CT Department of Health and Human Services Meeting of the NATIONAL HUMAN RESEARCH PROTECTIONS ADVISORY COMMITTEE (NHRPAC) Monday, January 28, 2002 VOLUME I The Hyatt Regency Bethesda Hotel Cabinet-Judiciary Room 7400 Wisconsin Avenue Bethesda, Maryland 20814 A G E N D A Monday, January 28, 2002 AM Session 8:30-9:00 Welcome--Overview of Meeting and Updates Mary Faith Marshall, Ph.D. Chairperson, NHRPAC 9:00-9:30 John Marburger, Ph.D. Director, Office of Science and Technology Policy, Advisor to the President 9:30-10:30 Update, Discussion & Closure: Third Parties: Research Subjects? Mary Faith Marshall, Ph.D. 10:30-10:45 Break 10:45-12:30 Update and Discussion: Social and Behavioral Science Risk and Harm Confidentiality Felice Levine, Ph.D. Co-Chair Working Group Executive Officer American Sociological Association Jeffrey Cohen, Ph.D. Co-Chair, Working Group Director, Education, OHRP/DHHS PM Session 12:30-2:00 Lunch 2:00-3:15 Consequences of Civil Actions in Human Subjects Research -- Panel Presentation and Discussion Alan Milstein, Esq. Sherman, Silverstein, Kohl, Rose Podolsky AGENDA (Continued) 2:00-3:15 (Cont'd.) Respondents: Karen Rothenberg, J.D., M.P.A. Dean, University of Maryland, School of Law Paul Lombardo, Ph.D., J.D. Associate Professor of Law and Director, Program in Law and Medicine, Center for Biomedical Ethics University of Virginia 3:15-3:30 Break 3:30-5:30 NHRPAC Work Group Meetings Social and Behavioral Sciences Third Party/Genetics Informed Consent and the Decisionally Impaired Informed Consent 5:30 Adjourn ROSTER OF MEMBERS MARY FAITH MARSHALL, Ph.D., Chairperson, Director of Program in Bioethics, University of Kansas Medical Center GREG KOSKI, Executive Secretary, Ph.D., M.D., Director, Office of Human Research Protections, Office of Public Health and Science, OS MARK BARNES, J.D., LL.M., Partner, Ropes & Gray MS. MARGARET BORWHAT, President, Women's Cancer Advocacy Network SANFORD CHODOSH, M.D. ELLIOT N. DORFF, Ph.D., Rector and Distinguished Professor of Philosophy, University of Judaism 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 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 JUDITH L. SIEGEL, Ph.D., Vice President, Head US Clinical Operations, Hoffmann-La Roche, Inc. KATE-LOUISE GOTTFRIED, J.D., M.S.P.H., Office of Human Research Protections, Office of Public Health and Science, OS EX-OFFICIO MEMBERS Dr. James Shelton, USAID Maryann Danello, Ph.D., CPSC Dr. Joseph Spence, USDA Ms. Linda Beth Schilling, DOC Mr. Tryn Stimart, NIST Ms. Patty Boll, DOD Ms. Blanca Rosa Rodriguez, ED Dr. Susan L. Rose, DOE Dr. Dixie Snider, CDCP, DHHS Dr. David A. Lepay, FDA, DHHS Dr. Belinda Seto, NIH Alan Sandler, D.D.S., NIH Dr. Francis D. Chelsey, Jr., AHRQ Dr. Paul Gatons, HUD Dr. Donald Prosnitz, DOJ Mr. Thomas G. Raslear, DOT E. Donald Sussman, DOT John H. Mather, M.D., DVA, VHA Joan Porter, D.P.A., M.P.H., DVA, VHA Mr. Robert S. Cortesi, EPA Richard S. Williams, M.D., F.A.C.S, NASA Dr. Philip Rubin, NSF Mr. Howard L. Bradley, SSA P R O C E E D I N G S [Time noted: 8:40 a.m.] CHAIRPERSON MARSHALL: We are going to begin in just a couple of minutes. There are still lots of folks outside and we would just like for them to get settled, so bear with us for two more minutes. Welcome to NHRPAC. Committee members, it's good to see all of you. We've all been working very hard in the interim since our last meeting. Some of us have been working extremely, extremely hard; and we have a lot of business to do over the course of the next two days, bringing some of our projects to closure and fruition and working hard on others. I would like to open the meeting by talking a little bit in the next 15 minutes or so that we have about public bioethics and then opening the floor up for discussion. We have talked in the past among this group about process and the importance of it. I would like to read you just a couple of excerpts from a paper that was written by John Fletcher and Franklin Miller. John Fletcher was the first Chief of Bioethics at the Clinical Center at the National Institutes of Health. Franklin Miller works now at the NIH with several of their IRBs and their Human Subjects Protection Program. So they have written a paper that's several years old on the "Promise and Perils of Public Bioethics," and this might just help open our discussion. They say that: "the main promise of public bioethics is that it will contribute to the development of sound public policy by timely, well-reasoned analyses of ethical controversies in the sphere of biomedical research, health care and public health. Public bioethics contributes to the formulation of public policy by first clarifying the ethical considerations relevant to an issue of policy; second, articulating consensus of ethical standards for the guidance of policy; and, third, recommending specific safeguards to contain or prevent abuses that have occurred or that could occur when policy is implemented. "A secondary promise of public bioethics is that the ethical analysis and recommendations issued in reports will provide valuable guidance to local institutional ethics committees and review boards which focus on protection of human subjects in research, ethical issues in patient care, use of animals, and so forth. "Public bioethics is subject to four main perils: Political coaptation, bioethics orthodoxy, neglect, and poor performance." "Coaptation" distorts ethical reflection by imposing partisan demands or constraints on the work. The peril of "bioethics orthodoxy" arises to the extent that a narrow ethical perspective controls the inquiry and the recommendations of the advisory committee. "Neglect of public bioethics" occurs when the government sets public policy or intervenes in ethical controversies without being informed by the deliberations of public bioethics commissions. "We argue..." Fletcher and Miller "...in favor of two functions of government in public bioethics, which have been only partially and inconsistently developed in the past. The first function is to be a wise and consistent advocate of public bioethics in each political season in the interests of the public. The second function for government is to be a wise user of public bioethics." Many of the ideas that John and Frank Miller have put forward are things that we have talked about before here and I think have guided our work. We have discussed the importance of bringing everyone to the table who should be at the table and ensuring that all who need to or would like to have a voice in our process. For those of you who have not been to a NHRPAC meeting in the past, our process of working through the day is that we allot the same amount of time for discussion among the committee, among our representatives from the federal agencies, and among those whom we call our public members. So I would encourage those of you who are here either as return visitors or first-time visitors to certainly feel free to engage in the dialogue as we go along. That is really part and parcel of what we are about. Someone asked me, just as we were chatting earlier this morning over coffee, whether the workgroups would be open to those who might be interested in sitting in on them. We have divided our schedule for the next couple of days in a manner that allows us to work very hard and get some work done, and take advantage of the fact that we are all here and at the same place at the same time, and that many of our workgroup members are also here and those who aren't physically here will join us by conference call. I think that that is a wonderful idea with the caveat that our workgroups have appointed members. Our workgroups have to be given approval by this committee. So the workgroups as they stand have been signed off on and the membership approved of by the members of NHRPAC. So we would invite you not necessarily to be a member of the committee but certainly of the workgroup to sit in if you would like to observe. And I think I would leave it up to the workgroup chairs to call on members of the public if they feel as though they would like to do so if there is time. So let me ask if there are other thoughts about our procedure, about doing public bioethics, and I just would like to perhaps open the floor up for discussion among the committee first if anyone has thoughts. Yes, Bob? DR. R. LEVINE: I have a couple of comments and one question. I think many of the members of the committee were recruited to join the committee because this committee would have as its chief assignment providing oversight activity for the Office for Human Research Protection. Certainly that was one of my main motivations for joining this committee. There can be no doubt that there is intense controversy out there around the country over some of the activities of this office and I would just like to issue a plea, a request that we get to that part of the agenda. There can be no doubt that the agenda we are looking at is important but it is also assigned to quite a number of other -- much of it is assigned to quite a number of other groups. I do not know of any other group, though, that has been recruited to provide oversight to OHRP. The other comment I have is that it is good to be a member of the workgroups but it is a problem when you are a member of two that meet simultaneously and I would look to the Chair for guidance on that. CHAIRPERSON MARSHALL: I hope you are not asking for solomnic wisdom. [Laughter.] CHAIRPERSON MARSHALL: Well, you know, we really cannot engage in cloning. That might be the more modern solution to that problem but I will think on it over the course of the day. Let me just respond, and I know Greg has something that he would like to say. Welcome, Paul. Paul Gelsinger has just joined us. In terms of oversight activity, if we think back to the advisory committee that was chaired by Nancy Dubler -- and I am sorry I am blocking, co-chaired by Nancy Dubler and someone else -- certainly the idea of providing oversight or feedback about how the federal government configures its regulatory affairs relative to human subjects concerns was part of their report and part of their thinking. I do know that the committee of the Institute of Medicine that is taking a very broad look at protections of human subjects and the systems that are in place nationwide, both federal and other, and whether they are working, and mechanisms that might be brought into place to further the agenda in terms of providing safety to human subjects research and integrity of scientific research are looking and will be in their report, I think, speaking to a certain degree to the issue of oversight. So that is one body that is looking at that but their report will not be out until September. So, Greg, I know that you have something that you would like to say. DR. KOSKI: Bob, I don't know if there has been a misunderstanding but the purpose of this committee is not oversight of the Office for Human Research Protections. The purpose for this committee, as stated in the charter, is to provide the Department, the Assistant Secretary for Health and the Director of OHRP with advice on a number of the complex issues that this office has to deal with. So that I think maybe I just want to be very explicit about that. The purpose of this committee is not oversight of our office. And when there are issues about the operations of our office that we need advice on or the Department needs advice on then certainly that would be something that we would want to come to this committee and seek its advice on; but this is not intended as an oversight committee. This is an advisory committee. DR. R. LEVINE: I think the current state of intense concern and controversy about the activities of OHRP can properly be viewed as a complex issue. And, I do not know if our charter was written in such a way as to exclude us from commenting on that. I was certainly told when I was called to join this committee that oversight was going to be a major part of the agenda. Maybe the rest of the group here was not told such a thing. Thank you. CHAIRPERSON MARSHALL: Committee members, any other thoughts on either this point or other points? Bob? DR. RICH: I do not recall the language, specifically, that was in the DHHS appropriations report language that at least indirectly had some role in creation of this committee, but I did think that there was an intent from the Congress, at least, that there would be an element of oversight. I actually had that impression, too, so if it is a mistaken impression, I do think there was Congressional interest in that as I understood the genesis of the process. DR. KOSKI: Again, this committee was not established through any action of Congress. This was a committee that was put together by the Department of Health and Human Services on the initiative of the Secretary, and clearly the stated goal here was to obtain, have a forum for obtaining, you know, advice with public discussion, you know, on these issues. Now, certainly there may be issues, you know, that the office would seek advice on with respect to operations. There has been a real, though, need to focus on some of these, you know, again the challenging issues of children and all where basically the Department has been directed to look at those activities and offer new guidance, potentially new regulations and so on. So I think that, you know, certainly our office is working in every way that we reasonably can to take advantage of the enormous resource that this committee provides. I think in all fairness there is certainly plenty of issues to discuss and they all have to be appropriately prioritized and worked through so we are doing that. Indeed, a number of things. We are anxious to have this committee complete its advice to us. I don't know how to, you know, further explain that, though, except, you know, clearly our office and the Department are subject to oversight, oversight by Congress and all, and certainly there are a number of groups out there. Particularly we have, as you know, asked the Institute of Medicine's Committee, as part of its ongoing project with us that we are funding, to actually look at this entire system. So I think we want to make sure that we use our resources in the most effective way and I hope that clarifies the situation. CHAIRPERSON MARSHALL: Sandy? DR. CHODOSH: I just wanted to voice my opinion on this because it's not an opinion. The charter is sitting right in our book. It is very clear. It's advice and recommendations. Nothing about oversight and I don't know how anyone could misunderstand that. CHAIRPERSON MARSHALL: It's behind Tab 2, page -- DR. CHODOSH: The one after page 6. DR. KOSKI: Let me just add one little comment. I think one of the concerns that led to the creation of this committee was the fact -- the concern that, you know, perhaps too often guidance was developed or issued without, perhaps, the full public discussion that is warranted if one is going to try to produce the most useful guidance to help the investigators, institutions and IRBs do what they need to do. So clearly this provides the opportunity to have that forum to seek that kind of advice and that's certainly what our office has been doing. CHAIRPERSON MARSHALL: I see Bob has his hand up and he's looking at the charter. He has an alternate interpretation I think. DR. R. LEVINE: The charter says the function under the subtitle "Function" that "the committee shall advise the Secretary..." et cetera "...pertaining to the continuance and improvement of human subjects protection functions." It goes on to say that "it will provide advice on the development and management of collaborations..." et cetera, et cetera, and then among the groups it specifies are "biomedical, academic and research communities and nongovernmental entities." Finally, "the committee will provide counsel on opportunities to improve the public awareness of the function and importance." I see nothing in there that's inconsistent with the request made to me by the people who appointed me to this committee. I think that the communications between OHRP and the biomedical, academic and research communities are very much influenced by the -- not the policies but the practices of OHRP. I see nothing here that excludes this topic from our agenda, and I would like to ask if this committee can set its own agenda; and, if it can, then I am going to make a motion at some appropriate time that we put oversight on our agenda. CHAIRPERSON MARSHALL: Go ahead, Adil, and then I'll speak to that. DR. SHAMOO: At least if I understand politics, since I live near Washington I hope I have some understanding by osmosis, the word "oversight" is used by Congress and officials of the federal government very precisely. And since they did not use the word "oversight" I don't believe this committee has the authority to oversight OHRP. It's really advice and counsel. That's my understanding. DR. R. LEVINE: Let me then withdraw the word "oversight" and replace it with "advice and counsel on the practices of OHRP." CHAIRPERSON MARSHALL: I think that the operative word is "advice and counsel." I know of nothing in the FACA rules that disallow us as a committee from looking at issues that we feel are important relative to human subjects protection. So, I think certainly not oversight, but, perhaps advice and counsel. The charter really speaks to, I think, how the various entities within the government collaborate and communicate not only among themselves but with the public at large. Felice? DR. F. LEVINE: I think we are converging on the right balance but I think that there's an important element of the charter and that is that the advice and counsel is to the Secretary. I am, as many of you know, on a similar committee and that is for the Census, which was appointed by the Department of Commerce Secretary, and the advice is to the Secretary on issues that the committee wishes to give it advice on, rather analogous to NHRPAC. And what I was hearing was Greg saying what OHRP would like advice on and Bob saying what NHRPAC would like to give advice on, and I believe NHRPAC can determine what it wishes to give advice on and, indeed, can advise the Secretary on issues pertaining to the human subjects protection system and all of its aspects. I think that is the right balance. CHAIRPERSON MARSHALL: One thought that I have -- and then, Greg, I'll turn -- is that Bob is making the case that there is timeliness in terms of this subject. I would think that at the point also in the future when the Institute of Medicine report comes out that there would be elements there that the federal government may ask us about in terms of advice relative to implementing some of those recommendations. Greg? DR. KOSKI: Just to -- CHAIRPERSON MARSHALL: And then Jonathan? DR. KOSKI: Just to clarify Felice's remark. This committee actually under its charter advises at three levels, the Secretary, the Assistant Secretary for Health, as well as the Director of OHRP. So it covers that whole thing. Certainly OHRP is not averse to, you know, hearing thoughtful advice, you know, from this committee or anyone else so that's not part of the issue. But, as I think has been pointed out, I'm trying to be very clear that the purpose of this committee is not an oversight role. CHAIRPERSON MARSHALL: Jonathan? DR. MORENO: I think that the documentary history of the reports that led to the creation of this advisory committee, and this I think perhaps extends and sharpens Greg's point a bit, not only had to do with the need or perceived need for a more public discussion about the way that OPRR, now OHRP, does its work, but also to bring expertise from the academic and other related communities to help OHRP. It was thought that OPRR could have been benefitted by drawing on some of these sectors and gets free labor this way. So, as I always like to point out, free to us. Free, I guess in a way, and not free to you, I guess, Greg. So I think it's a little sharper than only giving advice when it's asked. And I think that one way of perhaps reinterpreting Bob's point is if people who bring their particular experience sitting around this table ask OHRP a question about its policies or operations that we feel we need in order to share our experience and expertise and OHRP says, "Sorry, you know, we don't want to get into that," then we can say, "Well, you've cut out the feet from under us and we can say it publicly, we can't give you the benefit of our expertise because we don't have any data to work with on this issue." So, I guess, I'd say we have a little bit of persuasive power with respect to getting into the interstices of the operations of the agency even if we don't have a legal authority to subpoena how OHRP is doing its work. CHAIRPERSON MARSHALL: Let me open the floor up to any of those who have joined us today. The microphones are there and are on so if you have a thought or a comment we certainly would welcome it. [No response.] CHAIRPERSON MARSHALL: Elliot? DR. DORFF: What occurs to me is what happens with advice in normal inter-human, you know, relationships, people who don't ask for advice and get it are not usually too happy with the advice. [Laughter.] DR. DORFF: So, I mean, I think that, you know, if there are very specific issues that have arisen, Bob, in the kinds of discussions that you've been having and that others have been having around the table about the operations, then I think maybe we should pinpoint those and ask Greg whether advice would be welcome on it or at least discussion would be welcome on those kinds of things. The other issue that occurs to me is that, I mean, we had a conference -- the workshop on informed consent had a conference call and came up with ten different things that we have to talk about, which will take us 50 years to do. And, I mean, it's not as if we're lacking for important -- you know, for work that -- other important work that we're doing. I'm not saying that the ongoing operations are unimportant. I'm just saying that if we're going to deal with that at all, (a) we should make sure that the people that are going to hear our advice are going to welcome it; and, second, that it be very pinpointed because otherwise we just won't accomplish anything. DR. KOSKI: Bob, I think as you know and, in fact, many people here know, I personally have had great concerns not just about OHRP but about the operations of the entire federal process for protection of human subjects and we have been working for almost a year now to get together what has come to be known as the SUEE Task Force, which will focus on finding ways to achieve simplification, uniformity, efficiency and effectiveness. It's a process in which all of the federal agencies have engaged through the Human Subjects Research Subcommittee that focuses specifically on the kinds of operational issues that, I think, you are referring to. You know, I want you and everyone else to understand there's no resistance here to looking at those things. Indeed, I think everyone benefits from having a close look at those things. But I think in terms of the focus that is something that is clearly going forward as expeditiously as we've been able to do within the government and moving a process like that forward and encourage, you know, people to participate in that directly. Again it's sometimes a question of trying to prioritize and using resources most effectively. I think the particular constitution of this group is one that makes it well-suited for advising us on the issues of children as research subjects. What is minimal risk, what is having a condition, on conflicts of interest, on the other kinds of important policy sort of issues that our office needs advice on as we struggle to produce clear and valuable guidance to help the research community. So that, you know, again it's a question of just trying to do the many things that we have to do in the best fashion. And I am very hopeful that the SUEE Task Force, which we hope will come together probably, you know, this spring or early summer will be an important step down that road. And, of course, I'd be delighted to sit down with you or any other members of the committee personally and see if there are specific issues that ought to be brought forth before this committee, then we could do that. So, you know, I hope that just clears up any misunderstanding. CHAIRPERSON MARSHALL: I have Alan. DR. FLEISCHMAN: I just wanted to remind the committee that I greatly benefitted from a whole panel explaining the work of OHRP with Greg's explanations as to the strategies and then the specific leaders from that group. And we might consider over the course of our meetings having one of those folks come back and explain how they've been doing in terms of their goals and objectives which they clearly set out and to teach us how things are going. You know, I certainly would appreciate that kind of interaction and I think we'd benefit from it. I have one other question and that is: now that we've carefully scrutinized the charter, there is this little thing called "termination" and I was wondering if we have any insight into that. CHAIRPERSON MARSHALL: Thank you. John, let me just ask Kate to respond to where we are in terms of our charter renewal process and then the floor is yours. DR. MATHER: Thank you. MS. GOTTFRIED: The charter has been revised to be slightly more specific and it is wending its way through the administrative system for review by the Secretary and it is to be renewed every two years so it's up for renewal June of this year and we anticipate that it will be renewed; but we have no specific information one way or the other. CHAIRPERSON MARSHALL: Thank you, Kate. John? DR. MATHER: I'm John Mather and I'm the ex officio representative from the Veterans Administration. I just want to align myself and maybe other ex officio members would want to say the same thing that Greg has pointed out that there is a very active human subjects research subcommittee that constantly brings these issues of policies and how to better operationalize what is needed in this area of human subjects protection. There's a lot of work that goes on in that particular committee and they're all signatures to the Common Rule who regularly attend these meetings on a monthly basis. Greg has got us working so hard that we sometimes meet twice a month. So you can see the level of expertise that comes to the table to try and address these issues. Personally, I would very much welcome, Bob -- and I know, I think, the other members of HSRS would maybe through Greg's office -- any items that you would like to identify that are of an operational concern. We understand policies translate into procedures, translate into immutable guidelines, translate into this is the way you shall do it. And this issue of flexibility, I think, raises its head very, very quickly. And each of us in the 16 agencies signatory to the Common Rule are very interested in ensuring that there's harmonization across the agencies. Most recently we have particularly looked at the issue that raised its "ugly head" about when are continuing reviews needing to be done. What is the anniversary of a continuing review? What is it that represents an appropriately convened meeting of an IRB to approve a project? What does approved with contingencies mean, and so on and so forth? So it gets and drills down to that nitty gritty level and I think we probably come on this one issue to some consensus amongst the 16 agencies notwithstanding some dissent. There is consensus and I think those kinds of things at the operational level are very, very helpful when we can do that. So, Bob, I would welcome and I think any on the HSRS would welcome identified areas where you think there is ambiguity or undue rigidity or some need for flexibility. CHAIRPERSON MARSHALL: Thank you very much. Abbey? MS. MEYERS: Since FDA is not a signatory to the Common Rule do they attend? Are they part of the task force? DR. KOSKI: Yes. MS. MEYERS: They are? DR. LEPAY: Yes, we are. Actually we do follow the Common Rule for FDA funded research. FDA has its own variant of the Common Rule that's very closely related to the Common Rule based on our statutory authority which derives from the Food, Drug and Cosmetic Act but it is essentially equivalent in the terms of the protections provided. We are part of the Human Subjects Research Subcommittee. We work very closely also within the Department of Health and Human Services and with OHRP to coordinate activities between certainly with our agency and OHRP, as well as with our agency and across the Department of Health and Human Services and with the members of the Human Subjects Research Subcommittee. MS. MEYERS: How much is FDA funded research? Do you know? DR. LEPAY: FDA funded is a very small proportion of research. Most of our research is regulated research and, of course, we are primarily a regulatory agency. And that is part of the basis by which our regulations have developed off the Food, Drug and Cosmetic Act, because, again, we have to assure broad public protection based on our approval decisions and the labeling that goes with those products, as well as regulations that support applications to FDA in addition to assuring as a subset of our broad public protection mission the protection of human subjects who participate and/or human research participants in FDA regulated research. MS. MEYERS: But a commercially sponsored research that doesn't involve federal funds is not regulated under the same rules as the Common Rule? DR. LEPAY: It is regulated under our 21 C.F.R. Part 5056 for IRBs and informed consent. And actually I will challenge anyone here who has done a comparison of these two in terms of the areas of human subject protection that they represent and the operations of informed consent and IRBs they are essentially identical. There are obviously, as I say, some changes in wording that are more appropriate to the statute under which we operate and that's why we have our own encoding in 21 C.F.R. but again I do not think that anyone here who has reviewed the two would say there are fundamental differences in the process of IRB review constitution or informed consent. MS. MEYERS: But there is in that -- for years, as you know, I served on the Recombinant DNA Advisory Committee, and every time I would look at an informed consent, and say, "This is bad, this is misleading, this is inaccurate," the FDA would say -- and there was always FDA representatives in the room -- and they would say, "We do not have the authority to force a company to change its informed consent document." DR. LEPAY: Well, we have to make sure that the informed consent follows the elements that are part of FDA regulations. The specifics of the informed consent document if they follow the regulatory standards that are contained within the elements of informed consent, certainly if they are misrepresenting the product or the study that is within the purview as long as there are no regulatory violations. MS. MEYERS: What I'd like -- DR. LEPAY: The regulations that would govern those, though, would be identical to the regulations that would govern the same informed consent document if it were under review under 45 C.F.R. Part 46. CHAIRPERSON MARSHALL: Abbey, let me -- MS. MEYERS: Yes. CHAIRPERSON MARSHALL: -- I don't know whether we're sort of straying off of the subject at hand but I would say that the Informed Consent Working Group, you know, if this is a concern, and later on in our agenda we do have time, tomorrow afternoon, for members of each standing working group and members of the committee to interact with the co-chairs of the Informed Consent Working Group saying these are the issues that we see that should be put on your table and this is the priority in which we think they should be addressed. So that might be a more direct route to having this issue discussed. Thank you, David. A couple of things. Anyone else? Have I missed a hand here? Anyone in the audience? [No response.] CHAIRPERSON MARSHALL: I guess sort of my thinking on bringing this particular topic to closure is this: That I'm glad we're doing exactly what bioethics councils or advisory groups or committees should do, and that is looking directly at hard issues and not ignoring the hippopotamus in the middle of the room, which is quite often the behavior that leads us to need bioethics advice in the second place. So I think that we must look at these hard issues. And my thinking, having had the privilege to work on the Institute of Medicine's Committee on Assessing the System for Protecting Human Research Participants, I know that not only will there be advice about the federal government's regulation and oversight of human subjects protections but also all of the entities that currently exist or perhaps should exist in the future, including NHRPAC as an advisory committee. The IOM will be looking at those and addressing those. And so I think that probably the appropriate point in time for us is to wait until a report comes out and it has been presented to the folks who brought it into being and seeing if there are things, and if there are agencies, et cetera, Health and Human Services would like for us to implement or evaluate or provide advice on the implementation of certain recommendations, that would be the appropriate time to do so. So I guess that's sort of my thinking. So, Bob, I don't think that we're ducking your issue. I think we've had a good discussion and that we can put some of your things on the table. A couple of announcements that I would like to make. One is that we have flexibility in our schedule today. A little bit of wiggle room and I know that we are moving a little slowly but John Marburger is on his way so I am sorry that he is late but we do have some wiggle room in our schedule. The second thing that we do have some business to do here during the first half hour and that is signing off as a committee on the memorandum to the Secretary and the Assistant Secretary for Health on public use data files. Each of you should have a handout. This is something that we have been working on relatively hard and I think that the committee through its discussions via the e-mail, et cetera, has arrived at a document that my understanding is we all agree on. So let me ask, Felice, do you have any thoughts that you would like to share with the committee before we move forward on approving this? DR. F. LEVINE: Just quickly in the way that I still think technology seems to have some creep in terms of what happens between progress and transmission, the word "settings" got missed. And I kept on sending updated drafts every time I got a word in but everyone probably picked it up. On the background section it should include "are collected in academic" and it says "settings by research teams" at the moment. The word "settings" got deleted. I haven't rechecked my hard drive but somehow we had some creep in the loss of a word. So I just want that in the final draft and I'll provide that later today. Just to reiterate for the full group where we were in October was to delegate this to -- the final language to Susan and Elliot and I, and that's what we sort of saw ourselves as your eyes and ears in crafting this and we forwarded it to Mary Faith based on the understanding that we achieved what we had wanted to achieve so we hope we did. CHAIRPERSON MARSHALL: Thank you. So let me ask, committee, you have that document in front of you, you've seen it on the e-mail, do we need any discussion before we move on approving it? Adil? DR. SHAMOO: I just want to make sure what we are approving. There is a cover page. There is guidance on public use data files. There is responsibility of users and it ends in Bureau of Labor. Are we approving the background attachments? Because the background attachments, and there is 10, 15 pages, there is problems in certain areas. I would not like to be associated with it. I mean, they're okay if they are just there for information but if it ends by just the recommendations then I have no objection. DR. F. LEVINE: It looks like something additional got stapled on your copy. It is the guidance and the recommendations as background so that we're forwarding the input of the working group. CHAIRPERSON MARSHALL: Phil? Phil Rubin? Well, we'll continue this discussion. [Laughter.] DR. MARBURGER: It sounded like it was important. CHAIRPERSON MARSHALL: We have a long day ahead of us, so they won't be able to duck this. [Laughter.] CHAIRPERSON MARSHALL: They may try. Welcome. DR. MARBURGER: Thank you. CHAIRPERSON MARSHALL: Let me introduce to all of you, it is just a great pleasure and I'm so thankful that John Marburger is here. I'm sure that all of you know who he is. He is the Director of the Office of Science and Technology Policy and advisor to President Bush on issues of science and technology policy. A little background: Dr. Marburger has a Ph.D. in applied physics from Stanford University, a B.A. in physics from Princeton University. He was president of the State University of New York at Sunybrook, also served as the Chairman of the University's Research Association, which runs the Fermilab, from 1988 to 1994. And a little story telling here: The Brookhaven National Laboratories, which he also directed, was very much in the news when Dr. Marburger became its director so he doesn't shy from controversy. A tritium leak in the high flux beam reactor had attracted a large degree of attention in the media resulting in a call to close the reactor by local groups, a senator and a representative. And at a late 1997 press conference, as the incoming director, Dr. Marburger remarked that the laboratory had failed to communicate adequately with the local community. The reactor was closed in 1999 and Dr. Marburger has been roundly praised for the way in which he reestablished communication with the lab's neighbors. Let me read you his personal statement which was on the Brookhaven National Laboratory's web site. "As society holds us to ever higher standards of accountability for the impact of our work on health and environment we need to learn new ways of working and we need to learn new ways of describing our increasingly complex mission to the public that is skeptical and concerned about the undesirable side effects of technology." And I think part of the reason that we exist as a committee is to serve as a liaison between the government and the community. And in terms of doing public bioethics which, Dr. Marburger, we have spent the last half hour talking about, we can tell you that we are committed to engaging the public and to making sure that all of those who should be at the table are there and also have a voice. So thank you very much for being here. We're just delighted. [Applause.] DR. MARBURGER: Well, thank you very much for inviting me and permitting me to say a few words at this very important occasion. I'm here for at least three reasons that I want to speak briefly to. The first one is the fact that this administration takes its ethical responsibilities very, very seriously in all aspects of its operations; and I think everyone has been impressed with the strong moral positions that President Bush has taken since beginning his administration and I feel very privileged to work with him and with the administration on these issues. He understands quite clearly that science does not tell us what we should do, it tells us what we can do. and that, in addition to expert scientific input on policy decisions, the President welcomes expert -- as expert as any of us can be -- input on the ethical and moral dimensions of the decisions that he has to make and expects us all to be conscious of the ethical and moral impact of our work and the fact that decisions need to be made explicit just as we make explicit decisions to fund this or that or to do this or that kind of work we need to be very clear about the fact that there are ethical inputs to guide us as well. And the President is grateful to those who are willing to come forward and discuss these issues in a public and rational way, especially on issues that are controversial and could expose people who engage in these discussions to public scrutiny and perhaps criticism so I am grateful to you for being here and being willing to undertake these discussions and to provide guidance to Health and Human Services as it goes about exercising its responsibility. The second reason that I'm here is that science continues to evolve in a strong and rapid way and it's giving us increasing insight into the processes of life and their relation to the very molecular structures that comprise all living things. And not only how we metabolize and reproduce and how information is transmitted from one part to another in a cell or in an organism but also aspects of human behavior, psychiatry and behavioral issues that were formerly not easy even to conceive how they might be related to molecular structure are beginning to come under the purview of molecular biology and our understanding of the processes of life at even the atomic level. And, consequently, a wider and wider range of human activities, not only health but also human behavior in many aspects, are coming within the realm of laboratory work and this movement is driving science. This progress is driving science at an ever more rapid pace. The availability of instrumentation to view the structures of life on the atomic and molecular levels and the ability of information science and computer simulation and so forth to advise us on how one might alter the molecules of life to alter the behavior of the organisms which are constructed from these elements. These capabilities have created tremendous opportunities for science and offer a promise to address concerns not only with respect to human issues but also with respect to environmental, energy and other issues that face society that are very complex. And, consequently, there's a real concern here that we maintain our options for getting and extracting the greatest benefit from this new knowledge while at the same time being responsible and keeping in mind the ethical and moral implications of what we are doing. So the third point is this, and it derives from the others, that the range of activities that science undertakes that affect or involve human participation is increasing at a very remarkable rate. Since 1991 when the first Common Rule was promulgated by the office that inherited -- the Office of Science and Technology Policy on the Protection of Human Participants in Research -- since 1991 there's been a decade of evolution and expansion of these frontiers. And during that period there's been an enormous increase in the range of activities that might fall under the purview of these issues, issues of ethics and morality and fairness and risks associated with human participation in experimentation. So the challenge here is to achieve some uniformity and some effectiveness in protection of human subjects across this entire range without inhibiting the research unnecessarily and acknowledging the wide range. Now, each agency that sponsors work of this sort, or that falls within this wide range of activities of human participation, is responsible for establishing its criteria consistent with various guidelines and legislation that governs it. But each agency needs to be aware of the needs of the other agencies as well as it promulgates its guidelines, and it is important for us to try to educate ourselves about the entire spectrum of issues so that we do not inadvertently impose regulations that might inhibit the work and not give us commensurate gains in protection of human subjects. The issue here is one of, I suppose, risk-based thinking. In general, I favor risk-based approaches to regulation where you try to match the protections against the risks and so that the less the risk the fewer, the less intrusive and demanding the regulations should be. And so it's clearly important for us to understand what the risks are of the different kinds of activities that are being undertaken and not just take the most stringent regulations and apply them to everything. I am concerned about this because the original model and the original set of concerns that drove the movement to protect human subjects were associated with clinical trials where you have people who are at risk whether they participate or not in the trials. They have some affliction, disease or condition that may or may not respond to drug or therapy that's being investigated. This is sort of the most extreme situation that we have where we are actually conducting experiments to let us know whether or not a mode of therapy is effective. But, increasingly, there is a large amount of work that's being done where participants in the work are healthy, where the modalities of investigation pose relatively little risk, and yet the work is quite important to society. So it's important, I believe, to be able to be flexible to be able to craft regulations that are responsible at both extremes, both in terms of protecting the people who are most at risk and vulnerable to exploitation on the one hand, to protecting the ability of society to conduct constructive research with healthy patients who are at relatively little risk on the other. The risks, of course, are different. Risks of disclosure of confidential information, for example, are significant even when we're doing surveys that are related to social or psychological issues. So it's not a simple task that you have to advise your agency on the issues here and to develop guidelines for the future but I do want to leave you with this message based on this set of issues that I've described here, and that is that bioethics is a broad area now and increasingly complex, increasingly engaged in activities that we never would have thought of decades ago as being covered by the types of regulations that we see. And that it's going to be necessary for us to educate ourselves not only about the existing, but also about the potential future domains of application for our guidelines. So my office continues to be very interested in this process. We continue to work with all the agencies, and there are many of them that have responsibilities for the human beings as well as the other living things that participate in their experimentation, and we hope to learn from your deliberations as well as from those of others and have the best possible guidelines for the future. So thanks very much. I'll be glad to answer questions to the extent that I can as I'm somewhat of a nonexpert in this business and I wish you well in your deliberations. CHAIRPERSON MARSHALL: Thank you very much. [Applause.] CHAIRPERSON MARSHALL: I would like to say, Dr. Marburger, I do hail from Kansas but I also believe in evolution. [Laughter.] CHAIRPERSON MARSHALL: I believe strongly in it and when I give talks about research ethics I make the point that our ethics need to evolve along with our science and that they need to be, in a sense, ever changing and growing. Our colleague in the bioethics world, Carol Levine, observed years ago that the ethics of research were born in scandal and reared in protectionism and I think that that is true. You could say that the ethics of human subjects research almost evolved in a pattern of crisis and response. But I think that we also have moved to a new level, and I think that's a good thing, of not only protecting but promoting research and that is something that we're very much interested in, is the integrity of the science, and that it moves forward. I think your commitment to not just the clinical sciences but to the social and behavioral sciences is wonderful and the folks who are here, Felice Levine and others in the room who represent the social and behavioral scientists, I'm sure were listening attentively to every word. And I want to tell you that we are spending the entire morning looking at ethical issues that inhere in the social and behavioral sciences. Let me do open the floor up. I'll tell you we do value input from our public members so I'll open it briefly for questions from the committee first, then our ex officios and then members of the public. Committee folks, would you have questions of Dr. Marburger? Abbey? MS. MEYERS: The Washington Post did a series of stories this winter or last winter about clinical trials that are being done overseas and the data is being used here to get new drugs approved, et cetera, in some of cases. Has that caused any international problems? DR. MARBURGER: As far as I know it hasn't caused any problems in countries outside the U.S. There certainly have been concerns raised within the U.S. regarding work done outside the U.S. and some of these concerns are commercial and I'm not completely conversant with all of them, but as far as I know in the broadest sense there's not an international concern. This has not arisen as far as I know as a major issue. Pharmaceutical companies in the U.S. are concerned that very strict regulations may drive business, as it were, to other countries and there's a kind of concern associated with that. And there are organizations, of course, that always have concerns about the extent to which other nations may be as careful in their protection of human subjects as we are. So these are issues that are meat for this commission, of course, committee and I would welcome your input on them. CHAIRPERSON MARSHALL: Bob? DR. R. LEVINE: Thank you very much for your comments. I'd like to comment on the last topic. I'm chair of the Committee for the Council of International Organizations of Medical Sciences to write or to revise what's known as the International Ethical Guidelines for Biomedical Research Involving Human Subjects. The stories that came out in the newspapers looked terrible. I think many of us know that sometimes the newspapers don't get it exactly right. So without having personally looked into those stories I will jump ahead to say that if what was reported in the newspapers is correct that was in violation of international standards that have existed since 1993. And right now the CIOMS, Council of International Organizations of Medical Sciences Guidelines are being firmed up to make behaviors of the sort that were in the newspapers even less acceptable. The key point is that certain types of research carried out by sponsors and investigators from the wealthy countries can be done in the -- what they now like to be called -- the low resource countries following exactly the same rules that exist in the wealthy countries unless they are focusing on a problem that's specific to the low resource country that they're working in. Focused in such a way that bringing the data back to a wealthy country for purposes of marketing in the wealthy country would essentially be out of the question. It's focused on development of products that have no market in the wealthy countries. Thank you. CHAIRPERSON MARSHALL: Thank you, Bob. Kathleen Rand Reed? And those of you who do step up to the microphone, please tell us who you are. DR. RAND REED: Thank you, Dr. Marburger. I'm an applied biocultural anthropologist and for many years have sort of gone between, you know, communities and rooms that look like this and so I wanted to -- you brought up several points and I wanted to take the opportunity to address a couple of the issues that you did bring up. Around the issues of behavior and the move afoot to begin to look at molecular issues around behavior, I would say that there are many people at a grassroots level that when you start talking about social capital and exchange in networks and norms of reciprocity and these kinds of things that your door be very, very open for not just experts to come about behavior, but to provide the opportunity for people in the communities to give their version of behavioral issues. Because often times what happens is that what is a behavior that may be "deviant behavior" in one group may very well be situational and "survivalist behavior" in another. So when we start making these decisions about how people live their lives and how they experience their lives it would probably do you well to be able to have that broad view from lots of different corners so that when these decisions are made they truly represent all of the issues. The second thing -- CHAIRPERSON MARSHALL: The second brief thing. DR. RAND REED: The second very brief thing is the -- very brief -- is you mentioned about risk-based thinking and an approach to research. I would also ask that you carve out some space and time in your office that those with the highest risk should also be very, very present at that table so that they get the opportunity to have the voice to offer their version of what that risk may be. I thank you. DR. MARBURGER: Thank you. Just briefly in response, the guidelines for membership on the Institutional Review Boards, that have been established under legislation, specifically require diversity of the sort that you've been describing. We welcome and, indeed, insist on outside/outsider representation on these boards and I think that has been a strength of the guidelines from the beginning and it should continue to inform how we operate. I completely agree. CHAIRPERSON MARSHALL: I have Elliot and then Alan and then Paul Gelsinger for brief questions. I'm not sure how long Dr. Marburger has but I know he doesn't have all morning so brief questions. DR. DORFF: Just two comments and we don't know each other so my guess is that you know this already, okay, but you're a physicist and I'm an ethicist. My doctorate is in ethical theory. And I just wanted to make two brief points to make sure they're clear. One is that although it is the case that more and more of human behavior is now being investigated on its molecular level. One of the things that we're going to be talking about today actually are some of the necessary steps in research that are very different in social sciences from those in the physical sciences. And I think that's an important thing to bear in mind. The other thing that I wanted to talk about is that scientists are used to -- my father was a civil engineer so I'm used to this mentality -- scientists are used to things being very black and white. I mean it either shows up or doesn't in experimentations. The world of ethics is excruciatingly imprecise and, in part, it's because what is really important in the world of ethics is the lens through which you're looking at the world in the first place. And the reason why there are major ethical differences -- sometimes they are moral differences even within one particular system of ethics. Different judgments of -- in other words, even if you assume one particular lens of -- these lenses tell us who we are and who we ought to be. The various religions of the world give us very different pictures of that. The various secular philosophies of the world give us very different pictures of who we are and who we ought to be, and the moral norms are rooted in those large pictures. Now, it happens that on this particular issue, namely the issue of protecting human subjects, there's a lot of agreement across lenses in the world that that ought to happen. Although I must say not universal agreement. There are societies in which that is understood to be a much lesser value than some other value like political stability or something like that but at least in America this is sort of a given. But as you do your work you should -- I mean, I think it's important to understand that when you come to other kinds, of things other than human subjects, other -- you talked about living beings, I mean stem cells and things on that order -- part of the real issue here is, as you say, not what is the case but how do you perceive what is the case from a variety of different lenses. DR. MARBURGER: I don't think I'll have any comment on that. [Laughter.] DR. MARBURGER: But even the physical sciences are less black and white than they used to be. CHAIRPERSON MARSHALL: Alan, and then Paul? DR. FLEISCHMAN: My question will be much less philosophical and more pragmatic. From the very beginning there's been controversy as to whether institutional review boards ought to have a local flavor or be more nationally focused and I was wondering if you have an opinion as to that. DR. MARBURGER: I do and I'm speaking personally. You asked me for my opinion. My opinion is that they should be more locally oriented but that pains should be taken to have training or presence of information and insights that reflect the broader national thing. You can't just let every IRB be its own thing. There have to be standards and they have to operate in a national context. But, in general, you need to have -- in my opinion -- you need to have strong local flavor to understand the nature of the research and also to have some insights into the people and the culture in which the research is being done. There are many different research cultures in different types of institutions, different regions in the nation that flavor the work. And I think that the local culture of research, local sociology of research needs to be well understood in order to apply the national standards. CHAIRPERSON MARSHALL: Thank you. Paul Gelsinger, for those of you who don't know who Paul is, he is the father of a young man, Jesse Gelsinger, who died in a gene transfer experiment a year or so ago. Paul? MR. GELSINGER: Dr. Marburger, in your opening comments you indicated that technology was the driving force to our understanding of life even at the tiniest levels, the atomic level. My perspective is a little different than that. I see technology as only the door opening. The driving force that I've uncovered is the financial end. It's the thing that's pushing that door open maybe too fast. I think that's where our ethical can of worms is and I'm wondering how the administration is dealing with the conflicts that arise out of that. DR. MARBURGER: To the extent that finances drive things one has to be very, very careful, I believe, that this administration is very clear on fundamental human values and the need for a principled approach to ethical and moral questions, seeks advice, tries to act on a very high moral plane. I think the President's very public analysis of his decision regarding stem cells gives you some insight into how he thinks. And I've found no trace of flexibility on this issue that ethics and moral principles are essential ingredients to policy decisions. The President takes them seriously and requires that we all do. I feel that only well-thought-out processes to advise and to guide the research at a local level that make their principles clear are going to prevent exploitation of people at risk for financial ends and no one in this administration wants to see that happen. CHAIRPERSON MARSHALL: Adil? DR. SHAMOO: I'm really taking advantage of the fact that you are here, I may as well put something in your mind. I sympathize with you. I'm originally also a physicist who 15 years ago had to learn human research protection issues. However, I believe physicists can learn any subject. [Laughter.] CHAIRPERSON MARSHALL: It is the mother of all science. [Laughter.] DR. SHAMOO: My question is really rather informational and that is, animals, regardless of the source of funding, there's a federal regulation that you cannot do research with animals unless it is federally regulated. I know this may come as a surprise to you, human beings, regardless of the source of funding, whether it's federal, private, industry or private foundation or state or out of my own pocket, that is not the case. That umbrella of federal regulations, there are big holes in it. That is, literally, if I am wealthy, just to give you an extreme example, I could do research with human subjects of any kind I want as long as I do it within one state so that I'm not crossing state lines and I'm supporting it with my own building, my own money, et cetera. And there are big holes in it and what we have advocated and written about is that we would like to see a national human research protection act. DR. MARBURGER: Thank you. [Laughter.] CHAIRPERSON MARSHALL: Adil, someone said a while ago that I think physics envy is the curse of biology. [Laughter.] CHAIRPERSON MARSHALL: Let us give the last word to Dr. Marburger. DR. MARBURGER: Well, there is no last word on this issue. And once again I'm grateful to you for giving your time and your attention to this issue. It is complicated. Remember that you're not the only group advisory panel dealing with this subject but you're a very important one and I know that whatever you do will have a big impact on what everyone else does. Thank you. CHAIRPERSON MARSHALL: Thank you very much for being here. [Applause.] CHAIRPERSON MARSHALL: We are going to have a short break. We're bringing more chairs in, I hope. Let me ask each of you who is here in the room who has not signed up please to do so. Our meeting is a matter of public record so we would like to record the fact that you were good enough to be here. So let us take -- we do have a half hour of flexibility in our schedule. Let us take 15 minutes to break. Thank you. [Brief recess taken at 10:55 a.m.] CHAIRPERSON MARSHALL: Can people move towards their seats so that we may resume? Welcome back, everyone. Committee members, we're in the midst of discussing public use data files and coming to closure on that. Adil, did you have the floor? DR. SHAMOO: No. CHAIRPERSON MARSHALL: Anyone else have comments on public use data files before we vote on the document as a committee? MS. MEYERS: I see this was on our desk when we come back, which looks like a run down of federal laws having to do with confidentiality. CHAIRPERSON MARSHALL: That's the next issue not on the table right now. MS. MEYERS: Oh, okay. CHAIRPERSON MARSHALL: That's later. MS. MEYERS: All right. CHAIRPERSON MARSHALL: So then, committee, can we -- I would like to then call a vote of the committee to get our final endorsement of this document. So let me ask those of you who are in favor of approving the public use data file document as written and to moving it forward as a committee, please give us a show of hands. [Showing of hands.] CHAIRPERSON MARSHALL: Thank you. We have achieved consensus this morning already. Thank you, committee. Can you all hear out there? [Chorus of no.] CHAIRPERSON MARSHALL: We're not getting the microphone component of what's going on here. Does this work? [Chorus of yes.] CHAIRPERSON MARSHALL: Okay. Great. Good. Then let us move forward and we will, in the next hour or so, achieve consensus on yet another document. Yes. Oh, I'm sorry. Greg wanted to make a point. DR. KOSKI: I just, on behalf of OHRP, would like to thank the committee for its work on this. Clearly it has been one of those things that provides an opportunity and all for the research community as well as for the IRBs and everything to have clarity here and we appreciate this. Thank you. CHAIRPERSON MARSHALL: Thank you. We've been working hard. Let that go on the record, Dr. Koski. Sandy? DR. CHODOSH: I think that the work that has been done by the working group is fantastic. What's still going to be lacking and which we as an advisory group cannot do is how it's going to be implemented and we talk about qualified IRBs who can do -- establish public files -- PARTICIPANT: We cannot hear. DR. CHODOSH: You can't hear. Can you hear now? [Chorus of no.] DR. CHODOSH: Can you hear now? CHAIRPERSON MARSHALL: I will go ask Keisha. There's music coming through. DR. CHODOSH: I don't know what it is. CHAIRPERSON MARSHALL: Someone is coming. Thank you. DR. CHODOSH: Okay. I'll try to speak up but essentially unless there is implementation of what we mean by qualified IRBs, training of investigators to understand what it is that has to be done, all of this is in here and it should be in here but, you know, we've had trouble doing this with other things that are sitting around for a longer time with IRBs in terms of training and whether we're talking about certification or what have you there needs to be some kind of control of who is qualified. DR. KOSKI: I'll just say, Sandy, thank you. Certainly we recognize that and it's OHRP's intention to take this advice and put it together with that from the working group that the Human Research Subjects Subcommittee has, which I believe are largely consistent, and to move forward as quickly as we can. In all honesty, as I've said at past meetings, the usefulness of this committee to us depends upon its ability to produce coherent guidance in a timely manner. That's what public bioethics is all about. So we're anxiously sitting on the receiving end and happy to get this. Thank you. CHAIRPERSON MARSHALL: Thank you, Greg. We do have someone coming to fix this problem. Hello, Alan. Welcome. Elliot? DR. DORFF: We just approved the guidance. There were some background. There was a background attachment with recommendations that Adil wanted to -- CHAIRPERSON MARSHALL: Separate. DR. DORFF: That's separate. MS. GOTTFRIED: Let me just make one logistical comment here that -- it's not just logistical -- the word "guidance" remember is really inaccurate. These are advice and recommendations from NHRPAC to -- and I realize it's not that it says so in the document but it is officially advice and recommendations. CHAIRPERSON MARSHALL: Yes. We don't -- NHRPAC does not offer guidance documents. We hope to bring guidance documents into being. We midwife them, I think. [Laughter.] CHAIRPERSON MARSHALL: Then let us move forward with the agenda. Felice and Jeff and their working group has been working inordinately hard over the last several months both prior to our last meeting and between our last meeting and this meeting. The issue of third parties as research subjects I think may be perhaps the most difficult thing that we have worked on as a committee in terms of different perspectives and the possibility of coming to consensus, complete consensus on that. I hope there won't be blood on the floor after the next hour is over but I can say that -- [Applause.] CHAIRPERSON MARSHALL: -- we have come to consensus once already this morning. Let's do it again twice if we can. The ideal would be that we achieve consensus but the de minimis would be that we agree to disagree. So you have in front of you four documents. One of which is what we are calling the "breakfast statement." The iteration of the breakfast statement that Bob Levine moved us forward with. The Mary Kay breakfast statement, the Mary Faith breakfast statement revision, and the NIH document. It seems to me, just to boil all of this down to its essence -- MS. GOTTFRIED: It says "Dear NHRPAC members" at the top. CHAIRPERSON MARSHALL: Does everyone have a copy? It says, "Dear NHRPAC." Everyone on the committee has a copy. All right. It seems to me that really the nut of what we're trying to get at in terms of agreement as a committee is the issue of when referenced by. So we need to come to agreement if we can on whether a third party -- whether someone who is -- about whom information is provided by a person is a third party or whether we -- whether information that may be part of a medical record, genetic information and so forth also constitutes it because it is private information about an identifiable person, whether that also constitutes legitimacy in terms of human subject. So I'll open the floor for some discussion but I would ask that as we're doing this that we try and narrow and focus our discussion about the topic at hand because my sense is that the rest of the document is something that for the most part we're agreed on and if there are disagreements about the rest of the document we can come to that but let's begin the discussion with "when referenced by" and I have Mary Kay. I have Greg. Mary Kay? Oh, Bob? DR. R. LEVINE: Which document are we looking at? MS. GOTTFRIED: It's the document that says, "Dear NHRPAC members" on the top. CHAIRPERSON MARSHALL: Okay. Let us begin -- all right. MS. GOTTFRIED: The last one is your's. CHAIRPERSON MARSHALL: The last one is mine. DR. R. LEVINE: They're stapled together. MS. GOTTFRIED: They're all stapled together. CHAIRPERSON MARSHALL: They're all stapled together. DR. R. LEVINE: But are we going to focus our discussion on one or more of these separate documents? CHAIRPERSON MARSHALL: You need to use your microphone, Bob. DR. R. LEVINE: I didn't plan to say anything worth hearing. [Laughter.] DR. R. LEVINE: We have, yes, one document stapled and on the back of it there are about four separate statements of the proposed policy. What I'm asking about is are we focusing this discussion on any one of those or is it just a general? CHAIRPERSON MARSHALL: Let's begin -- let us start in the back with the document that I sort of compiled from others. Felice? DR. R. LEVINE: This last one? CHAIRPERSON MARSHALL: The last page. The final page. Status of third parties in biomedical and behavioral research. Something -- I've got a list of people so unless this is procedural -- DR. F. LEVINE: It's procedural. CHAIRPERSON MARSHALL: Okay. DR. F. LEVINE: Or at least I want to reflect on what I think are these documents. The first document was the one that we -- that the breakfast consensus group presented in October. CHAIRPERSON MARSHALL: Correct. DR. F. LEVINE: The second was -- CHAIRPERSON MARSHALL: Is your microphone on? DR. F. LEVINE: Sorry. The second was the Mary Kay posting as you say. The third, however, isn't the final posting of what we thought was the one circulating amongst us, which is a November 27th. It's an earlier version because as the Levine team here we were taking everyone's, and on the 27th transmitted to you a final version. It's very, very close but it's not identical. I have the 27th version on a floppy. CHAIRPERSON MARSHALL: You're saying the Levine breakfast statement is not the final version? DR. F. LEVINE: Right. Which was taking everybody's comments. CHAIRPERSON MARSHALL: All right. Let's ask -- we will ask Keisha to copy that for us but let's -- for the -- okay. So for purposes of discussion let's begin with the Mary Faith document if that's all right. I mean, we can start with any one of these We'll get at the same issue. Sandy, I've got you on the list unless it's procedural. DR. R. LEVINE: This is procedural also and that is that in that case there are numbers of e-mail that went back and forth that are also not here and I think that we should stick with what we have in front of us and discuss it from that point on. I mean, there were lots of other opinions that went around. CHAIRPERSON MARSHALL: Okay. DR. R. LEVINE: And those opinions -- CHAIRPERSON MARSHALL: I just want to move forward with the discussion. Let's start with "status of third parties in biomedical and behavioral research," the last page in your document. And I have Abbey first. I mean, I'm sorry, I have Mary Kay first. DR. PELIAS: I'm very happy that we're starting with this third document that Mary Faith put together because we did go around for a couple of months. Mostly, I think, not disagreeing on content and substance but having differences having to do with writing style and how many words we wanted to use. And I, for one, was very relieved when Mary Faith said she would take the two versions that were circulating. Mine was a little bit shorter and Felice's was a little bit longer. Mary Faith very carefully put together the substance of the two earlier -- the two earlier kinds of documents shall we say since there were several versions of them. And it's my opinion that Mary Faith's synthesis of the earlier documents has all of the ideas in it that we were all trying to get to and is put together in the lesson that I learned long ago about trying to write one pagers so that people will actually read from the top to the bottom and perhaps absorb everything that's on the one page. I would also like to say that when we received the document that NIH had put together I went through that line by line and I would like to say that I find the NIH document extremely workable and when it is read in concert with Mary Faith's document, the synthesis of the two earlier versions, when we read Mary Faith's synthesis together with the NIH document, I think we have something that is imminently workable and that's my bottom line on the whole issue. CHAIRPERSON MARSHALL: Thank you, Mary Kay. Dr. Moreno, I will point out there is coffee available in case you're getting the withdrawal syndrome. DR. MORENO: Thank you for noting my addiction. [Laughter.] CHAIRPERSON MARSHALL: It's in the record now. Let's see. I had Mary Kay. Who did -- Greg and then Felice? I'm sorry, Greg. Felice? Did I miss someone? DR. F. LEVINE: The issue that I think is lost in the third document, and I actually think that the MK document and the Levine documents, B. Levine, were -- had the same intent. I think that the last version that we began looking at in December had the same aspiration as well but in losing clarifying what the situation of third parties being persons referenced by human subjects and the relationship between those two and falling back into the general language of all situations in which a person may be a human subject where there is not direct interaction or intervention we lose the sharpness of the focus on what was the essential element of the topic and that is when human subjects make reference to others. Those are the third parties and that's what the earlier document did. And when those third parties were or were not human subjects and how IRBs would go about that determination, and that's what I felt in my postings was lost in the last document. CHAIRPERSON MARSHALL: Thank you. You are exactly right. You hit the nail on the head. So the major difference is -- if you look at the Levine/Levine document under number three it said, "Third parties about whom researchers obtain information..." here is the operative phrase "...from human subjects but who themselves have no interaction with research investigators or their agents." So that versus on -- this would be my "B" on the last page, "Third parties about whom researchers obtain information but who themselves have no interaction with investigators or their agents." So the real point is what is the source of the information about third parties? Sandy and then Bob? DR. CHODOSH: I do not think it is any secret to you that I have had a somewhat different approach and it goes back to actually in my first course in philosophy where we were taught logic, you know, and I unfortunately was at the University of Virginia in a rather illogical time but nevertheless there were simple things and number one was like you make definitions and then you try to see how they work through. I think it's clear that what we're talking about here is anything that has to do with humans and the real question is when do they become a "subject?" And if, in fact, one says that the research involves information about that human and the context is such that it is being used in the research that they are human research subjects. Whether they are at risk or not I think is a whole other matter and I think that that's where we keep getting into trouble. So that I -- wherever this information comes from, and I'm now getting back to addressing what we're talking about, is unimportant as to the issue. The issue is that the information was obtained in some way but indirectly and not from that individual. So that I would choose to avoid the use of "from human subjects" as the clarifying issue. CHAIRPERSON MARSHALL: Thank you very much. Bob, this is perfect timing because Bob does have a different concept definitionally in terms of who a human subject is. DR. R. LEVINE: Thank you. Actually, what I'm going to say is an attempt to be responsive to why we created a group to look at the problem in the first place. Since 1981 there has been no doubt, and nobody has quibbled over it, that when you look at somebody's medical records with the aim of doing research that the individual whose records they are is a research subject. There is no need now -- no one has raised the question as to whether or not they are a research subject. They are adequately described in exemptions and in expedited review procedures and all we do by making our definition broader is to confound the issue. We were convened for purposes of deciding what is the status of a third party. In particular, when a researcher asks a known subject about another individual under what circumstances does that other individual -- under what circumstances is that individual to be regarded as a human subject with all of the associated rules, regulations, ethics and so on? And it's for that reason that I greatly prefer in two places if we're looking at Mary Faith's document as our reference point, I would call for clarification and focusing in parts 1(b) and also in Part 3, the first sentence. Just so that we would be responsive to the concern that brought us together. Thank you. PARTICIPANT: How would you do it? DR. R. LEVINE: I've been asked how would I do it. I would do it by excerpting -- either excerpting the relevant language from the Levine/Levine document or by putting this document aside and using the Levine/Levine document. It can be accomplished either of those two ways. CHAIRPERSON MARSHALL: So that you would under, for example, 1(b) -- we would just insert the language "Who are referenced by human subjects." Is that correct, Bob? DR. R. LEVINE: I think that the finished product that Felice has noted did not get circulated to this group had somewhat more felicitous language but that's the idea. CHAIRPERSON MARSHALL: Okay. Thank you. We'll get the most current and felicitous language possible. Second, of course, to mine. [Laughter.] CHAIRPERSON MARSHALL: Just kidding. DR. F. LEVINE: I think it was an attempt to make a pun on my first name but the one that is circulating is quite close. It's just that the one that's called "Levine" was an effort to take everyone's comments and the November 27th had everyone's last comments. Whatever I got I put in. CHAIRPERSON MARSHALL: Thank you, Felice. Kate is standing right behind you. Susan? MS. KORNETSKY: Bob and Felice, I would just like to ask you -- I know that we can come to a different opinion than the NIH did and both groups will give advice to OHRP but do you find what -- and I haven't seen the final document or haven't looked at it in a while, do you find that consistent or inconsistent with the NIH document that we have in front of us because I read it and I see some differences but I want to understand how you find it. DR. F. LEVINE: I'm going to call it the November 27th version for the moment. I think it is consistent where it's addressing third parties and human subjects, which I think was the strength of what we were doing and turns out to be a squashier part of what they are doing. And one of the things that I think we very directly addressed was also the protection to the human subject, meaning when an investigator is in interaction with that human subject what are the obligations to that human subject when that human subject is making reference to others? And that's a very vital part of what we're committed to and what was lost in losing the focus on the reference to others and the human subject. I thought the breakfast version and the transformations through November 27th kept that attention, which was the issue that sort of led us to focus on that and not that broader question which we didn't think was really problematic. CHAIRPERSON MARSHALL: Alan, then Sandy? DR. FLEISCHMAN: I have a question really to follow up on Susan's concerns about the NIH December 7 document. My concern with rule of thumb number one -- and here's where I'm trying to figure out whether we're in agreement with this or not. Rule of thumb number one, I'm quite taken by things that have boxes around them and italicized because that's probably what people will read. The second sentence says, "Therefore, a third party does not become a human subject unless and until the investigator obtains information..." da, da, da "...when this occurs the Common Rule pertains." Now, you know, I'm just a country doc. IRBs don't function that way. They review protocols prospectively and I guess my concern is if it is predictable that the protocol will obtain information about a third party that is both private and individually identifiable, do we believe we ought to say that and we ought to make some process at the IRB level for dealing with that? I think our documents say that. I think the NIH document doesn't say that but I don't know whether it says it. I just think it doesn't say it. So I would hesitate to kind of bless this document because I don't think our's agrees with it. I think our's is more clear. It gives the IRB a stronger -- it demands that the IRB consider this prospectively and it sets out the standards for it. Am I correct in that? CHAIRPERSON MARSHALL: Well, it looks as though we've just put that issue to rest. Thank you, Alan. So let's move back then to our document. Well, since we -- the Mary Faith document just for purposes of having something in front of us to look at. Others we haven't heard from? Let's see. Sandy, you're next on the list. DR. F. LEVINE: A comment on the Levine/Levine criticisms. Number one, I've always had trouble, Felice, I must say, with the idea that "the human subject requires special attention." To me any information that is private and confidential, et cetera, whether -- no matter how it's obtained -- requires special attention and that the protection of those individuals is -- should be uniform. There should not be a special category. Now then we get into the informed consent which I'm sure Felice is going to mention. Well, medical records there's no informed consent. And I think, Bob, I interpret it a little bit differently. The information that's obtained in a medical record and other ways like tissue samples, et cetera, are obtained not with the intent of doing research, the individual who gave the information did not give it with the intent of it being used in research, and certainly did not intend that anyone else that he mentioned in the medical record would be subject to be being used in medical research. CHAIRPERSON MARSHALL: Thank you, Sandy. Bob, I've got you. I just am going to interject here. Kate and I were at a meeting in New York this past weekend and one of the presenters described to us the fact that st his institution all patients who are admitted sign a general consent document and included in that document is consent for the use of information in their medical record for research in the future, which is a scary idea. I mean obviously they are not in compliance but I promise I won't tell who it was. Bob? DR. R. LEVINE: Sandy, whether or not there is informed consent to the use of information in the medical records or to the use of tissue specimens removed at surgery is entirely up to the IRB. It's not correct to say there is always consent or always not consent. You said that medical record information is used without consent. Mary Faith, the scary idea you're talking about was recommended by the National Commission in 1978 and we don't usually get people to sign documents but in most institutions there are statements in the patient information brochure that each patient gets on admission that says, "You are in an institution which has among its missions research and education. It is customary in this institution to use medical records and various other things for research purposes." And it goes on to give a very minor description but then usually what happens is that all applications to do research involving medical records must pass through the IRB and the IRB then decides whether there's anything special about this proposition. I don't know what more to say about that. Sandy, if I hear your argument correctly I don't see why you don't include subjects in randomized clinical trials if your intention is to make sure that everybody in this situation is considered a research subject. CHAIRPERSON MARSHALL: I've got -- okay. I have Susan and then Abbey. Let me respond, Bob, just to your point. I guess I'm not sure what purpose prospective consent of that nature means or how it is meaningful given the fact that, as you said, ideally we hope that investigators know that their proposals need to go before the IRB for review or for waiver if they involve human subjects. DR. R. LEVINE: Mary Faith, this is not prospective consent. This is not consent of any type. This is something that the National Commission said was a circumstance in which individual consent is ordinarily not necessary and what it called it instead was a response to a right of notification. MS. MEYERS: What happens if somebody doesn't want to sign it? They say, "No, I won't sign it." Do they say, "Okay, go to another hospital for your surgery?" CHAIRPERSON MARSHALL: Probably not. My guess would be that most people don't attend to it very well. Okay. If this is on point, Adil, and then I want to move to Susan. Adil? DR. SHAMOO: On the same point as Abbey. This is the most coercive circumstances. You're in an emergency room circumstances and you're going to sign this. You sign any document then. You are in pain. This is horrible to have a blanket futuristic informed consent signed, wherever private information, any researcher can use it and maybe divulge that information. And just because the National Commission said it's okay, Bob, I thought we are here to review those things and try to make advice and counsel on new issues regardless of whether the National Commission -- it's not the Bible yet. CHAIRPERSON MARSHALL: All right. Susan? MS. KORNETSKY: I'll just make one comment. I mean, I agree with Bob. I think this is a very common practice. I think more practically what IRBs are doing, there may be certain statements like that but as the medical record requests are coming through what they're doing is then thinking about the criteria for exemptions of waiver of informed consent on an individual basis. So the overall consent may say something but I think IRBs are moving towards looking at each one individually. CHAIRPERSON MARSHALL: Okay. We are getting off of target here really. We need to be talking about "when referenced by" getting back to our subject. Others on the committee because I would like to open the discussion up to the floor? Ex officios? Margaret? Oh, I'm sorry, Margaret. I didn't see you. MS. BORWHAT: Well, I think one of the problems that came up from the case that brought this to our attention to begin with was the idea that research was somewhat of a fishing expedition and there was a lot of questions asked about third parties. It really wasn't relevant to the research at all and would be kind of involved in a post hoc analysis. And so I'm wondering if this document addresses any of that? I know that we discussed it on the conference calls and the e-mails and I'm not sure that I see it specifically in this document. DR. R. LEVINE: I want to say that one thing we're seeing now is an artifact of focusing on one sentence in one version of a document. To Adil I have to say what several people, including I, have said before is that the person who comes into the hospital and has a medical record created, when a researcher wants to look at that medical record that person is already considered a research subject. It's not as if everybody has carte blanch to do whatever they like. The individual who wants to use that medical record for research purposes then must go to an IRB unless we are working in an exempt category. Must go to the IRB and the IRB will then say yes or no, you may proceed without consent. In some circumstances they will call for consent and in some they won't. All right. So it really doesn't help anything to talk about all of the horrendous abuses that can come out of looking at one part of one sentence because there's so much other stuff written on this topic that establishes fairly secure safeguards. CHAIRPERSON MARSHALL: Judy? DR. SIEGEL: I'm trying to organize this in my brain and I'm getting a little lost. What I'm hearing now, and maybe this is something I didn't really understand before, is that what we're talking about now is a clarification of more recently occurring events and that maybe what this document needs, although not dealing with previously covered events, is a reference to previously covered events of the type that Bob is talking about. If there are situations that are already covered within the purview of the IRB to review and make decisions maybe it should be stated up front that that's not what this document is referring to. Would that help sort this out a bit? DR. R. LEVINE: Sure. CHAIRPERSON MARSHALL: Yes. Yes. Thank you, Judy. DR. KOSKI: It's going to fall to OHRP to take the advice that comes to it and develop guidance for the research community on this topic and clearly I think they would want to do that by providing the kind of contextual information that would give it meaning and place it in the overall spectrum so that whether or not the committee does that I can assure you that that's likely to happen anyway. Okay. CHAIRPERSON MARSHALL: Yes, Judy? DR. SIEGEL: I guess what I was trying to get at, is that actually a sticking point around the table here? Would that get us off this point and maybe on to something else? CHAIRPERSON MARSHALL: Right. Well, let me ask you to do this maybe, I'd like to open the floor up, could you craft us a sentence? Not that it would be the exact language we would use but to convey your idea. Thank you. Any one of our ex officio folks who are out there who would like to say something? Anyone in the audience at all? Our public members? Yes, here comes someone. MS. HILLSMAN: Thank you. I'm Sally Hillsman. I'm the Director of the Office of Research and Evaluation at the National Institute of Justice, U.S. Department of Justice. Just a quick comment. This is -- the issue of third parties is a very important one to the kinds of research that are done by agency -- by researchers who do work in the justice system on criminality, on a variety of important social matters. As I listen to this discussion, I came here hoping to get clarification on behalf of those researchers on the issue of what I thought the third parties were, which is that is information about individuals coming from a designated human subject where those other individuals are not human subjects. It seems to me that most of the discussion this morning has not addressed those issues. It has gone off on the question of people who are human subjects in their own right or may or may not be. Hence the term "third party" has no meaning in this context. I think the field, certainly the field of researchers that I deal with need guidance on the third party issue and this discussion is not getting us there. I think the Levine/Levine document very much does that because it focuses exclusively on the issue of third parties and it raises questions about making a determination about their status by an IRB that involves questions about how the researcher is going to deal with his or her obligations to the primary research subject. I think both of those questions are very important and are dealt with in that document giving the IRBs a fair amount of useful guidance in terms of thinking through those issues but if you add the question about folks who are research subjects in their own right then it seems to me it confuses the issue. I'd like to see the two things separated. This is not to imply in any way that that question about whether or not individuals who are research subjects because of their status in -- because you're going directly to records and not having an immediate interaction with them is not an important question. It's a very important question but it is in my judgment a different question and the question I'm concerned about, which is third parties, doesn't seem to be getting addressed adequately. CHAIRPERSON MARSHALL: Thank you. Adil, before I call on you, Felice, I'm looking at the document that was just handed out. DR. F. LEVINE: And you're wondering what the difference is. CHAIRPERSON MARSHALL: Can you elucidate those for us, please? DR. F. LEVINE: Yes. I mean, the one -- as opposed to the one in the packet? CHAIRPERSON MARSHALL: Yes. Thank you. Page 3 in your handout versus the page that was just handed out. DR. F. LEVINE: Well, you have to look very closely because what I was functioning as was -- in trying to build that consensus document was the -- I took all little comments so if you look at, for example, number 2 on the recommendations below, we received some language of clarification that made it clearer. It's not one of substance but it is the most refined document based on the input I received from every member of NHRPAC who offered specific suggestions. I mean, we had a number of other side e-mails but that -- so it was the final edition that I then passed along and it's not one that's substantially different than November 20th but it represents seven more days of -- in those last few days we did get a number of word changes that people believed were important and that made it a more readable document as Susan and I worked on public use, you know, made it a more readable document and captured in language what we were intending to do when we left our meeting on October 31. CHAIRPERSON MARSHALL: All right. Thank you. It seemed to me that "research investigator" is redundant and that's why I sort of -- DR. F. LEVINE: Say that again. CHAIRPERSON MARSHALL: "Research investigator" seems redundant to me. That's why I tried to clean that language up. DR. F. LEVINE: That is out. CHAIRPERSON MARSHALL: That's out. DR. F. LEVINE: Out of the 27th. CHAIRPERSON MARSHALL: Okay. I'm looking at the old one. All right. Thank you. DR. F. LEVINE: All of those things that we -- CHAIRPERSON MARSHALL: That's the difference. DR. F. LEVINE: Yes, right. CHAIRPERSON MARSHALL: That's the main -- DR. F. LEVINE: Well, there are -- CHAIRPERSON MARSHALL: -- and others in the -- DR. F. LEVINE: -- clarifications of -- CHAIRPERSON MARSHALL: Right. DR. F. LEVINE: Go ahead, Bob. DR. R. LEVINE: Most of it is matters of style and expression. The one thing that's substantive that was not absent from the earlier document but is firmed up in the current, the November 27th document, which we're calling the brunch document, is that it's at the bottom of the page, item (2), to talk about the -- what an IRB has to take into account to the extent that they call for certain types of procedural safeguards for third parties. They have to keep in mind that they might be compromised in the autonomy, welfare or safety of the actual human subject who is right in front of you. So they should not -- to take an easy case, and there are more subtle ones -- they cannot, for example, insist that an individual can't give a family history without her mother's permission. CHAIRPERSON MARSHALL: I've got you. Thank you very much. Brief on point? DR. F. LEVINE: Yes, just on point. Just everyone keep in mind that the bolding was just so that everyone internally would know what changes I was making and I was not intending that any ultimate document would be permanently bolded. CHAIRPERSON MARSHALL: Thank you, Felice. I have Adil and then Alan, and then Mary Kay. Am I missing anyone else? No. Adil? DR. SHAMOO: I think Bob clarified it to my dismay and that is the thrust of this Levine/Levine document of 11/27 is that if members of the IRB read it, it means you better watch it, you IRBs, not to call a third party a human subject because it keeps emphasizing it is a rare case in which third parties would become research subjects. It continuously gives that impression. If third parties are deemed to be human subjects investigators may request, an IRB may grant waivers of consent as set forth. The whole document thrust is don't call them human subjects and I don't think that's what we want to do. At least that's not what I want to do. CHAIRPERSON MARSHALL: Thank you, Adil. Alan? DR. FLEISCHMAN: Looking at the November 27 document I want to comment on three parts. One is the rare case. I agree with Adil that I don't think that sentence is necessary nor helpful in this document and I would recommend we strike it. The second, the admonition to IRBs that there is the potential for granting waivers of consent I think is an important thing to be in the document. It wasn't in the Mary Faith document and I think that would be helpful to remind IRBs that even if you do deem someone to be a human subject you may waive the need for consent and that should be clarified. The third is the point that Bob Levine just spoke about, that is his number 2, and I think if we're going to remind IRBs that the primary -- let's call them the primary human subject -- may be compromised by creating a third party human subject, this language does, and I agree with Adil, suggest that IRBs not create third party human subjects. I think we need to clarify if we wish to do this and I could be persuaded that we should do this but what this does is basically says that you shouldn't classify someone as a third party because you may compromise the autonomy of the primary person and I think that's not what we ought to say. We ought to inform the IRBs that you might create a problem here that you will need to deal with in some way. You may still have to deem someone a third party and then you've created additional problems in the informed consent process of the primary human subject but you need to deal with this problem, not just not deem them a human subject. CHAIRPERSON MARSHALL: Thanks, Alan. I have Mary Kay and then Sandy. DR. PELIAS: I have three comments in comparing the Mary Faith document with the November 27th document. The first comment has to do with the question about who are third parties. And I respect and acknowledge that the November 27th document, number 3 on defining third parties, is a wiser wording of what we're trying to get to. My second comment has to do with the sentence somewhat further down the page having to do with the rare case that Alan just mentioned. One of the e-mails that I sent back and forth had to do with the rare case and I emphasized in trying to define what a rare case is that in the world of genetics research third parties are not rare cases. Third parties are every day occurrences because when we start a genetic study and we have to collect a family history we have to talk about all the other folks in the family so these are third parties out there with whom we have no contact whatsoever unless we get permission either from the subject or from a professional individual to find out whether that third party would like to be contacted for our study. The idea here, bottom line is that in genetics studies third parties are not rare occurrences. They are very common occurrences and I think this language should be deleted all together. And my third comment has to do -- pardon me? MS. MEYERS: Which, the sentence about a rare case? DR. PELIAS: Yes, that's the sentence about a rare case. In genetics rare cases are -- we don't have rare cases in this context. I have one more comment, please. And my last comment is the idea at the bottom of the November 27th document, the idea about protecting the autonomy and the confidentiality of the subject who gives information about other people is something that I think perhaps in your context are more important than in what I'm seeing in the world of genetics where I talk to everybody about all their family members all the time and keep it all quiet and confidential. So I think this is an important idea in the number 2 at the bottom of the page that we do incorporate it into our final version, whatever that's going to be. Thank you. CHAIRPERSON MARSHALL: Thank you, Mary Kay. Let's let Bob and Felice respond. Bob, the floor is your's. And then I have Sandy. DR. R. LEVINE: The reason that I'm waiving so frantically is that I want to save you all some trouble about criticizing things that are on "do not resuscitate status" to begin with. [Laughter.] CHAIRPERSON MARSHALL: We thought they were brain dead, Bob. DR. R. LEVINE: First, the rare case. I wish the man who sponsored the word "rare" were here to defend it but there are no defenders of it in this room and I would be happy -- [Laughter.] DR. R. LEVINE: I would be happy to see "rarity" -- DR. SHAMOO: Become even rarer. [Laughter.] DR. F. LEVINE: It wasn't in the 20th version. DR. R. LEVINE: I want to see it yield in the interest of having a document that's well done. CHAIRPERSON MARSHALL: It's out of the gene pool. DR. R. LEVINE: At the bottom of the page I think that Adil and Alan come up with a very important point about item (2) at the bottom that without in any way compromising does suggest raising the interest of the subject who is standing right in front of you to such a high level that it would be impossible to overcome. I don't think we have language to replace it but I think we want to go the route that Alan, I think, came closest to wording and that is to say, "You've got to keep this stuff in mind and deal with it." All right? Now the rest of the document is still open to criticism. CHAIRPERSON MARSHALL: Felice? DR. F. LEVINE: I share as the sort of synthesizer of comments had that comment arrived before the 27th it would have been -- 2 would have been appropriately distinguished to make that point. I think that can be done readily. CHAIRPERSON MARSHALL: Okay. It's deleted. Can we all -- DR. F. LEVINE: Oh, no -- CHAIRPERSON MARSHALL: Oh, I'm sorry, a different point. I'm sorry. DR. F. LEVINE: I think we can rewrite it to clarify the -- CHAIRPERSON MARSHALL: Revise number 2. DR. F. LEVINE: -- distinction that Adil and Alan were making. And I want to -- and I think the "rare" sentence should be deleted. I want to emphasize, though, from a matter of substance that I think the social and behavioral sciences and the genetics view on this is more similar than different. The meaning of rare was when the third party became a subject, not whether it was rare to have third parties, which was an element of both reports. CHAIRPERSON MARSHALL: Okay. Thank you. DR. F. LEVINE: But I think it's best out. CHAIRPERSON MARSHALL: All right. I would like to ask Judy to please read her language. DR. SIEGEL: I don't write government so this is what you got. [Laughter.] DR. SIEGEL: This is relative to the clarification of what this document will deal with. "This recommendation is meant to clarify issues specifically dealing with the information given by a human subject about someone else (e.g., third party). It is not meant to readdress situations where information about someone is gathered through indirect means (e.g., chart review) as these situations have already been covered in existing..." whatever the word is that takes care of that. CHAIRPERSON MARSHALL: Do we have agreement there? All right. Adil? DR. SHAMOO: Could we put "i.e."? DR. SIEGEL: Yes, I don't write English well either. [Laughter.] CHAIRPERSON MARSHALL: Read it one more time, Judy, please. DR. SIEGEL: Okay. "This recommendation is meant to clarify issues specifically dealing with information given by a human subject about someone else (i.e., third party). It is not meant to readdress situations where information about someone is gathered through indirect means (e.g., chart review) as these situations have already been covered in existing..." and whatever the appropriate wording is. CHAIRPERSON MARSHALL: All right. I want to bring us to closure here. We're out of time. Elliot, if it's very brief. DR. DORFF: Yes. Fixing the next to the last sentence, I think, is easy. What you want to do is "whether classification of third parties as human subjects can be done without significantly compromising the autonomy, welfare..." and so on. [Chorus of no.] DR. DORFF: No. DR. SHAMOO: Too easy. DR. DORFF: That's too easy? DR. F. LEVINE: But we can do it. DR. DORFF: What's -- DR. FLEISCHMAN: Better, necessary but not sufficient. DR. DORFF: Okay. Well -- CHAIRPERSON MARSHALL: Here is what I'm going to propose: Here's where I think we are and we're going to come to closure in the next couple of minutes here: We are going to replace the first sentence that begins "this guidance is provided for..." We're going to incorporate Judy's language. Okay. Then the paragraph that begins "simply because reference..." we are going to delete the sentence about the "rare case." We are going to get some language on number two at the bottom. We're just going to revise and clarify that language to reflect Alan's point. And so let's go back to 1, 2, 3 at the top. Let's go back to 3. What is the committee's pleasure? Do we leave it as it stands or do we delete "from human subjects who themselves..."? Elliot? DR. DORFF: Can I ask why you wanted to delete "from human subjects" in your view? CHAIRPERSON MARSHALL: Well, because it seemed to me that we had a tension. We sort of had two camps. Okay. One was you've got to have a narrow context in which the information is provided by the research subject. The broader context was information that exists in medical records, genetic tissues that have been banked and so forth so I was allowing for that broader context. MS. GOTTFRIED: I think based on what Judy has now crafted that the committee is in consensus. Is that right, Sandy? CHAIRPERSON MARSHALL: I think we are there. I think we are there. Does anyone else -- Adil? DR. SHAMOO: I have one more thing. CHAIRPERSON MARSHALL: Wait. Well, let's -- I want to finish this one. Sandy? DR. CHODOSH: The Justice Department spoke up, which I think is very interesting, and I just wondered how, in fact, a researcher who is using police records to talk about criminals who have not given informed consent, how that would be managed within this setting? Whether that -- that's not obtained from a human subject and yet it is very critical kinds of information. And I think that if we had people thinking around here about different ways in which this can occur that I think that specifying only for human subjects somehow restricts the coverage that I think that we should be providing. CHAIRPERSON MARSHALL: Thank you, Sandy. Adil and Alan? DR. SHAMOO: I agree with Sandy but I have a new point like I mentioned. When the IRB has decided that third parties are human subjects then they could go and comply with 45 C.F.R. 46. CHAIRPERSON MARSHALL: If they know what's good for them, yes. DR. SHAMOO: Which they have the right to waive consent, right? Now when then do we keep emphasizing in bold letters at least in this document "if third parties are deemed to be human subjects investigators may request an IRB may grant waivers of consent."? That's redundant and almost inviting the IRB to waive consent. That sentence shouldn't be there. It is redundant and it's an invitation to waive consent. It's not necessary and we don't need it there. CHAIRPERSON MARSHALL: Take it out. Take it out. I mean it does seem to be understood. All right. It's gone, Adil. So, Alan? DR. FLEISCHMAN: I just want to go on record as saying I think it should stay but if it's gone it's gone. My -- you know, you put me next to him. [Laughter.] CHAIRPERSON MARSHALL: Let me just say this, Alan, before we move on, okay. What if we said "when third parties are determined to be..." does that help? If and when? Okay. Let's move on. DR. FLEISCHMAN: I have some suggested language. CHAIRPERSON MARSHALL: Okay. Thank you. DR. FLEISCHMAN: To try to resolve this issue. By the way, my feeling is that the Mary Faith (a), (b), (c), (d) is better than the 11/27 1, 2, 3 on the bottom and I would urge us to do (a), (b), (c), (d) and make this (e). And (e) is the possibility that classification of a third party as a human subject may impact on the welfare of the originally designated human subject and requires that the IRB deal with this issue to protect the interests of both subjects. CHAIRPERSON MARSHALL: One more time. It was so good, Alan, one more time. DR. FLEISCHMAN: I know. I'm looking at Elliot. [Laughter.] DR. FLEISCHMAN: All right. I'm not sure of the grammar here but Elliot will help me. "The possibility that classification of a third party as a human subject may impact on the welfare of the originally designated human subject and requires the IRB to deal with this issue to protect the interests of both subjects." CHAIRPERSON MARSHALL: Jonathan? DR. MORENO: Alan, the Mary Faith (c) talks about this problem with respect to the third party. Why can't we simply add "might cause harm to the third party or the original research subject?" You're worried about a blow back effect basically, right, and that could be a problem for either the third party or the designated subject. DR. FLEISCHMAN: I think, Jonathan, just to speak in favor of putting that in before Bob jumps over the table here that I was quite taken by that explication that was put in there. I mean, I didn't understand this potential impact so I think we need a little more there. That's why I think it needs a little bit more. CHAIRPERSON MARSHALL: Thank you very much, Alan. Bob? DR. R. LEVINE: I think at this point we're well along the way to creating a camel. We're jumping from one piece of paper to the other and revising some words in the Mary Faith and revising some words in the November 27th and we will inevitably lose track of what we revised where. CHAIRPERSON MARSHALL: No, we won't. DR. R. LEVINE: What I propose -- well, when you move from November 27th to -- back to Mary Faith you're leaving out -- I don't know if you know that you're leaving out some wording of the November 27th document in item (1). CHAIRPERSON MARSHALL: Bob, the proposal that's on the floor is to take (a), (b), (c) and (d) from Mary Faith. DR. R. LEVINE: Yes, in that case let me preface my remarks by saying -- CHAIRPERSON MARSHALL: But that doesn't -- DR. R. LEVINE: -- I'm speaking against that. What you're leaving behind in item (1) is that it's not merely the quantity of the information but it's the quantity or nature of the information and then it goes on to suggest that the third party is an actual subject of the research. So it's not as if you can just say (1) corresponds to (a), et cetera. I think that the best solution for this would be to assign those people who have been most vocal in this morning's discussion to come up with a substitute for the last passage and present it in writing to this group so that we all know what's on the agenda. CHAIRPERSON MARSHALL: Okay. Here's what we're going to do. Thank you, Bob. We've got, I think, very accurate notes. We've got it on tape exactly what the discussion was and what should go where so we have agreed that we are -- that beginning at the top of the document on the brunch document the sentence beginning "this guidance" will be replaced by Judy's sentence. We are leaving (1), (2), (3) as they stand. We are deleting in the paragraph beginning "simply because" -- we are deleting two sentences. One is "it is the rare case." The second is "if third parties are deemed to be..." Those are deleted and we will take Alan's language and incorporate it into (1), (2), (3) and clean up the language. So that's the proposal I'm putting on the floor and I would like for us to have a vote. DR. R. LEVINE: I have a point of clarification. CHAIRPERSON MARSHALL: Okay. DR. R. LEVINE: Does Alan's language include all the rest of item (1) that is not in item (a)? CHAIRPERSON MARSHALL: Item (1) stands. We're simply adding something to the bottom. Is that correct? DR. R. LEVINE: Item (1) being -- CHAIRPERSON MARSHALL: Item (1) stands as it is. (1) and (3) stand as they are. I'm sorry, Alan. I thought -- okay. Go back. DR. FLEISCHMAN: I think (a) and (b) together deals with item (1). I think it's clear. I think the language is better. Bob disagrees but I would take (a), (b), (c), (d) instead of (1), (2), (3) and add that additional piece. CHAIRPERSON MARSHALL: And add (e). Okay. Felice and Bob, can you live with that? DR. F. LEVINE: The inclination is to say yes but the problem in the long term is that on topics that are vulnerable, let's say like spouses of, where someone may be giving a lot of quantity and a lot of quality about another human being, that doesn't necessarily migrate solely on the basis of quantity and quality and that's why number (1) is written in the way it is. There has to be an IRB -- CHAIRPERSON MARSHALL: Felice -- DR. F. LEVINE: -- it requires an IRB to determine. CHAIRPERSON MARSHALL: -- I know but it seems to me it's redundant if you read the last sentence in the paragraph -- the preceding paragraph. It says exactly that. "In cases in which a research subjects design -- project's design collects a significant amount of private information the investigator and IRBs should consider whether these third parties should be regarded as research subjects themselves." And you're restating that in question number 1. I mean that seems redundant to me. And rather we just say "when making that determination here's what the IRB should consider." DR. FLEISCHMAN: You know, as a simple IRB chair if you look at (a), (b) and (c) you have the quantity, the nature and the sensitivity. I mean that's exactly what you're arguing but this language is straight forward and the language that's -- you know, with all due respect, the November 27th document confuses me. CHAIRPERSON MARSHALL: All right. So I'm putting on the table then the things that I said leading up to the final paragraph. We will replace (1), (2) and (3) with (a), (b), (c), (d) and Alan's new (e). That is on the table. I would like to bring this issue to a vote. All of those in favor please raise your hands so that Kate can see them. [A show of hands was seen.] CHAIRPERSON MARSHALL: All right. Bob raised his hand. We have achieved consensus. DR. FLEISCHMAN: I assume we cede to the Chair the final judgment on what will be now -- DR. R. LEVINE: It comes back to us. DR. FLEISCHMAN: -- transferred. CHAIRPERSON MARSHALL: Thank you. DR. FLEISCHMAN: Not for our comments but for our reading and awe in its clarity. [Laughter.] DR. DORFF: And wisdom. CHAIRPERSON MARSHALL: Thank you, Alan. We've come to consensus. We did it yet again. Thank you very much, committee members. Thank you. I want to say a special thanks to Felice and Jeff and I'm sure there are moments in the last six weeks or so when Felice would have liked to have had her hands around my neck and I'm glad we were four states removed from one another. Felice, you have just done a fabulous job in a very difficult area so thank you and your workgroup. Jeff, thank you. Committee, thank you all for coming to closure. That's just great. So we need to move forward. We have other work to do. And, Felice, yet again the floor. And, Jeff, would you like to come up? Risk and harm, confidentiality, update and discussion on the social and behavioral sciences. I see some folks who have joined us. Welcome, Dr. Lombardo, Alan Milstein and Vera. DR. COHEN: I will just sort of hold it. I'm flexible. I'm more flexible than the microphone. I, hopefully, don't need a lot of time to spend on the -- I got the wrong one. CHAIRPERSON MARSHALL: I think that we -- you know, if we need to, we will go to 1:00 o'clock because we have until 2:00 to come back. The afternoon begins at 2:00 o'clock. So we'll either go to 12:30 or if we need more time we can go to 1:00 and that will give us an hour for lunch. DR. F. LEVINE: And interaction. CHAIRPERSON MARSHALL: And interaction. Thank you, Felice. DR. COHEN: Okay. I think we're in business. Sorry for that. The Social and Behavioral Sciences Working Group spent a considerable amount of time working on this, which is probably one of the key or crucial topics with regard to the oversight of social and behavioral sciences and what constitutes risks and harm in the social and behavioral sciences. This report has been presented twice to NHRPAC at both the July and the October meeting but due to other more pressing issues never got fully discussed at either meeting so again we, hopefully, will bring this to some kind of resolution today. The committee has with the materials on social risk and harm a table prepared by Joan Sieber which highlights or summarizes the potential for risk in social and behavioral sciences. Actually risks in all research but particularly the risks in social and behavioral sciences. And this was raised in our initial presentations of this topic as a concern because many biomedical researchers and people coming from biomedical orientation do not have a clear concept of what the potential harms might be in social and behavioral research. So the purpose of creating this table was to indicate what those potential harms might be and to relate them to levels of risk and, in addition, the possibility of ameliorating those harms and so this table, we hope, will inform the committee. I'm not going to spend time going through the table. I don't think that's necessary at this point unless committee members have any specific questions about that. First of all, there are two key issues in our presentation. Two key recommendations that we would like the NHRPAC to make. First focuses on the question of minimal risk and in order to establish the degree of risk in any kind of research. We work from the regulations. The only place where risk is defined in the regulations or at least in subpart (a) of the regulations is in the definition of "minimal risk." One of the major problems with that definition is that it conflates two aspects of the possible outcomes of research into one concept of risk and that is the probability and magnitude of harm. And one of our key recommendations is that those two are separate dimensions and must be considered together to determine risk but are two separate dimensions. So for any possible outcome of research you have the magnitude of the harm that could come to subjects so that could range from no harm to minimal harm to significant harm. And then you have the likelihood of that harm occurring, which could be very low probability or no probability. It's not going to occur, a minor probability, a very low probability or a significant probability. And in addition when you're looking at probability you have the probability for an individual subject, which whatever happens is always 100 percent, or the probability for the class of subjects that are intended in the research. So one of the most key elements that we want to make, key recommendations, is guidance for IRBs in separating these two dimensions. So, for example, if you have a survey which does a survey in very sensitive -- obtains very sensitive information about a subject, things to do with criminal activity or sexual conduct or substance abuse, the magnitude of harm of that information if it were inappropriately divulged is very significant. And we'll get into this in the next topic when we talk about confidentiality. The magnitude of harm is very significant but if the procedures to protect confidentiality are sufficient the likelihood of that information being inappropriately divulged could be minimal. Thus when you take the magnitude and the probability together you can result in declaring this research minimal risk research. And I think it's -- one of the problems that we've picked up in our feedback from the field is that IRBs as soon as they see sensitive information being obtained automatically assume the study involves risk and requires full IRB review. So what we're saying is IRBs have to be more sensitive to separating these two dimensions. The second part of minimal risk is the daily life standard and we make recommendations that IRBs pay more attention and that OHRP provide more guidance on what this daily life standard refers to. There are transitory harms that occur to everyone all of the time but they occur, they are very transitory, a few moments later. A day later it's as if they never happened. That is all part of daily life and IRBs need much more guidance as to what that means. The final recommendation is with regard to expedited review and that is that there's a great variability amongst IRBs in how they apply the categories of research that are eligible for expedited review. And what we're urging is more clarification on the categories of research that are eligible for expedited review. And going back to the example I gave before where you could have a very sensitive survey that has adequate protection on confidentiality, that could be a minimal risk study which would now be eligible for expedited review. And finally we would like OHRP to look at the list of categories eligible for expedited review for possible refinement, perhaps expansion. Right now a great -- almost -- most social and behavioral science research is lumped into one of the categories and it's again a conflated category, which includes everything but the kitchen sink and that doesn't provide much guidance at all to IRBs. They don't know how to apply that category to different types of research and so either through guidance or actually changing the categories of research that that would be valuable. That's basically our report. The slide show goes on to detail the recommendations. DR. R. LEVINE: There is another component of the definition of minimal risk in the regulations and that's the relationship to the amount of risk one encounters in a routine physical, psychological, et cetera, examination. And are you suggesting that that should not be taken into account? DR. COHEN: No, I, just in the interest of time sort of buzzed by that but that -- again our main recommendation is that the minimal risk definition be examined and additional clarification on all of those points be included. DR. R. LEVINE: When you buzzed by it one important concept is that in a routine medical examination one gets asked about one's habits and behaviors and so on. One gets asked about drug abuse, abortions, all sorts of stuff. And if we can count minimal risk as something that presents no more risk then that part of a routine medical examination changes the picture somewhat. DR. COHEN: As I said, that examination of that standard is part of our recommendation. DR. F. LEVINE: Which happens to be the recommendation that is up, Bob. That sentence is literally there in the recommendation so the recommendation didn't change. Jeff and I were trying to be a little bit more expeditious this time around to make sure we had good interaction both within NHRPAC and our attendees but all the recommendations are intact in the way that you saw them. DR. COHEN: I don't know who is chairing this. Do I call on speakers or does our chair? CHAIRPERSON MARSHALL: You and Felice are running this. DR. COHEN: Felice, you can see the group better. Why don't you call on people? CHAIRPERSON MARSHALL: If we could follow our same pattern, committee, ex officios, public members. DR. F. LEVINE: Okay. Alan? DR. FLEISCHMAN: At Wednesday's meeting of the Children's Workgroup the work product that Susan Kornetsky has been honcho-ing for the workgroup will be discussed concerning the definition of minimal risk. An additional work product concerning minor increment over minimal risk and trying to bring those two very complex concepts into some kind of coherent examination will be done. Sadly and unfortunately, we were not able to complete that work prior to today but we'll complete it on Wednesday or, hopefully, complete it or at least continue it on Wednesday. I think it is important that we try to harmonize some of the work that is very good work that's being done here with the work that's being done in the child group. There are two, I think, extraordinary things that Susan's committee brings forward and she can speak to it better than I but I just want to notice them publicly. One is the concept of socially acceptable risks of daily life. That is to say we all place ourselves or, as parents, we place our children at socially acceptable levels of risk by getting out of bed in the morning and going and doing our daily lives. I think that concept is a good one. And then, I think, in a just stunningly important concept the term that's used in Susan's document -- it's not comparability. It's equivalence. Equivalence of risk. Speaking to what Bob has just commented on, when we think about the concepts of physical exams and going to school and going out to play or going out to work in the morning there are equivalent kinds of risks that we place ourselves at that also should be deemed minimal, and that's part of the process of examination here as we define these things. Now one other comment and then I will cease. One of the concerns that I think many of us are reading in these documents is concerns that individual investigators have in their own local environments and I'm not sure we're going to be able to do away with those concerns. We're going to be able to clarify for IRBs. We're going to be able to perhaps even allow investigators to grieve the IRBs but the fact of the matter is that we are in social constructs called universities or hospitals or medical schools and have group processes that will determine how much of this is interpreted. And I'm very sympathetic when people say, you know, "There are no social scientists on the IRBs and those bad IRBs are doing bad things." Well, there must be a way to infiltrate that social structure. Certainly on the IRBs that I've served on those groups have been quite effective at being parts of those structures or even seeding to other groups and coming back, you know, and forth with those structures. So I think we're not going to be able to fix all the problems with clarification that individual investigators are complaining about. I would urge that the organizations responsible for social and behavioral research do some group dynamics and leadership training about infiltration of communities that one has every right to be part of. DR. COHEN: Let me just make a quick comment on that. Two comments. One I think it's very important that we do make the -- since both groups are working on the issue of minimal risk that we put those together and make sure they're consistent and I think we have the same goals in mind. The issue about infiltration is a very good one. As we've been telling the NHRPAC, one of the things that our working group is doing has been reaching out to professional societies and one of the messages I know I've been promoting and I think the others from the working group have each time we do this is stop complaining and get on the IRB. And, you know, we've been promoting that and the professional societies have been very responsive to that and they're now reaching out to their membership with that message. So I think that's being accomplished. MS. KORNETSKY: Jeff, I just want to say that Alan made the comments about what we're working on and I don't see -- I see these comments. I don't know what will happen at the workgroup but there's nothing that is inconsistent and in areas that you said need further guidance from OHRP I think we're starting to delve into that a little bit and I'll be happy to share it with you. DR. F. LEVINE: Philosophically let me just add that as a working group -- and I'm on two other working groups -- it's that balance between taking all the things that are wrong and then trying to ratchet up to what usefully can be done generally so we're constantly trying to not try to fix everything and that has been my impression as a participant in the genetics and children's working group as well. Okay. Well, where can NHRPAC offer some generic advice that's more cross cutting if you have enough troubled situations that bubble up and then obviously there needs to be responsible conduct by other organizations and entities. First Jonathan and then Bob and Greg third. DR. MORENO: I hope that whenever NHRPAC produces a document about risk that we be careful not to reproduce the same category mistake and using the terms "risk and harm" in the same logical breath. I'm starting to sound like Elliot Dorff but risks are defined in terms of harm and, in particular, those two dimensional harm that you pointed out. And so I just want to suggest that we not again aggravate a confused situation. If I was king of the world the first thing I would do is change the term "risk benefit analysis" to "harm benefit analysis" along the same lines. My second suggestion is that you insert a very simple two dimensional diagram where the X axis is magnitude and the Y axis is probability and point out that where they meet is no risk and then you get up to region A that's minimal, region B is a minor increase over minimal and region C is a significant increase over minimal. It's very simple but it'll just help to conceptualize, to show a philosophy. That is not hard and you already thought about doing that so great minds think alike. You have it where? I didn't see that. DR. F. LEVINE: We had it at the November meeting. DR. MORENO: Oh, okay. DR. F. LEVINE: Without as much content in it. DR. MORENO: Well, okay, that's fine. DR. F. LEVINE: The goal of this table was to try to show that, of course, it's a dynamic process and steps that you take can ameliorate risk or harm. They're not constant so it was almost three dimensional space which is, of course, hard to visualize. DR. MORENO: Right. Actually I'm going to introduce -- I don't know -- an N dimensional space now. I just came back from a meeting abroad which was largely attended by people from the nuclear engineering field and they made -- acquainted me with an extensive literature on risk, on risk governance, risk management that introduces the dimension of uncertainty. And I hope that not only with respect to social behavioral but in general NHRPAC may well want to move to the next dimension, which I think is the real problem that IRBs have, which is even harder than this, which is how do you interpolate uncertainty into this kind of assessment. DR. F. LEVINE: Bob? DR. RICH: Coming from far outside the social sciences to this discussion I find your distinction between probability and magnitude of harm to be particularly useful in this setting. I'm a little concerned, however, with the -- what I thought I understood you to suggest, which was if the magnitude of harm was determined to be potentially great but the probability to be potentially very small that that would qualify a protocol for expedited review when I would think that as a social scientist one might believe that looking carefully at the quality of the processes that were to assure a low probability of harm might be the most important thing that the social scientist would do. So that may be where the real task of the IRB in a social science protocol might be actually the in-depth assessment of the probability and the quality of those protections. DR. F. LEVINE: Greg, then Bob. DR. KOSKI: Just a quick expansion of Alan's thinking talking about children's -- the concepts of risk in children being, you know, sort of in a more global framework. The current regulations address risk benefit in the principle subpart, Subpart (a), but then go on in additional subparts where there are special protections afforded populations deemed to be deserving of special protections by virtue of their age or situations and so on. I would urge the committee in their thinking about this since another topic on the table we'll be discussing tomorrow are those who are decisional impaired, for instance, that we strive for the kind of framework that would provide a large enough umbrella, okay, to be sensitive to the various, you know, categories as well so that we can get something that basically gets to the point of kind of being common sense that you can apply across the board. We'll all benefit from that rather than having in the final analysis something where minor increase over minimal risk is different for children than it is for another population so I urge you down that road, please. DR. F. LEVINE: Bob? DR. R. LEVINE: Thank you. At one of our early meetings this group voted to establish an absolute standard for minimal risk which meant that it was not context related. I think what you're recommending now is that we abandon the notion of an absolute standard. I think also when it's relativised to either the risks of medical examinations or the risks of daily life we have big problems. I not too long ago saw a new dimension of the problem when I spent some time at a game preserve in South Africa where a few of the nights were on a free range, which means that there are leopards and lions walking around the houses and it occurred to me that it had special meaning when you said to the kids, "Now go out and play." [Laughter.] DR. R. LEVINE: Now this in that part of the world is socially acceptable risk. Thank you. DR. F. LEVINE: Sandy? DR. CHODOSH: Along those lines, you know, this is something that has always concerned me and I'm not sure we're going to resolve it now and that is that whenever I question what is a normal daily life occurrence and for whom, and that I know that many IRBs interpret that to mean that for the condition of the study, like say leukemia, that the daily -- I know that you're shaking your head and you're right -- the regs don't cover that but the truth of the matter is that I think that we're over emphasizing sometimes what is a risk for someone like that, what is the minimal risk for someone like that as opposed to not to. Now I think IRBs get very confused about it. I'm not coming down on one side or the other, Bob, but I think that IRBs are frequently confused by this and that investigators have a tendency to make that argument that this is not an increased risk for this kind of subject and somewhere we should clarify what is meant by that. DR. F. LEVINE: Susan, and then Bob, and then I'd like to open it up for our ex officios. MS. KORNETSKY: Sandy, again it's unfortunate that our group had -- that we're just meeting on Wednesday afterwards but again I don't know what the workgroup will decide but we are taking a stab at trying to come down on one side or the other on that and this group will obviously have a chance to talk about that. DR. F. LEVINE: Mary? MS. KORNETSKY: We did a lot of research and went back and looked at National Commission and did some stuff so we'll take a stab at that. DR. R. LEVINE: The regulations do take into account the context in which a child or perhaps some other vulnerable individual can be recruited as a research subject. In the children's regulations it's especially well expressed that having made a determination that interventions or procedures that don't hold out the prospect of direct benefit for the individual child present more than minimal risk. There are three further criteria that must be satisfied. The one that's on the point right now is that the procedure itself must be commensurate with what the individual child has encountered or is likely to encounter given his or her relevant condition. So, for example, if the child is being treated for leukemia and somebody wants to do a bone marrow aspiration for research purposes the requirement of the regulations would be that the bone marrow examination itself would be commensurate with what that child has experienced or would be likely to experience. It's not the purpose of this to say, well, the kid is going to have ten bone marrows anyway then there's no problem with another. The purpose of this is so that the child who is able to assent can give assent or refuse assent from a position of familiarity with what you're asking him or her to do. Thanks. DR. F. LEVINE: Let me open it up for comments from our NHRPAC ex officio members. [No response.] DR. F. LEVINE: General public? DR. RAND-REED: Hi. I just wanted to add to the aspect of concept of daily risk. It has been my experience that often times, and I'm sure I'm preaching to the choir here, that when you start making the assumptions that many times these assumptions don't take into account lifestyle analysis in terms of various and sundry variation in population exposures. Let me give you an example and why I say that the ethno-cultural is going to become a much more important part especially vis-a-vis the behavioral and social science aspect of it. If you have let's say an epidemiologist that's looking at a particular population in Chicago and they're looking at a group of children in terms of a particular time of exposure and growth spurt, if you don't know that that kid is leaving Chicago each summer to go down south to visit grandma in Yazoo in Holmes County, Mississippi, you've got a problem. And the reason you have a problem is because 25 percent, three months of that child's life, over 13 years usually until they're about 13 or 14, is spent in a totally different environment with totally different exposures with totally different risks but if you don't know to bring that into your epidemiological study then you've missed the whole ball game but it's hidden by culture. So one of the things that many of the IRBs -- by the time it gets to the IRB it's almost a fait accompli. The researchers are the ones that have to be trained to better understand and know their customer and know their population so that by the time they get it to the IRB both the IRB and the PI are operating on the same page for that level of understanding of the population. So I want to throw that in. I'll keep my comments short but I throw that in because when you talk about daily risk the issue about emic or etec as we would say is a choice, which is usually middle class Western, or is it superimposition, which is usually something like environmental justice. These are the kinds of issues that when you're talking about human research populations need to be added in and part of the equation, otherwise we just, you know, are playing games with one another. Thank you. DR. F. LEVINE: Vera, would you state your name just so we have it on the record? MS. SHARAV: Yes. Vera Sharav. I am president of the Alliance for Human Research Protection and, please, I'd like to correct the record. I notice that I was referred to as doctor. I'm not a doctor so please correct. I'd like to remind NHRPAC about the Radiation Commission's report, the 1994 report, particularly on children. The Radiation Commission evaluated 31 nontherapeutic radiation experiments that were conducted on about 800 children. They were conducted between 1944 and '74. Needless to say, by the standards today as far as radiation risk knowledge, you know, most would -- most people, I think, in America would consider them horrific as they would have at the time as well. However, the commission made a very interesting statement, which was precisely in relation to this, which was that at the time the evaluation of those experiments was -- followed ethical standards of the day. Now the additional protections that children now have in the existing regulations, Subpart (d), were adopted in '83, after all those radiation experiments. I would caution that if the existing regulations were weakened and nontherapeutic experiments involving -- some of us would call it -- high risk, within the IRB community one wiggles and that's another issue. How do you define "minimal risk?" Is it with actual evaluation of data and harm done or is it just how do you measure the probability and the amount of harm that could be done? This is very vague right now and it remains vague. DR. F. LEVINE: I think there is no doubt in this whole arena there is often an absence of systematic empirical inquiry on this subject and on others that we have addressed and it's a challenge, I think, to the research community to focus more of their attention on studies of that genre. Any other comments? Abbey? MS. MEYERS: I don't think that there's an average way that you can measure risk because if each IRB is allowed to interpret it the way they want there will be those who say just getting up and getting out of bed and crossing the street in the morning puts you at risk of getting hit by a car. And I think we saw this translation of -- in the Kennedy Greiger Institute's study of lead poisoning in children because the way the university has defended itself, even though the court found them very guilty and compared it to the Tuskegee experiment, the institution has said, you know, "These children are poor minorities and in single family houses in downtown Baltimore and they would have been living in lead paint covered apartments anyway." So I think the university hasn't felt that they have done anything wrong in improving that experiment. So I think we really need to have very, very strong interpretations of minimal risk so that federally no university would be able to decide to interpret it in a more lenient way. DR. F. LEVINE: Sandy? DR. CHODOSH: I would like to get to recommendation number 4 and into the rationale. It says here that "investigators who collect survey data on sensitive topics need instruction on how to properly safeguard raw data in computerized files. My question about that is how do we do that? Again are we talking now about certifying that they have received the proper education? How will an institution know that they're certified? Will the institution require that they have that training? Just putting -- you know, putting mandates in, and they're good ones, don't get me wrong but we're doing it as if it's going to happen because we say so and I really think that we have to look towards how it's going to be implemented and how we're going to be sure about it. The other issue is just a general one and it's the last sentence about "under such circumstances of people at risk because of what they are; procedures for ensuring privacy, that is no signed consent form or recording of identifiers will be necessary." Okay. Or should be avoided actually. But there's no consideration that there's another aspect of the informed consent process. One's consent; the other is information. And somewhere I think we should address that individuals like this must be supplied with information. Somehow we're missing that. You know, as I -- if you do away with informed consent, does that mean you've done away with the informed part of it? I would say that that would be a mistake. DR. F. LEVINE: I think that wasn't the intent. DR. CHODOSH: I know but that's the way it reads. DR. F. LEVINE: Why don't you pick up that part and I'll refer to the other part? DR. COHEN: I believe -- I'm not so sure which exact sentence you're referring to but at least the intent of the working group was not to say informed consent shouldn't be obtained. It was documentation of consent where the documentation could harm the subject. That leaves informed consent if the document -- those are -- you know, I don't think of as our intent to not do the information. DR. F. LEVINE: No, I would just emphasize, though, that how do we know that the investigator, in fact, gave information? There's no documentation. I mean there needs to be some thought given to can that be managed in some way in which we're assured that investigators have, in fact, provided the information, particularly to this kind of a population and without putting them at risk. DR. COHEN: I think the working group would agree with that that there are other methods of documenting that this was -- information was provided other than a signed consent form. DR. F. LEVINE: I think in large part Jeff and I prepared the kind of overview memo and overview slides to sort of try to focus NHRPAC on where some key recommendations might issue because without in any way critiquing this document it was the July set of recommendations, and that's not to say they still don't obtain, they do but the text of some of the recommendations really has a little bit more of narrative appended. So Recommendation 4 really ends before the "what investigators have to learn how to do." Not that that's not important but it's really what OHRP -- how OHRP needs to inform IRBs in terms of what they need to be looking toward. And so I think that has sometimes gotten a little bit mixed in. We're getting better at crafting the recommendation to avoid having the commentary, I think, in the recommendation but I will say that awareness is what led us as a working group to put such a high priority on the issue of confidentiality and the protection of confidentiality, which then was spun off as a subject in and of itself and is the second subject we'll take up today. DR. COHEN: Let me reiterate what Greg said earlier and that is these recommendations will come to OHRP. It is our responsibility to then implement them and to come up with guidance and, you know, requirements or whatever that would actually implement them. If the NHRPAC wants to provide suggestions on that that's fine but we will receive them and then determine how best to implement them. DR. F. LEVINE: I think Greg is going to speak. DR. KOSKI: Thank you, Jeff, that's exactly right. I just want to point out that when recommendations come from this committee a recommendation to us to say we should better define minimal risk and minor increase over minimal risk won't help us. We know that. Okay. That's why we asked you to help us define minimal risk and a minor increase over minimal risk. So I hope that that's clear. Thank you. DR. F. LEVINE: Yes, Alan? DR. FLEISCHMAN: In response to Greg; yes, sir. But I must comment, although it may spend a moment on Abbey's comment about, I think, inappropriately putting in the comment about the social and behavioral scientists at Hopkins who were doing work that was reviewed by the IRB as work intended to directly benefit the subjects. It was not reviewed as minimal risk or minor increase over minimal risk research and those social and behavioral scientists were doing public health intervention research which they considered as potentially therapeutic or of benefit to the subjects so that it really is not relevant to the conversation we're having right now to raise that particular research project. DR. F. LEVINE: Bob? DR. R. LEVINE: The mistake they made is the same mistake that everybody who uses the concept of therapeutic research makes. That is they view a whole project as either be therapeutic or not where the regulations, which they apparently didn't read carefully, say you're supposed to evaluate each component of the protocol and those procedures that are done with the expectation and reasonable probability of a direct benefit for the individual are evaluated one way and those that are -- had no such probability or intent are evaluated another way. If you're looking at therapeutic or beneficial procedures the definition of "minimal risk" doesn't even apply. You only evaluate the procedures that are not expected or intended to benefit along the lines of whether they're beneficial. This is a fairly common error. It would be helpful if we clarified this matter once again. DR. FLEISCHMAN: On point. DR. F. LEVINE: Go ahead, Alan. DR. FLEISCHMAN: Reasonable people can disagree. I don't disagree that it's a fairly common error. The only thing that I would disagree on from my reading of what happened -- I am not involved in that IRB nor in that research project but have read a bit about it -- I don't believe they made that error. DR. R. LEVINE: I'm sorry, Alan. I thought I heard you say that they evaluated this as therapeutic research. I must have misunderstood. DR. FLEISCHMAN: My understanding is they evaluated it as the potential for direct benefit to the subjects of the research and that there were no subjects put at risk without the potential for direct benefit. DR. R. LEVINE: And in what relevant sense does the potential for direct benefit differ from the concept in the regulations of beneficial? They were evaluating. They thought that everything that was done to each child could be justified under the banner of therapeutic or beneficial. DR. FLEISCHMAN: There were control groups in that experiment who were not placed at any harm nor risk and the subjects who were in those control groups were -- the things that were done to them met the criteria for minimal risk but the subjects who were in the intervention groups with the potential for direct benefit were not being evaluated based on a minimal risk criteria nor minor increment over minimal risk as best I can tell in reading it. DR. F. LEVINE: I'm going to table that exchange and ask Elliot to -- DR. R. LEVINE: I want to say I understand what Alan is talking about and I agree. I think I misunderstood what you said earlier and I apologize for that. DR. F. LEVINE: Elliot, and then I'd like to go through these recommendations so that we can get to the confidentiality. DR. DORFF: That's exactly what I was going to suggest. Namely that apparently from what Greg just said, Recommendation 1, "OHRP should issue guidance to IRBs, to others associated with it..." and so on is not helpful to OHRP. And the -- and so that maybe what effectively Greg has been saying to your group, Felice, is that actually they would like some help in doing that and that's the -- that's exactly the point of the exchange that we had before about the child's -- the working group in regard to children and your group that maybe the two of you -- once you have your Wednesday meeting -- maybe by e-mails and the like before our next meeting you could begin to work on that kind of a thing. So I take it that we now want to go to Recommendation 2, right, and discuss that. And there "OHRP should clarify that much of the research in the social and behavioral sciences involves minimal risk." However we define that, right? At the moment we're simply going to understand that there's going to be a much clearer definition of that but however we define that the recommendation is that much of the research in the social and behavioral sciences involves minimal risk. The question that I have is the one that has been recurring throughout our discussion of this. Well, what about people who are -- you know, a study of criminals or a study of people who are engaged in licentious sex or, you know, something on that order? Right? In other words, where the -- it's not just the third party that's involved. That we talked about before but the actual human subjects themselves are not really at minimal risk as a result of the study. I mean, they may be indicted as a result of it. You know, they may be -- they may lose their marriage as a result of it. You know, all of those kinds of things I think are not -- so that's why I'm really hesitant about much of the research in social and behavior. I mean, I think maybe the recommendation ought to read something like, you know, that social and behavioral sciences involve sometimes different kinds of risks and that IRBs have to be aware of that but I'm just worried about much of what you had -- first of all, I should ask you what did you have in mind by "much of the research in social and behavioral sciences involve minimal risk"? Maybe I should ask that question first. DR. F. LEVINE: I hear your problem because we can all think about the challenging kinds of work on vulnerable issues and/or at risk populations so what does one mean by much and many but the empirical reality is that many IRBs are looking at what is just a political attitude survey given to an adult population that is just, you know, your normal -- when someone -- how many cups of coffee people drink when they're completing boring questionnaires to see the relationship between sort of frustration level and, you know, preoccupation and it is just -- I am not implying that that is trivial. It is asking very important questions. It's just noninvasive. Noninvasive, I don't mean just biologically noninvasive, just noninvasive into the -- kind of the psychological and interpersonal aspects of people's lives, and that's why it's the second half of that recommendation, you know, in a way that's to the meat that if we could get a better description of expedited, and that's in a way that motivated the cover memo, but if we can -- which so much of the expedited examples, the listing are so embedded not in social and behavioral science examples. And only one clause is that an IRB that doesn't have much foundation of experience in looking at this takes these every day kinds of research on adult populations and, indeed, gives it in a way the same kind of scrutiny, which isn't a really good allocation of their time. And I understand your notion of, well, how many is many when there are all kinds of research we can cite, and I do all the time to you, that are, you know, challenging studies. Let me do this if I can. We have an ex officio member who I think we should -- and who is a member of the working group. Susan and Greg, and then let's try to move to the next recommendation. DR. RUBIN: Philip Rubin, National Science Foundation. I think we moved too rapidly by Recommendation 1 and dismissed it too easily. Let me say that obviously the working group didn't solve all the problems of how you evaluate risk and harm but they should be commended for making two concrete steps that are a great advance beyond what has previously been done, first of all, to differentiate the probability and magnitude. That issue is crucial to come up with a metric if one wants to. And, secondly, the stunning advance of a chart that attempts to define kinds of harm and behavioral and social research and methods for ameliorating that --I'm not saying whether or not I agree with that chart or the details in it but those are the exact kind of concrete steps that you need to take to provide the kind of definition that OHRP wants. Thank you. MS. KORNETSKY: I just want to pick up a little bit on Elliot's comment. I also have a concern about number 2. I mean, I understand what you're saying, Felice, but I come also from an academic medical institution that also does social and behavioral science research very different and I'm not so sure I would say the majority of social and behavioral research that we do at an academic medical institution is minimal risk. So it's also -- it's within the context. I understand that IRBs may overact but I think making broad statements like that to the IRB community interpreted, you know, throughout the country is not in the best interest. DR. F. LEVINE: I am wondering as I wondered about three months ago with public use whether we aren't at the point where some of us here could massage the recommendations that the working group has given us to better clarify what we want to say because, indeed, one of the advantages we saw that operationalize very well with public use, I think, and with third parties is that we have different professionals with different sets of experience, and certainly that is true when I think of a large quadrant of social and behavioral work that's done on crime related issues or health related issues that those are more sensitive. And I think the point is more to get the emphasis on expedition with that but I'm not sure we need to go through each of those if we can accept them in spirit and then work through the detail, and I'm wondering whether we can get some consensus around that. Elliot? DR. DORFF: First of all, in response to Phil, point noted and absolutely right. I certainly did not mean to in any way, shape or firm minimize the work that the working group had done. And quite the contrary, I think the two pieces that you mentioned are, indeed, very much steps forward and that now, hopefully, your working group and that working with the children's will now be able to take advantage of in crafting a sense of minimal risk. Absolutely. In terms of Recommendation 2, what we are looking for is some kind of language in which we say that, you know, while medical experiments commonly involve risks, the social and behavioral science studies do not necessarily involve them or something because I mean, we want some -- MS. KORNETSKY: No. DR. DORFF: No, all right. MS. KORNETSKY: No, I think you misunderstood me. DR. DORFF: Okay. MS. KORNETSKY: Not at all. No, it depends on the context in which you're working. I mean a lot of the behavioral research that would be done at an academic medical community may not be minimal risk. It's contextual within how you're evaluating it versus a lot of the research that, you know, Felice may have more experience, done outside of the medical community. DR. DORFF: So do you have language that you would see there? MS. KORNETSKY: Not right now, I don't have language but I can think about it. DR. F. LEVINE: And Susan will. Greg? DR. KOSKI: Thank you. I just want to again add a little bit of context here and perhaps go back to something that Dr. Marburger said this morning, which echoes something that we've been saying for better than a year, and that is we need to find the ways to make sure that this whole process for protection of human subjects ensures protections that are appropriate to the risks. Okay. And one of the problems that I see as I go around the country and look at IRBs and talk to investigators and all, in both the medical and the social and behavioral sciences, and recently the humanities is that in many instances our IRBs are struggling with a syndrome that I've referred to as reactive hyperprotectionism. And that their uncertainty about their ability to faithfully exercise their responsibilities under the regulations leads many of them to sort of blindly shoot at anything that moves and looks like the research bird and bring it down sometimes inappropriately. So that looking specifically at the area of social and behavioral sciences I think we would all agree, yes, there are whole groups of research projects that could legitimately be classified as either exempt or expeditable and yet those projects are being subject to full board reviews inappropriately further draining or at least wasting the precious resources that they already have available to them to do a monumental task. That's self-defeating. So that I think one of the things that we have to do here is to provide the kind of guidance to these investigators and IRBs and all to help them have a higher degree of confidence in how they're exercising their responsibilities. And, of course, that's why the kinds of guidance and all that can be produced has to be coupled with ongoing efforts to evaluate and strengthen the actual program so that there is actually a system here that is being built so that ultimately the committees truly need to have the expertise and the confidence to be able to exercise their responsibilities in an appropriate and meaningful way. So this -- what this committee is doing now in looking at issues of social and behavioral sciences and tomorrow or later today, I'm not sure when it is of actually looking at activities in other areas such as journalism and history and all, where do we or how can we appropriately, you know, guide the activities to make sure that we're using our resources in the most effective way. So it's my hope that that's what these reports from this committee and all can help us get to and why I have pushed so hard over the last year to make sure that these issues stay on the agenda and very much in the lime light of these discussions. DR. F. LEVINE: Susan? MS. KORNETSKY: Greg, boy, do I want to believe you with the flexibility that you're giving, you know, to IRBs. I know that you've been in the office a year-and-a-half and have inherited a history that you're working very hard to work against but you're right. IRBs are scared. They are taking a very conservative approach and I'm not so sure we're there yet after still reading on the listserve the noncompliance letters and the types of things that are being cited that those two concepts are merging. So I'm being very frank about it but from the IRB community that's what we feel and that's the pressure we're getting and we're not going to take a chance. So I urge the office to start, you know, your office -- what you're preaching and whatever and I don't mean it that way but I mean what I want to believe and I -- that we begin to see that flexibility allowed. DR. KOSKI: Just a quick response. I think everyone as they again see the roll out of the efforts in quality improvement that dovetail with the developing private sector initiatives in accreditation, as well as coupled with the ongoing efforts in outreach and education, we'll begin to see it. These aren't things that simply change overnight. This is a major shift in the cultural paradigm that we operate in, in this research community, and it takes time to build but I think as the quality improvement initiative is rolled out to its full capacity where there are ongoing interactions on a daily basis. I've had at least three people come up to me, for instance, today, who commented to me how for the first time their IRB or someone actually called and interacted with people in the office and how pleased they were with the approach and the support, the help that they got. It takes time but again everybody has to share in that responsibility. It'll get there. DR. F. LEVINE: I'm going to call on Judy and then I'd like to propose a strategy as to how we might proceed and see if we can get a consensus around that so that we can also move on to confidentiality. We've been working very hard on that and the working group would like to have some feedback on those recommendations or advance them to you. DR. SIEGEL: I'd like to suggest for Recommendation 2 that instead of making assumptions about social and behavioral science, which you've done here, that if you use -- I'm going to give you some wording but it's very messy. To really talk about what I think we're talking about, which is that there is a range within this subcategory that may be broader than the range in maybe medical research and I've written a sentence which I think maybe conveys it. I'm not sure but you want to give recommendations and that's what Susan is saying. People need to hear recommendations. "Because the range of types of experiments in social and behavioral science is broad it is incumbent upon the IRB to consider..." and then whatever a body of recommendations could be "...and then based on that assessment proceed according to the assessed need." Because again I think what this whole recommendation is trying to do is say you have to look at what you're given, given the range that you could possibly get, and I don't think you can just say because it's social and behavioral science you should look less. DR. F. LEVINE: I think that's an extremely helpful way of turning the emphasis and then that also then leads to the expansion of the expedited to better operationalize what's under minimal since that is not sufficiently understood. Jonathan? DR. MORENO: I think what I find bothersome about the language and the use of the word "much" and so forth is that there's an implicit comparison with biomedical research here and I find that bothersome. I'm not persuaded that the range is any different and so forth. I think what you're trying to do, and I understand why and I understand Greg's point, you're trying to do is compensate for the fact that there is an expertise very often on IRBs with respect to social and behavioral research and I'm not sure this is the way to get at that problem. The way to get at that problem is to do what the regulations already require that people with expertise in the relevant subject matter of the protocol be either on or consultants to the IRB and I think we all agree at least ethically if not in a regulatory sense the relevant communities be represented. I think that's what you -- so I think we're sort of laboring here with language that isn't going to change anything. It could be very misleading to IRBs. OHRP says not to worry because much of this stuff is minimal risk anyway and I just think what we need to do is get to the system. The system requires more social and behavioral science or presentation and more folks in the communities that are affected. DR. F. LEVINE: I think we're in heated agreement that Recommendation 2 can be reworded to either make an empirical statement about the range of different types of research in the social and behavioral sciences or an implicit comparison to how that diverges from other fields, I think, and I think Judy was moving us in that direction. I think that was the intent. Let me suggest the following to see if we can do this operationally: I'd like to think that the spirit of what the working group was seeking to convey is being appreciated and valued by NHRPAC and that we can then take these, use the strengths of what the working group has, as Phil underscored, contributed to Recommendation 1 and to work on that with the Children's Working Group to offer the NHRPAC something that is a real value added building upon this contribution. That the kinds of things that we're now talking about, the Recommendation 2, the Recommendation 3, and the abbreviation of Recommendation 4, I think, could be worked on as a modified document within NHRPAC that we can then bring back in March and I'd like it to reside here because I think there's a different way of reading within this group that helps bring it to closure in a way that a more homogeneous group is less likely to do. Elliot? DR. DORFF: Just to -- I want to try to capture Greg's concern that, you know, IRBs are being over zealous in some of these kinds of things and maybe the way to do that is to use Judy's language and then use (a) through (e) for Mary Faith's language that we talked about this morning. In other words, just remind IRBs that what you're looking at is things like the quantity. I'm just adapting here but the quantity of information, the nature of information, the sensitivity of the information, right, because I mean if they're reminded of things like that and then look at a study of the senses or something like that they may decide that none of that really is relevant to this particular study and we're finished, right. So, in other words, if they have some very clear issues or some very clear criteria for evaluating the risk of harm to human subjects, if they have those very clear bullet points then it may, in fact, lead them not to be over zealous when they shouldn't be. DR. F. LEVINE: Abbey, Sandy, and then we need to come to closure on our recommendation. MS. MEYERS: The last three pages of this, I'm very bothered by this. "Categories of research that may be reviewed by the Institutional Review Board through expedited review procedure." DR. F. LEVINE: That's not our proposal. MS. MEYERS: Where did this come from? DR. F. LEVINE: That's the current regs. We're saying that that needs to -- MS. MEYERS: This is the current regs? DR. F. LEVINE: Yes. We're saying that that needs to be reworked or rethought. MS. MEYERS: Okay. DR. F. LEVINE: Sandy, Jonathan and then I'd like to -- DR. CHODOSH: Okay. I just think that we have to remember there's a part of Recommendation 1 that goes into Recommendation 2 and it's really, I think, key to how things actually operate. We talk about a designated IRB person should have knowledge of what they're doing and this, I think, is the key is that there are three people. It's the administrator of the IRB, the chair of the IRB and the designated persons who are doing expedited review. Those people must be the most knowledgeable and that it seems to me could solve a great deal of the problem without encumbering the whole IRB group. And if we don't stress that that is where the education clearly must be, the expertise must be there, just like you bring in an expert to review the protocol, an expedited review should require the same thing if they don't have the expertise. DR. F. LEVINE: The chair? CHAIRPERSON MARSHALL: So I would propose then that we accept Felice's suggestion that I would be happy to take a couple of names now for those who would be interested on the committee in fine tuning this document to bring back to the committee. Sandy, Susan, Felice and I've got my eye on Abbey. She's avoiding eye contact over there. [Laughter.] MS. MEYERS: I think I'm on three subcommittees. CHAIRPERSON MARSHALL: You're on three. MS. MEYERS: I'll do it if you want me to but by e-mail. CHAIRPERSON MARSHALL: Okay. By e-mail. So you'll maybe give us sort of -- once we are close to penultimate to bring it back to the committee you would take a look at it. Judy, Jenny. All right. Confidentiality? DR. F. LEVINE: Of course, no doubt, each of you have committed the report to memory by now so we're just going to give a little bit of an overview and then open it up for questions. One of -- CHAIRPERSON MARSHALL: I'm sorry. I was just going to say procedurally, folks, we're going to break for lunch at 1:00 o'clock and resume at 2:00. DR. F. LEVINE: So we're hoping to move things along. As, I think, has been part of the texture of much of our discussion about research involving human subjects across fields and certainly centrally true in the social and behavioral sciences that a biggie is protecting the confidentiality of the data. And in the social and behavioral sciences, this is not a more or less than any other science, but a key arena of risk as was clear from many of our discussions relates to issues of confidentiality and the question And you can reduce that risk or ameliorate it by ensuring exceptional data protection plans. So we spun off intensive attention to this issue with Sally Hillsman, a member of our working group, taking the lead and David Gleckman, who is on the Interagency Committee and also, I think, an ex officio member but, if not an ex officio member, certainly a presence at all the NHRPAC meetings from the National Institute of Justice helping us take a lead in our working group on these issues. And essentially we have five areas where we have focused our recommendations and that is the first that I've just mentioned, reducing risk through confidentiality protections and then how we can go about the process of enhancing confidentiality protections, being wise and candid and often that would reach to, of course, consent about the limits of confidentiality. And then something that we call, which may be vague in its title, building institutional support but by that we mean the home institution support for the investigator and the IRB, and the process that has been established in approving research. And then the last issue is when and we're not taking up the issue of whether but when access, limited access has been approved on a limited basis for nonpublic use data that all obligations with respect to data protection plans and confidentiality by other users must still obtain. And obviously there are other issues with respect to limited access. We're not addressing those in the confidentiality part but we wanted to underscore that no matter who uses it or when they've been authorized to use it and with what approvals by IRBs that they must adhere to the same confidentiality standards. We really worked on quite a high bar. Recommendation 1: "Reducing risk through confidentiality protections." We feel, you know, life is a dynamic process. It's clear from a lot of the issues we address and that the Recommendation 1 is that "OHRP should issue guidance to IRBs indicating that the degree of confidentiality protection required in research protocols be commensurate with the degree of risks associated with the type of data collected." And obviously in more than minimal risk there really needs to be real attention to the data and, if the issue is confidentiality, substantial attention to the nature of that data protection plan. "OHRP should emphasize to IRBs that a good data collection plan can reduce or ameliorate the degree of risk if that is the core area of risk." This is not to take up the other issues of risk. Let me go through them. "Enhancing confidentiality protections." And you can see in the document and in the recommendations that there is attention to the issue of certificates of confidentiality, of which there's quite a -- we include a table to illustrate that there's quite a degree of variation that investigators need to be alert to and IRBs as well. So we have as recommendation 2 "OHRP should clarify specifically what certifications are available to protect data, including how the certifications work, which agencies have the authority to grant them, when certifications may be sought, what certification protects." For example, in some it's only the identifiers or whether it's the identifiers in all of the data. There's great variation. And (e) where confidentiality gaps in certification exist that need to be shored up so this is kind of a collective effort to identify those areas where NHRPAC and OHRP could usefully provide an important service in enhancing the strength of the confidentiality provisions. "OHRP should lead an effort to ensure the adequacy and alignment of certificates of confidentiality issued by federal agencies." We were not sure where it could ultimately reside but we thought OHRP could play a very important leadership role in getting something going so that this kind of process was put in place. Recommendation 3 is that "OHRP should lead a federal review of existing legal authorities, including statutes and regulations which provide research confidentiality protections. This review should identify with the various laws protect, how the protections are obtained, who administers them, and where potential gaps in the protections exist. Where outstanding issues or gaps are identified a proposal to address these gaps in research confidentiality should be developed through some kind of advisory consensus process." And we have a table that aligns with that. As you can see there's again a great deal of ambiguity as to what exists. We also think in this period, obviously it takes a while to improve the process, the mere posting of these materials or final versions of them would be a tremendous service to IRBs and to research investigators and could be a useful document in final form posted on the OHRP web site. And, I think, that's the spirit of that clearing house function, an electronic clearing house linking information on all federal and state research confidentiality protections as they get better all to the good but even in its present form it certainly is instructive. Recommendation 5 is one on "identifying the limits in confidentiality protections." Four, I think, I just overviewed or at least tried to. PARTICIPANT: I wasn't listening. DR. F. LEVINE: You weren't listening. You know the recommendations too well. [Laughter.] DR. F. LEVINE: Five is "guidance should be developed for accurately and effectively describing the confidentiality protections in the consent process. Special care should be given to describing when and under what circumstances confidentiality will or will not be maintained, along with any reasonable and anticipated risks associated with the disclosure of the information." For example, as we know in a number of ethics codes if a subject in the course of providing information says, "I'm considering killing my mother," then there is a limit to confidentiality. There are competing principles and there needs to be thought about better informing researchers and IRBs about the interactions of those, however rare those cases may be. Recommendation 6: And Recommendation 6 really flows from taking up the issue of the research institution's obligations with work that has been reviewed and approved by an IRB and the data collection plan has been approved and the guarantees have been provided, and investigators have committed themselves as researchers to these obligations, IRBs have also sought to have that same high bar, and that we thought that it was important that all parties, meaning the research institutions be singing from the same page. So "host research institutions..." this is a very important issue and hopefully the text explain why "...should be cognizant of their obligations to actively support the investigator in protecting all confidential information from compelled disclosure or as otherwise agreed to in the data protection plan. OHRP should consider explicitly requiring this as a term and condition of the assurance and any future accrediting bodies should consider requirements in this area." And that is to really give more teeth to what investigators have sought to provide and create and to what IRBs have sought to ensure and that's an important -- we thought a very important new element in the range of issues that could really improve the operations of the system. The seventh one I won't repeat because I started with that as an example and that is that even in circumstances where secondary users have access to nonpublic use data, data under some kinds of restrictions, that if they receive that data or have access to use it that there's a transportability of the data protection plan, that they have the same high bar as other users with restricted access to maintain that same degree of commitment to the confidentiality plan that was originally established, and that's the overview. Elliot and then Sandy. DR. DORFF: I think this is all very good. I would only in Recommendation 5, I would only add where you have "special care should be given to describing when and under what circumstances confidentiality will or will not be maintained..." I would say "and why" because in the paragraph that you have above you list several different reasons why not. I mean, some of them are legal as in the mandatory reporting laws or the Tarasoft [ph] decision in regard to "I'm going to kill my mother," right. Some of them come from professional ethics codes as to why you would not do it, you know, maintain confidentiality. And there may be other practical reasons or something like that so that I think it would be important to spell out when there are limitations and there definitely are. When there are limitations to confidentiality what the grounds of those limitations are. DR. F. LEVINE: Let me say the motivation, the philosophical motivation is to strengthen confidentiality by acknowledging the limitations of confidentiality. Sandy? Susan, was your hand up? Then Adil and then Greg. DR. CHODOSH: Felice, I want to congratulate the group. I think it is an excellent piece of work. Just one point that I would like to make and that is that I wouldn't want there to be an implication that when risk is extremely minimal that there is no need for confidentiality, that there needs to be a lower bar which you cannot go below, and that may be. I'm not sure but I didn't quite get that in here. I just don't want that implication to creep in. DR. F. LEVINE: Friendly amendment. That was the intent and we'll fix it up. Susan? MS. KORNETSKY: I think there is very little to argue with in here. So much so that I almost see this as applicable. I'm not sure why if we make this recommendation that it's just for social and behavioral science research because this type of protection applies throughout. So I wouldn't just think that it's for that. DR. F. LEVINE: In a way nor did we but because that is a frequent dimension of risk that's why we took on sort of the charge of addressing it but we do see it as quite generic and I tried to introduce it in that way. Adil? DR. SHAMOO: Thank you. I concur with the previous comments. I have a question and then a comment. Your Recommendation 1, are you addressing the IRB or the investigator? DR. F. LEVINE: Both. DR. SHAMOO: Well, by the time the research protocol comes and the informed consent comes to the IRB it's almost too late for "OHRP should emphasize to IRB that a good protection plan can reduce or ameliorate the degree of risk." What you want is the investigator to spend time designing the protections and then the IRB review it and I don't think this is clear to me where that will come from. DR. F. LEVINE: Let me say that's why I said both because as this is more pervasively understood, investigators will be doing a better front end job in thinking this through in advance but it clearly is something that would inform how an IRB looks at a protocol. DR. SHAMOO: Why shouldn't we just clarify it? DR. COHEN: Yes. You're absolutely right, Adil, but in the real world if the IRB isn't requiring it then most investigators aren't going to do it and so the idea here was that where the OHRP has its authority is primarily over the IRB. So by making and reiterating to the IRB that they need to enforce this they need to look at the data protection plans and they need to require data protection plans from investigators then we accomplish the other end. We could add, and perhaps maybe we should as we did in the other -- in our previous set of recommendations -- encouraging OHRP to expect training for investigators in this important area. DR. SHAMOO: But we do have places even in the 45 C.F.R. 46 where we give principles or elements of what ought to be and we could put that there so the investigators ahead of time rather than be a surprise, especially new investigators. DR. F. LEVINE: Jonathan, Greg, and then we're going to open it up for comments from our audience. Brief comments so we can reach closure on what seems like seven minutes left the Chair said. Jonathan? DR. MORENO: I've been covered by a previous comment. DR. F. LEVINE: Greg? DR. KOSKI: The Common Rule calls for appropriate protections for privacy and confidentiality so that I would anticipate that these would be issued in the form of guidance rather than changes to the Common Rule. And while the recommendations here are appropriately directed toward OHRP as is the charge of this advisory committee, the issues here seem to be of the nature that all of the federal agencies that operate and deal with these kinds of issues would be interested in attacking that so that again I would anticipate that this is an item that these recommendations be taken up by the Human Subjects Research Subcommittee, of whom, you know, our ex officio members are here representing. So I would think that this would be an appropriate area to go. DR. F. LEVINE: Comments from the floor? DR. PETERSON: My name is Dr. Joseph Peterson. I'm a clinician and we are doing a lot of research now in behavioral, specifically HIV and AIDS. I think when you are talking about IRB I think there was a lot more time given for the ones that are in an institution like Johns Hopkins or other places. There are also other IRBs that are very minimum. One, I think, is the one in Columbia that are not very much aware and they're very much scared actually taking some tasks that actually what the community is doing. Some of the research that's going to be done in the future that will get applied for a couple of them are in the community like in the churches to see any kind of behavioral changes so how can we be able to address these IRBs that are independent that they're not going to be afraid of taking this kind of task, which really has a lot of confidentiality as far as I'm concerned because it doesn't have any names on it. So is there anything that the committee could do to support them or if they have any problem of not understanding what the task is, is there any support on the confidentiality part? I don't know if it's a question or a comment. DR. COHEN: Both the Common Rule and the FDA regulations apply to all. You know, it doesn't matter where the IRB is. Independent IRBs have to comply with the Common Rule and for FDA regulated research with FDA regulations. Any guidance that's issued out of OHRP or FDA will apply to all IRBs regardless of whether they're independent or institutional. DR. FANNING: I'm John Fanning from the Department of Health and Human Services. Your Recommendation 5 uses the term "confidentiality". It is often not a very useful word because it doesn't convey a lot about what will really happen. What people need to know is not the circumstances under which confidentiality will or will not be maintained but actually how their information will be maintained. For example, they may answer questions and think that only the person to whom they're giving the answers will ever see them. In fact, other people in the research term may see them and so on. So I think confidentiality may be a useful catch all word but it's not very useful when you're explaining things to people and has the risk of suggesting more protection than actually exists. I also have a few editorial comments about the use of the term "certification" in Item 2 which I can give you later. DR. F. LEVINE: Thank you. And I think some of those issues will be returned to under the discussion of consent. I'm going to turn this back. Being in the awkward position of presiding over the preparation of this document, I think I should not chair the final acts on it. CHAIRPERSON MARSHALL: So let me see what the pleasure of the committee is. It seems as though we are in a fair degree of consensus about the document. Are we far enough along that we can move that we forward the advice to the Department of Health and Human Services? Jonathan? DR. MORENO: Well, I move that we adopt the document in principle subject to further editorial clarification and improvement. CHAIRPERSON MARSHALL: Exactly. Turn your mic on, Sandy? DR. CHODOSH: I presume that we will be able to do that by e-mail and that the whole group will be involved. CHAIRPERSON MARSHALL: Right. Or at the level of the committee we would fine tune it, send it out via e-mail and so forth. So let me ask for a show of hands for those who are in support of this document in principle and in fine tuning it and it bringing it back to the committee for its final approval? MS. KORNETSKY: Does that include making it broader or leaving it? CHAIRPERSON MARSHALL: That includes making it broader, the suggestions that we've talked about here. [A show of hands.] CHAIRPERSON MARSHALL: All right. PARTICIPANT: A point of information. CHAIRPERSON MARSHALL: Yes. PARTICIPANT: When you say committee members does that include the ex officios? CHAIRPERSON MARSHALL: No, we're at the level of the committee now. PARTICIPANT: Okay. Thank you. CHAIRPERSON MARSHALL: Those opposed? Anyone opposed? [No response.] CHAIRPERSON MARSHALL: It would be posted. Let me clarify. It would then be posted on our web site for general input. All right. Any further business? We need to come to a close. Well, thank you all for a very productive morning and we look forward to seeing all of you back here at 2:00 when we will hear from our guest, Alan Milstein. [Whereupon, at 12:55 p.m., a luncheon recess was taken.] - - - A F T E R N O O N S E S S I O N [Time Noted: 2:07 p.m.] CHAIRPERSON MARSHALL: Everyone, be seated. Find yourselves a space. We are blessed with the problem of having perhaps more persons than chairs but I think that we can and hope that we can rectify that soon. Welcome back. I think we're going to have a very busy and interesting afternoon. As the Chair of the NHRPAC I wear many hats or I guess just being here today I wear the hat of being the Chair but I also am a bioethicist at the University of Kansas Medical Center and I also am a daughter, and I just wanted to say hello to my mom and dad who are sitting back there. [Applause.] CHAIRPERSON MARSHALL: Hi, mom and dad. PARTICIPANT: NHRPAC is a family. CHAIRPERSON MARSHALL: NHRPAC is a family. There we go. [Laughter.] CHAIRPERSON MARSHALL: Those of you who have been reading the academic literature and actually the lay press, The Washington Post, know that the issue of informed consent is something that is pertinent these days not only to folks like us who are immersed in the ethics of human subjects research but also to others in government and to the public at large. Anyone who has read the Chronicle of Higher Education recently may have seen the headline "Crusader for the Rights of Research Volunteers Sues Everyone in Sight." [Laughter.] CHAIRPERSON MARSHALL: Not a subtle headline. I actually wanted to entitle this session "Who's Afraid of Alan Milstein" but Kate wouldn't let me do it so to continue our literary tradition but it is my distinct pleasure to introduce to you Alan Milstein. Alan is an attorney for a private law firm and, as you know, I think he entered the arena of human subjects research and the adequacy or inadequacy of protection of human subjects by representing the Gelsinger family in their law suit against the University of Pennsylvania and he has since become active in other -- in the legal arena in other cases as well. Alan also, aside from being a practicing attorney, Alan has his master's degree in American studies from the place where I work, which is the University of Kansas. And aside from that, he also is a fan of Bob Dillon and other important musicians so that let's us know he's a great guy from the beginning. I am also happy to introduce panel members. We would like to present a balanced perspective here looking at the issue of the effect of civil litigation on the protection of human subjects research and I am delighted to introduce to you two panelists, Karen Rothenberg, who is the founding director of the Law and Health Care Program and also dean of the law school at the University of Maryland. And Professor Rothenberg has done a lot of work in the area of health care, health care law, the inclusion of women in research as research subjects, genetics research. She is well grounded in the area of human subjects research and things that attend to that. So we are really delighted that she could be with us. Thank you so much for coming today. And Paul Lombardo, my colleague at the end of the -- close to the end of the table. Paul is an attorney and a historian from the University of Virginia where he directs the Program in Law and Medicine. What I can tell you about Paul aside from his professional title is that his dissertation was on the Buck versus Bell case, which those of you who don't know, this is a very important case. It's the case that sort of established the legal precedent for involuntary sterilization in the United States. Carrie Buck and her mother and her daughter were all inmates, I think, is maybe the most apt term at the Lynchburg Colony. Their crime being that they were socially perhaps disadvantaged and gave birth, at least one or two of them, out of wedlock. Paul did the defining research, the definitive research that showed that neither Carrie nor her mother nor her daughter had any mental disabilities at all. Unfortunately Buck versus Bell still stands. It went all the way to the Supreme Court. My mother, who is sitting in the audience, actually grew up on the same street that Carrie Buck did. It's visible from the University of Virginia hospital. And Paul is an enophile [ph]. If you need any advice on fine wine he'd be happy to provide that as well. [Laughter.] CHAIRPERSON MARSHALL: So I'm going to turn the session over to our own very capable Mark Barnes, who you all know is not only a practicing attorney but has worked in the area of advocacy for persons who have AIDS and are HIV positive; is, I think, the primary author of our report on financial relationships and conflicts of interest in research and always has the mojosed [sic]. So we are turning things over to you, Mark, and we look forward to a very interesting afternoon. MR. BARNES: Thank you, Mary Faith. Welcome to our panelists. The way that we're going to do this, this afternoon is the following: We invited Alan to give a formal presentation and then have Karen and Paul really as respondents to Alan's presentation. Alan and I spoke on a panel together, I guess it was over the summer, before the American Association of Medical Colleges, and I'm sure that he will be provocative and that there will be much to say in response. Perhaps some in agreement and some in disagreement so I'm just going to go first and take about 15 or 20 minutes to do a presentation. Is that fair? CHAIRPERSON MARSHALL: Yes. MR. BARNES: Okay. And then both Karen and Paul will respond. MR. MILSTEIN: As somebody said once, I think they invited me so you could all see whether I'm as big a son of a bitch as you heard I was. [Laughter.] MR. MILSTEIN: What I thought we would do is just go through some of the hot topics in the litigation that I've been involved with and I have chosen the topics that really, I think, I'm in disagreement with this group on. The first has to do with the distinction between nontherapeutic and therapeutic research. As I'm sure you know, a lot of bioethicists can't stand that distinction. And the reason they give is a good one really and that is that the term "therapeutic research" from a lawyer's point of view is a misrepresentation. It implies that the research is therapy when it's research. Now whatever you guys decide to call this distinction, and you can call it pure volunteers versus patient subjects, there will always be a distinction. Juries and judges will see the difference. When you solicit an employee like Ellen Roche or Nurse Hardin-Able, when you pay $50 to a student like Nicole Wan, when you induce a volunteer, a sympathetic volunteer afflicted with a disease that's under study like Jesse Gelsinger, the risk must be extremely low. I'm not going to get into that catch word whether it's minimal risk or minimal risk plus. I'm telling you that if something goes wrong you've got a problem. Let's talk about the sources of the ethical requirements. Again most of the individuals here look to Helsinki and Belmont and the Common Rule. As a lawyer, I look to the Nuremburg Code and what I call the right to be treated with essential human dignity, which I've argued is a fundamental right guaranteed by the United States Constitution. There's a difference between the documents you look to, which are either recommendations or regulations written, in most part, by committees like yourselves, and the Nuremburg Code, which is, in essence, the judgment of a court and a court's opinion and, hopefully, there'll be some further opinions down the road that establish that the right to be treated with essential human dignity, that is the right not to be in a research study that violates the Nuremburg Code as an essential and fundamental human right. Now I take out of these principles that for research to be ethical for one it must be valid, that is it's got to be based on good science, generally accepted scientific principles. The animal studies must be completed. But here is one key question for all of you that I think would be interesting to discuss, and this is a question that's come up both in the Gelsinger case and in the case I have against the Fred Hutchinson Center, and it has to do with how much preclinical research is required. In a number of these cases what the researchers end up saying is, "We can only go so far to determine what we see as the universe of harm. Unless we begin testing on human subjects we cannot learn of what that universe is." In the Hutch they said, "We need to do human research in order to determine whether or not it is too risky." So the question for you is how do you solve that problem? Suppose you say to yourself, "We've done all the preclinical work on animals. We know what we think is the best we can know based on that preclinical research but there are a lot of things we don't know. We don't know how risky it is for humans." Can you then without doing that final step begin to conduct research on human beings? As you know in the Gelsinger case it was after Jesse died that the group learned in animal studies and other studies what the cause of that death was but it was very apparent from the way they conducted the trial and the kinds of physicians that they had present when they injected Jesse with the adenovirus that they did not anticipate the reaction and you may have heard the comments of the researchers saying, "What happened to Jesse Gelsinger was totally unforeseeable. We had no reason to believe this could happen." Well, as a lawyer, there's two kinds of unforeseeable. There's unforeseeable because you haven't done all of the preclinical work and so it's unforeseeable because you didn't take the time to make sure you could see the universe of harm. Now if it's that kind of unforeseeable it's unacceptable. In addition to being valid one of the points of Nuremburg that hasn't received much attention is that the research be valuable. In Nuremburg they talk about "it must yield fruitful results for the good of society, that it can't be obtained with conducting human research." I think what it also means is that the research not be trivial. There is such an over abundance of research studies going on today. Now there's been various numbers coming up. People have come up with maybe 2 or 300,000. And the biggest boom in such research is drug companies doing work or drugs coming off patent so perhaps if they can find another indication they can extend the patent. Or drug companies tinkering with a drug so that they can create another marketable drug that's no better than the ones out there but it's just different, can be marketable, can be marketed. Now this kind of what I would call trivial research wastes human resources. Let's talk about conflicts of interest. Here again my views differ with your views or at least the views of the committee. I know that you all have concluded that conflicts can be managed and they can be managed if you inform the patient subject of the conflict. That's my view that conflicts can't be managed, that neither researchers nor institutions should have any financial stake in the research that's being conducted. You know, when you are talking about informing the subject of the conflict, in legal terms what you're really talking about is asking the subject to waive the conflict. You don't waive a conflict merely by putting a two or three line sentence at the bottom of an informed consent document. If you are going to waive a conflict you'd have something like this: "I understand that the researcher has interests that may conflict with my health and protection, namely 100,000 shares in New Drug, Inc., which she got for a dollar and if this trial is successful will make her and her family financially secure for life." [Laughter.] MR. MILSTEIN: How many people do you think will sign that one? [Laughter.] MR. MILSTEIN: Let's talk about bounties for a second. It is indefensible in my view that researchers are paid $100, $500, $1,000, $2,500. When I say researchers we're talking about more often than not physicians, that they are paid to recruit subjects for clinical trials. A researcher should have no financial stake in whether or not the subject agrees to participate. And in these informed consent documents how many times do you see what that bounty was for the subject? Now you all spent a great deal of time talking about informed consent, requirements that it must contain the purpose, the procedure, the risks, the benefits, the selection criteria, the alternatives, and whatever financial interests. I've talked about the myth of informed consent or what I call misinformed consent. One of the problems with informed consent is just that phrase "informed consent" because it's the same phrase that all of us are familiar with when you go to a doctor to get a shot or to get an operation or to get any kind of procedure. He sticks a form in front of your face, he says, "This is informed consent, I need you to sign this so that what I'm about to do is not considered a battery," and you sign it. Well, it's got the same name in the context of research but it's a totally different entity. For one, the document itself in the context of research is simply evidence of this informed consent process that was supposed to have taken place. It's not a mortgage. It's not an insurance policy. It's not buyer beware, if you don't read it you're stuck. How many times -- and I assume we have a lot of IRB members in here. How many times in your informed consent documents do you use the word "experiment?" Do you describe the research that you're conducting as a human experiment? I have deposed various researchers in the cases that I've brought and the answer is "Frequently the same but we never use the word 'experiment' because that word carries too much baggage." Well, that's precisely why you should use it so that the subject understands that he or she is a subject; so the subject understands that the researcher is a researcher, not his physician; that the subject understands that what he's undergoing is not therapy but he's participating in an experiment. Now this idea of the "therapeutic misconception" is something that has appeared in virtually every case that I've been involved with on the therapeutic side and in each case every single subject says, "I thought the doctors had my best interest at heart." None of them say that they were participating in the research for the altruistic reason of benefitting science and medicine. The reason cancer patients by and large participate in clinical trials is to get better. The reason that parents enroll their children in clinical trials is to get them better. Now if you look at some of the statistics, and the statistics are hard to come by with respect to Phase I and Phase II trials, the numbers that I've seen show that less than five percent of the subjects in the Phase I or Phase II trial see any benefit whatsoever. Now if that's the case why would anyone enroll in such a study if not for altruistic reasons? The statistics that I've seen show that the percentage of Phase I trials that make it to Phase II trials, of Phase II trials that make it to Phase III trials is extremely low. Whenever I give this talk and I get attacked as I'm sure you all will enjoy doing when I'm finished. I mean the assumption is always from the audience that every study we do is important for medicine and research, that we need to test these drugs, in essence, because they work and they get patients well, when the facts are that particularly in Phase I and Phase II studies you're talking about very small percentages of drugs that ultimately make it through Phase III and Phase IV. So again the only reason to participate in a Phase I or Phase II study is altruism and yet you see very few altruists on the cancer wards of the hospitals in this country. Finally another hot topic, as I'm sure you're all aware of, is this issue of parents and their children. Of course the bioethicists screamed bloody murder when the court in Maryland said that parents cannot give informed consent for their children in the research context. Of course parents can give informed consent for their children in therapy. Why? Because the parents are going to have the best interests of the child at heart. You need someone to okay what the physician is doing but to agree to participate in research is a moral choice and parents can't give consent for their children to make that moral choice. That's one reason. The other reason again has to do with all the other things I've been talking about. Even if parents did give the okay of their children to participate in research we all know that the only reason they enrolled their child in the research was to get them well. They weren't donating the child for the benefit of medicine and science, for the benefit of their neighbor's child, or the next generation's children. They want to get the child well. So there's a small sampling of hot issues. I await your response. [Applause.] MR. BARNES: Karen, would you like to go first? MS. ROTHENBERG: Let me first say thank you. It's very nice to be here this afternoon and first of all to just look around the panel and see what a wonderful group of people have agreed to be part of this committee. And, also, to thank Alan for, I think, whether you agree with him or not he has really stimulated and a lot of people thinking about these issues who in the past might not have thought about them. Okay. Now once I said that -- [Laughter.] MS. ROTHENBERG: -- I think in terms of full disclosure it's also important to know that I have been a law professor for close to 20 years and one of the courses I taught for many years was torts. Torts is the study of a lot of what Alan does on a day to day basis but in terms of sort of understanding what it is behind the tort law system, which is compensating people for injuries in the civil law setting. So what I thought I might do is -- and I didn't really know what Alan was going to say ahead of time -- I have two talks here so I'm going to try to separate them for a total of 15 minutes. First I'm going to respond to just a few points that Alan made but I think more importantly than disagreeing with the details so much is that it would be more helpful, I think, for the committee to put what he's talking about in a broader perspective and that is what the public policy implications are for you as a committee in what your task is to us as a society. So let me first talk, if I might just for a few minutes, maybe food for thought for your next talk, first of all the reason I think there may be a distinction between nontherapeutic and therapeutic from the perspective of a medical malpractice attorney is because of the way you go about proving a case when you're going to bring a case under tort law. You need to ask yourself how are you going to prove causation for the negligent behavior and it is much easier to prove that case when a "normal subject" went into a research experiment and was injured than for a "sick person" who had no hope that went into an experiment and had to prove that, in fact, they were injured. They were already desperate or many of them were, and a big challenge for a tort lawyer is to try to prove causation, to try to prove that the relationship between the negligent behavior and the ultimate injury was caused by that negligent act so that's why it's particularly important to draw those distinctions. That's why Johns Hopkins from day one had a loser. She was a normal healthy woman and, worse yet, she worked in the institution. So, you know, from that perspective that was a difficult case for Johns Hopkins to be able to defend. With respect to Gelsinger, I -- just for full disclosure -- I was on the Recombinant DNA Advisory Committee, I think, along with Abbey that approved that protocol. What happened with respect to that plaintiff from the best I can tell from what has been made public was nothing that we approved because there was human behavior and human beings that made decisions with respect to what they were going to allow and what they weren't going to allow. We certainly did not approve somebody like that individual to be part of that protocol and so the message there is there is always human behavior even under the best circumstances. Next the Nuremburg Code. My quick response to that is there are more people around here that are experts. I think it's very important that we need to look at context. The Nuremburg trials were following the war. They were war crimes. That is not to say that I am not sympathetic to concerns about the rights of human dignity. I do think there would be a challenge constitutionally for that argument to be made. I think it could keep us legal scholars busy for a long time. In fact, I might want to have an academic meeting about this but I do think that it's very important to keep this in context. I think there are many researchers in good faith trying to do well. Sometimes people steer wrong for all the wrong reasons but it is not the holocaust and the war crimes following. I think that's important. Third, ethical principles. I would agree that the most important ethical question for an institutional review board to make and the one that the University of Maryland always makes is this a worthwhile, is this a scientifically valid experiment to be doing, why are we asking the question and how are we going to go about proving it? Unfortunately, too often, institutional review boards, perhaps ironically, spend most of their time worrying about the form, the informed consent form and not really worrying enough about is it good science. Now what is or what is not unforeseeable, I think, I might disagree a little bit about us having a reality check because I think in science some of the best experiments, some of the best things we've done in science were serendipitous. We might have been studying looking for one thing and something else came out. That is not a total defense to there are trivial trials that are going on but I would think that that would be the exception rather than the rule if we ask that very first basic question why are we doing the study and what is our hypothesis and really to question that. That makes ethical science. Conflicts of interest -- MR. BARNES: Karen, can I make one observation? MS. ROTHENBERG: Yes. MR. BARNES: I just wanted to say that for purposes of the discussion, this is not about anything that you've said, but I do want to observe that Jesse Gelsinger's parents are actually in the audience and I would just ask that -- not that you've said -- MS. ROTHENBERG: Oh, I'm sorry. MR. BARNES: -- no one has said anything that would be inappropriate at all but I just wanted in advance to just note that not only for the speakers but for those who have questions as well. MS. ROTHENBERG: Okay. Thank you. I hope I didn't do anything in that way but I would be glad to meet them, in fact. Okay. I lost my train of thought. Oh, conflict of interest. Conflicts of interest. PARTICIPANT: Paul just slipped me a note and told me to name you in the next law suit. [Laughter.] MS. ROTHENBERG: Okay. I'm only wishing you were one of my alums so I could ask you for a nice donation for the building. [Laughter.] MS. ROTHENBERG: Okay. Lucky temple I should say. Okay. Now with respect to conflicts of interest, I think that Alan makes a very good point and that in a number of organizations that many people sitting around this room and the audience have been involved in we are often told to have to disclose information and then there are waivers that are associated with that but again I think it goes back to the very first point about what it means to be a human being and there are conflicts of interest that are much more significant for some of us than money. I mean the tension and the pressure in the scientific community not only of how things get funded but how people get promoted and the graying of what used to be the good and bad guys between academics and the commercial market is very gray. When I started in this field we thought we knew who the good guys and the bad guys are. And it works both ways. I mean, there can be good guys all over the place and there can be bad guys when you didn't think they were the bad guys. So I think that's a complicated issue and I think Alan has made some good points about it with respect to that. Okay. Informed consent. I'm going to make a correction here. I have a different perspective than informed consent. My perspective on informed consent is that it is not a waiver for battery. Battery is an intentional tort under torts. Informed consent has evolved except for one state and, in fact, the only state left to -- I think the last time I looked was Pennsylvania, interestingly enough. But informed consent is a negligent standard, not a battery standard and, in fact, I would say just the opposite in my perspective. I think we are careless about the use of informed consent in the clinical setting, which is much more relevant to those of us on a day to day basis. And, if anything, we go overboard perhaps with the wrong focus when it comes to experiments with respect to human experimentation so I think that's an area where there needs to be a lot more focus. But in the State of Maryland at least it isn't the form, either in the clinical setting or the research setting. It's just evidence that there has been a conversation. It is not per se not negligence if, in fact, you have filed a form. So that's very state by state specific. But I think drawing these analogies between informed consent in the clinical context and the research context is very complicated because in the research context it's very much associated with the regulatory scheme at the federal level much more than at the state level so anyway that's a caution, I think, with respect to those analogies. I would agree about the importance of language. Again being on the Recombinant DNA Advisory Committee it was called gene therapy. This was an issue that Abbey and I were constantly raising with them. It wasn't therapy. Now many, many of the patients who were desperately wanting to be in gene therapy trials, in all due respect for the scientists and for us, they were pressuring us and the motivation is why were they pressuring us. Should they, which I didn't hear, should they have a right to say we're willing to, we know or maybe we don't know, maybe it's a perception but does an individual have a right to say I want in and what should be the role of a regulatory agency or researcher to say you can't get in, we have decided that this is not in your best interest, and how do we balance all those relative rights? Okay. Another really good point about the conflict between your doctor and your doctor who happens to be doing the research. And I think this is a very good point that I'm sure the committee has been grappling with is can the person that cares for you, that you think cares for you, also be the same person that does research on you? And I think institutional review boards and this committee needs to further grapple with that. Now why do people go into studies? I don't think it's helpful to make generalizations and I think that this is an area that could use a lot more empirical work, and I'm going to give you a whole series of empirical studies that I think the committee might want to do but it's not only to be altruistic, it's not only to be because you think you're going to get better. It's also because there may be a value to hope, whether or not you think you're going to get better. Who is the one that should be depriving the individual of that and what kinds of shenanigans do we go through in order to make hope a reality? I don't really have the answer to that. I mean, that's an existential question. Okay. How much time do I have left? MR. BARNES: You have a couple of minutes. MS. ROTHENBERG: Okay. Now I'm going to give you what I thought about before I knew what Alan was going to say, although I had some hint of it. Okay. First of all, you need to ask your question of where is the appropriate role for a private medical malpractice case or a tort case in the context of trying to get at our ultimate goal? And I think the ultimate goal that we all share is that we do better research and we do research in a way that we feel good about the benefits and relative benefits and risks of the research study. Now the role of tort law is twofold. One it is a deterrent role and that is, I think, what Alan is focusing on here or in part here, is that if we punish people through their pocketbook they're going to be more careful the next time. That's not unique to this. That's been the debate that's gone on in the medical malpractice field. That's been the debate that's gone on with tobacco. That's been the debate that's gone on with asbestos. Pick the issue. All right. It's always a question about what is the appropriate role for the civil law for a tort case in which after the person is injured you bring the lawsuit. How much value will it have to fixing things for the future? That's an empirical question. And the second thing that the tort law does, which is very important in this context, it compensates people who get hurt and this is a significant social and public policy issue for you all to raise that has been debated and debated and debated. How do we compensate individuals who volunteer to participate in studies, Phase I studies, Phase II studies, Phase III studies? What is our communitarian ethic if at all? Or is this just the luck of the draw that if you happen to be in an institution where there has been some oversight or some study or a series from the newspaper like in Seattle or in some other way where this information gets public and then some lawyer takes it from there and develops it into a private case or a class action, so be it, but you need to put tort law into a larger context. For example, what about the role of our current regulatory scheme? Are we willing to give up on it? Or how could we fix it? What about the role of the disciplinary laws at a state by state level? All these researchers who are physicians can be disciplined. In our state we have a disciplinary rule for people that don't do informed consent prior to breast cancer surgery. All right. Now that's pretty specific but there is the way of using a disciplinary law. So what are the other ways besides the private tort system that might be effective? And ironically this is an empirical question for you to ask: What will happen to oversight if we have more cases? And here's an interesting analogy for you to think about: A number of years ago we decided on a state by state level to give immunity to peer review committees that evaluated mistakes that went on in health care institutions, not mistakes, things that might or might not be negligent. And in our state and a number of other states this was a public policy decision. It didn't give immunity to the institution. It didn't give immunity to the researcher but it said the peer review committee or, by analogy here, perhaps the institutional review committee if they can do their job right, if they can do oversight, if they can ask hard questions, if they can develop a record, they're not going to do it if they're afraid that then they are also going to be sued. So this is a public policy decision for us to make. Do we want to give them any sort of immunity? Is that a good thing or a bad thing? Now in our state, for example, ethics committees have immunity because we as a matter of public policy wanted to encourage that. The records from peer review, the records from peer review have immunity because we wanted to encourage there to be more, not less peer review. So that's an interesting question, I think, to ask. What is the relatively role of all the players? Now this is something I read, not something you said, but it's something I might teach if I were a plaintiff's torts lawyer and that's you sue everybody up and down the line initially because you need to do discovery to find out who was or who was not at fault so that has implications. You're going to sue the bioethicist. You're going to sue the committee. You're going to sue the researchers. You're going to sue the institutions. Is that good public policy? Who is really at fault or what combination of people are at fault or what combination of a regulatory scheme, a disciplinary scheme, a tort law scheme, a liability scheme, state, federal, constitutional do you want to have? So here are some of the empirical questions I might leave you with: First of all, what is -- this is maybe not empirical. This is an existential question. What's research? All right. This is not a new question. You've all thought about it but there's a real irony in the way our current federal regulations are written. If you do bad research, meaning you don't have a hypothesis, you haven't even figured out what you're really doing as research, you have no review, nothing. You don't go to an institutional review board, nobody asked you a series of question, there's no informed consent form that gets raised or any of this. It just happens. And believe me, the government once in a while has to decide if they can yank money from an institution when they're not really quite sure whether it was ever really research because they didn't even go through this process. So the very first question is that it seems to me. And, of course, the existential question of is any of this research that we're talking about. What does it mean to have clinical interventions or clinical innovations or clinical therapies? Again there are some semantics. Second, what impact is this going to have on the future of research? Now everybody makes hyperboles about this both ways. It's going to paralyze the institutional review board. It's going to paralyze researchers. We're going to have less research. The research that really needs to get done isn't going to get done. I think it would be worth trying to study this question if we could. Perhaps even in the institutions that have already had some liability. Now when I first started to study the inclusion of women in clinical research I couldn't find on one hand lawsuits against researchers. In part, because it goes to my very first point about how difficult it is under tort law to have brought these suits and there was not a lot of attention in the context of the normal subject. There were a few cases. Most of them had to do with informed consent but I do think -- and I give total credit to this to Dr. Levine. We have had a paradigm shift in this country from protecting subjects to including subjects in which they're banging down the doors saying we have a right to get some treatment that started with AIDS, then it went into women's health, in which the pendulum is now starting to swing back because there is a real fear. And my concern is this conversation about, well, altruism and communitarism and, you know, what we owe to each other as members of a society, as members of a community has gotten partly a little clouded because of all the financial interests. So we have asked people to be altruistic and we have asked them to be supportive of science but we're talking out of both sides of our mouths because they're also filling out consent forms that say they can't have any financial interest in the result. And so we can't have it all ways and I think we really have to be attentive to what the financial connection in research is to altruism if we really want people to be altruistic. So that might be an interesting empirical question to ask too. The next one -- I'm almost done -- do we have too many trials or do we have too few trials or do we have the wrong focus on the trials? Now Alan has said we have a lot of trivial stuff going on and I'll give him that. Maybe that's right. Maybe that's not right but how much that needs to get done isn't currently getting done and who is to decide that? And I think that raises some interesting questions about children, about the decisionally impaired. There are experts around the table on that but the tougher we are in some of those areas may just mean that we're going to wipe out a large proportion of the community. And I'll sort of end on -- before I get to children I'll come back to in a second, I want to just say something about the compensation scheme. Now under traditional tort law somebody that brings these cases, and Lord knows he may be earning it, gets one-third. All right. Now you could have a -- MR. MILSTEIN: You don't want to change that, do you? MS. ROTHENBERG: Not if you give me a nice donation, right? [Laughter.] MS. ROTHENBERG: In some places they get more than that. And if he loses he gets nothing and if he wins he gets a third. Now there are some other options. So one option would be a no fault compensation scheme. Now what are the pros and what are the cons of that? We've seen in the -- we've had some experience with that. It has been proposed in a number of other commissions. It doesn't go anywhere. The answer is there are limits to what you can get under those schemes. Is that a better thing than if there are millions and millions of people in these studies, there's only one guy here and a few others that can bring all these class actions so there may be a whole lot of other people that never get a penny. So anyway that's -- what's the advantage of that? What's the disadvantage of that? I certainly think if somebody gets injured and altruistically participates in research for the good of our society we have to think hard about what we owe them in return. And, finally, I just wanted to make a plug if I might about the research on children and what happened in Maryland against Kennedy-Kreiger. The lawsuit is still going on. I think it's a very complicated case. Just to clarify, the decision was clarified so that minimal risk is something that parents can consent to on behalf of their children. It's still a big question mark and on May 3rd the University of Maryland's Law and Health Care Program in collaboration with NICHD and the American Society of Law and Medical Ethics will have a meeting on this. So this might be something you all would like to continue to participate in but I just wanted to say on behalf of the academy I think what you're doing is just bringing out a lot of interesting questions that need to be discussed, clarified and evaluated. Thank you. [Applause.] MR. BARNES: Paul? MR. LOMBARDO: Yes, this is the second time in ten days that I've followed a torts professor. I said the last time it was like that line from W. C. Fields about not following children's acts or dogs or tort professors. You get upstaged too often. [Laughter.] MR. LOMBARDO: There is very little I could add to what Karen had to say about tort law but I do want to touch on a few points. This is a peculiar situation to be in which is three lawyers who are supposedly bringing different perspectives to a problem which is very real and it reminds me of a line that my grandfather used to use. He used to tell me when I was quite young, "Stay out of hospitals and stay out of courthouses because nothing good happens in either of those places." [Laughter.] MR. LOMBARDO: And he probably -- he went to his greater reward before I took a job where I was a lawyer who was sitting in a hospital. [Laughter.] MR. LOMBARDO: I think that the perspective of most people getting involved in litigation is the same as his was, which is it's something that happens to you once in your life and you never get over it. And so I'm not -- never surprised when people react as negatively to people who litigate for a living but I think the perspective that probably those of us who teach in this area try to bring is that you need to think about litigation the same way you think about surgery. Sometimes fairly precise technique, a fairly predictable outcome. Other times a fairly rough process in which you're really not sure what's going to happen. If you're the surgeon you're comfortable with that because it's what you do for a living. If you're a litigator you're comfortable with that and so the three of us as lawyers are kind of comfortable with the notion that lawsuits are something that happen pretty regularly and they have a social place as Karen has spelled out for us. I just want to tick off a few of things which I think Alan has said either here or in print or other places, which I agree with. One is that obviously there's too much work for IRBs. These are all things you've heard before. There's not enough training. There's not enough attention to what it means to face risks or what those risks are or whether, as Jonathan suggested earlier, they should be described as harms rather than risks. I think that the conflict of interest discussion is one of the more interesting ones that's going on now in terms of research and the reason for that is because we have lawyers talking about conflict of interest and we think about this very differently than people in the medical world do. To say this -- I discovered this the wrong way which was to actually do it. I asked someone about a conflict of interest, one of my physician colleagues, and I thought he was going to punch me. And that's because the term, the phrase is freighted with all kinds of baggage suggesting some kind of immoral position you put yourself in that you should know better. And I think that this discussion about conflict of interest is going to force the medical profession and researchers particularly to look at what they think about conflicts, whether or not their relationship to patients/subjects is the kind of fiduciary relationship that other professions claim to have and we've never had that conversation quite that way so I think that's a good part. I think the other good thing that Alan is doing is focusing public attention on some tremendous shortcomings in the system and when I talk about the system I have to take into account it's an enormous system and it's an enormously varied one. As all of you know, you've got some institutions that have extraordinary resources and use them to good purpose in monitoring the kinds of research that goes on. You have a great many programs in the middle and then you have some that don't even know that there's such a thing as a federal rule. When I say that I say that not making that up as an example but rather because of the kinds of phone calls I get in consultation as a person who has been sitting on an IRB for about a dozen years and consults with other ones. Happily I don't get that call from my own institution but I do get it from others. People are at varying stages of understanding about what kind of regulations exist and what the obligations they might have as researchers. I think that is part of the tension we're seeing particularly this morning in discussions of behavioral science and other kinds of research, which people have not thought of in the same way before as being covered by the Common Rule. So I think all that stuff is good but I come back to a question that a colleague and former teacher of mine, and I guess of your's, too, Karen, Jeff O'Connell, one of the fathers of no fault insurance, always raises and raised in a book years ago called The Lawsuit Lottery, and that is when we work with a system of tort law in which litigation happens on the behest of individual plaintiffs, some people may make a significant amount of money and that may very well have a deterrent effect on other people who might behave similarly, and most people get nothing. And so systematically as a matter of policy, as Karen has pointed out, we have to look at that and see whether or not in the long term whether or not we want to craft a system in which the people who actually are harmed in research that we think is necessary to do actually get some compensation. I mean that's probably the only take home point that I would want to make is that we don't have a system for compensating people that will get the most to the people who may need it but let me remind you we don't have a system like that in all of medicine, in all of science. We don't have that in this country and we argue at various times about people like Alan who by their behavior professionally really push the boundaries of the system that we do have. And that takes me to the semicolon. One of my friends said, "You've got to watch out on the introductions when they get to the semicolon. That first part is all the nice stuff and then they say, "However." However, I think that the law is a blunt object. It's a cliche to say that but it's true. I don't have any idea whether or not Alan's theories of using the Nuremburg code will be successful in the context of litigation. Perhaps they will be sometimes. Perhaps they won't be. I guess listening to the news last night I didn't get you as many points as I did last week and that's because I was listening to people discuss how international law might be applied to a real situation. Like whether those people down in Guantanamo now are prisoners of war or something else. So it's very hard to apply international law to much of anything. On the other hand, coming back to the good side, I don't think you can avoid talking about Nuremburg. I don't think you can avoid talking about the precedent that was set there. Everyone in this room and many of you know a great deal better than I do the history of the development of the regulations that you're arguing about and those certainly gave more than a side ways glance to what happened during the holocaust. So Karen is right. You can't make too much of this. We need to take it in context but we also can't ignore it. And so from that point of view you're on to something now and I guess it'll be the courts to tell us how much of what you're on to. A couple of points just to conclude. Mary Faith, you know, opened the door so I can say something historical. [Laughter.] MR. LOMBARDO: I think that the history of American law is in some ways a tableau where scandal marks the threshold of legal change. Certainly that's the case in terms of regulation of research. There's a wonderful book by James Moore called Doctors and the Law in which he talks about the 19th Century and he says that the reason -- his theory is the reason that malpractice suits began to be generated late in the 19th Century had to do with developments in technology coupled with scandal and that the developments in technology had to do with understanding the germ theory and asepsis and also developing a technique for anesthetizing people. So that once you got your leg sawed off you didn't die. You actually lived and when you lived if you happened to have the good fortune of being able to ask to have your leg sawed off you had expectations that you might not have understood or your practitioner might not have understood. The hope that came out of progress in medicine led people to expect more from it and as a consequence when they didn't get all that they expected they were disappointed, they went to court. It also pointed up, as Moore says in his book, the fact that there was some over selling going on. There was over selling going on by the medical profession of how exciting and how new and how valuable therapies might be and, particularly at a time then when medicine wasn't regulated, it was possible for all kinds of people to make promises that were too big for them to keep. So I think keeping in mind that our perspective -- this is not all new. We've been to some of these places before. I would just end up by saying that I think a compensation system of some kind for research subjects would be a great thing for people to look at. If you're concerned about people like our friend, the litigator, here then you really, really ought to think of ways of making him obsolete. He won't be obsolete. There'll be other things to do. We certainly are not going to try to put him out of business but in this area it would be possible. My concern is that rather than having a compensation system so that people who are actually harmed get compensated that what we will end up with is the kind of perverse legislation that is only protected. That is it's legislation that says, "Well, if you're not on an IRB we just won't let them see you. We'll just immunize you." My own historical research focuses on that kind of legislation. What happens when we just say, "Go ahead and do it, we don't want people to sue you." Bad things happen. So there is a benefit to the tort system working, both because it pushes things out in the open, as has already been suggested, but also because the kind of headline liability as compared to the financial liability makes all of us think more carefully about the job we're doing on an IRB and makes us realize that it may become something that is not private and secret but actually something that's very public. The last comment I'm going to make, I just reminded myself of what happened this morning when you talked about confidentiality, it does seem to me that one of the things that these lawsuits are going to do is to force people to think more seriously about what happens when litigation intrudes on to research. One of the things that happens is somebody ends up learning what the rules really are about disclosure and really has to look at that form and say, "Oh, don't worry about it. We're going to protect you as far as the law permits." It's a bad time for us to start telling people that the law permits a good deal. [Applause.] MR. BARNES: We have Bob Levine and Adil Shamoo. I want to make maybe one observation and that is that -- I'm not sure, it sort of relates to all three of your's but one of the things -- I attend several IRBs for clients and one of the things that has struck me over the past several months as I've sat through IRB meetings and you look at the sections of the informed consent forms, which really are only replicas or only replicate the underlying research contract with sponsors, is that the provisions about compensation for injury in research studies are all over the map. It varies from sponsor to sponsor, from pharmaceutical company to medical device manufacturer, to biotech company, to venture capital start up biotech company, to investigator sponsored or institution sponsored studies. And not only is there no rhyme or reason it appears to me in most of those compensation provisions in the underlying research plan, contract and also the informed consent form but also there is in most cases not really adequate attention that has even been paid to that part of it. And people sort of think that the whole thing is going to take care of itself. Not only it's not just -- I don't think that's either for or against anything that anyone here has said. It's simply an observation about what I see as what's really happening out there. Bob, and then Adil, and then Greg Koski. DR. R. LEVINE: Thank you very much. I have extensive notes on what I want to comment on and I think you'll be relieved to hear that I'm not going to comment on all these notes. [Laughter.] DR. R. LEVINE: Karen told us there are two purposes of tort law. The first to serve as a deterrent is well understood. However, recent experience indicates that it's a much broader deterrent than we really want. It's turning people off service on IRBs. It's turning people off service as research subjects. It's making a lot of people do things or not do things that we think would be for the benefit of themselves and the public. The second one is it creates a way to provide payment to people who are injured. And I have to agree with Paul that we do much better if we look at no fault compensation. We have had since 1975 a large number of prestigious deliberative agencies starting with the Secretary's Task Force on Compensation for Injured Research Subjects and the National Commission and the President's. They all have said unanimously we need no fault insurance. I am not talking about payment for medical expenses. I'm talking about compensation for death or disability. And Paul is right that that's nowhere. It gets nowhere because everybody says, "Oh, my God, we don't -- we can't tolerate that level of exposure." But we do have models. We have places where they've set up such programs and the University of Washington in Seattle, for example, it cost them, I think, $7,500 to pay off all the claims they got in eight years. That shows what the level of risk is as well. I also want to offer a comment on several of the points that Mr. Milstein made. Some of them were just factually incorrect. For example, the Nuremburg Code is not a court opinion. The people -- the Nuremburg Tribunal tried the so-called doctors under what is called the Nuremburg Principles, which is international law. The Nuremburg Code is something they wrote while they happened to be there trying to make sure that they would take certain principles and make them particularly relevant to research. But you can't write the rules for trial of people, I have to tell this to a lawyer, after they've violated them. It's our custom in the United States to write laws only after they've been broken but you can only enforce them after they've been written. So the Nuremburg Code is not a court opinion. It's the opinion of several American jurists who were advised. The other thing is it has nothing whatever to do with what you're calling therapeutic research and they said themselves that their focus was only on competent adults who had no disease. The other point I want to make is that when you say five percent of subjects in Phase I trials receive no benefit -- less than five percent receive any benefit, actually the percentage is vastly smaller and the reason for that is that in almost all clinical trials, except in the field of oncology, the subjects are normal volunteers. That means that -- MR. MILSTEIN: Cancer trials. DR. R. LEVINE: You didn't say cancer trials. If you said cancer trials then I would tell you that less than five percent is almost in the right ball park for children, it's a bit lower for adults. And then you extend it from Phase I to Phase II where your statement is wrong no matter who you're talking about because in Phase II the only subjects are patients with the target disease. There are several other such examples but I'll let it go at that. MR. MILSTEIN: Thank you. MR. BARNES: Adil? DR. SHAMOO: Thank you, Mark. There are three movements in the past forty years in our country that has gone through similar trials and tribulations. The civil rights movement, the environmental and women's movement. And the reason those movements used the tools that were given to them by what they can use is that they're all scandals, abuses and abuse of human rights, whether it's in the environment, whether it's the woman movement or civil right movement. These movements, therefore, they used the media, that is they sought the help to publicize through public communication discussion of the issues. They used legislation and they used the courts. The only reason this committee is in existence and/or we're talking about it because in the past ten years and especially in the past seven years there has been horrendous abuses of human subjects. No one wanted to talk about them then. Those of us who talked about them then yelling and screaming, nobody paid attention to them. Only after the formation of the National Bioethics Advisory Commission, only when the media started carrying abhorrent stories all across the country and the scandals, and now we have some good lawyers who are willing to take it to the next step. Remember I said there's media, legislation and courts. My attitude is this movement yet has not reached the same level of the environmental or civil rights or the women's movement where we have reached steady state that we want to make people like Alan Milstein obsolete. I believe they have another ten years to go on further and, hopefully, there will be more of them to be as a deterrent and further publicize this cause in front of the American people because I truly and firmly believe, and I have talked to thousands of normal average human beings who have never heard of this issue, when they hear it they cannot believe the extent of how many abuses we have done to human subjects. Children being healthy used in experimental protocols, Nazis only used, using them as truly guinea pigs, that is not the country we want all to live in and these must stop through all means, including the courts. [Applause.] MR. BARNES: So in regard to Professor Rothenberg's or Dean Rothenberg's two tort principles, Dr. Levine endorses compensation and Dr. Shamoo endorses deterrence. And with that, Dr. Koski? DR. SHAMOO: No, I really said all means has to be used, including the courts. Not just the courts. DR. KOSKI: Well, thank you, Mark. It seems to me that all reasonable people could agree that in the long run it's far better to prevent harm to people in the conduct of research rather than to either punish institutions, punish investigators. You know, I think, in fact, the whole focus of the movement that is under way, and I feel comfortable calling it a movement, is to move from a system that has focused on issues of regulatory compliance to assist and that truly focuses on prevention. And if we're able to succeed in implementing a system that truly looks in a prospective way at ways that we can actually prevent harm then there will be no need for, you know, more likely than not individuals to have to go and file suit except for those instances where there will be individuals who, as Karen pointed out, clearly are going to behave in ways that our society finds to be unacceptable. And for those, I think, the punishment should be stern. They deserve what they get. So it's a question of trying to find that appropriate balance. Adil, if your suggestion that we should continue our present forum basically for another ten years, I know what you meant, we cannot afford to allow the situation that has plagued us for 20 years already to continue for another ten years. As Dr. Levine has pointed out already, the first recommendations for implementing a system of private voluntary accreditation, Human Research Protection Program, was actually made in the 1982 report from the President's Advisory Committee on Ethical Problems in Research. We've had citations of other recommendations, okay, that have been there and, as I've said in my public presentations too many times over the last year the whole pathway of human subjects research is just strewn with these relics of recommendations from one committee, one commission after another, where very thoughtful recommendations have been discarded because of either the reluctance or the inability of private parties in government to stand up and take responsibility to do what needs to be done, and it's time that that change. And, in fact, I think if you look at what has happened even in the last year things are changing. They are changing in important ways. After 20 years of waiting we not only have one program for accreditation of IRBs and human research program protection programs, we have two. We have private voluntary certification programs for people at every single component of the research process already. We see movement occurring in government as well. We've talked about the role that financial conflicts and financial interests have played in undermining confidence. Well, within the last year we've seen two of our major academic and research organizations actually step up to the plate. We've seen the AAMC begin with saying that we have a -- what's the word? A rebuttable presumption that in human research financial relationships that pose any kind of a conflict of interest will not be permitted, that finders fees, bounties will not be permitted. Okay. We've seen the AAU step up. And basically I will say with a little help from their friends in government have moved more aggressively than they otherwise would have to exercise their responsibility. Similarly we've seen the American Academy of Pharmaceutical Physicians, those horrible docs who do clinical trials on human guinea pigs, adopt a code of ethics that puts as its very first principle the well-being, protecting the well-being and the interest of human research subjects as their single most important goal. Okay. This is a dramatic change and I think that we clearly want to see that continue. I will say, as both Mary Faith and Kate know, that in planning for the upcoming meetings of this committee the issues of perhaps limitations on liability for IRBs and an appropriate compensation program for individuals who are harmed in research are already on the agenda. And, indeed, today's discussion sort of provides some foreshadowing for the direction that we're going to be moving in the weeks ahead. But I think we again need to every once in a while step back and say, look, there is a lot of thoughtful work that's going into this and we have to continue that momentum and recognize that we may need to rely upon some energizing of that process from a variety of different perspectives in order to keep them moving forward. So thank you. MR. BARNES: Thank you very much, Greg. We have Jonathan Moreno, and then Abbey, and then I'm going to open it to the floor. DR. MORENO: I just have a question rather than a statement and this is for anybody or everybody on the panel. The discussion about conflict of interest was confined so far mainly to financial conflicts of interest but my experience as a lot item on the scientists has been that what motivates those people really isn't -- I mean there's always exceptions but it is not money. They want to get the Nobel Prize. They want to get a footnote in the textbook that medical students will read 100 years from now. They want to have a disease named after them. I don't think there are any body parts left to name after people but there are plenty of diseases and syndromes. Are there some left? Maybe I'll get -- give me one, would you? [Laughter.] DR. MORENO: Renaming some body parts. I don't want to go there. [Laughter.] DR. MORENO: How from the point of view of a lawyer are these less tangible conflicts understood? The desire to be promoted? That perhaps has some financial implications in itself but peer recognition. How do you guys understand that in law? MR. MILSTEIN: Those other conflicts are just as sexy to us plaintiff's lawyers as the money. In the Gelsinger case you may have seen the quote from the principal investigator when asked about his financial stake in the company he said, "How dare you say I'm motivated by money. I want the Nobel Prize." So those are certainly things but I think there's something else that needs to be said also. It's not simply, that is the absence of self-interest does not mean the absence of conflicts of interest. If you look at the history of research abuses, many of those abuses such as Tuskegee occurred where the researcher's aims were for the greater good. It's any interest that places the interests of the research above the interest of the well-being of the subject that becomes a conflict of interest. And I think is -- should be unlawful. DR. MORENO: Can I have a follow-up then? I guess then the question is can there be research from this point of view that does not -- is not intended to or could not theoretically provide a benefit to the subject, a direct benefit? Could that, would that be permissible in this interpretation of the law to the subject? If there were -- could research that did not provide a benefit to the subject be permitted if that person were sick? MS. ROTHENBERG: Well, I'll play a devil's advocate here. First of all, I don't think it's per se unethical for people to be motivated for their own -- for winning a Nobel Prize. In fact, some of the most wonderful things that have happened in our society are because people have interests in their own self-esteem and their own value as a member of society. And I think we would be fooling ourselves. I mean that's part of the human psyche and I would also think that that is pretty condescending to think that individuals who are gaining research don't realize that, in fact, wow. In fact, they would share in the joy of that if, in fact, somebody that had treated them -- I'm sorry, somebody that had had them involved in some human experiment had won a Nobel Prize. I mean, the opposite is sort of a selfish view about us being individual autonomous -- I'm sort of communitarian in this view. On the other hand, I think that that's no different than when somebody goes into a tertiary care institution and has a medical student trying to draw their blood. I mean, you know, there are contexts in which things go on like that every day and I would certainly err on the side of telling people more rather than less about that but I don't think that's necessarily an inherent conflict of interest. On the other hand, I do agree, and I think I said this, that sometimes that is a greater motivator than money because really if people were motivated by money I'm not sure they would be going after NIH grants on a routine basis. They would be going to work in other settings and so I don't -- nor -- and also have to get through all the institutional review board stuff, you know, so there are easier ways to make a buck but I would agree with you but I don't think that necessarily says it's unethical. That's my understanding. MR. BARNES: Abbey, you'll forgive me but we've only got like only a couple of minutes and I wanted to hear from the audience. Is it -- can you make it very brief? MS. MEYERS: We do have the no fault system with childhood vaccines and the government fund that's put aside for childhood vaccines is huge. Hardly anybody has collected on that money so it can be done. MR. BARNES: An interesting point. Are there one or two questions from the audience? If you would stand up at the microphone but we only have time for two brief comments and, please, make it brief because people are chomping at the bit to get in. MS. SHARAV: Okay. First of all, I just wanted to mention the two law cases mentioned the Nuremburg Code, both T.D. versus New York State Office of Mental Health and Higgins versus Kennedy-Kreiger. In both cases also I might say the justices strongly indicated that parents have a right to make martyrs of themselves but they do not have a right to make martyrs of their children. In other words, in nontherapeutic research. MR. BARNES: Vera, I'm sorry. Can you please ask a question? MS. SHARAV: Yes. I would like to know how under the -- for the greater good of research one can justify conducting lumbar puncture in 45 children for nontherapeutic purposes? MR. BARNES: Well, I'm not sure that you're going to get an answer to that question because it's a -- well, it's rhetorical. It certainly assumes something. Are there other questions? There's a gentleman in the front and a gentleman in the back. Let's take these. If you could just make it brief and to the point we would appreciate it. MR. HANDY: Just real quickly. I've spent the last 24 years in the military and I've been looking at the forced experimentation some of our military members have undergone in the last four years with some vaccine policies and one quick question on -- MR. BARNES: Could you identify yourself? MR. HANDY: Yes. My name is Redmond Handy. I have a nonprofit organization called No Abuse and I want to applaud Mr. Milstein in looking at some of things that we've been concerned about. Just one quick comment on Nuremburg and then I'll ask the question. The Nuremburg Code, the DOD actually submitted agreement to that code in 1953, according to a Washington Post article in the early 1990s and yet they've been probably the least likely to abide by that, and we really got in problems in World War II with Unit 731 in accepting Japanese experimental data in lieu of prosecuting them like we did in Nuremburg. But my question is on didn't -- isn't it true that this argument about research, this definition of what is research is a very fine technical kind of thing but it centers around the problem that the FDA had during the Gulf War, which the DOD was trying to say, "Well, you know, we're not experimenting with bromide tablets, with botulism toxoid or anthrax vaccine because this is therapy." And the FDA -- MR. BARNES: Please get to the question. MR. HANDY: The question is isn't this the kind -- the same kind of issue that the FDA faced during the Gulf War? The DOD is claiming it's therapy. The FDA is saying, "Well, it's research." And so we got ourselves into a lot of problems with Gulf War illness. MR. BARNES: Karen? MS. ROTHENBERG: I think it's an interesting point but let me just turn it on its head a little bit. I think that if we look about what went on over the last few months when the public was scared to death about anthrax, maybe way out of proportion, it was the military, if I recall, that said, "This has not been used or tried -- we can't give it to the civilian population because there hasn't been sufficient amount of study on it." And I raise this because there's always contextual questions that get raised when, when has the research been good enough before we start to give it to members of our society? And it creates, I think, interesting tensions about what is research and what is therapy. And we just saw that happening over the last few months with the supply of the vaccine. MR. BARNES: One final question from the gentleman in the red shirt. PARTICIPANT: Just a very brief comment and a question. I think, you know, the highest biological level that we have, our feelings, thoughts, consent, really to our dignity, and good science would be respecting those highest levels. And so it may not be good business always but good science should. But the heart of my question is -- and we've talked a lot about language today -- is why not the use of common language when people go into studies to really know of the risk. We don't use the word "experiment," we don't use the word "we induce a disease or cause an illness." Just simple language to let people know. It seems like a solution to some of this would be to have a neutral party given ordinary language, what is the real risk, and let the experimenter take the risk of his studies not being done. We ask the subjects to take all the risk when maybe the experimenters need to have that risk too. So what about just some phrasing in the law that says use common language, have some neutral noninterested party, you know, ask it. MR. BARNES: Alan, do you want to briefly answer that? MR. MILSTEIN: Yes. I mean, Mr. Gelsinger and I have also advocated the use of a subject advocate but I would caution against what I would call dummying up the document, which is what some IRBs are trying to do, that is let's reduce the complexity of the document down the lowest common level because when you do that you eliminate a lot of the material information that the patient needs. I think the better alternative is to have a subject advocate who has as much knowledge as the researcher who can understand the informed consent document and then can explain it to the subject and talk with the subject about what his or her choices are and whether or not it's in his or her best interest to participate in the research. MR. BARNES: Penultimate word to Karen. I get the last. MS. ROTHENBERG: Thank you. I just have to say, again let me emphasize, it isn't necessarily what's written in the form. It's in its implementation. And you can have it spelled out very clearly but if the researchers and the institution don't then abide by what was agreed to that I think is where there may be real concerns and where the liability system may be correct. But you could call it whatever you want but you've got to be careful of the oversight and in its implementation. MR. BARNES: Well, this is certainly not the last word on these issues because this controversy will spin itself out and resolve itself in one way or another, whether it's with success or failure in the courts or legislation or, as Greg Koski said, whether most of this can be prevented. As a lawyer who hates lawsuits, I will tell you it's much better for everyone if lawsuits get prevented and not filed. Just a couple of things. Mary Faith, I think, wants to talk about the committee meetings and I wanted to say briefly that we do have a draft HIPPA letter regarding suggested reforms to the HIPPA confidentiality regulations, which we're going to distribute. You all can look at it tonight and I think we'll have time to talk about it at breakfast in the morning and then perhaps briefly in the morning. Mary Faith, do you want to give the last word? CHAIRPERSON MARSHALL: First, let me thank Mark. Let me thank you for moderating this fabulous panel. Panel members, thank you so much for being willing to come, some of you on very short notice. Just superb presentations. [Applause.] CHAIRPERSON MARSHALL: We have workgroups breaking out and just a few minutes of direction. I do not feel the need for closing comments today from 5:15 to 5:30 so the workgroups can go until 5:30. We're asking you to break out. Your job this evening or this afternoon, workgroup and workgroup chairs, is to come up with your goals for the workgroup and to assign priority to those goals and to develop a time line. And the workgroup chairs, the first thing in the morning, during the opening remarks at 8:30 in the morning, I will give each workgroup chair five minutes total without discussion to present to the rest of the committee your goals in order of priority and the time line in which we can expect them to be accomplished. So I thank all of you. Those of you who might wish to sit in and observe a workgroup session, I think that you would be welcome to do so as observers. Let me ask Kate and Keisha who are going to tell those of you on workgroups where to go. MS. JOHNSON: Yes. Please everyone listen. If you are a member of the Third Party Genetic Workgroup or Social and Behavioral Sciences Workgroup you will meet in this room. If you are a member of the Informed Consent Workgroup or the Workgroup on Decisional Impairment you will meet upstairs in the lobby in Felini's restaurant. [Laughter.] MS. JOHNSON: No, it's no food or anything. It's just a room. CHAIRPERSON MARSHALL: Children's Workgroup is not meeting today. The chair is not here. It meets all day on Wednesday. Committee members, we will meet. Those of you who are going to dinner, we will meet in the lobby at 6:30. We're going just right around the corner for dinner. It's a block away so those of you who would like to join us in the lobby at 6:30. [Whereupon, at 3:38 p.m., the proceedings were adjourned, to be resumed at 8:30 a.m., on Tuesday, January 29, 2002.] - - - CERTIFICATE OF OFFICIAL REPORTER This is to certify that the foregoing proceedings before the National Human Research Protections Advisory Committee held Monday, January 28, 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