are many institutes at NIH that are involved with mental retardation, the Heart Institute, the Lung Institute and so on.  But, you know, we've asked and we're hoping that there will continue to be an inner institute group that will continue to meet to discuss these issues.
	CHAIRPERSON MARSHALL:  Thank you.  Susan has a remark on point and then I have Mark, Adil, and Mary Kay, and then I'm going to open this up and we need to try and stay on schedule. 
	MS. KORNETSKY:  Given your comment that you just made and some of the discussion that we had before about differentiating things that offered or prospect to direct benefit or potential for direct benefit, I guess I'm trying to understand, if something was to be done that did not offer prospect to direct benefit but was in some type of trial, what would be your position on that?  I mean, I think we're talking about clinical trials where there may be a potential for direct benefit.
	DR. HARRIS:  Right.  
	MS. KORNETSKY:  But what about taking what you've said and what we've discussed before? 
	DR. HARRIS:  Well, I think -- and this is a question I think that depends on -- requires an example because it's a situational sort of thing.  It needs to be decided on an individual basis.  You know, I don't know that I could globally, you know, make a comment.  I think the leukemia is an example.
	I'll give you an example with Lesch-Nyhan disease.  Bone marrow transplantation is particularly hazardous for this group.  All the people who have had bone marrow transplants who have been infants have died who have had bone marrow transplants.  But this procedure has been done -- has been carried out with an adult.
	This procedure was carried out in a therapeutic way, you know, for some time and now it's being questioned.  But should it ever have been done?  Well, it had been done in adults first before it was done in children.  And this also becomes an issue when dealing with people with mental retardation about, you know, whether or not which age group should you start.  I mean, I think that's something that's been discussed, you know, particularly with the case at the University of Pennsylvania, Jesse Gelsinger, who had a partial enzyme deficiency but was generally healthy if he followed the diet.  But I think I'd have to say that this really is an individual decision, but it should be a decision that's a possibility for discussion.
	CHAIRPERSON MARSHALL:  Thank you.  I have Mark is next. 
	MR. BARNES:  Yes.  Thank you. 
	Just a brief comment.  There's a fundamental tension, especially when you take the discussion we had before in regard to people with mental disorders versus the way that you've presented this.  And I'm not saying that I -- I don't know what side I would take on this, but the fundamental tension is whether the privilege is a privilege to be included in research or privilege to be excluded from research.  And, you know, it's not unlike -- it has an analog actually, and you know, one actually has many analogs, but one analog that I think of is in terms of race discrimination in America, is the solution benign neglect or is it special solicitude?  And people take different positions on that.
	If you look at the NBAC recommendation number three, this is what it says, "An IRB should not approve research protocols targeting persons with mental disorders as subjects when such research can be done with other subjects. 
	In other words, when a person has a mental disorder, not even -- doesn't even say total incapacity, then the presumption should be against research involving those people when you could use other subjects.  I think there's a fundamental tension there with the way that you've presented the way that you would recommend and the group would recommend that patients with mental retardation and developmental disabilities be treated that they should really be treated as though they are any other person who comes to the table.  
	And I don't know what the solution is to that, but I mean, you know, it's sort of like when I was a public health official there would be times that people with -- you know, I was a supervisor on the AIDS programs in New York and in some cases we had people with AIDS who would say, you know, I want you to recognize me as being a special person and then in the same breath they would say, how dare you treat me like a person with AIDS.  And it's sort of like -- and I would say, look, you've got a choice, I'll either note it or not note it, but I can't do both.  So anyway, I don't know what you would say -- 
	DR. HARRIS:  Well, I think that this -- if you look at the guidelines in the U.K., for example, you know, this is made explicit.  In fact, I'm glad you brought this up because if you didn't need to answer the question, if it's nothing specific that has to do with a disorder in a mentally retarded person, then the research should be done on people who are not mentally retarded who can give consent.  I think that generally would be the case.  The only time this comes up is that when -- and this is, I think, in the -- it's part of the issue in the minor increment over minimum risk is that if it's in the vital interest of a particular disorder, you know, for example, the syndrome I mentioned where we using PET scanning was the first way we were able to look at the brain and find out what was actually going on in there chemically.  
	Then, in fact, we first got compassionate approval when we did the first one of these studies and we went through that mechanism.  So I'm not arguing that people should be involved in research when they can't give consent if other people who can give consent the question could be answered.
	DR. RICH:  Can I follow up on that?  Right back to the point that I first made.
	CHAIRPERSON MARSHALL:  Very brief because we're at time. 
	DR. RICH:  I understand. 
	CHAIRPERSON MARSHALL:  Because we're going to have to stop there, I think. 
	DR. RICH:  If we just changed the first analogy from leukemia then to breast cancer, something that's not associated with MRDD, would your answer have been different? 
	DR. HARRIS:  Well, it depends on what kind of trial it is.  If it's a treatment trial that might, you know, potentially benefit the individual, then -- 
	DR. RICH:  They should have the same access as anybody else for that treatment trial?
	DR. HARRIS:  They should have the same access.  But if it's nontherapeutic research then it may be a somewhat different question. 
	I mean, I'm actually suggesting in this, as we did at the meeting, that one needs to kind of stand back for a minute and ask why people with mental retardation and developmental disabilities have been excluded from projects and that as regulations are considered that that group be taken into account and that there be -- this group, of course, was a widely representative group that met at NIH.
	These are the recommendations that came out of a specific workgroup.  But, I think that if you're going to move on with guidelines then you might have more discussion with people from the mental retardation and developmental disability community.  Since I would have to end by saying NBAC specifically did not address this group. 
	CHAIRPERSON MARSHALL:  Let me ask -- I'm going to give Bob just one final question.  But any of our ex officio folks or public members out there in the audience like to pose a question to Dr. Harris? 
	[No response.] 
	CHAIRPERSON MARSHALL:  No.  Bob, one last question.  Then we will move on.  Sorry, we can't get enough of you. 
	DR. R. LEVINE:  Every time we bring up the topic of including populations or individuals who previously have been excluded, we hear the argument for inclusion tends to be blurred between two separate objectives.  It gets very confusing because the arguments for both objectives are grounded in considerations of justice or fairness.
	The first argument is that individuals with mental retardation should be entitled to equal access to whatever the benefits might be to individuals to participate in a clinical trial.  You respond to that by creating an open-door policy, letting people with, let's say MRDD enroll as subjects.
	The other argument is that people in this category are not to be deprived of the knowledge that comes from doing studies on this population.  Also an argument injustice.  The trouble is that the two objectives are in competition with each other.  If you open the door to all comers, that means you're probably going to blur any distinctions there might have been between this group and any other group.  This is seen most powerfully with open-door policies with say, women or minorities. 
	If you really want to understand whether this group is different in its response, let's say, for example, whether Lesch-Nyhan's patients can take bone marrow transplantation.  And you have to have a trial in which you stratify the people with this group so that you get an equal number of them in each arm of the trial so you can perform a statistical analysis.
	The prospects of getting that with a disorder as rare as Lesch-Nyhan are tiny.  But I just wanted to make it clear that we are dealing with competing objectives here that are deceptively similar.  Thank you.
	DR. HARRIS:  Well, I would have to say that there's always going to be a conflict between making general rules and dealing with individual people.  In the example with Lesch-Nyhan disease a disorder of purine metabolism necessarily is a disorder where immunosuppressant may be more problematic.
	So the treatment that is being used -- I mean, I'm trying to come back to this specifically because mental retardation is not one thing.  This is a global -- this is many different disorders and one has to take into account the specific disorder.  And that's, of course, a factor in being involved in a trial.  There may be metabolic reasons not to include someone in a particular trial because it might be a risk to them.
	But I just think that if you -- you know, in terms of -- if you want to look at this in terms of justices, I mean, I expect this is the theme that's being raised.  But we also -- we've gone -- we've always focused on safety and the safety issues I haven't emphasized as much because it was the other part about inclusion that was not as much discussed.  And the reason for inclusion simply is that there are advances in medicine that are occurring that have to do with brain function that may benefit not only mentally retarded people, but us in general in terms of understanding about brain activity. 
	DR. R. LEVINE:  I'm sorry, but your response makes it clear that my remarks were not clear.  Thank you. 
	[Laughter.] 
	CHAIRPERSON MARSHALL:  Thank you, Jim, very much.
	I would like to point out that Doctors Harris and Fleischman did their residencies together and I'm sorry that we don't have time for any war stories, but -- 
	[Laughter.] 
	CHAIRPERSON MARSHALL:  -- maybe later. 
	Thank you so much, Jim.
	[Applause.] 
	CHAIRPERSON MARSHALL:  Those of you who are ex officios, we have seats in the front for you.  So please come on up front and have a seat.
	While we're finding Dr. Menikoff's presentation I want to just recognize a couple of folks who have come in, in the last hour or so.  One is Nancy Dubler.  Nancy, we will be seeing you this afternoon, but welcome to our meeting.
	And the other is Dr. Sherry Hahn.  Sherry, I just -- yes, please stand.  And Sherry is assistant to the Assistant Secretary for Health, Dr. Eve Slater, and as a committee we report through the Assistant Secretary to the Secretary.  Had a wonderful meeting with Dr. Slater just last Friday, very productive.  So, good to see you, Dr. Hahn.  Welcome.
	We've had, I think, a provocative morning.  And it's about to get even more provocative.  I'm delighted to introduce to you all my colleague at Kansas University Medical Center, a fellow who works just down the hall from me, Dr. Jerry Menikoff, who is both a physician and an attorney.
	At the University of Kansas Medical Center, Dr. Menikoff chairs both the IRB and the hospital ethics committees.  He is the author of a superb book that has come out in the past year, "Law and Bioethics."  If one were to go on to Amazon.com and to click on bioethics and to click on favorites, last week his book was number one.  And it's being widely used as a text to teach health law or the law of bioethics to non-attorneys and to teach bioethics to attorneys.  So, that's not a paid political advertisement, it's merely a mention.  And congratulations on your good work.
	Dr. Menikoff has a paper that is forthcoming in the Lancet on the very topic which he is going to discuss today.  I guess I should say that it was perhaps a little bit too hot of a topic for a couple of our most prestigious journals in the United States to publish and I think that's unfortunate.  I hope that they go back to the drawing board and work on their courage a little bit more.  But we all are looking forward to your paper coming out.
	Jerry is here today to talk to us about full disclosure in the research context for off-label availability of agents that are under investigation.  Jerry. 
	DR. MENIKOFF:  Thank you, Mary Faith.  It's a pleasure to be here.  Thank you in particular for your generous comments.
	I really appreciate the opportunity to discuss this and I am looking forward to responses to these ideas.  I have a lot of slides to get through, but I'm going to try to skip a fair number of them and hopefully give us some time to talk about these issues.
	At the heart of what I'm talking about is the fact -- maybe this is sort of just one idea in what I'm talking about, but I think if nothing else, it's an interesting idea.  At least tens of thousands of subjects, and I suspect it's more likely hundreds of thousands are being denied a particular piece of information that I suspect large numbers of them would find highly relevant in terms of their deciding whether or not to enter or not enter research studies.
	Before I go on to the specific facts of what's happening, I want to start out with a story that's sort of background for this.  I want to begin in about late 1970s, 1979 we're dealing with a woman who has metastatic breast cancer, has limited treatment options, at this time standard chemotherapy wasn't working very well.  And some people came up with an idea of trying something different.  And, again, I suspect most of you are pretty familiar with this.  I'm probably right now not saying anything very controversial at all. 
	The idea was to perhaps use strong chemotherapy.  That's the general way we sort of treat cancers that are not well treated and the problem is, as you try to do that, the chemo itself causes bad things to happen; in particular it causes the person's bone marrow to be destroyed.
	And so the notion was, well, these women don't have anything wrong with their bone marrow to begin with, so why don't we take out some of their bone marrow ahead of time, save it, give them the high-dose chemo that will destroy their own bone marrow and then give them back their own bone marrow.  And this is called an autologous bone marrow transplant and this type of experimental treatment was called high-dose chemotherapy with autologous bone marrow transplantation or HDC-ABMT.  A little awkward there.
	The high-dose chemo is very harmful, as I indicated.  They initially tried this on relatively young and healthy patients; healthy other than having the metastatic breast cancer.  Even then a lot of them died from the treatment as reported in the Times -- New York Times and everywhere else, these people were, at the time, considered rebels, the doctors who were sort of trying this.
	But gradually they got some anecdotal results, discovered they were getting a much higher remission rate from this new stuff, the high-dose chemo than the low-dose chemo and these former rebels became heros.  And more and more people started trying this stuff.  So the doctors said, well, this seemed like the thing to do.  They didn't worry that there weren't really good clinical trials at the time.  And we have lots of people being tried on this sort of treatment going from, you know, the 200s in 1989 up until about 30,000 during the 1990s.  So it was a pretty popular treatment.
	Now, while this was happening, some doctors were still trying to do the randomized clinical trials.  They were having a hard time doing that, as I will get into in a moment.  And what these clinical trials tried to do are basically randomize a woman who had metastatic breast cancer between the standard treatment at the time, which was low-dose chemo, which, as I indicated, did not work very well.  Or this new stuff, the high-dose chemo with the bone marrow transplant.
	And it was very hard to get women to enroll in these studies which isn't hard to figure out.  Cleveland Clinic, for example, reported that despite what they described as monumental efforts, they weren't able to enroll a single subject.  And the point was made that you have other people out there providing the high-dose chemo and basically saying, look, this works.  So patients were going to go there as opposed to being in the randomized trial.
	Other trials, for example, are using this type of scheme for ovarian cancer just collapsed because they just couldn't get people to enroll in these studies.
	Eventually, though, persistent doctors did enroll enough people in the studies.  As most of you know, in 1999 the results came out, three out of the four studies showed no difference between the high-dose chemo and the low-dose standard of care and the fourth study, South African study was eventually found to have falsified data.  This was reported in the New England Journal.  We'll skip that.
	So the conclusion of this story is basically that if there is some sort of new treatment out there that patients can directly get and the current treatment isn't very, very good, you're going to have a hard time getting people to enroll in randomized clinical trials.  Sort of a common sensical thing.
	Now, that is not what I'm now going to turn to talk about.  Because the conclusion you might get from this whole story is, gee, this was horrible.  We have all these people ending up getting this sort of unproven therapy and we never really got the answer to this because people weren't enrolling in the trials.
	Well, I want to sort of flip the whole thing and say something that may sound a little controversial.  We are seeing, not directly as a response to this, but nonetheless, we are often seeing randomized clinical trials taking place in which the option of getting the "new unproven therapy" off the study is not mentioned to the subjects.  And the question I want to ask you about is, is it ethical to do that?  We get more subjects enrolling in these trials, perhaps because they don't know they could get the new stuff outside of the study and is that a good thing?
	Now, I've noticed the thing I'm raising here is almost worsening the problem that occurred in regard to the high-dose chemotherapy trial.  So I'm laying that right out here. 
	So let me give you some background about this.  How common is it that you can get off-study the new arm in some randomized clinical trial?  My first claim is that it is actually pretty common.  And let me raise two legal barriers to getting this new stuff off study.  The basic categories are there are malpractice laws that may make it malpractice for a doctor to do that; and, secondly, the variety of regulatory prohibitions, particularly FDA rules.
	What about the malpractice laws?  Yes, in general, it is -- you know, when you deviate from standard care you may, as a doctor, be subjecting yourself to malpractice.  But that's not a strict and hard rule.  The laws in most states recognize that it is okay to reasonably deviate from giving standard care and in fact, I suspect every doctor in this country would acknowledge they do that not infrequently.  You're not going to be facing malpractice risks every time you conclude, gee, with regard to this particular patient, I think it's reasonable not to give standard care.  Not every patient wants standard care, not every patient needs standard care.  Patients differ in terms of how they value particular healthcare outcomes.
	Clearly, when you deviate from giving standard care, you have a big issue in terms of making sure you're getting adequate informed consent.  Now, I'm going to be assuming throughout here that we are going to go overboard in terms of making sure our subjects and our patients know what's going on, that we're dealing with, you know, some new unproven treatments.
	What about the FDA regulations?  FDA regulations allow a lot of things that many people aren't familiar with.  The FDA doesn't regulate procedures such as surgical procedures.  You want to make an incision in a new different way, the FDA in general isn't going to have anything to do with it.
	If a device has been approved by the FDA for particular use, in general doctors can use it for other uses.  And the broadest category, even if a drug has been approved for one use, it is in general the case that doctors are allowed to use that drug in other scenarios.
	In fact, and, again, this stuff is not particularly controversial vis-a-vis the FDA.  Some people will say that, but that is not true.  The FDA openly acknowledges in numerous statements that it basically has no authority and the federal government has not given it authority over how doctors practice medicine.  Yes, if a drug has not yet been approved at all, it can't be used.  But once it is out there, they basically acknowledge it's up to doctors to decide how they want to use the drug. 
	Now, the FDA does control the marketing of the drug.  But, again, that is mainly done vis-a-vis the manufacturers, not in terms of the FDA getting down and controlling what particular doctors can do.  There's a lot of flexibility here.
	Let's particularly just mention, in terms of off-label use of medications, there's a lot it out there.  It's very hard to get data on this, but the estimates are between 25 percent to 60 percent of all prescriptions written each year are for off-label uses of medications.  In the cancer area particularly, there's a huge amount of off-label use.  And you could figure that out.  Basically there are a certain number of drugs that have been approved for a particular cancer and then once they have those, you know, oncologists basically start sort of mixing them in different combinations and different timing and that sort of thing.
	A lot of pediatric drug use.  And this will change, hopefully, since they've changed the rules requiring more studies to be done on kids.  But in the past you got a drug approved for adults.  The pharmaceutical manufacturer had no incentive to basically get it approved for kids.  Because they knew -- the pediatricians knew this is the only drug out there that treats anybody with this condition.  They have no other choice.  So why risk testing it and discovering that it perhaps has some minimal side effect that might discourage people from using it.  So there's a lot of this stuff out there.
	So now let me specifically highlight the ethical dilemma I'm talking about.  I've already sort of given you this.  Assume there's a study randomizing between standard care and some new treatment and that treatment might possibly be available outside of the study.  Should the subjects be told that the new treatment might be obtained off study?
	And let me make clear two assumptions here in terms of what I'm not claiming.  No where in my discussion -- all I'm talking about is informed consent, telling the subjects something.  I'm not making any claim that anybody, whether the investigator or any other doctor should be forced to provide this new treatment off study.  All I'm asking for is raising an issue is about letting the people know about what might be available.
	And, secondly, and I want to be very clear about this, the disclosure, and ideally, most importantly in the consent form would make it very clear to the prospective subject that we're not saying this stuff works.  It is a new unproven treatment, the risks may be unknown, the benefits may be unknown, all of that would be clearly laid out to the subject.  The only issue is, should they be aware that perhaps they could get this new stuff outside of the study.  So those are sort of the assumptions I'm going on.
	Now, I guess my starting claim is that failing to disclose this is actually not that uncommon.  Anybody who has been on an IRB lately would note that it's very hit or miss as to whether or not this piece of information, the availability of this new stuff outside of the study, whether or not that is going to be disclosed.  I'm not saying it's average to not disclose it, but a significantly higher percentage of the studies out there do not disclose this.
	I'm going to point out that at least some elements or some divisions of the federal government have policies that specifically encourage nondisclosure.  And I'll give you a prominent example of that and I'll also discuss the views of a lot of bright prominent people who argue against such disclosure.  So that's sort of the game plan in the next several minutes.
	To point out sort of how common this is getting to be, I guess a lot of people would say, you know something sort of has gotten above the radar screen when there's a lawsuit based upon this.  And this is an interesting case because unlike a lot of the recent lawsuits involving research ethics this is a lawsuit that actually reached an appellate court and there is an appellate decision out there. 
	The case involved Daniel Klais.  He was age 45 in 1990.  Was feeling his neck one day and noticed a lump.  Goes to his doctor, she biopsies it and they discover he has head and neck cancer.  He was told at the time that the Cleveland Clinic was doing an interesting study of how to treat this cancer.  At the time it was very, very hard to treat, very poor outcomes.
	And, in particular, the uncertainty at the time -- again, this was, you know, 1990-ish or so, was whether or not adding chemotherapy to standard care would be helpful.  And the study involved randomization, 50/50 between either standard care which at the time was radiation and surgery or the sort of the new therapy which would be adding chemotherapy to radiation and surgery.  So this was a study that basically Daniel Klais was told about.  And he ended up enrolling in the study.  And it looked like he had good results.
	He ended up getting the no chemotherapy arm, namely the standard care arm.  His tumor appeared destroyed and ironically sort of it was like five years after the treatment they said he was pretty much cured and a month later or so they discovered a metastatic tumor in his lungs, I believe.  He died pretty quickly after that, two years later.  There was really nothing to do at that point.
	It worked out in fact, and it is now generally acknowledged that chemotherapy is highly effective in this kind of cancer and the suspicion is that he would have had a very good chance of being cured had he gotten the chemotherapy.
	Now, let me add a few facts.  Again, this is a lawsuit, so it's very hard to figure out who is telling what in terms of the truth, although there is some documentary evidence here.  But the claim is that all the doctors involved, the nurses, a lot of people knew he really wanted the chemotherapy.  He was telling people.  He was going into the study because he wanted the new stuff.  He wanted the chemotherapy.
	And the claim also is that he wasn't told two pieces of information.  One that there were phase two results, tentative results looking at -- you know, beginning to look at efficacy that showed that the chemotherapy was very, very promising.  And the second thing is that he wasn't told that this treatment was available off study.  In particular it wouldn't have been hard for him at all to get it off study because right in Cleveland he could have walked down the block to another doctor.  There were oncologists who were directly offering patients the option of getting the chemotherapy together with the standard care.
	He sued.  A trial court initially threw it out claiming he had not stated a claim based on which there would be any relief.  It went to an appellate court in Ohio which reversed this and basically said he had stated a claim and sent it down for trial.  He was dead at the time, but it was pursued by the executors of his estate and subsequently this case was privately settled.  But, nonetheless, there is an opinion out there saying that this raises legitimate legal issues.
	Okay.  Let me get to the point I raised about possible federal involvement in terms of encouraging nondisclosure.  And what I want to say is a little bit about what many people would consider a gold standard for writing consent forms, namely the consent form process that the National Cancer Institute put together.  It created a comprehensive working group on informed consent and cancer clinical trials, an extensive process a lot of scholars in this field worked on this, two years of study, they had lots of focus groups with patients and it produced a great improvement in how to write consent forms.
	It's a wonderful thing if you're not involved in this area to just look at the consent forms they've come up with; lots of white space, lots of sort of headings which are wonderful questions, lots of nice tables, so they're a very good improvement.  And I'm not trying to sort of criticize them greatly, but I just want to raise one issue in terms of the things they talk about.
	They have some degree of instructions about how you write the alternative section of a consent form which is the basic part of the consent form where we tell people what else can you do instead of being in the study and it mentions, you should tell the person about the option of no anti-cancer treatment or treatment with standard therapy.  At that point they don't specifically make a reference to disclosing experimental or nonstandard therapies.  They might say, well, maybe they just didn't think of it there.  On the other hand they actually have a template for how to write a consent form.  They give you the actual language they suggest you put in the consent form.  This is very, very commonly followed in cancer informed consent forms these days.  And what they say is, "you may get blank even if you do not take part in the study" and they point out in describing what you should put in the blank, noninvestigational treatments should be used to fill in the blank. 
	So, again, a further suggestion that they are kind of thinking that you should only be mentioning in this alternative section, standard care, proven sort of stuff.  I mean, you might think this too is vague that, again, maybe they really weren't addressing the issue.  So let me give you a high visibility example.
	There's a think called the STAR study.  It is a very well-known study, and it involves a lot of women and it's sort of a sexy study because it's dealing with sort of the newest thing out there, namely using drugs to prevent somebody from getting cancer.  The name comes from the two drugs involved, Tamoxifen and Raloxifene and the question is whether or not Raloxifene can prevent breast cancer from developing in women who are at high risk for developing it, can it prevent that as well as Tamoxifen can.  It's a five-year randomized double-blind study; 22,000 women are being enrolled in this study.  They will get either Tamoxifen or Raloxifene. 
	Now, Tamoxifen is a very interesting drug.  It's the first drug proven to prevent a cancer and it is, in fact, FDA approved as a preventative for breast cancer.
	Raloxifene is a little interesting in that it is on the market.  It is FDA approved for treating osteoporosis.  It is not, however, proven, or at least not FDA approved to prevent breast cancer.  They are both from the same class of drugs.  They are a class of drugs called SERMs and there was reason to think they might have similar behaviors.  So once people saw that Tamoxifen worked as a breast cancer preventative, you know, people thought of looking at Raloxifene.
	Now, let me tell you more about a study called MORE because there is actually some evidence out there about Raloxifene and preventing breast cancer.  This was a large study.  It was a randomized study and the main thing it was studying was whether or not you could use Raloxifene to prevent osteoporosis.  And it clearly did prove that, and, again, the FDA approved this Raloxifene for treating osteoporosis.
	But there was a secondary goal in the study to prevent breast cancer.  The results were published in JAMA in 1999 and if you look at the statistics here, basically women on Raloxifene had a quarter of the chance of developing breast cancer as the women who were on placebo in this study.  Highly statistically significant, a p value of .001, and basically that's what the authors of the study said.  Particular group among postmenopausal women with osteoporosis the risk of invasive breast cancer decreased by 76 percent.
	This was accompanied by an editorial in JAMA which was actually co-authored by a CDC official describing this as a large well-designed trial showing that Raloxifene significantly reduced the risk for estrogen receptor positive breast cancer among postmenopausal women with osteoporosis.
	There's a lot of qualifications in here, but just understand this is, you know, pretty strong stuff, you know, good results here.
	Let's be very clear, the study did not resolve everything.  It certainly wasn't clear with Raloxifene will be useful in women without osteoporosis or women who are premenopausal.  It still remains the case that the FDA wanted more information about how well Raloxifene works in preventing breast cancer.  It still hasn't approved it for that indication.
	Again, this was a secondary indication in the study because it wasn't being given to women who are primarily at high risk for breast cancer, it was given to women who had osteoporosis.  But nonetheless, there's a lot of evidence that this Raloxifene might be pretty good in terms of preventing breast cancer.
	So now let's go back to our STAR study.  Randomizing people between Raloxifene and Tamoxifen, and it has a consent form.  And here is what the consent form says in the alternative section telling you as a high-risk woman what your choices are.  It says, "instead of being in the study you could ask your doctor to prescribe Tamoxifen for you.  You could request surgery to remove both breasts."  Remember, there are women who do not now have breast cancer.  Nonetheless, they are being advised they can get, you know, bilateral mastectomies.  Again, a proven therapy.  There is proof of that.  It does not mention the unproven therapy, namely possibly asking your doctor to give you Raloxifene.
	Now, let me make a final point here which actually I don't think is all that relevant, but nonetheless, it's a nice point to point out.  There is, in fact, a lawsuit between the manufacturers of Tamoxifen or Raloxifene getting back to that earlier issue I mentioned about how the FDA regulates the pharmaceutical manufacturer's ability to promote a drug and the claims that Lilly, who makes Raloxifene, was inappropriately promoting it for anti-breast cancer treatment.
	And one of the statistics that comes out of this is that a lot of physicians out there are in fact prescribing Raloxifene to women for the primary purpose of preventing breast cancer.  So the bottom line is, it wouldn't be hard at all for a woman to go to a doctor and basically get that doctor to prescribe Raloxifene for preventing breast cancer.
	So let me start giving you some analysis here.  Is it or is it not correct to disclose this off-study availability and let's look at the Nuremberg Code, for example.  It says we should give a patient the information needed to make an understanding and enlightened decision about participating.  Let's look at the federal regulations.  It indicates that you should disclose appropriate alternative procedures that might be advantageous to the subject. 
	One thing I will note in both of those, neither of them says anything about proven treatments.  They talk about the subject being able to know things that they might find advantageous to themselves.
	Let me now go to the arguments against disclosure because a lot of people really don't think this sort of thing should be disclosed.  I think the heart of it is sort of the first line here.  That basically it would be too risky for any doctor to offer this stuff to a patient as a clinical treatment outside of the research setting.  And here you have a quote from a doctor involved in leading the STAR study.
	And to just lay out the arguments in two steps, basically it would be wrong for a doctor to give this to a patient in the clinical setting.  And since it would be wrong for that doctor to do that, then obviously it would be wrong to disclose that possibility in the consent form because you wouldn't want to send a person to some doctor who is going to do something wrong to them.  So that's sort of the argument here.
	This is an argument from another study.  I don't know if we'll get into the discussion.  OHRP has actually raised this issue in one scenario in a study involving estrogen for treating Alzheimer's Disease.  We can discuss that later if people want.
	Another set of arguments about the STAR study and I think this nicely lays out the arguments against disclosure.  Before it is ethical to conduct a study there must be preliminary data, but the level of evidence may not rise to that which supports clinical decision-making.  There is reason to believe from smaller trials that Raloxifene may be beneficial, but we do not know for sure.  Clearly true.
	The fact that a physician can prescribe the drug does not make it an acceptable alternative therapy.  And I want to now spend a bit of time discussing those arguments and sort of raising some issues about them.
	Are there reasons to think that it is sometimes and perhaps often acceptable for a patient to be offered the experimental arm therapy outside of the study?  Not a standard of care, but being told, look, this is an experimental thing, but sometimes we allow doctors in clinical care to sort of give patients who may want it experimental things.  And, in particular, let's just look at it from the point of view from a nonaltruistic patient out there.  And let's look at it in terms of the risks and benefits to that person. 
	And this is a person who is considering enrolling in a study and we should have randomized between standard care and this experimental stuff.
	From the risks viewpoint, in many studies often the risks to the subject from sort of getting into the study or let's say getting the new stuff outside of the study may be pretty much identical.  It depends on what's involved in the study.  But often the study involves sort of giving you some sort of drug in doing pretty standard tests that any doctor can do.
	Now, let's look at a tricky side to benefits.  Let's note to begin with that assuming we're dealing with studies with a significant level of risk, presumably the experimental arm should already be in clinical equipoise with standard care, else the study is unethical.  What does this mean?  That there is an honest disagreement about the comparative merits of the treatments within the expert community.  This is sort of the gold standard of protecting the subject.  We should have clinical equipoise.  I think there's a good argument based on that, that it's certainly not that unreasonable for a doctor outside of that study to be using the experimental therapy for a given purpose.  Because we already know it's sort of, gee, in the ballpark of the standard care.
	And, in addition, there are special benefits for getting the new stuff off-study.  Here's the New York Times said something which a lot of people pretty much take as a given:  "Few people sign on to studies out of pure altruism.  They want the experimental drugs a study provides, often regarding them as treatment, even when their safety and effectiveness have not yet been proven."  And that's a perfectly legitimate thing for a patient to want.  So from a benefits viewpoint for a nonaltruist subject, nonaltruistic subject who is interested in access to the experimental therapy, a 50 percent chance of getting it in the study may be from their viewpoint far less desirable than a 100 percent chance of getting this new stuff outside of the study.
	Putting it all together, the risks of the subject may be the same whether they're getting the stuff in the study or out of the study.  The benefits may be much greater out of the study because they're getting the stuff they want.  Thus, it seems very reasonable to the subject -- for the subject to offer out-of-study access and it would seem that there are good arguments for disclosure being ethically mandated.
	Now, let me put some limitations on this.  I'm not saying this is true in every study.  In many studies there may be special higher risks to getting the stuff outside of the study.  Maybe it's a surgical procedure that only the doctor running the study knows how to do because he invented it and has been doing it on rabbits or something and he knows how to do it on people. 
	Maybe there is some specialized kind of testing, some imaging or something that can only be done at specialized studies that will pick up dangerous to the subject earlier than the average doctor could do.  But I'm claiming in a lot of studies that's not the case and therefore the burden should be to demonstrate this special higher out-of-study risk instead of routinely assuming the appropriateness of nondisclosure.
	And let me sort of raise an extra dilemma for those who don't want to disclose.  I think it's sort of a tricky dilemma here.  We are called with the notion of clinical equipoise, the notion of there being honest disagreement about the comparative merit of the two treatments, the two arms within the expert community.  The point of clinical equipoise is to assure us that a subject is not being inappropriately harmed by being denied standard care.  And the question I would raise, and I think it's a tricky question is, can there be clinical equipoise, yet could we also at the same time conclude it would be so wrong for some doctor with a patient asking for this new stuff, would it be so wrong for that doctor to give that to that patient outside of the study.
	I'm not sure there's a clear end to that.  My suspicion is that's a difficult position to maintain.  But, let's accept that.  Let's accept that in a particular scenario, particular study, we've made the conclusion that, yes, this stuff is so risky that it would be wrong for a doctor to give it to a patient on an experimental basis outside of the study.
	Okay.  Let me just follow that through with a few arguments here.  If the doctor in the clinical setting couldn't give this to a patient even if the patient was desperately asking for it, then presumably a doctor also couldn't flip a coin and give that to the patient half of the time.  Clearly that would still be bad for the patient because half of the time you're exposing him to this too risky stuff.
	Well, now let's compare it to what happens to the identical study.  From the viewpoint of a nonaltruistic subject, the same thing would be happening to them in the study as what would happen to them if they directly got this from a doctor.  If we've just made a conclusion that it would have been bad for a doctor to give this to them in terms of the best interests of that patient, then presumably what's happening in that study has to be bad in terms of the best interests of that patient.
	So I would think ideally, if you really believe that no doctor out there should be permitted to give this stuff to a patient, this is what the consent form should say.  Something like this, pointing out this is a nonbeneficial study:  the experimental arm is so risky, we would never let a doctor give it to you outside of the study.  The only reason we're allowing you to be exposed to it is to help determine the right treatment for future patients.
	Finally, if you want to do what is best to treat your medical condition, you should not be enrolling in this study.  I mean, I think that basically follows if you're telling people that, hey, we're not disclosing this to you because no doctor should ever be giving this to you.
	Thus, there are two possibilities here.  Either what I just said sort of follows that, yes, this stuff is so horrible that no doctor could sort of be giving it outside of the study in which case this is a nonbeneficial study and the consent form should say all that which, by the way, any of you who ever reads consent forms, thousands of studies out there routinely comparing standard care to some new experimental stuff, no such consent form ever says that.  Doctors will routinely be telling a patient, this is a great deal.  You have a 50 percent chance of standard care or 50 percent chance of this new, may be wonderful stuff.
	So the one option is you'd have to say all this horrible stuff in the consent form or reach the other conclusion, namely, look, we all know that it would have been perfectly reasonable for a doctor to give this stuff off study and therefore it's perfectly reasonable also to disclose that option because it's a reasonable option for the subject to pick.
	And a side point here because OHRP raised this, in terms of this argument, I don't think it matters a lot whether or not doctors currently are giving this stuff frequently outside of the study to anybody.  At the least, the patient should have the right to ask the researcher, well, would you give me this stuff outside of this study?  Or are you just looking out for answering the research question as opposed to doing what might be best for me.
	And let me just go make this a little concrete.  Let's go back to the STAR study.  Hypothetical woman Judy invited into it.  She has osteoporosis.  A known benefit to her of being Raloxifene is she had concerns about endometrial cancer which Tamoxifen is known to increase the risk of, and seems to me Raloxifene may not.  The STAR study testing, the measuring for risks imposed on a subject can be identically duplicated by any doctor out there.  It involves routine breast exams and standard blood tests.
	There is already strong evidence that Raloxifene may be good in terms of breast cancer prevention in Judy's case because she has osteoporosis.  So the question is, why isn't it highly reasonable for her to choose Raloxifene instead of enrolling in the study which would only give her a 50 percent chance of getting it.
	Summing all of this up, I think protecting the patient is not a very legitimate reason for nondisclosure of off-study availability.  Protecting the viability of research is, of course, a valid goal.  Let's get back to what happened to the high-dose chemotherapy trials, but this can be done in an ethical manner.
	If we want to assure sufficient subjects enroll in clinical trials, perhaps what we might want to do, and this gets very controversial, maybe we shouldn't be allowing off-study provision of these treatments.  Maybe we should change the law.  If we did that, basically we would get lots of subjects in these trials, the same way we would get people into trials where we're testing a new drug that is not FDA approved. 
	If you're dying of cancer and this is the hot new drug and the only way to get it is a 50 percent chance of it in the trial, you'll be happy to get that versus a zero percent chance of it.
	But, I guess I would claim absence a change in the laws, subjects deserve to know their reasonable options and failing to tell them about this in the consent form is unjust.  Savvy patients like the women who sued, and there are lots of lawsuits about this, to get the HDC-ABMT, they already know that they could go down the street and get the new hot arm directly from their doctors.
	And I think this is sort of cute quote to close with.  This is what one recruiter noted in the STAR study, she was having difficulty getting patients to enroll.  The sense in the community was, well, I could just take Raloxifene.  Why do I have to be in a trial?  Well, who are you enrolling?  All the people who didn't know better, basically the vulnerable subjects who consent forms you design to protect.  That's all.
	[Applause.] 
	CHAIRPERSON MARSHALL:  Very nice, Jerry, thank you.
	We harken back to logic 101, I think.  We have a challenge on the able and we've got wonderful people, I see David Lepay is out there.  There are some folks -- several folks here from OHRP, so, I look forward to an interesting discussion.  Hands are up.  I have Jonathan, Abbey, Susan.  And let's just mix things up.  Please come to the -- those of you ex officios or public members, feel free to come right on up to the microphone.
	Jonathan.
	DR. MORENO:  Jerry, I really enjoyed that.  I was an early consultant on the Klais case and in a much less "coate" fashion, if that's a word, I had many of the same thoughts that you have so -- in such a sophisticated way -- elaborated in the last few minutes.  But I want to offer -- I have lots of things I want to talk to you about, but I want to just put a few things on the table.
	I have a question that we can talk about with respect to how much that phase two study at the Cleveland Clinic that was going on that he wasn't told about, how clear it was that the experimental arm turned out to be effective.  My interpretation of the documents I saw didn't make it all that clear, but that's not so important.
	I do want to challenge you on the appropriateness of the Nuremberg Code evolution.  I don't think that Nuremberg Code applied to therapeutic maneuvers.  So I'm not sure that that half of that slide advances your case, but, again, that's something that we can discuss as an historic question.
	If we agree that disclosure is required, and this is something that I thought about again in the context of the Klais case, must a physician -- what must a physician do in light of that.  If the physician says -- and the way you've said it -- the right way -- look, I've got to tell you, there's some stuff out there that you might be randomized to in this study, but you could probably get it somewhere else.  Does he or she, you know, have to go down the hall and find a colleague who would then offer that to that person, or does he or she have to go on the internet and find somebody who would do it?  What's the obligation of physician at that point to find the -- once we agree that somehow whatever is found has to be reasonable, how much work does the investigator have to do once the subject said, no, I really want to get it, to go and find somebody who would deliver it. 
	Again, I have many things I would like to say to you, but the last comment is only that I'm not -- my intuitions don't go the same as far as yours do.  I'm not persuaded yet that we've got a logical problem.  It seems to me that clinical equipoise does not necessarily imply the acceptability of treatment outside of trial.  That there is something that I need to articulate that I can't right now, perhaps, about the context of a trial that changes the moral texture of offering this experimental therapy or experimental intervention, I should say.
	And, moreover, there are things that can happen in the trial like a data safety monitoring board, a crossover design, and so forth that could change the moral equilibrium of that situation that would not apply to obtaining the intervention outside the trial.  But I look forward to your comments.
	DR. MENIKOFF:  And, in fact, I agree with a lot of what you were saying.  I don't, in terms of the phase two element of the Klais study.  I don't know exactly what it says, but it's to a large extent not all that relevant.  The big issue is he clearly wanted the chemotherapy and was not told that he could get it.
	On your final point about whether or not clinical equipoise means that in fact, you know, it would be okay to provide it outside the study.  Again, I don't really know.  All I'm saying is, once you make the argument that it would be wrong to provide it outside the study, I think we then have problems with lots of consent forms out there because we're not really revealing to subjects what the researchers must of necessity think about randomizing them to this new treatment.
	Your major point about what the obligation is on the part of a researcher to provide the therapy or indicate that somebody else could provide it outside of the study, I actually don't think they have any obligation to do that, and I speak there more as a lawyer, which in a sense, I basically think the heart of our obligations under current society is basically that doctors are in fact required to provide standard care and they don't have to provide stuff beyond that.
	You get into very tricky issues of to what extent do doctors have an obligation to -- for example, find, and dig up all the research studies out there every time there's not a good treatment for something and make sure that the subject knows about all those research studies.
	DR. MORENO:  But can I push on that as a lawyer for just a minute?
	DR. MENIKOFF:  Sure.
	DR. MORENO:  Once the doctor has said, look, okay, I understand you really want to get this stuff and therefore I have to tell you that there are ways of getting it, hasn't the doctor then moved out of the investigator role into the therapist role?
	DR. MENIKOFF:  Yes. 
	DR. MORENO:  And then don't considerations like what counts as a abandonment apply?
	DR. MENIKOFF:  I don't think you're going to have any legal problem at all so long as you're basically offering the person standard care.  The fact that the person wants outside of the study one of the arms of the study, an arm that basically -- that maybe the case of no doctors is currently providing.  Abandonment is -- people talk about abandonment all the time.  It is extraordinarily hard from a legal matter to abandon a patient.  You basically -- to get around abandonment problems, all you have to do is basically tell the patient, look, this isn't working out, I don't want you as a patient.  As long as it's a non-emergency, give the patient an opportunity to find a doctor in the appropriate amount of time. 
	You in that setting as a clinical provider do not, in fact, even have to find another doctor.  As long as it's not an emergency.
	DR. MORENO:  Let's take the moral context then, if I can just have 30 seconds more of Jerry's time.
	DR. MENIKOFF:  Right. 
	DR. MORENO:  I've just said to you, the stuff is out there, I've read articles about it, I know other people are using it, it's not nuts, but you can't be guaranteed it in my study, see you later. 
	DR. MENIKOFF:  Then you see, the researcher has a bigger dilemma which I'm sort of hinting at here, namely, you effectively -- if you want to be honest with your subject, you're telling him, look, you know, I acknowledge that it's a reasonable choice for you to directly want to get this stuff, but I as a researcher want people in my study because that's the only way we're going to answer this question to provide an answer for everybody else.
	I think that actually does put the researcher in a tricky moral dilemma.  And I prefer from a legal viewpoint for society to answer this by not allowing that option.  Because then we're treating everybody fairly, namely, that's why we get answers to the studies which involve a non-FDA approved drug. 
	DR. MORENO:  Right. 
	DR. MENIKOFF:  Because it's a good thing it's a no-brainer, both the subject wins and society wins, and that's a reasonable tradeoff.
	DR. MORENO:  And even though I know the guys from whom you could get this stuff, I don't have a moral obligation to tell you who they are; is that right? 
	DR. MENIKOFF:  I would find that trickier.  I mean, if you know who they are and the patient is asking you that, I would think you would have to -- I mean, that's close to -- I mean, that's basically fraudulent at that point.  Well, you know, I guess -- I know who they are, but I don't want to tell you.  I would think ethically that's very hard to say, "I don't want to tell you who they are." 
	DR. MORENO:  I'm not going to make the call for you either. 
	CHAIRPERSON MARSHALL:  I want to recognize Allison back there, but first I just want to see if on point I've caught Alan's or Mark's eye over here.  Did you guys -- anything that you wanted to say on point?
	DR. FLEISCHMAN:  Well, I just wanted to argue having done a substantial number of clinical trials that there are trialists who believe it is unethical to advocate the intervention arm prior to knowing what the level of risk is of that intervention arm.  Whether or not it's an acceptable treatment that might be effective, the idea about the clinical trial is to compare efficacy and toxicity.  So one of your slides which argued that there was no greater risk being outside the clinical trial is wrong.  If you've been randomized into the nonintervention arm, and the study ends up with similar efficacy, but greater risk in the intervention arm, you will have greater risk outside the study.
	Inside the study you have only a 50 percent chance of getting that risk.  And many trialists really believe that they would not wish to entertain off-trial treatment because they believe that randomized clinical trials are absolutely mandatory to determine future levels of risk and future efficacy.  That doesn't mean that they wouldn't say you can get it.
	And I always thought, to tell you the truth, I was looking at Susan when you started, I thought the regulations require you to say in the consent form, now you tell me they don't and I just read them and they're kind of very ambiguous about it, as you've described.  But in my sitting on IRBs, I always thought we were obligated to say, you know, you may be able to get these research drugs outside of trial, zeit gezunt, as my mother would have said. 
	DR. MENIKOFF:  On your first -- well, I guess on your second point, in terms of the need for society to get answers to these questions, I fully agree with you.  Again, I think the studies should take place, the question is, how do you do it in an ethical manner?  Now, in terms of your getting a 50 percent chance of getting it in the study versus 100 percent chance of getting it outside of the study, my only claim is that in both scenarios it either is or is not against your best interest.  If going away from standard care to getting this new stuff is bad for you, yes, a 50 percent chance of getting this bad stuff is less bad for you because you still have a 50 percent chance of getting the standard of care.  But nonetheless, in terms of properly disclosing the consent form, that has to be for nonaltruistic subject of bad choice.  A 50 percent chance of you having some bad thing happen to you is still a bad thing.
	And the only thing I'm questioning is, why don't these consent forms, there are thousands of studies out there, identically say, by the way, this is not in your best interest.  Because 50 percent of the time we're going to expose you to something that we would never let a doctor give you outside of the study. So I disagree with you on that point.  Yes, it may be a little less bad, but it clearly is bad for the subject and why doesn't a consent form say that as opposed to deceiving the subject into thinking, gee, it's a perfectly reasonable choice from your viewpoint as a nonaltruistic person to accept a half-the-time choice of standard care and a half-the-time choice of this sort of new experimental stuff.
	And finally, on the risk issue, in many of these studies, in fact, we already know the risks.  I don't think anybody expected some new huge risk to come up, for example, in like the Raloxifene study.  This is a drug that's on the market.  Yes, it is theoretically possible that some new risk will show up in this subgroup of women, but nonetheless millions of women have already gotten this stuff and actually we're pretty confident we already know the risk profile of Raloxifene.
	CHAIRPERSON MARSHALL:  Zeit gezunt on point.
	MS. KORNETSKY:  Yes, I really take exception to some of the statements you're saying and I would like to ask your evidence of you've referred to thousands of informed consents, hundreds of IRBs who are not putting this in, what is your basis for that?  Because I've sat on several IRBs and this thing -- these types of things, as Alan said, are always very typically discussed and we struggle with, you know, how to present it in a manner so it's not overwhelming to an individual, but to give them their options.  So I would really like to challenge you on that.
	DR. MENIKOFF:  Sure.  And, again, I can't come up with a percentage of cases in which this is occurring.  I do know that -- and I've spoken to a number of forums about this, that I get interesting responses from people including responses from a variety of people who challenge me on this.  And I have noticed in terms of, if this is such a no-brainer, why have I had such difficulty in terms of sort of from reviewers who basically said, well, we disagree with you.  A lot of bright people have disagreed with me in terms of that. 
	I've heard from Price Waterhouse Coopers in terms of their things, and, again, from people on other IRBs.  And the fact remains that there are plenty of consent forms out there that do this.
	And I can give you the one extent, the kind of responses you're seeing sometimes are what I think are sort of non-responses, namely, in a lot of studies you'll see this sentence buried in the alternative section that some or all of the treatments in this study may be available outside of the study.  A sort of boilerplate statement that sort of gets around the issue without highlighting to a person, by the way, subject, if you're interested in being in this study to get the hot new stuff, then instead of a 50 percent chance of it in this study, you can get 100 percent chance of it outside of this study.
	So, yeah, I do not have absolute statistics.  I know in the STAR study, you know, I'm on an IRB and I have not seen any documentation from the STAR people recently that they've altered their consent thing.  The consent form provisions I gave you were approved by the FDA and the National Cancer Institute.  So there are at least 22,000 women out there that are not being told this amount of information. 
	CHAIRPERSON MARSHALL:  Okay.  I want to move on.  Allison, you were at the -- you sat down.  No.  
	Okay.  I'm going to ask -- 
	DR. LEPAY:  I just want an answer to that, because indeed -- 
	CHAIRPERSON MARSHALL:  -- have the floor. 
	[Simultaneous conversation.] 
	DR. LEPAY:   -- approved consent form.  There is no such thing as an FDA-approved consent form.  FDA doesn't approve consent forms.  In fact, the regulations don't even require the submission of consent forms for FDA to FDA as part of the review package.  So, that to me is kind of a non-issue.  FDA has not approved this consent form.  I'm not even sure the extent to -- 
	DR. MENIKOFF:  Okay.  But just in terms of all I'm saying is FDA saw this thing.  It has been described as FDA and NCI approved in the sort of documentation that the people who run the studies say and all I'm saying is to the response that people will say, gee, this is a no-brainer, everybody's disclosing this stuff.  All I'm saying is here is a very high visibility study that did not disclose it and nobody seemed to care.  I mean, it's out there.  If everybody is saying, well, of course, this is not happening, gee, is it that every IRB out there has to be picking this up.  Why aren't we basically saying what a lot of people seem to think is a clear thing, namely, hey, you should always be disclosing the off study availability of the new therapy.
	I'm disagreeing with you here basically.  The bottom line 
	DR. LEPAY:  Well, I think some of this needs to be a discussion of how you're discussing it and what you're including.  Obviously in talking about any unapproved use of even an approved product, one has to have a very balanced approach to how much information you're going to provide about the nature of the product the nature of the risks associated, the fact that it is not FDA-approved for that particular use and indication.  I can think of certainly a very high profile case where something very different happened, one of our most high profile in the past couple of years where in fact the informed consent read that in fact the product that was being provided to the subjects was an FDA-approved product.  And the product was not FDA-approved nor was the product approved for that indication or that form of administration.  But oftentimes the concept of what's included in the informed consent under the rubric of "FDA-approved" is a misconveyance of risk as well.  So I think you have to look at it from that standpoint too.  
	DR. MENIKOFF:  And I apologize -- 
	DR. LEPAY:  And it's really the nature of the information that -- 
	DR. MENIKOFF:  Right.  I apologize to the extent I'm suggesting there was a more formal FDA approval of this.  Although ultimately my major point is that, look, the facts speak for themselves in terms of what is happening out there.  If this is a legitimate issue why isn't everybody getting together and clarifying, yes, this is a problem.  Every consent form, not just when it reaches the IRB, but before it reaches the IRB and certainly if it goes through the NCI and the FDA, somebody should notice this and require disclosure. 
	DR. LEPAY:  Well, I think this is an issue that certainly needs to be taken up, but I think it's a very appropriate one for this kind of forum to actually look at.  And that is, you know, the nature of the kind of information that should go into informed consent and the process by which informed consent is implemented or is achieved.  We largely view, in fact, the informed consent and the way that informed consent is put together as a process that is appropriate under the regulations for the IRB to be taking up.  It is not something that FDA has generally wanted to prescribe.  We are now talking internally about how it may be appropriate for FDA to take a closer look at the risk information that is contained within the informed consent. 
	But, again, at the moment, the way the regulations are written, there is no requirement for the informed consent document for drugs and biological studies to be submitted to FDA.  So that is not even part of the review process often times and it is something that we generally relegate or generally consider to be the function of the IRB to take on.
	You know, again, I don't know that FDA has, either one way or the other, come out with any specific statements about how or in what manner information about unapproved uses can most appropriately be conveyed for approved products in an informed consent.  And that might be a useful bit of information or guidance to be able to develop in concert with a group such as this one.  But, again, I don't really see this as an issue at this point in time that FDA will take on from the standpoint of saying, we approve that particular informed consent or we approve the way the IRB is actually making its decisions about what should or should not go into the informed consent because we think that's integral to the IRB process.
	CHAIRPERSON MARSHALL:  Thank you, David.  So glad that you're here.  And right after lunch we're going to move directly into the informed consent discussion. 
	I'm going to give the last question to Allison and then we are going to break for lunch and we will resume back here at 1:30.
	MS. WICKMAN:  Alice Wickman from the Office of Human Subject Research at the NIH.  Interesting talk and I think Jonathan and I may like to be in the room when you two discuss this issue.  Because I think the examples you give of clinical trials in which this disclosure would be appropriate are ones in which you have a lot of information.
	And what I'm wondering is if you weren't as sure, if there was much less data, you were doing a clinical trial where you really didn't know the prospect of direct benefit, your argument becomes very tenuous.  Because it is not just risk that people are worried about, it is also, generally doctors don't want to give treatments that do not work.  If they do, then within the practice of medicine we have a lot of work to do.  And it seems to me that this topic if looking in the broad term, it is informing people about their choices for non-validated treatment.  Because often within a clinical trial at a certain level, this will, outside the context of research it would be an invalidated treatment.
	And then one's obligation for putting in the consent document which I think if that would solve your problem to say, you know, you may be able to get this stuff outside the research context, your problem is easily solved.  That can be done.  But then your responsibility doesn't stop with just this compound that's invalidated, but every other one.  I guess there's no difference between invalidated treatment and Laetrile or acupuncture, or anything else that might be available within the environment or within the healthcare treatment area.
	And then just one other thing, I do think -- and I mentioned this point earlier that physicians that routinely consistently give non-validated treatments, I would ask, are these people doing research, or are they just giving invalidated treatment, which generally is a problem within the practice of medicine.
	Doctors ought not be giving treatments that haven't been proven or shown to be a benefit on a consistent basis.  So they have a huge stake in wanting this question answered. 
	DR. MENIKOFF:  So you have a lot of things on the table.  The last point I really can't say a lot about, other than I think there are legitimate issues to be bated there in terms of what doctors and cannot do in terms of providing invalidated treatments. 
	In terms of your earlier point -- what was your earlier point?  Oh, you were talking about, for example, a very risky compound, for example, right?  Or that might not be beneficial.  It's so unclear whether or not it works.  Again, I think that would be dealt with in terms of the consent form disclosure that I indicated.  That may be one of the scenarios in which you're pretty sure that this is very, very risky in terms of not knowing the benefit side of it, therefore, let's put in the consent form and honest disclosure that those of you who are randomized to this new stuff are really going out on a limb so far that we wouldn't let you get that outside of the study because this really is not a beneficial study.  You are basically doing this out of pure altruism.  You are basically getting something that is so quasi-unlikely to benefit you that it sort of -- you have to understand how altruistic your decision is to participate in this study.  It's disclosure, but it's a question of appropriately disclosing that.
	CHAIRPERSON MARSHALL:  Thank you, Jerry.  We are all awake now. 
	[Laughter.] 
	CHAIRPERSON MARSHALL:  And Jerry is going to be here throughout today and also tomorrow.  So, grab him at lunch or during the breaks and continue the conversation. 
	Thank you very much. 
	[Whereupon, at 12:25 p.m., the conference was recessed to be reconvened 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:  1:25 p.m.]
	CHAIRPERSON MARSHALL:  All right.  Thank all of you all for coming back from lunch.  It's good to see you.
	We are going to continue.  And I want to point out that the cover of our notebook, those of you -- the briefing book, those of you who are out facing this direction may not have seen it, but there's people working diligently, pulling themselves up a very steep hill with a rope.  And this is sort of to remind all of us that we are here to work and have work products.
	So we've had an interesting morning.  Some of it has been entertaining or controversial and enlightening, I hope.  And now it's time to roll our sleeves up and get down to work.
	A couple of things that I was remiss in not doing this morning, but we were a little flustered by not having our recorder here and trying to deal with housekeeping details.  One is to give you Dr. Greg Koski's regrets for not being at the meeting.  He is in Thailand, working hard, I believe, perhaps on issues of international research.  I'm not sure what the theme of the meeting is.  International research.  So, he's working hard and we hope that he'll bring us back some wonderful cuisine for our next meeting, something like that.
	And Dr. Slater, her schedule at the last minute did not allow her to be with us.  But I think, as I said earlier today, we had a wonderful hour long meeting last Friday.  She has lived in the clinical world both in her academic life and in her life -- her corporate life and is very much interested in the issue of human subjects protections and sees our work as being very important and she was very supportive of it.  So we look forward to hearing from her in the future and she sent her regrets as well.
	So I wanted to take care of just those two announcements so you didn't wonder perhaps why neither one of them was here.  We are going to finish up our work on decisional and capacity before we move into informed consent and research with prisoners.
	So Jonathan has agreed to guide us through our draft document for another 20 minutes or so of discussion.  Thank you so much, Jonathan.
	DR. MORENO:  Sure.  So I've collected the comments we have so far up through recommendation 2 and previously.  What I am going to do now, unless I hear other comments coming forward on recommendation 2 is move to recommendation 3 and collect comments.
	And I am incorporating, of course, Bob Levine's suggestion with respect to the new language in line 1 of recommendation 3:
	"We also conclude that research that includes interventions or procedures and present a minor increase over minimal risk, that does not include interventions or procedures that present the prospect of direct benefit to the subjects but is likely to yield generalizable knowledge about the subject's condition or disorder may be conducted of funded if:
		a.  The intervention or procedure presents experiences to subjects that are reasonably commensurate with those inherent in their actual or expected medical, dental, psychological, social, or educational situations; and
		b.  The intervention or procedure is likely to yield generalizable knowledge about the subject's disorder or condition which is important for the understanding or amelioration of the subject's disorder or condition; and
		c.  A legally authorized representative has given permission."
	And one footnote I want to point out, we did have Bob Dinerstein who was associated with the mental -- MRDD group that Dr. Harris described this morning who helped us with the footnote with respect to the problem of the use of the word "condition" or "disorder" which is recognized in footnote 4.
	Bob.
	DR. R. LEVINE:  Thank you.  As you pointed out, I've already had my say about number 3.  I learned this morning though that we're allowed to go back to the front page.  And I want to comment on recommendation number one from NBAC.  And that's the recommendation that says, if IRBs review something regularly, they ought to have at least two members who represent that population, one of which would be a member or a family member of that population.  That's all well and good for some sorts of highly specialized institutions.  But for a general university hospital that means an IRB that could be unmanageably large.
	And what I would ask for -- and I asked for this in some other arenas -- is that it be handled the way the prisoner requirement is handled, that you could have ad hoc members that come up when particular classes and protocols are considered or you could -- the way the CIOMs international guidelines put it is that you ought to have members or consultants.  But you don't want this -- you don't want 100 and some odd members of a committee.
	I forget whose work it was that showed that the peak efficiency of a decision-making group is at 13.  I can find out who it was, if you like. 
	CHAIRPERSON MARSHALL:  I hope they had IRB approval for that study, Dr. Levine.
	DR. R. LEVINE:  That was the study that was done by a political scientist and it was before they had IRBs. 
	[Laughter.] 
	DR. MORENO:  Alan.
	DR. FLEISCHMAN:  I did want to comment on that footnote four because I don't understand it.  There is a sentence there, "Thus, for example, persons with mental retardation may not be covered by the term disorder."  But at least in the materials that we'll read for tomorrow from the children's workgroup without question persons with mental retardation would have a condition.
	So I am not sure what work this footnote is doing here that's helpful, and it is confusing.  I mean, I don't want to stigmatize people who have mental retardation and assume they all have the same diagnosis.  But they have a functional problem and they, at least in my thinking, they clearly have a condition. 
	DR. MORENO:  I'll just say that this and others who are on the workgroup can perhaps help me with this.  This modification was made at the suggestion of Bob Dinerstein.  So we took the counsel who knows something about MRDD, Alan, that's where that came form. 
	DR. FLEISCHMAN:  But, Jonathan, that sentence doesn't stand alone.  I mean, that's my problem.  "Thus, for example, may not" but it is covered by the term "condition"; I mean, what is the committee's belief about where mental retardation fits in the kind of language that we've learned to use about disorder or condition in which we put those two words together, now we're separating them. 
	DR. MORENO:  Some members of the workgroup, one, were not comfortable with the use of the term "condition."  But, it was noted that if we eliminated the term "condition" then we would lose a group of people like people with MRDD, therefore, that sentence was added. 
	DR. FLEISCHMAN:  But that sentence doesn't do that work.  
	DR. MORENO:  Well, we'll go back to the sentence then.  Bob.
	DR. RICH:  I first want to strongly endorse Bob Levine's comment about the -- I presume that will -- 
	DR. MORENO:  Yes.  It's duly noted. 
	DR. RICH:  And the second comment I have is after Dr. Harris's presentation, I'm not sure where we stand on NBAC recommendation number three.  Because I don't think we came to closure on whether or not we endorsed this idea that targeting persons with mental retardation -- when such research can be done with other subjects.  I mean, the whole question of, are they entitled to be included as a matter of course. 
	DR. MORENO:  I heard him say that if other populations could be used, other individuals could be used, could it not have this kind of cognitive limitation.  Then they should be -- 
	DR. RICH:  But if they're simply a part of a cohort that has another disease, and that other disease is being studied, they happen to have MRDD plus hypertension, and you're studying hypertension, should you exclude them because you could exclude them?  You could do the study without people with that, or should they be entitled to participate?  This would suggest that they should be excluded. 
	DR. MORENO:  Yeah, I did not hear him finally say that he thought there was such an entitlement.  But I would be glad to hear the impressions of others.
	DR. SHAMOO:  May I?
	DR. MORENO:  Please.
	DR. SHAMOO:  I think, and I understood him, I thought, very well, and we talked a while later.  I don't know if he's still here.  I don't think anybody will object that there are MRDD as part of a population with let's say, diabetes or any other disorder to be included as part of the population and not excluded intentionally.  However, the word is "targeting."
	If you have a group of MRDD in an institution, and just because there are good hostage, 3-400 of them, and now you want to study hypertension or diabetes, then use all of them, then you are targeting that population and justifiably.  That is what that recommendation is trying to preclude.  And I think that is justifiable.  You don't want those groups which are institutionalized or in a school or whatever, to be targeted to study on a continuing basis with no relationship to their MRDD.
	DR. MORENO:  And I think that is the spirit of this recommendation that came out of NBAC and was approved by the DHHS working group.  Sandy.
	DR. CHODOSH:  If that's the case, then I agree with you, I think, then we should say that.  Not assume that it has a meaning.  You should say what the meaning is, namely that incarcerated individuals who want -- or whatever reason, and we're going to get to that when we get to prisoners, the same sort of argument is going to come up there.
	DR. SHAMOO:  I think what's happening and Alan fell into that trap this morning, sorry Alan, and this is another one.  We are reading these recommendations in a vacuum.  NBAC report is a very lengthy report.  And if you read the entire report, and the explanation for these recommendations, you will not come up with any different interpretation just like I was mentioning to Alan, it's very clear in the report that you assume the mentally ill have capacity for decision-making.  Only if they manifest some symptoms -- 
	DR. MORENO:  Raise the question. 
	DR. SHAMOO:  -- of decisional incapacity, then you are obligated to have an assessment. 
	DR. MORENO:  I think it is a problem to tear the recommendations out of their explanatory context.  Alan?
	DR. FLEISCHMAN:  Reasonable intelligent people could interpret that report differently.  I am really not interested in debating the NBAC report.  I'm only interested in debating our products. 
	DR. MORENO:  That's right. 
	DR. FLEISCHMAN:  And I have been on record with Jonathan from the beginning being concerned about this method of writing a NHRPAC report, because it assumed certain level, either of understanding or of contents.  So I would argue that if we're going to endorse some recommendations we had better put in all the backup information so that people don't fall into traps of misinterpretation.  But having said all that, I don't think NBAC said what you just said.  I also think that we agree that we ought to presume capacity.  I don't think NBAC said that.
	DR. MORENO:  Margaret.
	MS. BORWHAT:  Well, moving on to recommendation 17, I just had a question and probably this is the same -- 
	DR. MORENO:  NBAC 17, yeah.
	MS. BORWHAT:  -- the same problem where the full context isn't given.  But for subjects who have fluctuating or limited decision-making capacity, et cetera, I'm not sure what that is saying.  Is that saying that the subject, when they have the capacity makes the decision?  And then where do the caretakers come in?  That's not clear to me whether the consent comes from a caretaker at some point or the subjects at some point. 
	DR. MORENO:  The concern there was to ensure that the potential subject or the fact involved subject has the opportunity to continue to have the support of family members and caregivers who are not necessarily involved in the study.  And it may be the case that they themselves give consent.  It may be that they are legally authorized to give consent for the subject.  But, again, we're faced with the same problem, we'll just have to sort it out.
	Sandy.
	DR. CHODOSH:  There is really a general problem that we are skirting around, and that is that the workgroup on decisionally impairment workgroup and NBAC is purely for mental.  And I think that if we're going to "accept in principle" we should at least change the wording so that it encompasses in a proper way what it is that we are trying to cover.  Just to accept theirs, it's like we're leaving out a lot of other things and trying to cover up a little bit with a few other recommendations.  It ought to be unified.  I agree with -- I think it was Alan or Bob who said that, the question about whether we should just accept that NBAC statement as is or whether we should accept them in principle and modify them to fit what's our goal.
	DR. MORENO:  Okay.  Abbey and then Mark. 
	MS. MEYERS:  I would try to avoid using the words, "MRDD" because the law is set up for a funding problem.  Originally the law covered only mentally retarded and during John Kennedy's days and then when it was going to be reauthorized several years later, there was an objection that it only covered the MR population, and so it was expanded to cover epilepsy, autism, and cerebral palsy.
	Then when it had to be reauthorized and it only covered four diseases, the rest of the community said, these are really disorders that start before the age of 21 and inhibit the ability to function independently on certain levels.  And so the definition was changed and it's much more the mental retardation.  In some states it covers everything from anything that starts in childhood including things like Huntington's disease is covered by some states.  And what it is, is an entree into the service system so you can get sheltered workshops and respite care and things like that. 
	If we use those words here, the same mistake is going to be made because about half of the states now only take care of you whether you have any of these other disabilities only if you're mentally retarded.  So, what we need to do is stick to those words about impaired decision-making capacity so that we don't get stuck on diagnoses.
	DR. MORENO:  I agree.  I agree.  Mark.
	MR. BARNES:  I just wanted to ask Jonathan, you guys accepted in principle the one, three, four, five, seven, eight, nine, and 17 of the NBAC recommendations which are those that were adopted by the Health and Human Services workgroup.  I wonder if you guys independently went back and looked at the other ones that were not accepted and decided that you were just going to take the ones that were -- I mean, whether there was an independent decision or whether you just adopted not only NBAC, but also the subsequent report of DHHS?
	DR. MORENO:  Well, the rest of this report is addressed at the disagreements that remain between NBAC and the DHHS workgroup.  So the answer is yes.  Then there were a number of other recommendations, for example, those to state legislatures on legally authorized representatives that we did not -- I did not until this morning -- take to be a matter of direct concern for our workgroup for this report.  But I do now.
	All right.  Are there any -- I know that Mary Faith is going to look over my shoulder looking at the clock.  Are there any other reactions to three at this point of the NHRPAC recommendations?  Adil?
	DR. SHAMOO:  I would like to hear Dr. Shore when he tried to as and he was cut off.  He made a point with me and I don't want to speak on his behalf, he could make it probably much better.
	DR. SHORE:  I'll be very brief.  Jonathan, I think this -- 
	CHAIRPERSON MARSHALL:  Could you just let everybody know who you are. 
	DR. SHORE:  David Shore, National Institute of Mental Health.  I certainly appreciate the changes that have been made since we last discussed this.  I really just have one concern at this point and a question.  Namely that at for all of the four it says, if the subject's legally authorized representative has given permission.  And the question is, since that applies to number one in which research is not greater than minimal risk, that as I read this it seems not only inconsistent with the common rule, subpart (a) provisions to waive informed consent when studies are not greater than minimal risk as well as the other three criteria. 
	CHAIRPERSON MARSHALL:  Written documentation; right? 
	DR. SHORE:  No, it's to waive -- 
	CHAIRPERSON MARSHALL:  That's to waive?
	DR. SHORE:  To waive some or all of the elements of informed consent, not just written documentation. 
	CHAIRPERSON MARSHALL:  Okay.  
	DR. SHORE:  The other issue is that it's also inconsistent with the language in the children's regs under subpart (d) which us a different criteria about soliciting the permission rather than having to have it.  In other words, if it's impracticable to obtain the permission there are ways to alter, again, the documentation in that case, as you suggest.
	But I was wondering whether the group meant to apply a new criteria that's not in either subpart (a) or subpart (d) and that is in fact stricter than the children's regs that would outlaw any studies of people who lack decision-making capacity even for a not greater than minimal research if a legally authorize representative cannot give permission, or if in the case of Alzheimer's disease there may be no legally authorized representative. 
	DR. MORENO:  Well, the sentiment of the workgroup, I think, was that historical considerations indicated that such an additional protection over this population were warranted.  But, I'm prepared to open it up, of course, to the advisory committee if they regard this as an excessive additional protection.  So the answer is, David, yes.  It was done deliberately.
	Bob.
	DR. R. LEVINE:  I think it could be excessive unless you incorporate it or acknowledge the validity of the exceptions to the informed consent rule that are currently in the Code of Federal Regulations.  And what David was referring to particularly was the passage that allows you to waive or alter some or all of the elements of informed consent if it meets three criteria and a fourth.  The fourth criterion you would give the people information after you did the research as appropriate.  But the first three would be that there would be minimal risk, that the research would be impracticable without the waiver and the third one was, the one that is internally contradictory, but we've learned to live with it.  That the waiver itself does not constitute a violation or waiver of the rights of the subject.  And for those people who think informed consent is a right, that's a bit of a problem.  But, as I say, we've learned to live with it.
	But I don't think you would want to just wipe out all research, let's say that involved medical record review, for example, on people who had decisional incapacity because they couldn't consent.
	DR. MORENO:  Sandy.
	DR. CHODOSH:  No.
	DR. MORENO:  Adil, is it on this point?
	DR. SHAMOO:  Yeah, on this point.
	I, for one, don't recall we made a conscience decision to remove the exemptions by this write-up because the only way you will do that, this write-up has to be support, an independent support and then the exemptions will not apply.  I, for one, don't recall we had a lengthy discussion on minimal risk -- no greater than minimal risk that there will be elimination of exemptions.  I, for one.  I don't know how the rest of the working group understood it.
	DR. MORENO:  My recall is that there was no -- I can't remember anybody indicating that the exemptions should continue to apply -- should.  But perhaps that was by exclusion and I simply failed to incorporate that into the discussion.  So, if there's consensus -- 
	MS. KORNETSKY:  Jonathan, what Bob is bringing up is not the exemptions.  I mean, he's bringing up categories of minimal risk research such as prospective medical record review. 
	DR. MORENO:  Right.  I understand. 
	All right.  If there's consensus that those conditions need to apply, then we don't need to revisit the workgroup on that.  This is now up to the advisory committee. 
	Are there any other comments on -- 
	DR. R. LEVINE:  [Off mic.] 
	DR. MORENO:  Well, I'm asking you now.  But we're going to revisit, I have a feeling, at the next meeting.  Consensus is not an event, it's a process; right?  So we like informed consent. 
	Are there any other comments on three? 
	[No response.] 
	DR. MORENO:  On NHRPAC recommendation three? 
	[No response.] 
	DR. MORENO:  Do I need to read NHRPAC four?  This is essentially a 407 sort of process that applies to the pediatric regs now which we've discussed before in this group.
	We have a footnote indicating our concern about the current 407 process that I hope will be of some value to OHRP.  Sandy.
	DR. CHODOSH:  I'm sorry, but I'd like to jump back to recommendation 17, only that I'm not quite sure how that ended up in terms of maintaining ongoing communication with involved caregivers.  And a caregiver, you know, is this the legally authorized -- 
	DR. MORENO:  No. 
	DR. CHODOSH:  -- the professionals were taking care of the individual outside the research.  It's not well-defined, I guess.
	DR. MORENO:  Right.  It's not well-defined in the recommendation.  It is in the text and NBAC text and so we are going to have to make the basic decision here about what to do about all of these NBAC recommendations, whether they should be more than incorporated by reference which is sort of what we did at this point.  But incorporated more completely and tangibly into our own recommendations. 
	DR. CHODOSH:  I could see just discussions with "a caregiver" who is not necessarily the legally authorized representative.  And that would be troublesome, it seems to me, if that were limited in that way that you could go to either one and get away without informing the other.  
	DR. MORENO:  Understood.   All right.  Thank you. 
	CHAIRPERSON MARSHALL:  Thank you, committee.  Thank you, Jonathan, for your hard work. 
	DR. R. LEVINE:  [Off mic.] 
	DR. MORENO:  Bob, I think that what Mary Faith and I are just going to have to talk about how to approach the document with respect to the NBAC recommendations and maybe we just have to systematically revisit all of them but with our own formulation.  
	DR. R. LEVINE:  [Off mic.]  I think it's a particularly problematic one in that especially if you don't make it clear that you're distinguishing therapeutic and non-therapeutic components.  Now, with regard to therapeutic components this recommendation number seven was the subject matter of the National Commission's most tedious recommendation.  Because you have to take into account that in some jurisdictions people have a right to healthcare and in some other jurisdictions they have a right not to have healthcare when it comes to mental illness.  But you've got to find a way to make this recommendation seven at least one sentence longer.
	DR. MORENO:  Thank you. 
	CHAIRPERSON MARSHALL:  Thank you, Jonathan.
	All right.  We are going to move rapidly along this afternoon.  So I would like to invite, first of all Nancy Dubler to the table. 
	So this is a distinct pleasure to me.  We have a new person at our table.  But in one respect she predates us all.  Nancy is in a way the mother of this committee.  She helped -- 
	MR. BARNES:  She's 39 years old, so don't say -- 
	CHAIRPERSON MARSHALL:  And holding.  
	[Laughter.] 
	CHAIRPERSON MARSHALL:  And she brought us into being.  She co-chaired the advisory committee that advised the then director of the NIH, Dr. Harold Varmas, about the positioning of the OPRR, the former Office of Protection from Research Risks and its function within the NIH.  And she and her advisory group made the recommendation that brought the Office of Human Research Protections into being, moved it into the HHS more directly under the Secretary, advising the Secretary through the Assistant Secretary for Health.  And they also recommended that a National Advisory Committee on the Protection of Human Research Subjects be formed and we were born, thanks to Nancy and her committee's hard work.
	So we owe you a lot, Nancy.  And no good deed, as you know, goes unpunished.  So we have asked her to help us with our informed consent workgroup.  And also to lead our venture into research with prisoners.  And we'll be doing that in the prisoner work venture in just a moment.
	I want to say, over the past couple of years I've had the distinct honor of serving with Nancy on the IOM committee that the Department of Health and Human Services charged with looking at the overall system for protecting human research participants and the short-term charge was to review the idea of accrediting human subject protection programs.  And she was a stalwart committee member in that venture and just hugely impressive as she is with all of our work with the New York State task force on Life and the Law and all of her many other ventures.  So, Nancy, we're delighted to have you.  Welcome to our table. 
	MS. DUBLER:  Thank you very much.  And thank you for inviting me to be here.  I must apologize that both Tom Beauchamp and Rabbi Elliot Dorff had conflicts for today, although Elliot will be here tomorrow for the deliberations.  And so as the new kid on the organizing team, I get to come and tell you where we are and where we're not.
	So let me tell you where we're not.  The informed consent committee spent some -- working group spent some time on theory and quite frankly recreating a very adequate wheel.  And then we realized that there really was a vast literature out there that could fill the purposes that we had been struggling toward and we shifted focus.
	And what we're shifting to now is trying to define and explain and give examples of and templates for what would be an informed consent process.  I think we all agree that what is now called the informed consent which is a document which began with the worthy design of informing, being one of the pillars for informing the potential research subject has for many reasons come to serve other purposes.  And one of those purposes is the protection of sponsors and institutions and that's not an insignificant purpose, but it's somewhat at odds with the original purpose.
	And so we wanted to take that document and set it aside and whether we end up calling it the informed consent document or the disclosure document, putting it aside and saying what would a process look like that really wanted to inform a possible potential research subject about research in general, the notion that you may be benefitted, you may not receive any benefit, or you may actually be harmed.  The idea that you really can receive treatment without coming into this protocol, although we all know that over the last years there have been certain kinds of treatments that are really only available within protocols, and that's important for people to know.
	So there is one group that is going to work on the process that you would need to educate a potential subject, both about the ideas of research in general, and about the particulars of this protocol.  We are going to look at an iterative process and interactive process.  Alan has been, I think, a very helpful voice in saying think about electronic ways of doing this.  We want to develop what would be a template and for many IRBs a script of how you go about this.
	We'll do the same for the issue of voluntariness and help the person to really understand the operations outside of this particular protocol. 
	And then there's a third subgroup that is working on the issue of who should do this.  In fact, is it better for the principal investigator who knows the most about the trial to be the person to interact with the subject participant, or in fact is it better for someone who is not the principal investigator and may have a more hands-off relationship to whether this person enters the trial or not.  We don't know, but that group will not come up with scripts and process, but rather with guidelines that try to identify the alternatives and to give the pros and cons of those alternatives.
	We're hoping to have a preliminary report for this committee at its next meeting.  That's our goal.  So we will have materials for you then and that particular report.
	Any questions?  Comments?  
	[No response.] 
	MS. DUBLER:  Crys of anguish? 
	[No response.] 
	CHAIRPERSON MARSHALL:  Your group has been working very had and I think is exploring some new paradigms.  I think the intent is to do something that will be lasting and meaningful to the research community, to IRBs, to research subjects themselves, to investigators, so we're looking for great things.  So, they will debut at our October meeting.
	So let me invite then the folks -- actually, let me invite Irene Stith-Coleman to the table and the members of our next panel on research with prisoners. 
	In Dr. Koski's absence I've asked Dr. Stith-Coleman to charge the committee.  We've received in writing a request from the Office of Human Research Protections, but it hasn't been formally made at one of our meetings.  So, Irene, thank you so much for being willing to do this. 
	DR. STITH-COLEMAN:  Good afternoon.  And I apologize for my voice, it's a little sick.  And let me know if you can't hear me.
	In April of this year Greg Koski forwarded a letter to Mary Faith requesting that NHRPAC provide HHS with guidance and recommendations on research involving prisoners.  So, basically what I will do is I will just highlight the request.  It came in two forms.  Realizing that the Department appreciated the fact that NHRPAC had its plate full, but needing assistance with some advice on research involving prisoners, Dr. Koski requested that NHRPAC provide advice and guidance on current requirements in Subpart C as well as to ask for advice as to whether or not new regulations were necessary.
	It is specifically asking NHRPAC to provide recommendations for guidance on the current Subpart C and consider whether or not Subpart C, the current one, is adequate and if not provide recommendations on how it should be revised. 
	In more specific terms NHRPAC was asked to provide recommendations for advice on the following:  46301(a).  Subpart C -- should Subpart C apply to research involving a subject who is not a prisoner when he or she enrolls in a study but becomes a prisoner shortly or sometime during the study. 
	Two, 46303(c), what should the term "prisoner" encompass under the definition provided in the regulations?  For example, should the term "prisoner" include someone civilly committed to a mental institution based on a not guilty for reason of insanity defense, or to someone under house arrest?
	46304(b), what should constitute appropriate background and expertise for an individual to serve as a prisoner representative? 
	46305(a)(7), what would constitute adequate provision for follow-up examination or care of participants after their participation has ended?  And in this case OHRP notes that after participation can extend beyond the period of incarceration. 
	46306(a)(2)(4), how should research on or practices which have the intent and reasonable probability of improving the health or well-being of the subject be interpreted?
	46306(a)(2)(4), how should control groups which may not benefit from the research be interpreted?  For example, should a control group where subjects receive some -- or receive only standard medical intervention for a particular disorder be considered as benefitting or not benefitting from the research.
	In addition to recommendations on the current Subpart C, OHRP asked NHRPAC to consider whether or not Subpart C, the current version, is adequate.  And if not, provide recommendations on how it should be revised.
	For example, is the current Subpart B adequate to ensure appropriate inclusion and avoid appropriate exclusion of prisoners in research?
	Should the requirement for institutions to certify to the Secretary that the institutional review board has fulfilled its duties under Subpart C be retained?  And that's found in 46305(b).
	Should the requirement that the Secretary judge that the research involves solely one of four categories of a research stipulated under 45 C.F.R. 46306(a)(2) be retained. 
	And, lastly, are the current four categories in 45 C.F.R. 46306(a)(2) sufficient?  Should more categories be added?
	Indicating that Greg was aware of, again, your agenda, but want to emphasize the important need for HHS to receive additional guidance in this area and appreciating the fact that you may not be able to address both of the concerns with respect to the current Subpart C, whether or not that's adequate or not, and it needs new or needs to be revised at the same time that you provide guidance on the current version.  What we would like to do is ask that you give first priority to providing guidance on the current Subpart C.
	CHAIRPERSON MARSHALL:  Irene, thank you very much for being willing to do that.  I appreciate it. 
	And I would like to recognize Nancy now who is going to, I think, help us lead -- she's going to lead the discussion this afternoon, along with the panel that she has helped to convene.
	I think perhaps more than anyone, at least within the field of bioethics, Nancy has taken a look at bioethics issues with incarcerated persons and has covered the waterfront not just from the early discussion back in the 1980s involving prisoners who were HIV positive or had AIDS or perhaps at risk for becoming HIV positive, but also looking at issues such as end-of-life care and then, of course, research with incarcerated persons.  And she has written a great deal in this area and done a lot of good work in the area of health policy and is widely recognized as an expert in this area and has served on many advisory groups. 
	So, Nancy, I will ask you if you would introduce your fellow panel members and give us their background and if there's anything else that you would like to say about yourself in terms of your experience and expertise, we would love to hear it. 
	MS. DUBLER:  Thank you very much.  And thank you all.  Mary Faith, one question, can we run this first part of the discussion until the break?  I think it will take about an hour, but that will put the break a little bit later, is that all right? 
	CHAIRPERSON MARSHALL:  That's fine.  And I'll remind everyone that there will be cookies at the break.  So there's something that you could look forward to.  Yes, the time is yours.
	MS. DUBLER:  As some of you know for the last quarter century prison healthcare has been one of my foci.  I stumbled upon it quite by accident.  I came to work at Montefoire Medical Center in the mid-1970s and Montefoire had the contract to run the prison health services on Rikers Island.  Shortly thereafter, the Supreme Court decided that prisoners had a Constitutional right to medical care and I thought with my lack of experience and concombinant lack of wisdom, wasn't that interesting.  If there was a Constitutional right to care you could think about issues of the obligations of medicine in a more pure setting.  I learned my lessons gradually. 
	[Laughter.] 
	MS. DUBLER:  The panel today is an opening of the discussion on prison and jail healthcare.  We would assume that this committee would want to address certain of the questions that Dr. Koski has posed in a particular order.  We're also assuming that the committee doesn't know a lot about prison and jail healthcare.  I may be wrong.
	I know that Mark Barnes supervised the contract with Rikers Island for many years when he was in the Department of Health in New York, but most people don't have a lot of experience with prisons and jails.
	We've assembled a panel today with the experience and the data to give you a profile of what prisons and jails and look like and most particularly what we know about them and what we don't know about them and perhaps how the structure of the present Subpart C affects what we know and don't know.  So let me ask the panel to introduce themselves now and then the order in which we'll speak, I will begin, then Jaye Anno, Bill Rold, Stan Richards, and Anne Spaulding. 
	But for now, Jaye.
	DR. ANNO:  I'm Jaye Anno.  I'm a criminologist by training and a correctional healthcare administrator by choice.  I've been involved in the field for 30 years and I have worked in the development and the evaluation of the first, and I think only national federal project, federally funded project to improve healthcare in jails that was at the American Medical Association.
	Subsequently was involved in founding an organization called the National Commission on Correctional Healthcare and have worked as the Assistant Director for Health Services for the Texas Department of Corrections for a period of time and also as the Bureau Director for Mental Health Services in the New Mexico Department of Corrections.  I've written fairly extensively a couple of books and a number of articles dealing with a variety of correctional healthcare topics. 
	MS. DUBLER:  Stan. 
	MR. RICHARDS:  Good afternoon.  My name is Stanley Richards, Deputy Executive Director of Programs of the Fortune Society, a not-for-profit organization in New York City that provides services to ex-offenders and at-risk youth.  I am also a Robert Wood Johnson fellow in their developing leadership to reduce substance abuse program.  I'm an ex-offender.  I spent over six years in prisons, in jails, in New York City and New York State and have over 15 years, combined with my personal experience, professional experience in working with ex-offenders and at-risk youth. 
	I just recently completed working on a project with Hunter College centered on AIDS, drugs and community health, a project called "Health Link" that was a jail and community-based case management program looking at community reintegration.  It was a randomized trial sponsored by the Robert Wood Johnson Foundation and evaluated by Mathematica Policy. 
	MR. ROLD:  I'm Bill Rold.  I'm a practicing attorney in New York City.  I may have learned about medical experiments in prisoners at an earlier age than anyone here.  My mother was a court reporter at the War Crimes trials at Nordhausen and Dauchau and she brought back materials and lots of stories about what went on there that impressed me at a very early age.  And, in fact, when I cleaned out house after she had to go into assisted care, I found a lot of that original archival material which I'm presenting to the Holocaust Museum on Thursday.
	I've been a prisoners' rights attorney for 25 years, ten years of which I specialized in healthcare delivery.  And during that time I was an ad hoc member of New York City Department of Health IRB when prisoner cases came up, something that Nancy handed off to me.
	It's a subject that's close to me and I've followed it for a long time.  I also sit on the Board of Directors of the National Commission on Correctional Healthcare representing the American Bar Association.
	DR. SPAULDING:  My name is Anne Spaulding and I'm an infectious disease physician who served as medical director for the Rhode Island Department of Corrections for five and a half years up until last fall when I came to the Centers for Disease Control to be the team leader in the corrections and substance abuse unit out of the National Center for HIV, STD and TB Prevention.  In addition I am the president of the Society of Correctional Physicians.
	MS. DUBLER:  I think it is a panel that will have a lot to offer in the next hour.
	I've asked the panel to keep their remarks at 12 to 15 minutes.  And I feel honor bound to do it in even less time.  My choices are to say very little or to say it fast and I've chosen the latter. 
	[Laughter.] 
	MS. DUBLER:  Prisons and jails is a growth industry.  It has grown more than 200 percent over the last 20 years.  There are 1.2 million persons in jails and prisons on any day in the U.S.  About half of those people will either enter or leave the prison during the year.
	Jails have 11 million people who pass through them on any year.  Jails are those facilities run by counties or cities which are for people who have been charged who are awaiting trial or are sentenced to short-term misdemeanor sentences of under a year.
	The war on drugs has taken a lot of captives and a lot of those captives are in prisons and jails.  Who are they?  Well, there's a group in Washington called the Sentencing Report which five years ago had a report which stated that one-quarter of black men between the ages of 19 and 29 were under the jurisdiction of the criminal justice system; jail, prison, parole, or probation.  Except in Washington, D.C., where it was 52 percent.
	When they repeated their data analysis three years later, it was one-third of black men between 19 and 29.  Prisons and jails don't incarcerate all people at equal rates.  They disproportionately incarcerate those who are poor and those who are of color. 
	In addition, over the last years because of the disparate sentencing for cocaine and crack cocaine, there are much longer sentences for crack cocaine, because of that policy of the federal government and because of developing state "three strikes and you're out laws" which can mean in the State of Alabama that if you've got three pickpocketing convictions, you might spend the rest of your life in prison.  Because of crack cocaine, because of disproportionate sentencing, you have a graying of the prisons which is that, again, a disproportionate number of prisoners are old.
	But the data show us that even if you're not old in years, the health status of prisoners by no means reflects the health status of the general population and is far worse.
	The legal framework.  There's been a focus on prisons and jails in the last 25 years growing out of a case called Estelle v. Gamble, in 1976, in which the U.S. Supreme Court stated:  "That the deliberate indifference to the serious medical needs of inmates constitutes the willful and wanton infliction of pain which the Eighth Amendment is designed to prohibit."
	Their logic was, to put someone in a prison or jail where they cannot secure their own care and not to provide that care results in precisely the pain and suffering which the Eighth Amendment says cannot be a government action, the end of government action.
	This was based on a developing jurisprudence in the Supreme Court that argued that the measure of the Eighth Amendment is not a constitutional intent of the framers as we've heard argued for other amendments, but on the contrary that the prescription against cruel and unusual punishment is nothing less than the dignity of man.
	The words of the Eighth Amendment are not precise and their scope is not static.  The Amendment must draw it's meaning from the evolving standards of decency and dignity that mark the progress of a maturing society.
	So what has been the difference in interpretation and how might it affect how we think about research with prisoners?  I'll tell you a story out of the National Commission and, Bob, if I get it wrong, you can correct me.
	The National Commission went to Jackson Prison in Michigan which is a maximum security prison where the inmates were locked down for 23 and a half hours a day every day.  And they held a hearing.  There was a medical unit in Jackson Prison.  And they held a hearing with the inmates to talk about that unit.  There was quite a lot of medical research in prisons before Subpart C.  Indeed, a huge proportion of clinical trials were done in prisons.
	There is a book that some of you may know called "Acres of Skin" which describes the development of Retin A by the University of Pennsylvania. 
	And so the National Commission came prepared to develop very rigorous rules to prevent research in prisons.  And one of the prisoners raised his hand and he said, "We've noticed that prisons are places of deprivation and death.  There is only one place where that doesn't happen and that's the medical ward.  Just precisely what are you protecting us from?"
	The issue has been raised today, is it a privilege to be included in research, or a privilege to be excluded from research?  It's been a theme from the morning's discussions.  And it is the theme that has to govern how we think about research with prisoners.
	Prisoners are a captive population in the most precise sense.  If you want to know how you're drug is being metabolized, you'll be able to gain access to the person who is taking the drug. 
	The flip side of that is, I like to argue, that it's almost impossible to distinguish in a prison between a denial of care and a refusal of care.  Why did that inmate not show up for the appointment at the medical center?  Because he or she chose not to come, or because some correction officer decided he or she shouldn't come.
	The National Commission has encouraged a policy where inmates have to show up at a medical facility to refuse care.  But the two sides of the prison coin are a captive and stable population on the one hand, but within a power relationship which compromises voluntariness.  And one of the questions will be, is that compromise so significant that we can't permit prisoners to opt for participation in clinical research. 
	In the 1980s, as some of you may remember, when AIDS was first called GRID, gay related immune definitely, and we were in the Bronx saying two thing, number one, hello, we have women, since we had the first cohort of women; and number two, we had at that point the highest prevalence of HIV of any population and that was in the drug detox unit at Rikers Island.
	By the end of the '80s something very interesting had happened.  When the prisoners' rights project at the Legal Aid Society came to me and said, would I convene a working group within New York, and we eventually did with the Commissioner of Health and all of those people involved in prison healthcare, and the prisoners' rights attorneys, because the prisoners at Rikers Island wanted access to those protocols that were developing treatments for AIDS.  They didn't want to be protected from protocols, they wanted access to research.
	And so that frames the sorts of comments that we'll make on the panel these opening comments today, talking about who the population is, what the pressures are and what has been the effect of the present Subpart C on access to protocols for prisoners and about what we know about the health status of prisoners.
	Remember the details.  Eleven million prisoners circle through jails in any one year and 600,000 inmates from prisons are discharged into the population.  That population is us.  It may be confined in Danamora at the Edge of New York State.  But issues of public health and issues of health status demand, I would argue, that we think about prisoners as part of us and not separate from us.
	MS. MEYERS:  [Off mic.] 
	MS. DUBLER:  Jaye, do you want to pick up with that?
	DR. ANNO:  The percentage of women who are incarcerated, it's about 10 percent of jail inmates and about 6 to 7 percent of prisoners, state prisoners. 
	MS. DUBLER:  At any point when you have questions or corrections.  Dr. Levine. 
	DR. R. LEVINE:  You invited me to correct it.  Actually, the prisoner from Jackson State who you quoted was the head of the trustee's group and he began by saying, "Ladies and gentlemen, you're in a place where death at random is a way of life."  What you said after that was exactly what he said.  But also I wanted to say that the National Commission visited that prison with the expectation of finding that almost all of the research subjects would be people of color. 
	What they found when they got there is that although black men were two-thirds of the inmate population, they were somewhat under one-third of the research subject population.  When they were asked whether there was discrimination there, almost with one voice they said, yes, indeed, there is discrimination.  We want to be research subjects, but every time our names come up the white guys who control all of this say, well, the skin testing here, we can't do this with black skin.
	So they were telling of a very different sort of discrimination than the National Commission went to find.  Thank you. 
	DR. ANNO:  I told you I had been involved in correctional healthcare for the past 30 years.  But what you need to recognize is that 30 years ago there was no such thing as a correction healthcare profession.  Healthcare in prisons was provided most often by former military corpsmen who were not licensed healthcare professionals and quote/unquote, "inmate nurses" who again were not trained individuals with a nursing background but simply people that were recruited from among the inmate population to work within the healthcare clinic.  It was a desirable position for a number of reasons. 
	It was quite common at that point, if you wanted to get any kind of healthcare, because healthcare was not considered a right at that point, it was still a privilege within institutions.  And to get access to the clinic, oftentimes you had to bribe the individuals who worked there, the inmates who worked there to get you an appointment or to get you seen.  Part of that was because there were obviously very few resources available to the prisoners at that time.  Having a physician work within corrections was also quite unusual. 
	In a State like Texas where you're going to hear about the Estelle case, at the time that the Estelle case was filed in the Texas Department of Corrections there was one physician for 11,000 inmates in nine different facilities scattered across the State of Texas.  That gives you some idea of what access to a physician might have been like.
	Additionally, the reputation of individuals who went into correctional medicine, they tended to be impaired physicians, individuals who had lost their license to practice in the community, foreign medical graduates who may have been without a current license.  Many states gave what they called an institutional license to individuals who could not practice elsewhere in the community but were permitted to practice within the institutions of a state including prisons and sometimes mental institutions, et cetera. 
	Another impediment to access to care at that time, as I indicated, since healthcare was not a right, had not been established yet as a right for people who are incarcerated, you oftentimes had to convince the officers, the prison guards, they were the people who controlled whether you got to the healthcare clinic where then you might have to pay somebody, another inmate for your appointment to actually get seen.
	Healthcare in jails was even more dismal.  The typical jail in this country, 30 years ago had no semblance of healthcare on site.  Healthcare, again, being a privilege, you had to convince an officer that you were sick enough to be able to go to the emergency department.  That was the clinic for jails in this country 30 years ago. 
	There were two primary forces that were responsible for making improvements in the healthcare delivery systems in prisons and jails across the United States.  One was the courts and Bill Rold will be speaking to you about that.  But the other was really the health professional associations, most prominently the American Medical Association and the American Public Health Association.  Probably less unusual for the American Public Health Association to be involved than it was for the American Medical Association.  But you have to remember that these were the '70s and like all institutions the AMA also responded to the sort of social consciousness of the days. 
	Also, the AMA has had, for a number of years and probably still continues a liaison relationship with the American Bar Association.  In '70-71 there was a Blue Ribbon ABA/AMA committee that was dealing with conditions of confinement and it included individuals like Richard Hughes who was Chief Justice of the New Jersey Supreme Court, Charlie Bellows who was a very prominent lawyer out of Chicago, Elliot Richardson whom most people would know at least from that time, and then there were a couple of other individuals.  The representative from the American Medical Association was an attorney by the name of Bernard Harrison.  He went back after one of their meetings basically saying, well, what should we do?  What can we do at the AMA?  And essentially what they decided to do was to determine what the level of need was for healthcare within jails.  The initial focus was on jails.
	The AMA did a survey in 1982 established that there was a lack of the healthcare -- any semblance of healthcare delivery.  In 1975 the AMA received a grant from a now defunct federal agency, the Law Enforcement Assistance Administration, to develop a program to improve healthcare in jails.  Primary components of that program included the development of national standards, the development of an accreditation program to measure compliance with those standards, and then the development of resource materials to assist the people that were working within the facilities literature, conferences, things of that sort.
	That program ultimately was expanded to 28 different states.  It finally terminated in 1981.  There was a grant received from the Robert Wood Johnson Foundation to determine whether you could develop a free-standing organization that might continue this work.
	In 1983 the National Commission on Correctional Healthcare was born.  And it is still in existence today.  At that time there were 20 representatives from 20 different professional associations.  Now there are 37.  It includes virtually all of the health professional associations that you might think would have people that would work within corrections such as the American Nurses, American Medical, College of Physicians, American Dental, Management Information, virtually all of those.  And then it also includes the American Bar Association and some representation from the corrections field through the National Sheriffs Association, American Jail, et cetera.
	That organization continues the work of the original AMA project.  It has expanded its standards.  It now does accreditation of not just jails but also prisons, and juvenile facilities. 
	The climate within correctional facilities today, jails and prisons is very different than it was 30 years ago.  There have been significant improvements in the healthcare delivery system.  And we make an assumption that improving healthcare delivery also improves the health status of inmates.
	What you will find more typically today is that you have anybody who works within -- almost anybody who works within correctional facilities is licensed.  There are a number of people that are board certified, there is certainly more staff, more qualified staff.  We've seen the cost of -- or the expenditure for correctional healthcare per inmate per year increase from about $900 in 1982 to $2,736 in 1998.  That's still less, by the way, than what the national average was in the community. 
	In spite of the improvements that we have made in healthcare delivery in improving the delivery systems, correctional health professionals today know less about their patients than any other healthcare group.  We are isolated from mainstream medicine, we have few links to public health or academic medicine in spite of the fact that we oftentimes serve the very same patients. 
	There's very little research that's conducted within correctional institutions.
	CHAIRPERSON MARSHALL:  I'm sorry, I did have a question.  You mentioned a moment ago that there were associations with many of the healthcare professional organizations.  Do you have any links to any of the human subject research organizations like PRIMER or Arena or anything? 
	DR. ANNO:  No. 
	CHAIRPERSON MARSHALL:  No formal relationship with primarily research organizations? 
	DR. ANNO:  No. 
	CHAIRPERSON MARSHALL:  Just curious.  Okay. 
	DR. ANNO:  And part of the reason, I think, is that there is very little research that's done.  Except for a couple of federal agencies like the National Institute of Corrections that is provided some funding for some sort of basic social research and the National Institute of Justice and Centers for Disease Control that have done some research -- supported some research as it relates to the incidents of specific communicable diseases such as TB, HIV, and certain sexually transmitted disease, there's almost no funding out there to support any research. 
	We don't know anything about the prevalence of specific chronic illnesses within correctional institutions.  On any given day most people cannot tell you with any degree of accuracy the number of diabetics they have, the number of people that they have with specific diseases.  It's a tracking system, it's a lack of resources.
	We don't know anything about the mentally ill within our institutions.  And we don't know anything about the differences between males and females.  One of the things that you hear within corrections all the time is that a lot of people would say that they would rather take care of ten males versus one female because women are such complainers and they utilize healthcare at a much higher degree.  The truth of the matter is, we haven't really conducted the research except in very minimal ways in a few places to bear out the fact that actually women who come into prisons and jails are much sicker than the average male.  Plus they have additional emotional concerns dealing with their separation from their children, post-traumatic stress disorder, very high rates of abuse, et cetera.
	We don't know very much about the good cost data.  I gave you some cost figures before.  I collected those cost data, but let me tell you, they are very suspect, shall we say.  We're not able to do the kind of research where we could make sure that we were measuring exactly the same thing.  We're just dealing with some very gross kinds of numbers.  That's part of my frustration in working in the correctional healthcare field is that in the period of time that I've been here, while I've seen improvements in healthcare delivery, I've seen very little improvement in the research, even basic research that's done. 
	I was principal author of a book that came out in 1991 on prison healthcare which both Bill Rold and Nancy Dubler have chapters in, and then we repeated the book in 2001.  There was virtually no change in terms of our information level and what we had learned over that period of time.
	So, I guess the real issue is, why is this the case and why is there so little research that's being done.
	In my opinion, the federal regulations that were designed to protect prisoners within the institutions had a very chilling effect.  That even though the type of research that I'm talking about isn't prohibited by the regulations, those regulations are not well understood and that a lot of systems simple react to them by making a statement saying that our policy is not to have any research.  I know this because the National Commission on Correctional Healthcare that does the accreditation of health facilities has always had a standard dealing with research and that research -- I mean, that standard basically says that you may conduct research and if you do so following legal medical, ethical and regulatory guidelines.  But in virtually every instance -- in point of fact, I've never been in a system yet where they have said that they conduct research.  Instead, they simply have a policy statement that says, research is prohibited. 
	The second reason I think is that there's no incentive for correctional facilities to do any kind of research.  We're not bound by DRGs, we're not bound by length of stay.  We're not bound by any other kinds of regulations.  There are no third-party payors.  We don't have to keep information by diagnoses.  And as a consequence, if no one is funding us to do these things and we have a lack of resources, we simply don't do them.
	DR. SHAMOO:  Can I ask a question just relevant to what she was talking about?  Do we know the current federally supported and types of research going on in prison nationally?  Currently, federally supported, that number and type should be known.  
	DR. ANNO:  Yes, I believe we do.  As I say, the only kind of research that I think now is being supported is through what the Centers for Disease Control is doing.  And I think Dr. Spaulding will speak to that issue.  I am not aware of any other sort of federal national research being conducted at the present time. 
	MS. DUBLER:  Yes, there's Ted Hammet's research through the National Institute of Corrections.
	DR. ANNO:  That's the National Institute of Justice.  Right. 
	DR. SHAMOO:  You mean there are no NIH-supported research in prison?
	DR. ANNO:  There may be individual grants. 
	DR. SHAMOO:  I know differently, there are individual grants, the research subjects are prisoners.  And they are all across the country.  I don't know how many, there may be two, the only one I know, but you people should have those figures and numbers and types.
	MS. DUBLER:  We will certainly try to get them.  Part of the problem is that these are not research protocols designed for prison.  They are research protocols where one or two of the subjects may be in prison.  We will try to find that out.
	DR. SHAMOO:  Thank you. 
	MS. DUBLER:  Bob.
	DR. R. LEVINE:  He just said what I wanted to say. 
	MS. MEYERS:  Is there any differentiation between studying Retin A on wrinkles as compared to studying aggressive behaviors or schizophrenia or even cancer or diabetes in prison?
	MS. DUBLER:  I want to support Jaye's comment which is, there's been a chilling effect on research from Subpart C.  So whereas I agree with you, Subpart C was in large measure designed to prevent the testing of Retin A.  It has resulted in the lack of information about schizophrenia, drug abuse, and various other conditions which really do affect prisoners in a disproportionate way.
	MS. MINOR:  I'm sorry, may I make a comment?  My name is Carol Ann Minor.  I'm with the Federal Bureau of Prisons.  And I just wanted to point out that in fact the ACA, American Correctional Association, standards absolutely prohibit medical, biomedical, pharmaceutical, or cosmetic research.  And most -- I think all states except seven states have implemented that.  So I think there's only a few states where they actually allow any kind of biomedical or medical type testing in the correctional facilities.  I know we strictly prohibit it.
	MS. DUBLER:  Thank you. 
	MR. ROLD:  Some centuries ago King John at the point of a sword signed the Magna Charta.  And out of that came the notion that there were certain things the government couldn't do to its own subjects.  And out of that came our Bill of Rights.
	We are unique among many nations in that we have a Bill of Rights.  We have prisons and jails because we have to, but we have a Bill of Rights because we choose to.  And that's a very different mindset.
	As I stood on my roof in Brooklyn on September 11th and watched those towers fall, I still could see the Statue of Liberty, and that was a bit of a comfort to us New Yorkers on that day.  
	The Eighth Amendment prohibits cruel and unusual punishment.  But it was largely dormant for the first 160 years after it was ratified to the Constitution.  Between 1900 and 1960 the Supreme Court heard one case involving the Eighth Amendment.  Now it hears two or three a year.  And the lower courts hear hundreds.
	Out of the hundreds of cases involving healthcare and the deliberate indifference standard, there have emerged three basic rights.  The right to access to care, that is, the right to get into the system to have your condition evaluated, to be triaged.  The right to care that's ordered.  I always tell people when I teach on this that the easiest way to lose a lawsuit against a prison is not to give the inmates the healthcare your own staff has ordered.  
	The courts will recognize the right to receive ordered care if it's for a serious condition.  And the third basic right is the right to a professional medical judgment.  Which means that the inmates have the right to have the doctors and nurses use their training for medical reasons and that's very difficult sometimes in corrections.
	Nancy has talked about it as a medically alien environment, and in many ways a correctional facility is.  They are designed to confine.  They are not designed as healthcare facilities.  The people who work in them often are cramped in very tiny places that have been jerry-rigged to create a clinic.  And we see this all over the country because they weren't designed for that.
	None of these rights guarantee an inmate the right to participate in research or a therapeutic trial.  I know of no case where a court has ever ordered it.  They haven't dealt with this.  In fact, there have only been about a half a dozen cases involving therapeutic trials and inmates that I've ever seen.  There is enormous discretion here.  The prisons have it, and you have it in setting what the standards are going to be.
	I commend Subpart C's effort to protect inmate subjects in informed involuntary consent.  We all know the horrible history of Nuremberg.  We know what happened in Tuskeegee when there weren't any animal models so they just gave VD to people and watched it. 
	In World War II inmates volunteered for malaria trials when the armed forces were trying to come up with an alternative to quinine when it was in shortage.  And, in fact, back then the AMA passed a resolution saying that inmates convicted of murder would not be given the privilege of participating in those kinds of trials.  So we've gone full circle in many ways with these things. 
	At the time the Belmont Report was drafted, 85 percent of all phase one trials were conducted in prisons.  That's extraordinary.  They were an ideal control group.  No one wants to go back to that.
	In the 1950s inmates weren't necessarily paid, but they were given good time credits against parole.  So the incentive was maybe they could get out earlier.  So there were concerns.  And while I endorse a relaxation of Subpart C, we need to know the context of where it came from.
	We cannot give inmates incentives like parole and the other kind of things that deal with voluntary consent such as better housing, or maybe the right to stay at a particular prison where the study is being conducted because it's closer to your family and not 300 miles away.
	We continue to need these kinds of protections through an IRB to see that there is not overreaching.  Can it be done with the Subpart A IRB?  I think perhaps it can as long as these kinds of things are considered.  But prisoners are unique in some ways.
	One of the primary reasons, in my view, why prisoners want to get into clinical trials is because they believe they will get better healthcare that way.  They look around and they see very poor healthcare at some facilities and they think, well, they're going to watch me more, they're going to give me more tests, I'm going to be monitored more often.  I'll see specialists more often.  I'll get out to hospitals more often.  Why not?  And you know what, they're right, in many cases.
	So that is an incentive for them to do it and it's got to be very clear to them that this may not be a benefit to them.  That the drug isn't completely shown to be efficacious, at least not in a phase two trial.
	The other thing in the law that I just want to mention, we talked about the linkage between public health and correctional health and how we have, in my view, ghettoized correctional health.  We've made it a singular entity.  For a long time prisons and jails were not treating what they called "pre-existing conditions" because that's the way he came in, we don't have to deal with it.  The courts have basically made them stop that.  Then they said, well, we don't have to do discharge planning, we have them on a regimen, they're out now.  That's not our job.  And we are now seeing cases where discharge planning is coming into the court's attention.
	What we are doing is we are linking these people who move in and out of the system to public health.  Now, we can do it through government foresight, or we can do it through court mandate.  And I suggest that the better way is to approach it proactively.
	HIV, TB, Hepatitis C, don't respect institutional fences, and they move in and out of the system as the inmates do.  The other thing that we've seen is that we have eliminated Medicaid for institutions, legally, by active Congress.  And what that has had the effect of doing is increasing this ghettoization and lack of continuity.
	If we could link up the people who are on Medicaid the day before they got in, keep them on it with the same kinds of funding, we would see a lot better continuity and a lot less ghettoization.  And, of course, we would see something else that I think would be very salutary which is, if you're providing Medicaid, you've got to be accredited.  So we would find institutions have a financial incentive by that 50 percent federal copayment to get accredited with their healthcare systems.
	So that's my soap box.  I know it's not necessarily your charge as a group, but I just can't resist in Washington to bring it up.
	[Laughter.] 
	MR. ROLD:  I think if inmates believe they're in a healthcare desert, they may eat the sand to find an oasis.  And part of what we can try to do is make that desert bloom a little more.  And I think there are ways that this group can do that.  It takes money and standards; it takes integration of the system.
	But I think the most useful recommendation would be to amend Title 17 to bring corrections into the system.  And then when you're talking about research, you have linkages with the academic institutions, linkages with your existing public health, and that would be -- if I leave you with one thought, that's what I want to leave you with.
	MS. DUBLER:  Thank you, Bill.  Anne. 
	MR. ROLD:  There's questions. 
	MS. DUBLER:  Oh, I'm sorry.  Abbey.
	MS. MEYERS:  I sympathize with what you said, but prisoners have a federal right for healthcare but I don't.  There's no federal right for healthcare for any American citizen except prisoners.  And that is something that needs to be changed. 
	MR. ROLD:  I hear that a lot.  And it does need to be changed.  But there is one distinction and that is, in almost every state you can go to an emergency room and you cannot be turned down.  And -- 
	MS. MEYERS:  You're going to be billed for the rest of your life and sued if you don't pay. 
	MR. ROLD:  Well, you cannot be turned down.  An inmate is locked in that cell. 
	MS. DUBLER:  Bob. 
	DR. R. LEVINE:  I would like to make a couple of points in response.  First, what went on at Tuskeegee is bad enough without saying that they deliberately infected people with VD.  All they did is withhold treatment for syphilis from some people who were infected previously.
	When you mentioned that 85 percent of all phase one studies were done in prisons and no one wants to go back to that, that's contrary to experience.  Yes, it's true that 85 percent of all phase one drug studies were done in prison.  But when the prisoners at Jackson State Prison had a lawsuit against FDA trying to block promulgation of the regulations, they claimed that keeping them out of that kind of research was an unconstitutional deprivation of their liberty without due process.  They definitely wanted to go back to that.
	We could have predicted that because during the Commission hearings one of the prisoners said, "if you get drug company research out of the prisons, you will be removing the only people in the prison who care about the well-being of the prisoner."
	I also would like to add that, yes, it may be true that some of the principals of the Magna Charta are reflected in our Bill of Rights.  But the Magna Charta was invalidated one month after it was signed by the Pope on grounds that the signature was obtained under conditions of coercion.
	MR. ROLD:  I guess they shouldn't make us read it any more then. 
	[Laughter.] 
	MS. DUBLER:  Stan, can you top that?
	MR. RICHARDS:  No.  What I would like to do is just talk a little bit about the scope of the population and some of the health issues focusing on New York City and New York State prisons and talking more nationally.  In terms of what are we talking about with the population?  What is the number of the population?
	In New York City in the Department of Corrections in 2001 there was over 120,000 admissions to Rikers Island, 120 admissions in 2001.  The average daily census for 2001 on Rikers Island alone is 14,000 inmates in any given day.
	Detainees comprise 70 percent of that total population.  That means people come in, people flow out; go back to the same communities from which they came before they was incarcerated.
	The average length of stay for detainees was 41 days; City sentence 38 days.  So, again, we're talking about a population that's very fluid.  And upon release don't go back into some vacuum, they go back into the community from which they come.  They have the same public health concerns, the same medical concerns as does the community.
	African-Americans comprised 58 percent of the population that went through Rikers Island.  Latinos, 29.9 percent.  Again, we're talking about a population that's largely afflicted with poverty, largely afflicted with education issues and incarceration.
	In New York State, the New York State Department of Corrections operates 70 facilities; 70 facilities.  In fiscal year 2000-2001 the State prison budget was $2.25 billion.
	Blacks and Hispanics, again, account for approximately 80 percent of the inmate population although they represent just 31 percent of the population in New York State.  Eighty percent of the population is incarcerated in New York State. 
	Some time ago there was a study that showed that 75 percent of the population incarcerated in New York State prisons came from seven distinct communities in New York City.  And you can draw a correlation between the community they came from.  It was the poorest communities in New York City.  So when we talk about healthcare we talk about access to clinical trials, we talk about health concerns of not only the prisoners, but of the communities, there's a direct correlation.
	Twenty-two percent of incoming female inmates and 14 percent of incoming male inmates have Hepatitis C in New York State.  Seventy-three percent of inmates are self-reported substance abusers.  Again, when we talk about the impact on our healthcare system, not only in the community but in prisons, 73 percent report substance abuse usage.
	Eleven percent of the inmates have been diagnosed as significantly or seriously and persistently mentally ill.  Major, major issues. 
	Again, this is to emphasize two things, both an opportunity as we talk about research and protocols on research and access to clinical trials and when we talk about community in jail health there's a direct correlation and we have to put these numbers in perspective.
	For women, there are currently an estimated 950,000 women in the United States under criminal justice control.  That's in jails, in prisons, probation, parole; 950,000 women.
	Since 1980 the number of women entering prisons in the United States almost -- increased almost 400 percent, double the rate of men.  Again, when we talk about the complexity of women's health, and healthcare in the prison system and health concerns of the community, we have a large population of women in the prisons.
	According to the Bureau of Justice statistics merely a quarter, 24 percent of the women in state prisons are mentally ill.  Again, this mental ill issue comes up.  Two-thirds of the women in prison in the U.S. are women of color.  Again, we look at racial differences, we can look at economic differences, we could look at access to medical care, all of those things converge on a prison population and they are not different than community issues and community health.
	In New York State 3,500 women were incarcerated as of January 2000.  Significant numbers.
	I can tell you, when I was incarcerated, and when I first went to state prison was in 1986.  And I sat on the bus after I got sentenced and on that bus were about six women.  At that time that was really strange.  Because you didn't see women in prison.  And the conversation of those women were what type of sentence they received.  And you heard numbers like five to ten; seven and a half to 15; ten to 20; unheard of at times before.  Now those numbers are becoming reality and they are a reality both for communities and in prisons.
	New York State has one of the largest female prison populations outside of Texas and California.  As of January 1st, 2000, 54 percent of women confined in New York prisons were African-American, 29 percent were Latino.  Again, mirroring the population of men. 
	When it comes to HIV, female inmates with HIV in New York State prisons represent one-third of all HIV positive inmates in the United States.  And we're talking just in New York State.  Significant. 
	More than one in five women inmates in New York State prisons, 21.5 percent, is known to be HIV positive compared to 9.1 percent of male inmates.  Again, when we talk about access to healthcare as Jay pointed out, there's a difference between women and men both in access in healthcare in the jails and in access in healthcare in the community.
	A recent New York City Department of Health study found that 18 percent of women entering New York City jails are HIV positive compared to 7.6 percent.  Again, a distinct difference.
	At year end in 1999, the overall rate of confirmed AIDS cases among the nation's prison populations was five times the rate in the U.S. general population.
	When we talk about access to clinical trials, and we talk about access to healthcare, how can we ignore this population?  How can we say that this population is different than the communities from which we come from and from which they come from.  
	New York State has the highest number of prisoners infected with HIV of all other prison systems in the country, including the largest number of HIV-positive female inmates.  HIV and AIDS disproportionately affect women of color as everybody knows.
	That's the picture, that's what we're dealing with.  And that's the picture from the New York City perspective, from the New York State perspective and some national perspective in terms of the enormity of the population that we're dealing with and the enormity of the issue and the charge that this committee is faced with in trying to figure out how to do two things, how to protect a specific population while increasing access to healthcare, clinical trials, and improving the health and well-being of the communities from which they came.  Thank you. 
	DR. SPAULDING:  I want to make sure some people have some color now at the end where I know it's almost the break time and in one second I'll just have some slides up.
	MS. BORWHAT:  What is the attitudes and perceptions of incarcerated people as a result of the syphilis studies?  How much mistrust is there as opposed to a willingness to participate?
	MS. DUBLER:  Let me just ask a question.  You mean, what has been the impact of Tuskeegee on those people who might participate in research?
	MS. BORWHAT:  Exactly.
	MS. DUBLER:  Since we know that outside of prisons there is great suspicion in the African-American community -- 
	MS. BORWHAT:  Yes. 
	MS. DUBLER:  -- and communities of color.
	MS. BORWHAT:  Uh-huh.  Uh-huh.  Exactly.
	MS. DUBLER:  And I think that's a very important question. 
	MS. BORWHAT:  And when I've asked other people I've been told -- and this does not relate to the incarcerate populations -- that the attitude is changing and I'm just wondering if that's the same case in incarcerated populations? 
	MS. DUBLER:  Stan?
	MR. RICHARDS:  I think you're right.  The attitudes are changing in relationship to the Tuskeegee study.  When it comes to distrust, there's more distrust about the system and about whether or not the system has the inmates best interest in mind.
	There is a clear definition when you go inside about the role of corrections and it's about care, custody, and control.  And in that you have medical health, you know, health provision, mental health provision, some substance abuse treatment services.  And so the question is, what system do you trust and can you differentiate between care, custody, and control, Department of Corrections role and the role of a health professional or the role of a service provider.
	So if you had to define "distrust" it would be more in line with the system itself, whether or not the system has the best interests of the inmate in mind as opposed to whether or not participating in a clinical trial there's distrust in that sense. 
	DR. SPAULDING:  For this wrap-up session, I want to just ask the question, do the regulations as they're written right now protect inmate subjects or does it lead to unintended consequences?  And basically I'm going to show two case scenarios that I want to have people think about and see what we should do about it.
	The first scenario is a situation where a new drug becomes available.  It's an investigational drug.  And do the patients who are incarcerated have access to it?  Let's say that the phase two trials are over, it does look as if this drug is going to be something that is really going to help a condition that inmates suffer from at greater rates than the outside world.
	And there are phase three trials being set up and the correctional physician who today might not only be licensed with the normal type of license any other physician has, but as Dr. Anno put out -- mentioned this physician could also be board certified.  There is a much greater sophistication with the people who are delivering healthcare than there were years ago.  And this physician, when he or she practiced or when she practiced on the outside world knew that she could participate in these trials, she asked the question:  why can't my patients get this new drug?
	And let's look at a condition like Hepatitis C that it does affect inmates more than at a greater rate in the inside than outside.  Outside only 1.8 percent of Americans have Hepatitis C.  But there have been studies showing over 40 percent of inmates may have this condition. 
	Furthermore, a great portion of all of Americans who have Hepatitis C cycle through the correctional facilities every year and it's estimated one-third of all the patients with this condition are in a jail or prison at some point in a given year. 
	Also, the Hepatitis C is somewhat different inside as outside.  Whereas out in the community there may be a significant portion of patients who acquired their Hepatitis C through blood transfusions years ago before we had adequate screening.  Currently in jails and prisons the majority of patients with Hepatitis C acquired their Hepatitis C through parental drug use.  So the risk factors are different.  And the disease is highly relevant to correctional medicine.
	So this prison physician who wants to get this drug for her patient has a couple of options, namely three.  And looking at the regulations as they are now written, she could try to enroll her site in the larger trial.  Let's say the university where she trained down the road is going to be one of the sites that's one of the lead centers for this trial.  She could say, I want my clinic within the prison to be a site.  But if you read Section C right now, she has to have Tommy Thompson convene a panel of experts.  He then has to publish notice in the Federal Register before she can enroll and start this trial on the first patient.  And this is a cumbersome process.
	The regulations as they are written now have a provision that she could conduct this trial without controls.  But if you look at good study design, there's a reason why we have randomized control trials.  Because we can be able to differentiate between what toxicities are with the drug as opposed to without the drug.  The usual care arm is that having more side effects than the people who are getting the drug?  Also, it will be able to tell us whether or not patients benefit while on the drug is due to the drug rather than just because a disease may go away on its own.
	Also, her other option would be to wait until the FDA approves this drug and it's on the open market.  She then extrapolates the findings from the trial outside and tries to apply it to her population.  And you can say, what's wrong with that?  People are people inside as opposed to outside.  Men are men, the metabolism is different.  It's not like we're dealing with children who have a different metabolism than adults.  But there are some differences as she extrapolates the findings from the outside to the findings -- to using this drug on the inside.  There are differences in the ethnic background of the patients that maybe Hepatitis C does work differently or the virus may have a different course in African-Americans.  There is some work looking at whether or not there may be a lower success rate with certain populations over others.
	The risk factors, her patients acquired Hepatitis C while using intravenous drugs.  Well, there are other viruses you can acquire while using intravenous drugs such as the Hepatitis GBH virus.  And maybe these two viruses could interact and there might be less of a response to this new investigational drug.  The patients may be younger inside with Hepatitis C than what are the number of the patients who are being enrolled outside.
	Also, while people are incarcerated, I think we've all heard stories that you can get anything though the walls, but it is harder to ger heroine and alcohol inside as outside. 
	Mr. Richard mentioned that mental health conditions are more prevalent inside versus outside.  And this is a different population she's treating.  A lot of the drugs for Hepatitis C have psychiatric side effects.  So there are some reasons why she might not just want to wait and have a trial or even set up a trial after the drug is approved.  It's not the same population and these patients maybe deserve to have a trial looking at how this drug works in their own setting.
	That's the first trial.
	The other scenario that I want to bring up is the hypothetical situation that deals with the question of portability of drug trials.  Let's say there's a patient who has end-stage AIDS.  He's been through many, many drugs.  He's tried some investigational drugs, nothing is working, he has a detectable virus load and if things don't improve, if the viral load does not improve, there's a chance that he is going to have increasing immuno deficiency and die. 
	So, he gets enrolled in a trial at the local university clinic.  It's some new drug that may have a different mechanism.  He tries it along with the other drugs that are in this study and he finally achieves viral suppression.  He's doing great on this new drug.
	He gets incarcerated.  He's picked up for some charges, he may not be guilty because all inmates are innocent until proven guilty.  But while he's incarcerated the correctional health services says, you know, we only can use the regular drugs.  You've got to go back on the regular drugs, we can't have this investigational drug inside.  While he's incarcerated he finally goes out to court.  The charges are dropped and he'll become a statistic that he's one of the 17 percent of all AIDS patients in the country who go cycle through a correctional facility every year and he cycles, he's back in the community. 
	Back in the community he goes back on his cocktail that includes the investigational drug that worked great before he came in.  But because this drug has not been in combination with drugs that are effective and this drug has not been given, none of these drugs work anymore and he's now unresponsive to medication.  And so with lack of portability of this trial across the walls of a prison or across the walls of a jail, he no longer has his disease under control.
	So as I believe has been pointed out, the population of what is going on in jails and prisons, if you look at the media, people say have this popular perception that you lock them up and throw away the key.  The reality is people flow into a correctional facility and flow out as fast as they flow in.
	And most who enter return to the community very soon.  And this is the bigger picture, most arrestees who go to jail are out very, very soon.  And with 12 million releasees every year, most of these are from jail.  We do need to think about the portability of drugs and investigational drugs and trials as people go into a correctional facility and come out.
	So, the question is, continuing meds beyond the wall, is it a right or could it possibly lead to some of the problems of the past?  Especially for inmates who are awaiting trial, they are innocent until proven guilty, and most are in only for a short period of time.  The other issue is whether or not we are going to return to some of the past problems.  There were trials that were run for profit motives.  And I believe, Mr. Levine, you've brought up the situation where inmates wanted to be in on these trials.
	I think that we have to look at the example of in Hornbloom [ph] in "Acres of Skin" where the jail system really pressed to have people get enrolled.  And there was a profit motive behind getting these people enrolled.  And it's not for the subject's beneficence, it was really for the researcher's beneficence. 
	And there is still the question of autonomy of prison subjects.  So there are some caveats we do need to watch, but the conclusion I want to -- is that with the present wording of 45 C.F.R. 46(c) access to investigational drugs is a challenge for the prisoner/patient and I think we do need to see if we need to re-examine the way this worded right now.
	Thank you. 
	MS. DUBLER:  Thank you, Anne.  Are there any questions and comments before we take a break?  Alan.
	DR. FLEISCHMAN:  I guess I have a question.  I don't know for which of the panelists.  And that has to do with what's in it for the people who run prisons to allow research in prisons?
	I mean, I'm very sympathetic to the need of the community from which most of the prisoners come for universal access to healthcare and for high quality care in those communities.  And I could understand why some might want to use the prisons as a site for the assessment of health need and the initiation of healthcare which would then go into the communities.  And if I were in New York City, I might want to create such a system that would take care of a large number of people in need.  But that's got very little to do with research.
	And I wonder why we believe the research enterprise can actually motivate both action in that regard in terms of healthcare and then why would anyone who runs a prison system think that research was a good within their system? 
	DR. SPAULDING:  I have my light on so I'm going to hog the podium right now.  I was in a system when I was in Rhode Island that did have university-based positions come and consult.  And there were some trials that couldn't be run, but the one thing that having those university positions come in it gave credibility to the medical system.  We've got the doctors who were voted best doctors in Rhode Island coming through.  And what helps -- what's in it for them, what's in it for the correctional administrators is it does lend credibility.  It opens up a certain segment of their prison for scrutiny and allows people to realize, yes, this is decent medical care.
	MS. DUBLER:  I used to describe prison healthcare as an exercise in Kabuki drama.  That is, the prisoners' rights attorneys sued the prisons.  The prisons threw up their hands and said, we don't have the money.  The judge said, state, you must give them the money.  The prison officials said, oh, dear, we have the money, now we have to do it.  And everybody went home happy.
	What's in it for the administrators, Alan?  You don't have decent healthcare in your prisons, you have a lot of trouble.  You have prisoners who feel they are being not only deprived of their freedom, but deprived of their health.  Will all prison and jail administrators welcome the re-emergence of research in their facilities?  Of course not.  Will some?  The better ones will.
	The question is, I think the questions are, should there be some level of research that we encourage?  Should we remove the barriers to research which the ACA standards have provided?  Should we say that there are some issues of access to research that are important and fair and just for prisoners, and how can we do that within the structure of the regulations that we have? 
	MR. ROLD:  I would just add a couple of other thoughts.  Getting involved with an academic institution is of great value to the staff of the facility because they have people they can call on for ancillary matters then.  You have a good derm guy, who would you recommend on this ortho case.  And once you start getting that kind of collegiality developed and that can come from this kind of work, as I'm sure people know, that's a tremendous value to the people in that institution. 
	And the other thing about research is we've been focusing mostly on new drugs.  But the other arm of this is behavioral research.  And if we can cut recidivism and find out why people relapse, learn more about why people go through this revolving door doing a life sentence on the installment plan, we might reduce to costs of incarceration.  So it's in it for that too.
	MS. DUBLER:  Question?  Comment?  Oh, I'm sorry.  And, Susan, you were also -- Susan.
	MS. KORNETSKY:  I just want to thank the panel.  And for someone who sat on an IRB struggling with this, there are ways that certain types of research can be done, but you're absolutely correct, there are hurdles to get through.  By the time you get through doing it someone has come in and out of the prison.  So I strongly encourage this group to really think about it.  You know, are the regulations over burdensome?  Some may say it allows it, but it's just an impossible hurdle to get over currently.
	DR. SHAMOO:  Thank you.  The presentations emphasized the lack of healthcare in prison, and I understand that.  And inasmuch as lack of research on prison and institutional settings have contributed to lowering the healthcare, I understand it's relationship to access to research and clinical trial. 
	But I don't accept the lack of healthcare which is a decision or lack of decision or lack of will of the society to make prisoner have the worst healthcare system as an excuse to have those basically as guinea pigs.  And my question to you, and you have to think it through, what are the safeguards that we are not going to go back to 30 years ago what was happening to the prisoners.  And we have a whole huge issue of human rights violation of these people in addition to other problems they already have.
	MS. DUBLER:  I think it's critical that we keep that in mind.  Every time we talk about research as access to care, I can feel my inner ear itch.  Research is not access to care and it doesn't replace it.  And, indeed, these are closed institutions with big barbed wire walls where it's quite easy for excess to occur that will work to the detriment of a vulnerable population.  That's why we didn't come with any answers to the questions that Dr. Koski posed.  What we are trying to do is raise the profile of who is in prison, the sorts of requests that they've made, the change in the structure of healthcare and open again for discussion the issue of "if research, what kind?"
	Bob.
	DR. R. LEVINE:  I wanted to say that it's inappropriate to refer to the use of prisoners as "guinea pigs."  The primary study that was done in prisons was phase one drug testing.  It's already been attacked earlier today.  I think one thing that might be of interest is the research done by Zarah Fanitis [ph] and his colleagues on phase one drug testing in the State of Michigan prison system.  They looked at research which included two-thirds of a million consecutive days of prisoners' exposure to phase one drug studies.  They found one death.  One of the prisoners died in his sleep while getting a placebo.
	They found 28 adverse medical events.  They found only two cases in which these adverse events led to temporary disability and zero permanent disability.  How that provides a basis for referring to these people as "guinea pigs" is beyond me and it should be beyond the rest of you. 
	MR. ROLD:  The thing about Michigan is that there was no correctional system in the country that had more federal infusion of aid during that period.  It was, itself, a pilot project for what was then called the LEAA in trying to upgrade prisons and they published an enormous amount of literature about healthcare.
	Now, I don't know that you would have had the same result in Alabama where people were performing surgery on each other.  So I think that what Upjohn was doing which was a reputable company in Michigan is very different than some of the risks people are concerned about.
	DR. R. LEVINE:  The performance of surgery in Alabama by inmates on each other was not research.  I'm not saying that it was -- 
	[Simultaneous conversation.] 
	DR. R. LEVINE:  -- there's a lot of bad stuff that has gone on in prisons and continues to go on in prisons.  But we, the National Commission, had people come to it from multiple prison systems.  It site visited not only Jackson State, but also Vaccaville and some others and it didn't find these abuses.
	DR. CHODOSH:  I need to answer, as usual, Bob.  Lack of reporting of adverse events which we have evidence even nowadays in the outside world is no answer that there is no adverse events. 
	MS. DUBLER:  Well, taken.  We are not going to solve any other problems in the context of prison research.  If we can just solve some of those.  Someone was waiting very patiently and why don't we take a last comment and then we'll break for cookies.
	MS. MINOR:  Sorry.  My name is Carol Ann Minor again and I'm with the Federal Bureau of Prisons.  I just want to make a couple points.  The first one being that I think it's really important that you clearly differentiate between somebody who is involved in research or a trial before they were incarcerated and then they became incarcerated.  Because this is just -- I mean, it's a huge issue that is just a kind of -- I think, personally, a bureaucratic issue. 
	Here was somebody who signed up for something before he or she became a prisoner.  And now in order to continue in that, you know, you have to go through this huge hurdle of approvals and reapprovals and then get through my system.  I mean, you know, it just kind of seems not logical.
	So I think you need to really differentiate between situations like that and situations where you have somebody who wants to come in and conduct an entire trial in a prison.  Because, frankly, I mean, as a person who works in a prison, you're leery of letting people in unless they have some very valid reasons for wanting to be there, simply because of how easy it is to abuse the system, I think.  So I think that's an important distinction.  
	And, also, I do think you do need to address the voluntary prohibitions that the prison systems have because even if HHS changes their regs, I mean, that doesn't -- you still had to get into the prisons and right now we won't let you. 
	And I know that from talking with my own directors and stuff about this topic that -- I mean, we, and I'm assuming most of the state facilities are very risk averse.  And we are not going to change anything unless we have a really good feeling that the public is going to be supportive of that.  So you are not going to see prisons rushing out to change the regs without something out there that says, okay, we think this is an ethical thing to do. 
	And then the last thing I would like to say is the point that Ms. Meyers made about, you know, well, where is it that allowing these people to become involved in these trials, I mean, at what point are you giving them better options than for people who aren't incarcerated.
	And I know there was recently a big stink in California because some inmate received a transplant -- an organ transplant while there were people in the community who were still waiting on a waiting list.  So, I mean, these are real issues that have to be thought about as well. 
	MS. DUBLER:  We will return in ten minutes, thank you.
	[Brief recess taken at 3:35 p.m.]
	CHAIRPERSON MARSHALL:  We are going to reconvene.
	So we only have a short amount of time because we do want to stay on schedule.  So I'm going to devote about ten minutes to discussing brief discussion of the topic at hand because what we anticipate doing is moving forward in a substantial way in this area and today is not the day to get that work done except that my goal in the next ten minutes, at least from the committee members and ex officios is to secure permission to appoint a working group.  And I have persons in mind and have spoken to them for chairs of this or co-chairs of this group.  And then we would convene a larger group which would, by our working rules as a committee require then sort of the final sign off by you committee members on the list of people who would serve.  Does that sound like a plan, committee? 
	Then let's have maybe about, I don't know, somewhere around eight minutes for discussion and then I'll propose a working group to you.  How about that?  So I'm going to turn just sort of the eight minutes over to the panel and we'll entertain questions from the committee and ex officios and public members.  Mark.
	MR. BARNES:  I just wanted to go back to what Alan was asking.  And I guess I want maybe a different -- maybe I don't want a different answer, but what -- I guess what I'm looking for is what really -- what you guys as prison advocates, as attorneys or as healthcare givers to the prisons, what do you really think the value is of having clinical trials in prison?  I mean, what does it really matter?  It's a little bitty mouse, you know, pulling this huge healthcare infrastructure which obviously needs funding and needs better funding.  But even in the best of all scenarios, it would be like, you know, half of a percent of all the inmates who would ever be enrolled in clinical trials just because that's what the proportion of the population is.
	So I got one answer from Bill saying that it's sort of like a -- it leads to collaborative care arrangements with university physicians and others.  But I wonder if anybody else has, you know, has a different answer in addition to what Bill Rold said.
	MR. RICHARDS:  I think one of the benefits is, when you look at the prison population, the prison population is really a microcosm of the larger society and larger communities.  And if there was a way where we could protect the rights of inmates and increase access to clinical trials, what we could really study is both the benefits and the risks to behavioral -- you know, behavioral interventions or medical interventions that can then be transported to the larger community.  That in itself is a tremendous benefit.  It's a benefit to the inmate population, and it's a benefit to the larger community. 
	And, you know, for me, when I look at prisons and community I look at it in the larger context.  And I don't look at them as, you know, each different systems.  I look at them as one system feeding each other.  And as a community and as a society, we ought to look at the larger scope of the issues.  And so the benefits to working and bringing clinical trials to inmates is not benefits to the inmate themselves, but it's to the community. 
	I have a brother and a sister and a nephew who all are affected with HIV.  My sister died from AIDS.  And, my brother just was released from prison and he was on a number of cocktails that made a difference in his life.  And today he's living.  His viral load is undetectable and he has tremendous benefits with that.  And because he participated in that, that's going to have a benefit for somebody else.  Not necessarily in prison, but it's going to have a benefit for somebody in the community.  And when you look at it like that, everybody benefits from it.  It should never be a discussion about why or either or.  It should be about it's the benefit of the larger community.  It benefits the larger community.
	DR. ANNO:  I guess my position is a little bit different.  I'm not interested solely in clinical trials.  I'm interested in increasing research within correctional healthcare simply because we don't know anything about our patients and because we're not doing a good job.  We're duplicating a lot of services.  We don't have access to good data on the outside.  There's no linkage between the healthcare communities.
	My interest, as I say is a broader one.  I agree that if it's focus is simply on the clinical trials, that isn't going to affect the entire healthcare delivery system or most of the people that are incarcerated.  But I guess the position that I come to is that the current federal regulations are not -- they are complicated and not well understood.  And whatever can be done to clarify the exact provisions of the areas that are permissible and prohibited will help, perhaps, my broader research mission which right now gets thwarted at every turn because there is a perception that all research is prohibited within institutions.  Even though that's not what the regulations say, but that's currently the perception of prisons and jail systems out there.
	We've heard the woman from the Federal Bureau of Prisons say that the American Correctional Association standards prohibit research.  Those at the National Commission on Correctional Healthcare do not.  However, there is this feeling that you can't do any research within institutions.
	DR. SPAULDING:  I can just give you an example of research that it's not research that is prohibited right now, but it's important research.
	The CDC along with HERSA is conducting a seven site study trying to find out the best way to help inmates who are HIV infected with discharge planning back into the community.  And there are many variables in how you deliver services inside, how you link those services to the outside, how you follow-up on the outside.
	What is the best way?  By having a seven site trial, seven states that are highly affected by the HIV epidemic, we can say, you know, the states that maybe offer HIV screening routinely rather than only after people sign many forms and they may be able to get all the patients enrolled in drug trials that's easier to get them -- not drug trials, but on drugs, that it might be easier to get them access to care if they do routine testing with opting out.
	If you deliver your HIV education in with peer education, maybe you engage inmates more than if you have outsiders come in and community-based organizations.  You can compare many different models, do you have to start your discharge planning six months beforehand, three months beforehand, or can it just start the minute someone hits the door or about the week before they leave.  And by having these many different sites with the heavy evaluation component, we can learn the best way to give HIV care that's linked to outside care.  So -- 
	MS. MEYERS:  I'm disturbed.  All I'm hearing about this thing about drug testing.  And I think there's a lot of other testing.  If we did some testing on the behavioral aspects of these people in jail, maybe we could find out a way to prevent criminal behavior.  So I think we really need to look at this according to -- there really shouldn't be the ordinary commercial drug research on weight loss pills and wrinkle removers and things like that.  It should be something that is more directly related to epidemics that occur in prison to be behavioral aspects, to social aspects, to mental health, things like that, and have -- make sure that we don't run into the same problem of some warden deciding he wants to make some money or a state government wants to have some income coming in by charging Hoffman LaRoche so many millions of dollars for access to these kids.  You know what I mean?
	MR. ROLD:  I think that the message that could be given out is the opposite of the message that's being given now is that the research can be done.  Not that the research has to go through all these hurdles, although some hurdles may be necessary.  What's interesting about the behavioral research that you talk about is that comes usually under the first two categories of permitted research which do not require a Federal Register and a lot of the other cumbersome things, yet they're still not doing that.  Why is that?  And I think you should think about that.
	Right now these regulations have all the clarify and grace of the Internal Revenue Code and we really can do better, I think. 
	MS. MEYERS:  Would it be enough to just simplify the regulations? 
	MR. ROLD:  It's a good start.
	CHAIRPERSON MARSHALL:  Bob Levine.
	DR. R. LEVINE:  Thank you.  I wan to say a little something about the National Commission's position since that's where these most restrictive stands originated.
	The National Commission never found that there was anything wrong with doing research on prisoners.  The National Commission -- and this is something that I wrote at the time, in 1977 -- I think confused the agenda of prison reform with protection of human subjects.
	They erected a lot of specific requirements that would have to be met in order to justify doing research involving prisoners.  The requirements included access to telethons, private living quarters and so on and so on.  The Commission's great miscalculation is that they thought that the drug industry had such a strong vested interest in doing research in prison that they would undertake all of these reforms.  They were warned by the prisoners that this would not happen.  And what the drug companies did instead is they simply left and started doing their research on their own employees among other people.
	Now, the other point I wanted to address is whether or not prisons are a good place to do clinical trials.  Prisons are a lousy place to do clinical trials.  In a clinical trial what you want is a lot of people with the same disease.  And you don't find that.  One of the strongest arguments against allowing biomedical research in prison is that you can justify it with all of the other so-called vulnerable groups, a special health need.
	Children get certain diseases that make them eligible to be research subjects.  People with mental incapacity, the same thing.  People in prisons don't have any particular disease.  There may be a high incidence of things like Hepatitis C or HIV infection.
	So prisons are not a place to do controlled clinical trials.  They are, however, a good place to do phase one drug testing because then what you require is people with no disease.  And they're also a good place to do research on basic physiological mechanisms. 
	The complication rate -- Adil said earlier that I was speaking from a position of absence of evidence.  That's not the case.  There's plenty of evidence and I'm not going to take up the rest of your afternoon citing it.  But I can tell you where to find it.
	There's plenty of evidence that phase one drug testing causes almost no injury.  Thank you.
	CHAIRPERSON MARSHALL:  Susan.
	MS. KORNETSKY:  Bob, since we're bringing up the National Commission, when the regs were written the issue of someone sort of starting a trial outside and then being incarcerated, was that your understanding of what those regulations were written to apply to?  Or is this a new interpretation?
	DR. R. LEVINE:  Thank you.  That particular issue was not addressed by the Commission.  But the whole idea of all of the Commission's findings with regard to prisoners and with regard to other captive populations is that people would take advantage of people who were, as the Commission put it, administratively available.  You know, you want a thousand people, they've got them in this prison, or they've got them in this state hospital for mentally retarded, the Willowbrook studies and so on.
	And what the Commission was -- the way they entered the correction in the children's report because it had more time to think about it is they said, you can't involve only children who are wards of the state.  You've got to show that this is legitimate because you are making this equally available to children who are not wards of the state.  I think if they had written the prisoner report after the children's report, they might have had something like that.  But the idea of somebody who is involved in a clinical trial of cancer chemotherapy who then gets picked up on a drunk driving charge and immediately you've got to apply the prisoner regulations to the protocol, that was the furthest thing from the minds of those who wrote those recommendations.
	Thank you.
	MR. ROLD:  To follow-up on that just a bit --
	CHAIRPERSON MARSHALL:  I am going to take this opportunity, that's just the perfect segue for us to move from what was perhaps intended, at least in part, when the regs were written to where we find ourselves today.  And I would like to propose to the committee that we move forward with what we have been charged to do by the Director of the Office of Human Research Protections and that we convene a working group.  That the working group at least at a beginning be comprised of the persons who sit on the panel before you, that we have three co-chairs.  That Nancy Dubler and Stanley Richards be joined by one of our committee members and that that person be Mark Barnes.  Who could resist the combination of Nancy Dubler and Mark Barnes?
	And so I ask for the Committee's permission to move ahead with that plan with the understanding that there would be further persons suggested to the committee for additional members of the workgroup be they committee members, be they ex officio members, be they public members sitting out there in the audience, let us hear from you.  Or folks that Nancy or others may feel would be appropriate as members of the group.  So could I put this before you?  
	And I will put it before you.  I don't know whether you have items for discussion.  We could perhaps vote.
	Anyone have any discussion about that plan? 
	[No response.] 
	CHAIRPERSON MARSHALL:  Objections?
	Alan.
	DR. FLEISCHMAN:  I would just ask our panelists to see if we can find some folks who are in the for-profit enterprise of running prisons to join this group so we can get a little reality testing from their perspective as well as, you know, perhaps there is, in the public sector a similar administrator at a place like Rikers. 
	But I'm a little troubled.  I love the ideas we're hearing.  I have a feeling that there's mor consistency than discordance.  And we should at least -- I mean, coming from the experience of a workgroup that continues to be impacted upon by careful thoughtful criticism, I think we should have that available. 
	CHAIRPERSON MARSHALL:  Phil.
	DR. RUBIN:  Philip Rubin, National Science Foundation.  I would like to suggest somebody like perhaps Carolyn Smith who was speaking before who represents the Bureau of Prisons.  Somebody like that.  I'm not volunteering for her.  Thank you. 
	[Laughter.] 
	CHAIRPERSON MARSHALL:  Thank you.  Nancy.
	MS. DUBLER:  Prison and jail health care and research in prisons cries out for a stakeholder analysis.  If you have all the people around the table, and that should be the goal of the working group and they can yell at each other beforehand, they won't yell at each other afterwards.  So having everyone at the table is a prerequisite for going ahead with the working group.
	Prisons -- privatization of prisons is not a great issue, but privatization of medical care in prisons is a huge issue.  About 40 percent of the medical care in the U.S. is provided under private contract.  So that sort of person has to sit at the table. 
	I just want to sum up by thanking the panel enormously and thanking all of you for your thoughtful questions and comments and pointing out that the goal of this working group is not to do bad.  And there's a great opportunity to do bad when you wander into prisons and jails.  The goal of prisons and jails is to confine and punish.  The goal of healthcare is to diagnose, comfort and cure.  Those don't live compatibly and comfortably together.
	The research that I think we want to look at will be of many sorts, not just clinical trial.  Clinical trials are a very small part of the sorts of research that I hope the panel will consider.  Epidemiological research.  We deinstitutionalize the mental institutions.  We didn't build community facilities.  Guess where they went?  
	There's a huge amount of research to be done on the incidence and prevalence and the construction of mental illness.  And prisons and jails are the place where many mentally ill people are now "treated."
	Social and behavioral research, issues of social development, there are huge numbers of areas that we could look at that I think would not only enhance the lives of prisoners, but teach us something about the problems of a huge segment of our population and be able to take those data and put them into an effective national public health program.  So that will be, I think, our goal. 
	CHAIRPERSON MARSHALL:  I just want to clarify for the record then that we are in agreement as a committee that we will move forward with this working group and that we have your permission.  Great, wonderful.
	Nancy, thank you and all of your panel members for I think a -- in some sense shocking, I mean that in a good way.  These are things we need to know and move on and think about and do some good work on.
	So thank each and every one of you for spending your afternoon with us.  We appreciate it. 
	[Applause.] 
	CHAIRPERSON MARSHALL:  Onward.  We have invited Jack Schwartz who is an attorney.  He's chief counsel in the Health Policy Division of the Attorney General's Office of the State of Maryland. 
	Maryland was the first and I'm not sure whether they are still the only -- but Jack will enlighten us -- state to look at their own legislation regarding research with human beings.  And that's something that's come up in discussion, I think, in at least two contexts today.  And so we thought that it might be helpful to us in our work in informed consent and research with the decisionally impaired if we -- or those who lack decisional capacity -- if hear about the experience in Maryland.
	So, thank you so much for joining us today, Jack.  We appreciate you being here.
	MR. SCHWARTZ:  I'm glad to be here.  I think I find two things interesting about this legislation.  One is its content and the other, perhaps even more interesting, is the fact that it passed.
	State legislatures do not, as a rule, pass legislation that affects the research enterprise generally.  State legislatures commonly pass legislation affecting a particular type of research, stem cell or fetal tissue, or particular venues for research, prisons or nursing homes.  But there are only three other states that have enacted legislation kind of affecting the research enterprise across the board, New York, Virginia, and California.  So Maryland becomes the fourth.
	I'll spend, therefore, a little bit of time in case the committee is interested in the possibility of replicating the Maryland experience in what I think the factors are that led to this enactment.  And, since our grandchildren may be sitting here before Congress ever passes anything -- 
	[Laughter.] 
	MR. SCHWARTZ:  -- analysis of the circumstances under which a state legislature did so may be of interest.
	Let me just get the basic information out of the way for the lawyers and others in the room who want to find this thing.  It was enacted as House Bill 917 in the Maryland Legislative Session of 2002.  We are blessed in Maryland by the fact that the legislature meets for only 90 days annually and the bill was enacted in this past session.  It will be codified in the provision of a health general article that I've got on the slide.  And it will become effective on October 1st.  I'll talk a little bit more later about what it will mean to become effective.  There are some issues related to that.
	But first I'll talk for a little bit about how this thing passed and what the circumstances were that allowed it to pass.
	There's a political scientist named John Kingdon who has done some interesting work in examining the conditions that have to be in place for controversial legislation on any major topic to pass.  He focused on Congress, but I think the same criteria applied at the state level as well.
	First of all, a situation has to become a problem.  A situation is a description of a state of facts about the world usually undesirable.  And a problem is a situation about which something needs to be done in the belief of legislators.  There are hosts of situations that never make it onto the policy agenda.  And so the first step in enacting any piece of legislation is for those who enact it to perceive that there is a problem, i.e., something that they need to do something about as opposed to a mere situation. 
	So a question about this bill is, what made research in the protection of human subjects in research a problem that a state legislature thought it needed to do something about?
	A second precondition for the enactment of legislation of any consequence is that there not only be a problem, but that there be something that approaches rough consensus about a solution to the problem.  Legislators need to see that those affected by a bill or those who are supposedly expert in the area believe that there is actually a solution.
	A problem without a solution leads to no legislation.  See, for example, the problem universally recognized of the inadequacy in health insurance in this country.  However, it is disagreement about the solution that is the primary barrier to the enactment of legislation.
	And, finally, if there is a consensus about a solution to the problem that has been recognized or defined, then the solution needs to be consistent with the dominant ideology.  There needs to be receptiveness on the part of the political power structure in the legislature to the proposal.  In other words, there needs to be a political window of opportunity which is sometimes open only briefly.  And if it closes, then it's too bad and no matter what solution you have to the problem, you're not going to get anywhere.
	Research is not generally thought of as a problem by state legislatures.  It's not thought of at all.  It doesn't get them re-elected.  It's not schools, it's not crime, it's not highways, it's not any of the things that they always care about.  So, what changed?  Why did this become something that they actually paid attention to?  Three factors, I think, all of which generated a huge amount of attention somewhat nationally and especially in the local press in Baltimore.
	The death of Ellen Roche, I don't know if you know the name, but that's the volunteer in an asthma-related study at Hopkins Bayview Campus who died in the course of her participation in research.  Shortly thereafter OHRP suspended all federally funded research at Johns Hopkins for a short period of time finding systemic deficiencies in the manner in which research was reviewed at Hopkins.
	And not long after that, the Maryland Court of Appeals, Maryland's highest Court, decided a case involving a study of the comparative methods of lead paint abatement, the comparative efficacy of these methods where children were the subjects of the research.  The case went to the Court of Appeals on a relatively narrow issue about researcher's duty and the court decided that issue and went further by excoriating what it saw as the deficient ethics of the particular research, and, indeed, deficiencies in the superintendents of research generally.
	The court went out of its way to be critical of the way in which subjects, especially children, are protected in research.
	So you can only imagine the cumulative effect of these three events on legislators in Maryland.  They kept reading story after story about supposed serious problems in research.  A couple of legislative committees decided to hold an informational hearing in the wake of the Kennedy Krieger case.  They were being lobbied in all sorts of directions potentially to respond to the case through legislation and they wanted to try to sort things out.
	At the hearing the hearing sort of started out as the question, do we need to legislate and respond to the Kennedy Krieger case.  And after a while it became clear to the committees that no they didn't. But there were at least a couple of the members, the Chairman and another member were absolutely astonished to hear that not all human subject research was subject to regulation.  I had to tell them that six or seven times.  They couldn't believe it that there could be this gap in the regulations.  And they were also interested or disturbed by the issue of whether IRBs really do have an adequate process for reviewing research and providing appropriate priority to the protection of subjects.
	So research and the protection of subjects became a problem, at least in the mind of key legislators in Maryland.  Okay.  It's a problem.  What's the solution to the problem?  The problem now being defined more or less loosely as closing the regulatory gap and improving IRB processes.
	Well, the first try at a solution was a draft piece of legislation that one of the most interested members circulated in draft for comment.  It featured certain informed consent requirements that would have been absolutely unique to Maryland.  It would have imposed requirements on IRBs that would have been unique to Maryland, a three-year term limit for service on an IRB.  And the requirement that there be a specialist member, "in the field of research under review."  And it would have given members of the public unqualified access to minutes of IRBs.  This draft did not meet with universal support.  Indeed, it met with universal opposition from the research universities and from me and the attorney general's office.
	The provision on the three-year term limit seemed to me quite unwise and potentially crippling to IRB work.  The specialist member business was quite confusing.  Sometimes there are genuine pieces of confidential commercial information in IRB minutes so unqualified access seemed quite mistaken.
	So the legislator tried again.  And actually by this time the legislative session had begun so he introduced the bill.  And if you get a copy of the -- the members of the committee have a copy of the bill in their binder, you can be able to see the bill as introduced because the way this thing is reproduced, it prints the bill as introduced and then shows amendments.  So you can see the changes through the process.
	The bill as introduced had somewhat paralleling the way it's been done in those other states, it would have imposed certain specified informed consent and IRB review requirements on all research by saying, if you do human subject research in Maryland, you must follow the following requirements.
	And then it specified certain language with respect to informed consent and IRB review that attempted to parallel the common rules language.  And it provided that IRB minutes were to be made available without any requests by IRBs or their institutions but permitted redaction of confidential or privileged material.  And it also specified what needed to be included in IRB minutes, an interesting provision that I personally regret fell by the wayside.
	Essentially the bill as introduced took some of the comments that have appeared in various OHRP compliance letters about what ought to be in IRB minutes in order to evidence that the IRB has actually paid attention to the matters that it is supposed to and it specified that in the law.  You are to include in your minutes a discussion of risk, a discussion of benefit if there is any, and so forth.  That was in the bill.
	The Attorney General's Office in Maryland supported the bill.  Advocates including your colleague, Adil Shamoo, testified in support of the bill.  Johns Hopkins said it supported the bill, "in principle."  Which was a delicate way of saying that it was unhappy.  Hopkins, you'll understand, was in an awfully difficult position in terms of its public relations situation given what had happened.  So Hopkins was, I believe, desperate to avoid the newspaper story that says, Hopkins opposes human protection bill.  Hence, they supported it in principle. 
	The University of Maryland, curiously perhaps unburdened by what had happened to Hopkins was not reticent about opposing the bill and an organization representing biotech companies likewise opposed the bill.  It was the opposition that one would have expected, at least in terms of buzz words although in my view a little content.  The University argued that the bill was burdensome and unnecessary.  The biotech council not understanding the bill simply spoke about over regulation and not wishing to send a bad signal about Maryland's business climate.
	And Hopkins allowed as how it was worried from its perspective about being faced with duplicative or inconsistent regulatory regimes which was, at least in theory, a legitimate concern.  Whether it was in reality a legitimate concern given how the bill was worded, I'm less sure. 
	This was fairly formidable opposition.  I figured the bill would die.  But it didn't.  The sponsor, with some help, got some amendments to simplify the drafting of the bill so that the consent, informed consent and IRB review requirements simply incorporated the common rule as distinct from having separate Maryland language on those topics.
	The provision on IRB minutes, and I'll talk a little bit more in detail about these things preserved access upon request now, but eliminated all the language about what had to be in IRB minutes and the role of the Maryland Attorney General, a potentially looming force in this area, was limited.
	How come it passed politically?  Well, the bill sponsor was tenacious.  He wanted a bill and was willing to fight for it.  If you don't have somebody like that, if you have a sponsor who puts in a bill because somebody asked him or her to put the bill in and doesn't really have a personal commitment to it, then legislation on this topic will not pass, not in Congress, not in the state legislature, not anywhere.  You need a committed sponsor who will be willing to fight for the bill and educate other members.  And you need, or at least we had here, a committee chairman who was supportive of the concepts of the legislation.
	There was strong advocacy both from members of the public and from the Attorney General's Office within the government thus giving the bill a certain air of legitimacy.  It was helpful that the major research universities were willing to negotiate.  They didn't.  I mean, they opposed it, but ultimately they were willing to negotiate.
	And the private sector opposition was fairly perfunctory.  I mentioned the biotech council, but they just showed up and testified.  No serious money was spent on lobbyists.  I still don't know why because there generally is with state legislation on this topic.  But they weren't there.  Big pharma chose to spend its money elsewhere.
	So the bill ultimately passed with essentially no opposition.
	Here's what it does:  First of all, it fills the regulatory gap so all human subject research conducted in Maryland must comply with either HHS or FDA regs, not just the Common Rule.  But if you're doing pediatric research privately funded, you know, outside a research university therefore you're not already subject to an assurance, you are required to comply with Subpart D.
	My view is, this has no effect on the major research institutes because they already have entered assurances with respect to all of their research. 
	The bill preserves the exemptions and waivers with respect to consent that are authorized under the federal regulations.  So the bill does not force someone to refrain from invoking an exemption if such is available under the federal regs. 
	There is the nice question about, the bill becomes effective October 1st.  Does it apply to research started before October 1st or only research that's undertaken after October 1st?  No one has asked me what I think about that sort of wearing my official attorney general's hat because they would not like the answer I would give and hence they don't want to ask me. 
	[Laughter.] 
	MR. SCHWARTZ:  I think all research, whenever it started has to comply.  What that may mean for ongoing research has to do with continuing review as opposed to initial review.  But that's what I think. 
	The access to minutes provision I really think is interesting.  I don't know of any other legal requirement of this kind except to the extent, of course, that Freedom of Information Act already applies to IRBs within the federal government and state access to information laws already applies to IRBs that operate out of state universities.  So people have had limited tools to gain access to IRB minutes or minutes of certain IRBs in the past.  But I'm not aware of any other requirement that rather sweepingly says to IRBs, if a member of the public asks for the minutes, you've got to give it to them.  And I think that's an important step toward greater accountability to the public.
	The law provides that, "confidential or privileged information may be redacted before the minutes are made available."  So what's confidential or privileged?  Privileged is a relatively technical term of art.  Confidential is a rather more open textured.  So if IRB minutes discuss an adverse event, for example, is that confidential?  I don't really have an opinion about that yet.
	Another issue, again, people started to ask me that is question and then abruptly ended their question, whether access is granted to all minutes whenever they were created, or only minutes of IRBs that are created after October 1.  Because, remember, the bill is effective October 1.
	And my office, the Maryland Attorney General's Office, has some language in the bill that gives us some limited enforcement authority.  It's in there because OHRP doesn't have jurisdiction over research that is not federally funded or at an assurance institution.  So somebody has got to be able to enforce the bill for the privately funded research, so it's us.
	The authority is relatively limited.  The Attorney General's Office does not have authority to regulate, does not have authority to impose penalties, we can't cut off the flow of money like OHRP can because there isn't any flow of money from us.  And all we can do is go to court and seek an injunction requiring somebody to comply with the law.
	We haven't been given any money for an enforcement unit.  So it's going to be a complaint-driven operation.  There is no other way to do it.  There will be some whistleblowers, I assume, and if there are, we will investigate with existing resources, but we are not setting up a bureucracy to deal with complaints about research abuse in Maryland.  And the law makes specific reference to the fact that we are supposed to coordinate with, and depending on what OHRP or the FDA decides to defer to the judgment reached by federal officials so that the language is there to make it clear that we are not to second-guess federal judgments where federal agencies do have jurisdiction.
	And here is the somewhat bulky web address.  If you want, we've posted some information about the legislation on the Maryland Attorney General's web site.  So there's a link to the bill, there are a couple of letters that have been written about the bill, and I've now just put up links for those research institute -- not institution, those researchers who on October 1st will find themselves subject to the bill, links to OHRP and the FDA so people can start to get basic information about what they need to do to comply.
	And with that I would be happy to invite questions. 
	CHAIRPERSON MARSHALL:  Why don't we just start at the end of the table.  I see Bob, I see Alan, I see Mark, I see Susan, I see Margaret.  Bob Rich.
	DR. RICH:  No. 
	CHAIRPERSON MARSHALL:  All right.  Alan.
	DR. FLEISCHMAN:  Jack, this seems like a very reasonable bill.  I don't know what problem it's really going to solve in the state, but I've got two questions for you that are related.
	One is, did that fair-sized group in Bethesda weigh in, in interest concerning this bill?  I understand they're federally funded. 
	And the second question is, can you give us your impression of the impact of the Court of Appeals in the Kennedy Krieger Bill on research in Maryland on Children? 
	MR. SCHWARTZ:  Taking the first question first, the fair-sized research facility in Bethesda, Maryland, well, no one from NIH participated during the deliberations about the bill.  Perhaps that's because they might have been given legal advise that as a federal enclave they are not subject to Maryland law which is probably correct.  Of course, it would affect -- and it wouldn't affect any of their funded research, extramural research because all such research was already subject to the common rule.  They've subsequently been interested in -- I mean, learning about the bill, but there was no participation during the time of the bill's consideration by any representative of NIH or any of the institutes there.
	With respect to the Kennedy Krieger decision and its impact on pediatric research in Maryland, while there were sort of two steps in the Court's decision, there was a decision in August 2001 which certain wording in the decision with respect to severe limitations on the authority of parents to give permission for their children's participation in research coupled with the court's slovenly wording, coupled with its utter inattention to trying to correlate what it was saying to Subpart D and the categories there led to great alarm among pediatric and other researchers in Maryland and considerable concern that pediatric research might essentially have to shut down.  And that was part of the stimulus for the legislative hearing that I mentioned early on.
	Hopkins and others were saying to the legislature, you have to bail us out with legislation. 
	Then in September the court in denying the motion for reconsideration that had been filed issued a so-called "explanation" of what it meant.  And while the explanation itself had certain delphic aspects to it, it could be interpreted and has been interpreted, I believe, as allowing parental consent in Maryland -- parental permission, more exactly, for either minimal risk research in terms of the Subpart D categories or research whatever its risk character, where there's a reasonable prospect of direct medical benefit.  And the research institutions at least believe that nearly all of their research fits within one or the other of those two now permissible categories.  Hence, at least as far as I've heard, there has not been a dramatic impact of the aspect of the decision with respect to parental authority. 
	Now, there are other aspects of the decision, the excoriation of the research -- the ethics of the researchers, the damning of IRBs as in-house organs that are slave to the cash flow considerations of the institutions.  All those sorts of criticisms reverberate but don't have, I think, any immediate impact on the conduct of research. 
	CHAIRPERSON MARSHALL:  You don't have to sugarcoat things for us, we can take it.  
	[Laughter.] 
	CHAIRPERSON MARSHALL:  Mark.
	MR. BARNES:  Yes, just a couple of things.  One is not so much -- my question with the NIH and the Veterans Hospitals is not so much about the Common Rule coverage because they're covered anyway.  The question is about the access to the minutes.  And my first question is, do you know what the VA Hospitals and the NIH have done around or on the issue of access to the IRB minutes?
	The second question -- I forget the second question.  Oh, the second question was this.  I just wonder what the sponsor of the bill thinks that he or she was really accomplishing in regard to the transparence in the IRB minutes because in fact the transparency of the IRB minutes would not, I think, by anyone's reckoning actually have prevented the hexamethonium study at Johns Hopkins.  I mean, it would have taken -- I mean, IRB minutes don't have that much detail in them, even the best written IRB minutes, to understand the entire protocol and whether anything is FDA approved or not, or whether there's an adverse event or not, or whether there's been a -- you know, the scientific review doesn't really go into the IRB minutes.  So I wonder, I mean, what was gained?
	MR. SCHWARTZ:  The first question, I have no idea about VA IRB minutes.  There have been, I understand, Alan Sandler would be a better source on this, but I understand there have been periodic requests for under the Federal Freedom of Information Act for minutes of IRBs located at NIH and those requests have been complied with.  So I don't think it's a startling development assuming that they would choose to comply with Maryland law.  It really shouldn't make any difference. 
	With respect to the transparency, well, I don't know, you may be right that if minutes are scant and cryptic, then merely having disclosure of these uninformative minutes may not change much.  However, if IRBs are paying attention to what OHRP is saying in its criticism of the inadequacy of minutes of particular IRBs that come to their attention, then IRBs better be reforming their practices with respect to minutes in order to identify in some detail whether they have engaged the issues that under the regulation they are required to engage and how they decided those issues.
	I mean, to take an example, if they are going to waive written documentation of informed consent they're supposed to make certain findings and the minutes should reflect that.  And they're going to get gigged by OHRP if the minutes don't.
	So the hope or the expectation maybe even of the sponsor was that if IRBs are aware that a reporter for the Baltimore Sun with time on her hands may ask for minutes, then it will improve the specificity and clarity of the minutes.  And if you improve the specificity and clarity of the minutes, there may be a rebound effect positively on the discussion that there may actually be better organized and clearer discussion.  These may be vain hopes, but there seemed to be little downside to trying it and see.
	CHAIRPERSON MARSHALL:  John and then Sandy --
	DR. MATHER:  John Mather with the VA.  Mark, maybe I can help a little bit because there's a nice little wrinkle here with respect to Maryland.  In general IRB minutes in the VA under the Freedom of Information we have learned have to be turned over.  But then the Privacy Act kicks in so we can redact out personal identifiers.  We also have in the VA requirement that anything that involves mental health, sickle cell, and HIV also has to be redacted out.  So very suddenly the minutes can get very porous.
	But in the VA we require that where we rely on the VA that it may have its own IRB or can rely on that of the academic affiliate.  It turns out at the Maryland Healthcare System of the VA we rely on the University of Maryland's IRB and there's an arrangement there as happens in some 40-odd instances around the country. 
	So what happens in Maryland is if somebody asks for the minutes of the IRB at Maryland, I believe Maryland now has four IRBs, we understand that the University of Maryland in making those minutes available will have to go back to the VA and double-check if there's anything there about the VA that its done its work for appropriately redacted otherwise there is a violation of federal law as we are required.  So there's a nice little wrinkle there at Maryland. 
	CHAIRPERSON MARSHALL:  Thank you for clarifying that.  Susan and Sandy I think were both on point.
	MS. KORNETSKY:  I just want to talk about the IRB minutes.  Because as someone who has been writing IRB minutes for 18 years, I would say that many institutions, it's true, there are elements that have to be there in the regulations, but many IRBs have gone to the point of even going above and beyond that.  And so I think if this were to happen in the state that I work, my minutes would become a lot vaguer just to meet the minimum requirements of the federal regulations.
	MR. SCHWARTZ:  Well, the law of unintended consequences could happen here as elsewhere. 
	[Laughter.] 
	MR. SCHWARTZ:  I mean, it's hard to know.  One could do a baseline study of minutes before and then after.  I'm not sure there is any other way to really test it.  My sense from looking at minutes of -- well, I haven't done a study, but there is no indication that minutes of IRBs that have been subject to disclosure laws either FOIA or in Maryland, at least, our equivalent law, there is no indication that those minutes have become sparser over the years merely because there was the possibility of disclosure.
	There are, you know, other hydraulic forces at work that may tend toward greater discussion in minutes.  But you're right, that could happen.  And if it does, that would be an unintended and unfortunate consequence.
	DR. CHODOSH:  I'm right along the same line as Susan except that I have greater fears than just the fact that the minutes may get changed, but that individuals are going to be even more reluctant to be IRB members because they will be afraid of what the consequences would be of having such minutes available, widely available, and do not want to become subject to a class action against the IRB and it will be more difficult to get people to serve on IRBs, particularly smart guys or smart women who realize that they now have some increased risks of doing something that they get very little for except self satisfaction.  It's happening now.
	You add to this another level in which minutes can be "readily available" and I would be willing to bet that there will be, again, fewer people who even if they're chosen to be IRB members, would be reluctant to be very open about what they say at a meeting so that it's a whole mishmash of balance of how do you get proper discussion of protocols with true feelings being manifested if people are fearful of what's going to end up in minutes.
	MR. SCHWARTZ:  I can't say that that's not possible, but it seems to me that -- I mean, on the rare instances, at least so far, when IRBs or IRB members have been sued, it's when somebody has gotten badly hurt and the Plaintiff's lawyer is going to get those minutes.  You don't need a public information law for the one who sues to get access to the minutes.  So if fear of being a defendant in a lawsuit is a factor in preventing people from being IRB members, I have a hunch that that fear is already out there.  I know you may say it is heightened by this kind of law, and I can't argue with that. 
	DR. CHODOSH:  I mean, it's like having ambulance chasers, you know.  Once you realize that such things are available, they're a place to "mine" to find cases that may be very good to go after and to encourage some subjects to actually complain, et cetera.  I just think that it's full of problems.
	CHAIRPERSON MARSHALL:  I have Margaret, then Abbey, and then Bob, and we'll stop there.
	MS. BORWHAT:  Since enforcement is complaint driven, is there a component to this legislation that educates and informs the public?
	And my second question is, are there significant differences between the Maryland law, New York, Virginia, and California? 
	MR. SCHWARTZ:  Well, with respect to the first question, about public education, no, there's no money for that.  So, in terms of probably doing public education in any effective way that generally costs at least some money and there isn't any money for that.  We'll do the routine stuff, you know, already have stuff posted on the web and we'll send out material, but, no, I don't realistically think that there is what we would recognize as a coherent effort at public education that's part of this legislation.
	And comparisons between this law and New York, California, and Virginia; well, California with its informed consent requirements looks more like the way this bill did when it was introduced.  That is to say, California law and similarly New York and Virginia has a set of state law requirements that are addressed to people who are not otherwise subject to federal requirements.  In effect, there is a state law on informed consent or in the case of New York and Virginia on informed consent and IRB review and then there's an exception created for those who are subject, carve out for those subject to federal requirements.
	The Maryland law is, if you will, the flip side.  It says everybody is subject to the federal regulations. 
	MR. BARNES:  Plus none of those has the access to IRB minutes provisions in them.
	MR. SCHWARTZ:  Correct.  Nobody else has the access to IRB minutes provisions.
	CHAIRPERSON MARSHALL:  Abbey and then Bob.
	MS. MEYERS:  I think the access to the IRB minutes is an excellent idea.  Because I think investigators would be loathe to write up informed consent forms that didn't contain things that were discussed at the IRB.  And I think that that's been a problem.  For example, in the Gelsinger case the informed consent document that finally got to Jesse Gelsinger didn't mention that some monkeys had died.  And yet the original informed consent document that the RAC saw had that in it.  And so I think it's a good idea, but I would also like to see, and I would have, if I lived in Maryland, I would have pushed for the informed consent document being made available to the public too.
	Because when you have a multi-site study you could have a study going on at ten different sites and you find that they have ten different informed consent forms, and some of them have important information and some of them don't, and I think that having an open policy allowing people to see the minutes, to see the informed consent documents will stop some of the things that are being subverted now.
	CHAIRPERSON MARSHALL:  Bob.
	DR. R. LEVINE:  In response to somebody's concern that making committee minutes available under Freedom of Information you said, well, in case something really goes wrong, the IRB members might be mentioned in lawsuits anyway.  That's the sort of thing that frightens people on IRBs until they're told that they're -- as far as I know, there has never been a case in the United States where the judgment was found against an IRB member for performing as an IRB member.
	Also, there's never been a case reported in which an investigator has been liable for doing anything that was done in a court with an IRB-approved protocol.  I think though you have to take seriously what things create disincentives to serve on the IRB.  All too often people rebut that.  They say, it's not the purpose of public policy to make IRBs a happy place for investigators or IRB members.  That misses the point completely.
	The point is that you have to have the best and the brightest people in the community serving on the IRB in order to get what protection can be obtained from the review by the IRB.  And if you remove the incentives to serve on the IRB, then you're not going to get the benefits of having the best and the brightest serve on the IRB.
	I've written IRB minutes even longer than Susan.  I did it for a period of 30 plus years.  I can remember in the early days when there was competition to be on the IRB.  When I first became chair of the IRB the chief administrator of the University Hospital was a member.  Some department chairs and section chiefs were members.  The chief administrator is now called the president or the emperor or something like that. 
	[Laughter.] 
	DR. R. LEVINE:  But now we're having a great problem getting people in the upper echelons, people who are the most respected members of the community to serve. 
	Norman Faus reported at a recent meeting that right in the course of running one of his IRB meetings two members stood up and walked out saying they didn't sign on to do this sort of petty paper-pushing stuff.  I think you've got to keep this very clearly in mind.
	CHAIRPERSON MARSHALL:  John.
	Thank you, Bob. 
	DR. MATHER:  Mary Faith, may I just make a comment. 
	CHAIRPERSON MARSHALL:  Briefly. 
	DR. MATHER:  We've been tracking minutes for quite some time in my office.  And, you know, people know to think of minutes as being some sort of chore.  We have seen people doing some rather remarkable things and explaining, you know, the risk benefits.  And I would like to think that if people got access to such minutes the public would be more assured that indeed these protocols got that kind of attention.  So I do not see this openness as being that negative.  I see it in some ways as being a very positive step which people who get access to said minutes might be very surprised at some of the stuff that Susan and Bob have written over the years which is very eloquent which is drilled down on exactly the protection responsibility that the IRB has.
	So I see this from my standpoint as being a relatively positive sign.  I think we have to be concerned though in this particular bill though about what kinds of things, I don't know if you're going to be writing regulations out of your office which prescribe the things that can be redacted.  I mean, it can get pretty catholic about the things that are redacted.  I mean, I understand people being concerned about patents and, you know, privileged information and so forth.  But I don't think we should think of this as being something that can be a very positive statement about the conscientiousness of IRBs and what they've done over the years. 
	CHAIRPERSON MARSHALL:  Thank you for that positive note.  We are almost at time and I want to give Jack the final word before I bring us to a close today.
	MR. SCHWARTZ:  Just one informational point and one editorial one.  The informational point is that the legislation does not give the Maryland Attorney General's Office any regulatory authority and we do not otherwise have it.  Hence, there will be no regulations with respect to meaning of confidential and privileged or anything else.  People may ask me what I think, and I can say what I think or not.  I think for the most part I'm going to let institutional counsel sort that out rather than attempt to any edict from on high at the Attorney General's Office.
	The editorial comment is that I think public policy ought to take account of disincentives for IRB service because it is an appropriate goal of public policy for IRBs to be effective and they can't be effective unless they have active, engaged, intelligent members.  I'm merely questioning almost as an empirical matter, the evidence that would show that the new disclosure requirements under the Maryland law would be any sort of a noticeable disincentive for people to be willing to serve on IRBs. 
	I'm sure the increasing reluctance that you identify for IRB service is as they say, "multi-factorial" but I question whether the availability of minutes when the minutes typically do not identify by name individual members and where the threat of litigation which is indeed more of an apparition than a reality, but that comes from newspaper stories about Alan Millstein, not through the enactment of legislation paralleling federal and state laws that have been on the books and have provided for access to some IRB minutes for time out of mind.
	So I just question the -- yeah, one can talk about the additional straw, but I doubt that this is it.
	CHAIRPERSON MARSHALL:  Thank you very much.  I think we learned a lot from that session.  I appreciate you being willing to come and your important work. 
	We have had a good day.  We are going to have a good day tomorrow.  We're going to spend the morning on children, hearing an update from the children's working group and also hearing about a large study, the national children's study that some of us have been involved in, in a meaningful way, and the rest of us need to know about.  It will be an interesting afternoon, we're going to revisit our discussion about whether all disciplines should be subject to the Common Rule.  And then we are going to have updates from our genetics workgroup and our social and behavioral sciences workgroup.  So we look forward to tomorrow.
	Thank all of you all, ex officio members, public members for sticking it through today.  IRBs might occasionally be gigged by the OHRP.  This group is going to convene and some of us are going to go get pithed.  Oh, that was bad, bad, bad.  
	The informed consent workgroup will meet immediately afterwards, but needs to stop by 5:45 because we need to leave from the lobby at 5:45 those of us who are going to dinner.  We will be walking out the door at quarter of six to Georgia Brown's.
	MR. BARNES:  May we leave our materials here?  Are we going to meet in this room in the morning?
	CHAIRPERSON MARSHALL:  Yes, you can leave your materials here.
	[Whereupon, at 4:55 p.m., the meeting was recessed to be reconvened on Wednesday, July 31, 2001, at 8:30 a.m.]

	CERTIFICATE OF OFFICIAL REPORTER

	This is to certify that the foregoing proceedings before the National Human Research Protections Advisory Committee held Tuesday, July 30, 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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