1 1 2 Department of Health and Human Services 3 4 5 NATIONAL HUMAN RESEARCH PROTECTIONS 6 ADVISORY COMMITTEE (NHRPAC) MEETING 7 8 Monday, April 9, 2001 9 10 11 12 13 14 15 16 POOKS HILL MARRIOTT 17 5151 Pooks Hill Road 18 Bethesda, Maryland 19 20 21 22 2 1 A G E N D A 2 Monday, April 9, 2001 3 8:30-9:15 Welcome: 4 Introduction of New Members (brief 5 comments about yourself; areas of 6 particular concern) 7 Mary Faith Marshall, Ph.D. 8 Chairperson NHRPAC 9 10 Office of Human Research Protection 11 Updates 12 Greg Koski, Ph.D., M.D., Director 13 OHRP, Executive Secretary, NHRPAC 14 Chairman, HSRS 15 16 Clarification of NHRPAC Roles 17 Mary Faith Marshall, Ph.D. 18 9:15-9:30 The Department's Commitment to 19 Protection of Human Subjects 20 The Honorable David Satcher, M.D., 21 Ph.D., Surgeon General 22 Committee Discussion 3 1 10:30-10:45 BREAK 2 3 11:00-11:45 Update Declaration of Helsinki 4 Greg Koski, Ph.D., M.D., Director 5 6 11:45-12:15 Public Comment 7 8 12:00-1:30 LUNCH (On your own) 9 10 1:30-4:30 Panel Discussion 11 Moderator 12 Francis Collins, M.D., Ph.D. 13 14 Family Members/Third Parties: Should 15 Family Members/Third Parties of Survey 16 Subjects, Themselves become Subjects 17 of a Protocol -- if so, Must Informed 18 Consent be Obtained for Investigator 19 to Retain Private Information on These 20 Individuals? 21 22 4 1 2:15-3:15 Guest Panel 2 Jeff Botkin, M.D., M.P.H. 3 Department of Pediatrics 4 The University of Utah Medical Center 5 Terri Arledge, Ph.D. 6 GalaxoSmithKline 7 Sharon Terry 8 Vice President for Consumers 9 Genetic Alliance and 10 President of PXE International 11 Terri Seargent 12 Consumer Advocate Alpah1 Association 13 14 3:15-3:30 BREAK 15 16 3:30-4:30 Discussion 17 18 4:30-5:15 Public Comment 19 20 5:15-5:30 Closing Comments/Adjourn 21 22 5 1 PARTICIPANTS: 2 MARY FAITH MARSHALL, Ph.D., Chairperson, Director 3 of Program in Bioethics, University of Kansas 4 Medical Center 5 6 GREG KOSKI, Executive Secretary, Ph.D., M.D., 7 Director, Office of Human Research Protections, 8 Office of Public Health and Science, OS 9 10 MARK BARNES, J.D., LL.M., Partner, Proskauer Rose 11 LLP 12 13 SANFORD CHODOSH, M.D. 14 15 ELLIOT N. DORFF, Ph.D., Rector, Distinguished 16 Professor of Philosophy 17 18 ALAN R. FLEISCHMAN, M.D., Senior Vice President, 19 The New York Academy of Medicine 20 21 22 6 1 SUSAN Z. KORNETSKY, M.P.H., C.I.P., Director, 2 Clinical Research Compliance, Department of 3 Clinical Investigation 4 5 FELICE J. LEVINE, Phase.D., Executive Officer, 6 American Sociological Association 7 8 ROBERT LEVINE, M.D., Professor of Medicine, Yale 9 University School of Medicine 10 11 ABBEY S. MEYERS, President, National Organization 12 for Rare Disorders 13 14 JONATHAN D. MORENO, Ph.D., Emily Davie and Joseph 15 S. Kornfeld Professor of Biomedical Ethics, 16 Director, Center for Biomedical Ethics, University 17 of Virginia Health System 18 19 MARY Z. PELIAS, Ph.D., J.D., Professor, Department 20 of Genetics, Louisiana State University Health 21 Sciences Center 22 7 1 ROBERT R. RICH, M.D., Executive Associate Dean of 2 Research, Emory University School of Medicine 3 4 ADIL E. SHAMOO, Ph.D., Professor, Department of 5 Biochemistry and Molecular Biology, University of 6 Maryland School of Medicine 7 8 JUDITH L. SIEGEL, Ph.D., Vice President, Head U.S. 9 Clinical Operations, Hoffman-La Roche, Inc. 10 11 DENYSE THORNLEY-BROWN, M.D., Assistant Professor, 12 Division of Nephrology, University of Alabama at 13 Birmingham 14 15 KATE-LOUISE GOTTFRIED, J.D., M.S.P.H., Executive 16 Director, National Human Research Protections 17 Advisory Committee 18 19 20 21 22 8 1 EX-OFFICIO MEMBERS 2 3 Dr. James Shelton, USAID 4 5 Maryann Danello, Ph.D., CPSC 6 7 Dr. Joseph Spence, USDA-ARS 8 9 Ms. Linda Beth Shilling, Commerce 10 11 CDR Douglas Forcino, USDOD 12 13 Ms. Blanca Rosa Rodriguez, Education 14 15 Dr. Susan Rose, Energy 16 17 Dr. Dixie Snider, DHHS 18 19 Dr. David A. Lepay, FDA 20 21 Dr. Belinda Seto, NIH 22 9 1 Alan Sandler, D.D.S, NIH 2 3 Francis D. Chelsey, Jr., M.D., AHRQ 4 5 Dr. Paul Gatons, DHHS 6 7 Donald Prosnitz, Ph.D., DOJ 8 9 Mr. Thomas G. Raslear, DOT 10 11 John H. Mather, M.D., VA 12 13 Mr. Roger S. Cortesi, EPA 14 15 Richard S. Williams, M.D., F.A.C.S, NASA 16 17 Dr. Philip Rubin, NASA 18 19 Mr. Howard L. Bradley, SSA 20 21 22 10 1 P R O C E E D I N G S 2 [Time noted: 8:35 a.m.] 3 CHAIRPERSON MARSHALL: Good morning. 4 Welcome to the second meeting of the 5 National Human Research Protections Advisory 6 Committee. I perceive that we have more people at 7 the table than we did last time. 8 Committee members you haven't been out 9 there cloning yourselves in the interim have you? 10 [Laughter.] 11 CHAIRPERSON MARSHALL: We would get into 12 real trouble with the Surgeon General if that was 13 the case. But, no, I perceive we have new members 14 and we will introduce you and give you a chance to 15 tell us about yourselves in just a moment. 16 But I am foremost honored to introduce to 17 you the Honorable David Satcher who is the Surgeon 18 General. And he is going to welcome all of us and 19 tell us where human subjects protections fit within 20 the Department of Health and Human Services's 21 priorities and we are delighted that you are with 22 us and honored. Thank you so much, sir, for being 11 1 with us. 2 DR. SATCHER: Well, thank you. I am 3 delighted to be able to join in welcoming you to 4 the staff. Now that your sworn in, I want to help 5 to tell you what you ve gotten yourselves into. I 6 think most and you know. 7 But I think it is fair to say that the 8 work that you are doing is really critical to the 9 future of the nation, because research is so 10 critical, and you know that. But in case you have 11 not reflected on it, when you think back to the 12 last century and the major developments and see CDC 13 took the time to try to define the major 14 achievements of 20th-century, you know, in addition 15 to the fact that we've gained 30 years of life 16 expectancy. They pointed out major developments in 17 areas like immunizations, development of new 18 vaccine, especially the polio vaccine. They 19 pointed out the eradication of smallpox using a 20 vaccine that was developed much earlier. 21 But all of the achievements that we've 22 made in the 20th-century are based on immunization 12 1 programs and the development of antibiotics and 2 antivirals and other drugs that made such a 3 difference in the lives of people. All because of 4 a research enterprise that was able to really 5 function and to gain the cooperation and trust of 6 people throughout this country and the world. 7 We gained save food and safe water; we've 8 gained fluoridated water that made such a 9 difference in tooth decay in children. And 10 certainly we've gained enhanced diagnostic tools, 11 including things like the CAT scan all because of 12 research. 13 And looking at all of that as I certainly 14 did when I became Surgeon General and had 15 responsibility of planning healthy people 2010 and 16 noting the dramatic decline in deaths in 17 cardiovascular disease in the last 30 to 40 years 18 and in the last decade of course the declining 19 mortality from cancer. So when you think about 20 what research has produced and what we have gained 21 from research, I think it's really critical that we 22 protect this enterprise, and we protect the trust 13 1 that people have had in it over the years. 2 But I think it is also fair to say that 3 the 20th-century have produced some burdens for us 4 too as it relates to research. And, of course, 5 some of them stand out such as the Tuskegee Study. 6 And that burden is very much with us because there 7 are just so many people who when they think of 8 research unfortunately they think of Tuskegee when 9 people were taken advantage of. So issues like 10 informed consent and beneficence in research and 11 justice sort of are in bold perspective as a result 12 of some of our experiences in the 20th-century. 13 The Tuskegee study sort of standing out 14 among them, but certainly not alone. So we have 15 some major challenges as we enter the 21st-century; 16 and we enter the 21st-century with tremendous 17 opportunities in research. We know more then we ve 18 ever known before, including our understanding of 19 the brain which we talked about a lot in the 20 Surgeon General's Report on Mental Health and the 21 difference that's making an treating mental 22 illness; our knowledge of the human genome and all 14 1 of the accomplishments that we have made as a 2 result of that. 3 The technology, the sophistication of our 4 technology, especially our ability to manage 5 information. All of those things are going to have 6 a tremendous impact on research in the 21st 7 century. 8 We have so much more in terms of money and 9 resources to support research and I think we have 10 so many more well-trained people. However, I think 11 the critical questions that we face, are do we 12 really have the trust, do we have the ethical 13 standards, the moral values to protect people in 14 the research enterprise. 15 Can we really trust researchers and 16 institutions to put people first and to protect 17 human subjects and volunteers? 18 Is the environment in which we live 19 conducive to that? 20 And when you think about it, there are 21 some major environmental challenges in every area 22 of our lives, in entertainment. In the youth 15 1 Violence Prevention Report we talked about the role 2 of violence, money, and drugs in entertainment and 3 what impact does that have on children who develop 4 in that environment. We don't know the answer 5 fully, but it is a very appropriate question in 6 terms of what is shaping us as human beings. 7 And most important, I think, for you is 8 the system in place to really protect human 9 subjects and that system includes not only the 10 researchers and their ethical standards and the 11 knowledge of responsibility of the subjects, 12 themselves, the communities in which they live, the 13 institutions, industry; is the system in place to 14 put all these things together to work for people? 15 While having raised all those questions, 16 let me say that I think going into the 21st Century 17 we have the right goals. I think we have the right 18 commitments. And I am going to tell you why I say 19 that, because healthy people 2010 is the nation's 20 health plan for the next decade. 21 And we really struggle with what should be 22 the goals of healthy people 2010; this is our 16 1 national nation's plan. We came up with two very 2 important goals. The first goal was a goal which 3 sort of developed out of our knowledge and concern 4 for the fact that as a nation we are aging, if you 5 will, in the sense that there are 35 million people 6 over 65 years of age that grows by 6,000 a day. 7 There are 50,000 people over 100 years of age and 8 the fastest growing group of people in this country 9 are people over 85 years of age. 10 So it was in great part due to that, that 11 we decided that one goal should be not just to 12 continue to increase the span of life, but to add 13 to that the quality of life. We are really 14 concerned about the experience that older people 15 are having in this country in terms of the quality 16 of their lives. 17 That concern led us to the concern about 18 disabilities and a concerned about children, 19 because some of the greatest threats to the quality 20 of life occur in children. If you think about a 21 child with asthma and a child born with a 22 disability. So that goal encompasses not only our 17 1 concern for older people, but for people who have 2 threats to the quality of life -- of their lives at 3 every age. 4 There are some key research questions in 5 this area having to do with aging, having to do 6 with the brain, et cetera, having to do with the 7 management of disabilities, the rights of people 8 with disabilities. 9 The second goal, I think, is also a very 10 worthy goal for this nation, and it is the goal of 11 eliminating disparities in health among different 12 racial and ethnic groups. It's a really critical 13 goal for this nation, not just because of Tuskegee, 14 but because we have always believed in public 15 health. That to the extent that we respond to the 16 health needs of the most vulnerable among us, we 17 actually do most to promote the health of the 18 nation. So this goal to eliminate disparities in 19 health, I think, is a really critical. I think its 20 right, a think it is reasonable. 21 It raises a lot of challenges though for 22 us. Major challenges about access to quality 18 1 health care that have not been adequately dealt 2 with. Major challenges having to do with human 3 behavior lifestyles; do we really have in place the 4 knowledge and the programs to help people modify 5 their behaviors? 6 Last week I released the Surgeon General's 7 Report on Women and Smoking. And I can't tell you 8 the number of people who have said to me, "I never 9 thought that more women died from lung cancer than 10 breast cancer." But the fact of the matter is that 11 in the year 2000, 27,000 more women died from lung 12 cancer than from breast cancer, and that continues 13 to go up. 14 So this role, this issue of human 15 behavior, physical activity, nutrition, smoking, 16 drugs, sexual behavior, do we have a balanced 17 research agenda? A research agenda that balances 18 research in human behavior and basic biomedical 19 health services research, community-based 20 prevention research? Do we have a balanced 21 research agenda to achieve that goal? 22 That s the major question and challenges. 19 1 The environment, what do we know about the 2 environment in which people live and what role is 3 the environment playing on healthy people? CDC 4 just came out with a very interesting report based 5 on a very sophisticated laboratory looking at the 6 different toxins that are found in the blood of 7 different people. And showing again that 8 minorities are more likely to have elevated levels 9 of many of these toxins because we know that 10 African-Americans and Hispanics are much more 11 likely to live within two miles of hazardous waste 12 sites. So in all these areas we have the 13 challenges. 14 But I think the question for today is: as 15 we work to improve the quality of life of all 16 people and to eliminate disparities in health, what 17 kind of system is it going to take to protect 18 people and to gain the trust of communities in the 19 research enterprise? 20 We have the apology for the Tuskegee study 21 which, I think many of you know, grew out of a 22 background study down at CDC when I was director. 20 1 We tried to make the point that it was not enough 2 to apologize, we really needed to define some 3 strategies for the future that would be ensure that 4 nothing like this happened again. So we focused on 5 the need to emphasize ethics and to better train 6 researchers in bioethics. So we created the 7 Bioethics Center at Tuskegee University, and now we 8 have programs where people do fellowships there, 9 and, hopefully in time, everybody entering research 10 will be required to have a background in the ethics 11 of research; and I think we are moving in that 12 direction. 13 But it is the system that I think you're 14 responsible for advising us on. What kind of 15 system will pull all these pieces together in such 16 a way that it works? Even when there is failure in 17 one aspect of it, the system still works because it 18 has the right checks and balances. 19 How do we involve the young, the elderly 20 people with disabilities in this research 21 enterprise? How do we involve more effectively 22 racial and ethnic minorities in women and the 21 1 young? How can we establish communities of trust? 2 I think this is all very challenging, very 3 difficult, but one of my favorite quotes, of 4 course, is from John Gardner who was Secretary of 5 Health Education and Welfare in the '60s. John 6 Gardner liked to say that, "life is full of golden 7 opportunities carefully disguised as irresolvable 8 problems"; and I think that's what you have. 9 Thank you. 10 [Applause.] 11 CHAIRPERSON MARSHALL: Dr. Satcher, thank 12 you so much for being with us this morning and for 13 sharing with us your sense of the priorities that 14 we face and the challenges that we face. And I can 15 tell you from my heart, that as a committee, we are 16 committed to working towards creating and 17 supporting a system that affords all research 18 subjects the same protections regardless of their 19 age or their background, or the source of funding 20 for the studies in which they participate. 21 So we thank you for honoring us this 22 morning. 22 1 2 [Applause.] 3 CHAIRPERSON MARSHALL: We have some wiggle 4 room in our schedule this morning, so I'm not 5 concerned about time. But let us get down to 6 business. 7 At our first meeting each of us who sits 8 on the committee had somewhere in the neighborhood 9 of five minutes to introduce herself or himself to 10 the committee, and the ex officio members, and to 11 our public members and we would like for those of 12 you who are new members to please tell us a little 13 about yourselves; what you background is; and what 14 you think in terms of your priorities are the 15 important reasons for you to be here and to sit at 16 this table and perhaps where we should go as a 17 committee. 18 So, Felice, could we start at your end of 19 the table and perhaps work around? 20 DR. F. LEVINE: I had the privilege -- let 21 me start, I'm the Felice Levine and I am the 22 executive officer of the American Sociological 23 1 Association. I am a social psychologist by 2 training with background both in sociology and my 3 Ph.D. in psychology. 4 I consider myself broadly into the 5 disciplinary, not only across the social and 6 behavioral sciences, but having spent 12 years at 7 the National Science Foundation, I like to see 8 myself as broadly collaborative across all fields 9 of research and science. 10 I had the privilege of addressing this 11 group in December so I have also the liability of 12 perhaps being redundant of what I ve already said 13 about myself. Prior to going to the National 14 Science Foundation in essentially 1980, as my 15 detailed statement about my biography and conflict 16 enumerating everything that I did said it was 17 really December 1979, but prior to that I was full- 18 time as I consider myself a bench scientist at a 19 research Institute in Chicago that was dedicated to 20 doing empirical research on various aspects of law 21 and human behavior, the American Bar Foundation, 22 and I think my initial interest in research and the 24 1 regulation of research, as I said to this group in 2 December, really stemmed from that interest in law 3 and in human behavior and in regulation of science 4 of course not being inattentive to some of the 5 troubles spots and issues that were very dominant 6 during the '70s, that brought the Belmont Report to 7 the fore and subsequently. 8 While my own research has been on children 9 and youth largely, including work on violence and 10 at-risk youth. My broader interest in law and 11 human behavior led me, at the National Science 12 Foundation also, to develop a broader interest in 13 human subjects, protections, the regulation of 14 science, conflicts of interest, data access, data 15 sharing, and other issues, I think, that very 16 centrally pertain to the agenda of this group. 17 So it really was with a great deal of 18 enthusiasm and passion that I was very excited 19 about the opportunity to serve because it reflects 20 both a nice convergence between my strong and long- 21 standing interest in research and research policy 22 particularly with respect to human subjects issues 25 1 and human subjects protection, and how much that 2 was at issue and is at issue, in some of my own 3 agendas of research, particularly in the areas of 4 children and youth and at-risk populations. 5 I probably could not have better 6 summarized what I would have said had the Surgeon 7 General not had said it before me. I think that he 8 really sets forth the kind of agenda that I know 9 all of you and all of us share and I really welcome 10 participating with you and collaborating with you 11 on that agenda. 12 I guess I should say just in conclusion 13 that, in part, in my being one of the expansion 14 persons to this group, it was to include more of an 15 interest in or an awareness expertise in the social 16 and behavioral sciences. And I will try not to be, 17 because I don't perceive of myself as a one-issue 18 seat around the table. So I hope that all of us 19 together will really learn from each other and that 20 I will be able to contribute some of that level of 21 attentiveness; but I don't see myself as only 22 promoting those interests any more than I see each 26 1 of you only promoting your own backgrounds and 2 fields. 3 So I really welcome the collaboration. I 4 welcome bringing that expertise to the table. My 5 own research has spanned from the laboratory 6 experiment to the large-scale surveys and to the 7 analysis of secondary and extant databases and 8 while one cannot assume that one brings expertise 9 in each of these areas, I guess the breadth of my 10 eclecticism I hope will bring me in good stead to 11 this group to raise the kind of issues or to even 12 signal the kinds of expertise that we might need to 13 bring around the table to do our job as a 14 sensitively and sensibly as we can. 15 CHAIRPERSON MARSHALL: Thank you Felice. 16 Welcome, that was beautifully said. 17 Jonathan. 18 DR. MORENO: Good morning. My name is 19 Jonathan Moreno. I direct the Center for 20 Biomedical Ethics at the University of Virginia. 21 I'm a philosopher by trainer. 22 Among the things that we do at UVA is 27 1 educate bright people in bioethics, and, of course, 2 Mary Faith Marshall is our favorite daughter. 3 [Laughter.] 4 DR. MORENO: I suppose that my career took 5 a turn toward a special interest in the ethics of 6 human subjects research seven years ago this month 7 when I had the opportunity to work for the Advisory 8 Committee on Human Radiation Experiments. And one 9 theme that Dr. Satcher mentioned which has 10 fascinated me ever since is, the problem of trust 11 in government. Trying to sell a book on the 12 history of the use of human subjects in national 13 security experiments has given me the opportunity 14 to speak with callers on AM radio in drive time, 15 all around the country. And I can tell you that 16 our subject matter, human experimentation, a 17 somewhat pejorative expression these days, it 18 seems, has excited among many people out there, a 19 grave concern about the extent to which they can 20 trust government and its organizations and other 21 structures of authority like academic medical 22 centers. 28 1 So a trust in government is certainly a 2 theme that I find to be one that continues to 3 occupy me. 4 I'm also happy to note that although the 5 CDC did yeomen service in making the Tuskegee 6 Syphilis study apology possible, the University or 7 Virginia, I think, was where the conference was 8 held where my predecessor John Fletcher made the 9 original suggestion. 10 In historical fairness and balance, the 11 University of Virginia Medical School also trained 12 the public health service doctors who designed the 13 Tuskegee Syphilis study. So here we come full 14 circle. 15 I'm also interested in as a result of 16 particularly my work for the National Bioethics 17 Advisory Commission where I had the opportunity to 18 help draft a report on the use of persons with 19 decisional impairments in research. 20 I'm also very interested in -- and I know 21 Greg is also interested in an acute paradox. As a 22 philosopher, I probably enjoy ambiguity more than 29 1 the scientists at the table, and certainly more 2 than the lawyers. But I have to say that I do take 3 a perverse fascination in the inherent ambiguity an 4 the moral paradox of human subjects research as one 5 of the great expressions of what it is to be a 6 human being and the expression of our talents and 7 our excellence and our compassion, and at the same 8 time, the hazard, the moral hazard that the 9 involvement of persons in research creates, and 10 similarly, I'm very interested as Greg is, in the 11 relationship between the delicate balance between 12 continuing to ensure that investigators feel that 13 they can disabuse themselves of their personal 14 moral responsibility for the involvement of their 15 subjects. And at the same time, a widely perceived 16 need for more external regulation of their 17 activities. 18 And I worry about the point at which we 19 reached the tipping point between the sense that 20 investigators can take a moral holiday and let the 21 IRB worry about it, or some government agency worry 22 about it, or people at this table worry about it, 30 1 or the lawyers for the university worry about it, 2 and that they don't have to worry about it. I am 3 very concerned about that. 4 So I look forward to exploring these 5 issues with you in the next coming months and I am 6 really very honored to be here. Thank you. 7 CHAIRPERSON MARSHALL: Thank you, 8 Jonathan. 9 We're certainly not on a moral holiday 10 today or tomorrow. We are going to be working very 11 hard and we are so very glad to have you at the 12 table. 13 Margaret. 14 DR. BORWHAT: My name is Margaret Borwhat. 15 I serve as president of the Women's Cancer Advocacy 16 Network. And I've been a patient advocate for the 17 last 10 years working at local, state, and national 18 level. I serve currently as a patient advocate on 19 one of the cancer clinical trials cooperative 20 groups, on several of their committees including 21 patient issues and ethics committee. 22 I also serve on the Cancer Genetics 31 1 Network. I'm frequently asked to review protocols 2 and informed consent on both publicly and privately 3 funded cancer research. And I served on the State 4 of Virginia's panel on informed consent. I'm 5 particularly interested in the informed consent 6 process of as opposed to just looking at the 7 document in itself. 8 And as Dr. Satcher mentioned, and I would 9 concur with, I'm particularly interested in access 10 to research and clinical trials and the increase in 11 which that is occurring at the community setting 12 and within physician's offices. And feel that this 13 will increase access but on the other hand, we have 14 to provide and balance that what ethical 15 considerations through education and guidelines. 16 CHAIRPERSON MARSHALL: Thank you very 17 much. And we are very glad to have you. You bring 18 a balance to our group that we didn't have before 19 and it is a critical balance. So thank you so 20 much for being here. 21 Susan. 22 MS. KORNETSKY: Good morning. I m Susan 32 1 Kornetsky, the Director of Clinical Research 2 Compliance at Children's Hospital. And I've been 3 at Children's Hospital and working with IRB s for 4 the past 18 years. I'm the immediate past 5 president of ARENA, Applied Research Ethics 6 National Association, which is an association of 7 professionals that are dedicated to IRB s and 8 IOCOCS. 9 I'm also involved in Primer, performance 10 standards committee, developing standards for the 11 accreditation for IRBs. I know there's been a lot 12 of discussion about that. And I'm on the Council 13 of Certification of IRB Professionals and during 14 the past year we developed a program to certify IRB 15 professionals like myself based on a test of 16 knowledge. 17 To date we have 160 people who have been 18 certified based on two test dates and we continue 19 to offer the examination. I also serve on the 20 primers IRB 101 faculty that provides education to 21 institutions and investigators and had served on 22 about 12 different institutions to do that type of 33 1 training. 2 I think my role on the committee is really 3 to represent the IRB professional. Eighteen years 4 ago there was no such thing. Now it's been 5 recognized that way. During the past years the 6 emphasis on institutional -- there's been an 7 emphasis on the institutional role on protecting 8 human subjects, but the reality is, in order to do 9 this there's usually an office or individual who 10 has to pull the pieces and the policies and help 11 with the interpretation and that's usually someone 12 like myself in the institution. 13 I devote 100 percent of my time to working 14 with IRBs. I consider myself on this committee 15 sort of the voice of practicality. In other words 16 we can debate the issues and set the policies, but 17 the implementation is the real challenge and that's 18 where I'm going to speak out on how and what seems 19 reasonable to implement within different 20 institutional cultures. 21 As an IRB professional I consider myself 22 really in the trenches doing this work. I d like 34 1 to think Dr. Koski and the committee for 2 recognizing the need for this role this committee I 3 think it's very important. 4 Obviously, my own interest within 5 pediatrics I look forward to those discussions. 6 I've also done a lot of thinking about genetics, 7 biological specimens; I mean I've really had to 8 think about because of my role with the 9 Institutional Review Board everything I look 10 forward to collaborating with everyone. 11 CHAIRPERSON MARSHALL: Thank you very 12 much. And I think we second your goal for 13 professionalization in IRB activities for IRBs to 14 have the resources and the strengths and the 15 institutional commitment that they need in over for 16 them to do their job and recognize that all of 17 those needs are not currently being met. And that 18 we hope that our work will rectify that situation. 19 I d I'd like now for the members -- our ex 20 officio members to introduce themselves. I don't 21 recall whether we did this last time or not. But 22 you are very important members of our committee and 35 1 we would like to hear you. If you could just stand 2 up to tell us which agency you represent and if you 3 have any other comment you would like, to make we'd 4 be glad to hear it. 5 Introductions off mic. 6 DR. RUBIN: Phil Rubin, National Science 7 Foundation. 8 CHAIRPERSON MARSHALL: Thank you all for 9 being here and we hope to hear from you. 10 Our standard that we set at our last 11 meeting is to allow an equal amount of time in 12 discussion for our committee members, our ex 13 officio committee members and our public members. 14 So, so I hope that you all will be an active part 15 of the discussion today and at every meeting. 16 We have one new member -- Dr. Alan 17 Fleischman -- who is a pediatrician who is not with 18 us yet, but he will be here and we will ask him to 19 tell us about himself when he arrives. Those of 20 you who were at our first meeting know Alan and 21 have heard from him. And Alan has been chairing 22 our working group on children and working very hard 36 1 since our last meeting. 2 A couple of remarks that I would like to 3 make before I ask Dr. Koski to give us an update on 4 human research protections and -- 5 I want to make some comments about 6 something that's not really an issue but a concern 7 that I have had. And as a bioethicist my job has 8 always been not to ignore the hippopotamus, if 9 there's a hippopotamus in the middle of the room, 10 but to direct attention to it. And I have had a 11 concern about the relationship or the role of 12 having an executive director and a an executive 13 secretary for this committee; especially given the 14 history of how this committee came about and how 15 the Office of Human Research Protections came 16 about. 17 That it was formerly the Office of 18 Protection From Research Risk and lived at the NIH 19 and there was a perceived, if not real, conflict of 20 interest in having the OPRR live at the NIH when 21 the NIH was funding much of the human subjects 22 research that is done in the country. And then 37 1 having the agency that regulates that research be a 2 part of the same institution. So that was that 3 perceived or real conflict of interest was a reason 4 for the restructuring and the reshaping of that 5 office and moving it into the office of the 6 Department of Health and Human Services and the 7 Office of Public Health and Science. Thank you, 8 Kate. 9 I just want to say that Greg and Kate and 10 I have discussed the issue of having our executive 11 director, Kate Gottfried, sort of live and work out 12 of the OHRPR office and having the executive 13 secretary function and the designated federal 14 official function for our committee be Dr. Koski. 15 Dr. Koski is also the head of the Office 16 of Human Research Protections and is someone who by 17 our charter we advise. So, we have acknowledged 18 the fact that that could be a concern. We are 19 talking among ourselves about professional roles 20 and responsibilities and we don't think this is an 21 issue that can't be managed in terms of perceived 22 or real conflicts. 38 1 But I just wanted to put that out on the 2 table to let you know that we certainly had 3 discussed it and that to also say to that in an 4 area that could have been politically or personally 5 challenging that Dr. Koski has been nothing but 6 open and forthright and that we certainly all share 7 the very same goal, human research protections. 8 So I don't have concerns but I wanted to 9 let you all know that we had talked about that 10 issue. 11 And then just a couple of words in 12 general. These are primarily for our new members 13 about our task and how we work as a group. Our 14 guiding principle was articulated by secretary -- 15 former secretary Donna Shalala in her sounding 16 board article in the New England Journal of 17 Medicine, September 14th of last year. And it's 18 very simple, and it's something that I want us to 19 bear in mind. 20 Felice, you made a wonderful remark about 21 your professional qualifications and the fact that 22 you brought them to the table but they did narrowly 39 1 confine what you construed as your role at the 2 table. And that's correct. 3 Each of us at the table, each of us in the 4 room, has a responsibility to follow former 5 Secretary Shalala s dictum, and that is that no 6 priority in research is more important in the 7 protection of subjects and that our system of 8 protections must be exemplary. And that is our 9 goal and our charge. 10 We have an extraordinary opportunity as a 11 committee. Victor Hugo has said that an invasion 12 of armies can be resisted, but not an idea whose 13 time has come. And we are very much an idea whose 14 time has come. And because we face significant 15 opportunities and significant challenges our 16 response as a committee must be and will be 17 exemplary. 18 I'm mindful to that end of the social 19 contract that we have between the scientific 20 enterprise and public, and that exceptional 21 outcomes of us as a committee depend on the 22 integrity of our process as a committee. 40 1 So the proposed by words that our earlier 2 committee members will be familiar with are the 3 following: integrity of our process, fairness, 4 that all who are at the table and should be at the 5 table are there and that their voices are heard. 6 And I hope you will recognize the 7 additional members of our committee as our 8 sensitivity to the concerns that were expressed by 9 the public and by members of the professions that 10 we didn't have all the voices at the table that 11 should be at the table and that we have, I hope, 12 rectified that problem. That we are creative. 13 That we are flexible in our thinking. That we 14 think outside of the box. That we show respect for 15 our guests and our fellow committee members. That 16 we engage in civility in terms of our 17 deliberations. And perhaps most importantly, that 18 we engage in critical thinking. The essence of 19 which is suspended judgment. 20 In our meetings, in our work, we should 21 aim for clarity, for focus on our task, for open- 22 mindedness and flexibility, respect for our staff 41 1 and we shouldn't be reticent in raising 2 controversial or sensitive issues. 3 So if I perceive that we are ignoring a 4 hippopotamus in the middle of the room as a 5 committee, then I will direct our attention to the 6 hippopotamus. 7 And finally, I hope that we will, as a 8 group, feel ownership and pride in our work. We 9 have a wonderful agenda today. We have working 10 committees that have been working very hard in the 11 interim since our last meeting. We will hear from 12 them today and tomorrow. So I want to thank all of 13 you all for being here and I look forward to two 14 very productive days in moving our work forward in 15 a positive and concrete way. Thank you. 16 Dr. Koski. 17 DR. KOSKI: Mary Faith, thank you very 18 much. Good morning, everyone. 19 I really appreciate the opportunity to 20 actually update the committee as well as the rest 21 of the folks who are attending today on basically 22 what's going on with respect to the Office for 42 1 Human Research Protections, and in particular this 2 important task of remodeling the system for 3 protection of human subjects in research. 4 Last September, as you know, we launched 5 this effort. It's basically a three-phase program 6 to try and remodel the entire system for human 7 research protections. A remodeling that is based 8 largely on the architect's recommendations within 9 the Office of the Inspector General Report that was 10 originally issued in 1998 and subsequently 11 reemphasized in 1999. 12 The system that we are working to build is 13 one that clearly is based on performance, not just 14 process and paperwork. It's a system that will 15 focus not just on compliance and as a goal in 16 itself but rather on true protection of human 17 subjects and prevention of harms. We are working 18 to build a system that is more flexible certainly, 19 but at the same time will be more accountable. 20 We are currently completing phase one of 21 our efforts. This effort began with the creation 22 of our new office which Mary Faith already 43 1 described and its placement within the Office of 2 Secretary and the Office of Public Health and 3 Science, a position which provides it with a 4 platform from which it can not only exercise its 5 responsibilities, but also provide leadership 6 broadly in this area, both within and outside the 7 government. 8 Part of this was initially a 9 reorganization of the office into three operating 10 divisions: education, compliance oversight, and 11 insurance and policy, an office of the director 12 which includes not only our administrative 13 functions but also a new office for policy and 14 planning and special projects, and, of course, a 15 new office for international activities that we may 16 talk about later today. 17 We are in the process of hiring new staff. 18 I will tell you honestly that we've been impeded 19 somewhat in these efforts to some of the 20 complexities of government both in the delays and 21 approving the new budget for this fiscal year and 22 then also by the hiring freeze that always happens 44 1 when a new administration comes in. But these are 2 certainly not insurmountable goals and we will 3 continue there. I think we are making great 4 progress. We've been undeterred and I think that 5 much of the progress that we've made is clearly 6 attributable to the enormous efforts of the people 7 who are working together towards these goals. 8 We have implemented revisions to our web 9 site. It's a first stage. You can stay tuned, 10 there will be dramatic revisions to our web site 11 coming in the future. We implemented an e-mail 12 hotline for advice, a new list serve for reaching 13 out and providing information to the entire 14 research community. Soon we expect our 800 line 15 for immediate advice and assistance to be put into 16 place, all these being part of our orientation on 17 service, and outreach to the community that we 18 serve. 19 We implemented a simplified -- I'm sorry, 20 a unified federal registration process for all 21 institutional review boards regardless of whether 22 they're constructed under the federal funding 45 1 mechanisms or private funding mechanisms. 2 We introduced a simplified federal-wide 3 assurance process that greatly simplifies the 4 rather complex process of obtaining or making 5 assurances, a system that fosters collaboration as 6 well as flexibility. And, again, we're reaching -- 7 we've been in a pilot phase of this for the first 8 few months. We except to have this finalized as we 9 move into the end of this month and look forward to 10 the enormous opportunities that this will provide 11 for institutions to work together and in much more 12 effective and efficient ways. 13 We've dramatically expanded education 14 programs. We ve held an educational summit. We ve 15 been having conferences that are now held jointly 16 with the Veterans Administration, the FDA. We have 17 reached out to the research committee by having a 18 series of ambassadorial visits at institutions 19 across the country. As I was recently quoted in 20 the Washington Fax, I think we estimated that I 21 personally address somewhere around 8,000 people 22 now over the last six months; which is a lot of hot 46 1 air, believe me. 2 So we also, as we will be following up on 3 the educational summit that Jeff Cowen put together 4 so expertly in terms of developing new resources 5 and tools for the entire research community. We 6 have created this committee, empaneled it, had its 7 first meeting; thanks again to the enormously 8 expert work of Kate Louise Gottfried and all of the 9 members who ve contributed to that. 10 And clearly as Mary Faith said, there is 11 no conflict of interest here. That in fact there 12 is an absolute critical synergy between this 13 committee and our office and the Department. As we 14 work together to tackle these challenges, we look 15 to this committee for the advise that is so 16 essential to what we do. 17 Importantly, we have revitalized the human 18 subjects research subcommittee, the ex officio 19 members from the other federal agency and offices 20 who are here today are part of that group. This is 21 a group that is a subcommittee of a Committee on 22 Science operating out of White House. It pulls 47 1 together representatives from all the federal 2 agencies, offices, and departments that share 3 responsibilities in this area. We are working 4 together to develop a integrated approach to human 5 research oversight across the entire government to 6 achieve greater simplification, uniformity, 7 efficiency and effectiveness across the board. 8 At the same time that we are pursuing 9 these activities within government we are 10 encouraging the development within the private 11 sector of credentialing and training programs for 12 IRB professionals, research coordinators, principal 13 investigators. 14 We also, as you know, have engaged the 15 Institute of Medicine at the National Academy of 16 Sciences to issue forth a first set of uniform 17 standards for accreditation of human research 18 protection programs that will be issued probably at 19 the middle of this month. And that's some very 20 important items to stay tuned for. 21 We're winding down phase one now after 22 having achieved these important changes in the 48 1 foundation and setting us on a new course. As we 2 enter phase two, we look toward the full-scale 3 implementation of a support and quality improvement 4 program within our office. A program that will 5 utilize both site visits, videoconferencing, as 6 well as directed self-evaluations tools to not 7 focus on empty assurances up front, but rather work 8 with institutions making assurances to ensure that 9 they are up to the task so that they can do their 10 jobs. 11 We will be clearing away the back log of 12 compliance oversight investigations that had 13 accumulated within our office over the last couple 14 of years; made great progress there and as we do 15 that we will begin to focus compliance oversight 16 activities in a new way. One that focuses, again, 17 on surveillance not for-cause visits to further 18 increase the accountability within the system. 19 We look forward to the pilot testing and 20 implementation of the accreditation process; a 21 private voluntary accreditation process within the 22 private sector which will provide an enormously 49 1 important complement to the government's efforts 2 for regulation. Again, establishing a level 3 playing field on that high plateau of excellence 4 that's so essential to build the public trust that 5 Dr. Satcher spoke about in his opening remarks this 6 morning. 7 We, again, at the same time recognize the 8 need to expand activities in the international 9 arena. We have created and are looking forward to 10 actual implementation of the functions of our new 11 office for international activities that will serve 12 as a focal point for pulling together the many 13 offices within the government that share interests 14 and responsibilities in this area as we work toward 15 developing a more harmonized approach toward human 16 research conduct across the world. 17 We expect to wrap up phase two toward the 18 end of this year. As we do that, we will enter a 19 phase three period that basically involves 20 evaluation; assessment of where we are. We will 21 make midcourse corrections as necessary to be sure 22 that were on the right track. We, again, will be 50 1 looking to the Institute of Medicines, working 2 group on human subjects protection for guidance in 3 this area as they develop standards for -- or 4 measures, I should say, for actually accessing the 5 effectiveness of the system for human subjects 6 protection. 7 In every one of the activities that we 8 undertake, we will, of course, be working in the 9 same collaborative spirit that we have applied in 10 these first six, seven months with all of the 11 members of the other federal agencies so that we 12 basically achieve common goals through working 13 together. 14 We work not only with the NIH and the FDA 15 and the CDC and AHRQ and all the other agencies 16 within HHS, but, again, all of the agencies across 17 government through the human subjects research 18 subcommittee. And as we undertake that work, we 19 will do it with the advise of NHRPAC very much in 20 our minds. 21 As I said, we've made a great deal of 22 progress so far, but we still have a great deal 51 1 that lies ahead. Our motto is doing it right 2 together," and that's exactly what we are doing. 3 I would like to acknowledge the fact that 4 the only way that we are really able to do much of 5 what we're doing is through the support of some 6 truly extraordinary people who certainly assist me 7 in my efforts. Among them are my deputy director, 8 Melody Lynn, who -- Melody, if you would just stand 9 up so that people know who you are. 10 Melody carried the ball through the 11 summer, certainly until I got there in September 12 and has been an enormous asset all along. And I 13 think in the back there somewhere is, Mike Perome, 14 our assistant director who is wearing a couple of 15 hats. Again, two pillars that keep our office 16 going. And my senior policy advisor, Irene 17 Stiffcolman, who, Irene, if you could stand too. 18 I just want to thank all of you here and 19 the other members of the office who are present as 20 well as the ex officio members who have come today 21 to participate in these activities. This is a team 22 effort and I'm very grateful. Thank you. 52 1 CHAIRPERSON MARSHALL: Thank you, Greg, 2 very much. 3 I told Greg over Christmas that I thought 4 he probably logged more miles in December than 5 Santa Claus did. Now he's making me think of a 6 South Carolinian that we all know and I hope love, 7 James Brown, who is the hardest-working man in show 8 business and I m thinking perhaps that Dr. Koski is 9 the hardest-working man in bioethics. But we ll 10 forgo giving him the title of the James Brown of 11 bioethics. 12 [Laughter.] 13 MS. MEYERS: Dr. Fleischman has just 14 arrived. Alan, we have -- the new members have 15 each introduced themselves. And I know you are not 16 especially a newcomer to this group having worked 17 hard at our first meeting without being a member. 18 But we would like to give you five minutes or so if 19 you don t mind just to tell us about yourself and 20 why you re here; besides the fact that you were 21 asked. 22 DR. FLEISCHMAN: First let me apologize 53 1 for being late. I had a taxi driver who could not 2 find this place even though I thought I could. 3 I am a physician; I am a pediatrician 4 neonatologist and have done bioethics over the last 5 30 years. I am presently the senior vice president 6 at that the New York Academy of Medicine which is a 7 research-intensive than tank in New York advocating 8 for the health of public for over 150 years. 9 I also -- for 20 years -- spent some time 10 at the Albert Einstein College of Medicine and the 11 Montefure Medical Center in the Bronx, where I had 12 the pleasure of being on two IRBs and create the 13 clinical bioethics program there. Have published a 14 bid in the neonatal and perinatal issues both in 15 ethics and in physiology, and have an enduring 16 interest in all of the issues around bioethics 17 including research. 18 CHAIRPERSON MARSHALL: Thank you so much 19 for being here and welcome to the group as a member 20 of our committee. 21 Well, let us get down to business. That 22 wasn t a pun, but I guess one could be implied. 54 1 [Laughter.] 2 CHAIRPERSON MARSHALL: Mark Barnes has 3 been working very hard with members of the working 4 group on financial relationships and has prepared 5 for a response and update on financial 6 relationships. And just to remind you we were 7 charged with commenting on the draft interim 8 guidance financial relationships and clinical 9 research. Issues for institutions' clinical 10 investigators and IRB to consider when dealing with 11 the issues of financial interests and human 12 subjects protections. And Mark is going to give 13 us an overview of the work that his working group 14 has done and then we will have committee discussion 15 about that work. 16 I want to just say we received a lot of 17 public commentary on this issue certainly the 18 academic medical community weighed in heavily and I 19 think the themes from the academic medical 20 community were somewhat consistent. That there 21 were concerns about the guidance perhaps being 22 premature, burdensome, and overreaching that the 55 1 department was perhaps setting new policy through 2 ad hoc procedures such as guidance rather than 3 formal rulemaking, and a plea to work together with 4 the AAU and the Association of American Medical 5 Colleges on the issue of financial conflicts of 6 interest. 7 Other concerns that were raised, perhaps 8 at the other in a spectrum, were by members of the 9 public such as Paul Galsinger, Jesse Galsinger s 10 father who urged the committee strongly to look 11 closely and hard at the issue of financial 12 conflicts of interest as related especially to 13 public trust. So there is, I think, a balance that 14 we must look for and seek somewhere between those 15 two. And we'll hear from Mark about how his 16 committee came out on that issue. 17 Thank you, Mark. 18 MR. BARNES: Thank you, Mary Faith. First 19 let me introduced the members of the working group 20 who participated in these deliberations and whose 21 commentary and participation really yielded the 22 draft letter -- the draft commentary letter that we 56 1 have before us. It is Adil Shamoo, Sandy Chodosh, 2 Judy Seigel and unfortunately Elliot Dorff, I 3 assume, is traveling today and therefore is not 4 here. 5 They were all extremely patient with each 6 other with the complexity of the issues involved. 7 Elliot wins the forbearance award for actually 8 staying on a conference call for about six hours 9 with us from Los Angeles because he couldn't be 10 here during the day that we had our face-to-face 11 meeting on March 21st. 12 For members of the public there are some 13 copies here of the draft letter and there also are 14 some copies up here of a redline version for the 15 interest that I provide an interest of transparency 16 so that you can actually understand the 17 evolutionary process or the archeology of this 18 particular draft. 19 There was an earlier version of this draft 20 commentary which was provided to the members of the 21 committee and actually to members of the working 22 group and also the entire committee. And then 57 1 there were comments over the past week and these 2 were incorporated into the new draft which is the 3 draft that you have in front of you. 4 So I direct the committee's attention -- 5 NHRPAC s attention, not to be draft that is in the 6 materials provided to you by Kate Gottfried, but 7 rather to the draft that's in front of you. 8 What I propose to do this morning is 9 basically to go through a number of issues 10 regarding this draft, regarding the draft intern 11 guidance, and basically I want to the -- I'm going 12 to give a presentation hopefully not too lengthy to 13 leave adequate time for discussion among NHRPAC 14 members that will have basically addressed three 15 issues. 16 One issue is to give the members of the 17 committee and overview as to exactly what the 18 actual legal requirements are now for the 19 disclosure and management of financial 20 relationships in human research so that we have a 21 background for exactly what we are all commenting 22 on; and we'll get a baseline understanding of that. 58 1 That will be, hopefully, a brief presentation and I 2 have in the course of preparing this presentation I 3 tried to simplify a number of things so some of the 4 complexities have fallen away. So please forgive 5 me for that, but in the interest of time I was 6 trying to really give the -- and I will try to give 7 the bottom lines. 8 Second part is to review briefly the draft 9 interim guidance that was put together by the 10 Department which is the document on which NHRPAC is 11 commenting on and to summarize some of the major 12 public comments that were received during the 13 comment period about that draft interim guidance. 14 And thirdly, the third part of our 15 presentation this morning will be to review the 16 major features of the draft that we have in front 17 of us that is the draft of our comments on the 18 Department's draft interim guidance on financial 19 relationships in human subjects research. So with 20 that, let's get started. 21 Basically in terms of background for what 22 is required for the basic requirements, legal 59 1 requirements, regulatory requirements, the way the 2 world exists now in terms of things that must be 3 complied with by researchers, by research sponsors 4 and by academic institutions and other places where 5 research takes place there are multiple federal 6 regulations and state regulations that dictate 7 policies and procedures in this area. Not all 8 states have such regulations, but some of the 9 states in fact do have particular state 10 regulations. 11 There are obviously -- one of the goals 12 here, or there are multiple goals in these statues 13 and regulations and one could even say that there 14 are competing goals and one of things that we try 15 to articulate in our committee deliberations were 16 in fact to try to tease out exactly what the goals 17 are in financial disclosure in human subject 18 research and in the management of these conflicts 19 that are identified. Yes, Bob? 20 DR. R. LEVINE: Mark, do you want us to 21 comment as you go a long or should we hold it off 22 until the end? 60 1 DR. BARNES: I think that if you have 2 something burning -- a burning issue that you just 3 can t hold off on, you ought to interrupt me and 4 say it. That s what I think. 5 [Laughter.] 6 DR. R. LEVINE: Well, one man s burning 7 issue you know -- 8 DR. BARNES: Well, go ahead. 9 DR. R. LEVINE: This one doesn t burn. 10 [Laughter.] 11 DR. R. LEVINE: But I ll say it anyway. 12 [Laughter.] 13 MR. BARNES: Go ahead. 14 DR. R. LEVINE: You have in the text of 15 your draft report -- what I find a persuasive 16 statement that we should be referring to financial 17 interests rather than conflicts of interests. And 18 one slide ago -- I'm just think that was a very 19 good idea and I'd like to get on with it. 20 DR. BARNES: Okay. Well, I assure you 21 that actually in our deliberations we have tried to 22 very carefully distinguish between financial 61 1 relationships, complicating financial relationships 2 that are relevant to the research and actual 3 conflicts of interest. Okay. It's a part of the 4 conceptional clarity that we would urge the 5 Department to adopt in it interim guidance. 6 Okay. Under the way that the federal regs 7 read now certain financial conflicts of interest 8 must actually be disclosed to the institution where 9 researchers conduct their study or to the sponsors 10 who are sponsoring the research sponsors who are 11 conducting the actual research. And then under 12 federal requirements a subset of those financial 13 relationships that have been identified as 14 conflicts must in turn be identified either to the 15 governmental agencies that are funding the research 16 or that are reviewing the research that is 17 conducted by these researchers. 18 In addition to that, and we will talk 19 about those federal requirements, in additional to 20 that though, I want to give you the background idea 21 that there are state regulations governing the 22 professional practices of medicine and the practice 62 1 of any licensed professional, whether it's a 2 clinical psychologist conducting the research or 3 any person who is granted a license -- professional 4 license by a state -- and all of this is state law 5 and not federal law when you talk about licensure 6 and regulations of professionals. 7 And under those rules there are in almost 8 all states particular provisions which basically 9 prohibit a licensed professional from exercising 10 what's called "undue influence" over a particular 11 patient or converting the treatment relationship 12 with that patient, that fiduciary relationship, 13 into a relationship that benefits the practitioner 14 rather than the patient. And I think that we need 15 to understand that as the background professional 16 obligation, the plenary professional obligation of 17 every licensed professional, particularly every 18 physician who engages in or participates in human 19 subject research. 20 There also are specific state and federal 21 requirements governing conflicts of interest in 22 financial relationships held by IRB members 63 1 themselves who are considering the proposals to 2 approve human subjects research. 3 Now, one of questions is, what's the risk 4 and all this? Why a do federal regulations address 5 this that all? Clearly we have seen a number of 6 particular anecdotal reports in the media attention 7 and in the professional literature about instances 8 in which individuals have, professionals have, or 9 institutions have conducted research when they in 10 fact have particular financial interests or 11 relationships that might be expected or assumed or 12 feared would contaminate or adulterate the conduct 13 of the research, the gaining of informed consent 14 and/or the interpretation and analysis of 15 presentation of data. 16 There are -- and I give you only a few 17 examples here, and not to single out any one 18 particular institution or group of professionals, 19 but there clearly have been a number of media 20 reports that have really called into question 21 fundamentally public trust in terms of these 22 underlying financial relationships in clinical 64 1 research. 2 In January of 2000 there was also a META 3 analysis that was published in JAMA which I think 4 was entitled, "Is a Pharmaceutical Company Gift 5 Ever Just a Gift? And not to single out 6 pharmaceutical companies because one could apply 7 the same thing to medical device manufacturers and 8 biotechnology companies and others who are for 9 profit and not-for-profit entities of funding 10 research. 11 But essentially what this study found -- 12 it was, again, a meta-analysis of 29 studies -- is 13 that physicians receipts, receipt of financial 14 remuneration, really does influence in a 15 significant way prescription patterns or 16 decisionmaking by those clinicians in regard to 17 their patients. Which really gets to the core of 18 what we fear, I think, and I speak for the working 19 group although if someone disagrees then I 20 encourage them on the working group to speak out. 21 What we fear really is the foundation of a 22 fear in regard to the conduct of research when 65 1 there are financial relationships that are 2 implicated in the research. Clearly the Jesse 3 Galsinger case was one of the exciting causes of 4 the attention of the national research community to 5 these issues. 6 There were in fact in that case -- they 7 were called into question some significant 8 financial ties that the co-PI had to the sponsor. 9 And this led directly to the adoption by the 10 American Society of Gene Therapy to a general 11 probation in its guidelines -- it's institutional 12 guidelines, its associational guidelines that those 13 members of the society not in fact own, at all, 14 equity stock options or other ownership interests 15 in the companies who products they were engaged in 16 testing. 17 This could be paraphrased and was by 18 Marsha and Joe at the August 2000 conference held 19 at NIH on this issue that physicians and others and 20 institutions should be free to invest in race 21 horses, rubies, and real estate but should leave in 22 fact all medical suppliers and vendors and 66 1 pharmaceutical companies and research sponsors 2 alone in terms of their personal and institutional 3 investments. 4 There also have been multiple articles 5 published. Yes, Abbey. 6 MS. MEYERS: In that case the university 7 also had a stake in the ownership of the company, 8 was anything done about that? 9 DR. BARNES: Was anything about the 10 Galsinger case? 11 DR. MEYERS: Yeah, is there any 12 prohibition? There is no legal prohibition against 13 universities owning a share in a company. 14 DR. BARNES: That is correct, and we ll 15 get to that. But there is no actual legal 16 prohibition on institutional conflicts of interest 17 or institutional financial relationships involved 18 in research. Although some institutions have 19 clearly adopted their own policies that are more 20 aggressive than the existing federal regulations on 21 the issue. Okay. 22 There was this conference hosted in August 67 1 of 2000 at NIH on this particular issue which 2 resulted in the draft interim guidance that was 3 authored by a member of people, but I think that 4 it's fair to say that the effort was led by Stuart 5 Nightingale in the Office of the Assistant 6 Secretary. I think that is where Stuart is. I'm 7 sorry, planning and evaluation. 8 There are essentially three -- and, again, 9 this is the actual regulations of what must be done 10 as opposed to what should be done, or what could be 11 done, or what might be done, and it's important to 12 keep those distinctions in mind as we proceed 13 through that this issue. 14 There are regulations of public health 15 service regarding funding, PHS-funded research 16 studies, the regulations of the NSF, the National 17 Science Foundation, regarding studies funded by 18 NSF. And there also are specific regulations of 19 the FDA that apply to research sponsors who are or 20 that are submitting applications for approval of 21 drugs or devices. 22 Now to take the PHS first, PHS regulations 68 1 importantly do not apply to privately funded 2 research, okay. They apply only to research funded 3 by the PHS agencies or that are proposed for 4 funding by PHS. 5 The basic requirement is that the 6 investigators, the researchers, who participate in 7 the studies, they are supposed to submit review to 8 an official at their institution that is applying 9 -- that is submitting the application -- a listing 10 of their own, what are called significant financial 11 interests and then they fall into categories. But 12 basically significant financial interest that would 13 reasonably appear to be affected by the research. 14 Okay. 15 The financial disclosure has got to be 16 made prospectively at the time that the 17 investigators -- that the institution submits the 18 grant application. Then go further into the 19 regulations, what is a significant financial 20 interest that could reasonably appear to be 21 affected by the research? Well, there is a 22 definition, a threshold definition in the PHS 69 1 regulations that basically is cash remuneration on 2 an are of stocks other ownership interests that 3 exceeds $10,000 or that constitutes more than a 5 4 percent ownership in a single organization. 5 What it does not include is salary and 6 other compensation from the research institution, 7 including the compensation that is flowing from the 8 research study itself. It also does not include 9 other kinds of income from seminars, et cetera, 10 that are sponsored by public or not-for-profit 11 entities. 12 Now, importantly in the regulation, 13 however, there is no definition as what significant 14 financial interest would appear to be reasonably 15 affected by the research. So that is a great gap 16 in the existing definitional structure of 17 regulations. 18 The institution -- once the disclosure is 19 made by the investigator to the institution the 20 institution is not required -- is not required -- 21 to re-disclose that to the federal government 22 unless the institution actually thinks that there 70 1 is an actual risk that the significant financial 2 interest could directly and significantly affect 3 the design conduct or reporting of the PHS funded 4 research. Which means the bottom line in this is 5 that the category of conflicts or potential 6 conflicts that must be reported by the institution 7 to the public health service is narrower than the 8 range of financial interests that must be reported 9 by the researcher to his or her own institution. 10 The PHS regulations also require that 11 financial relationships that are complicating, that 12 rise to the level of conflicts of interest, that an 13 institution must have guidelines, internal 14 guidelines to manage those conflicts of interest 15 appropriately or to reduce them or eliminate them. 16 Now, it does not decree what those 17 guidelines must be, but it just says that the 18 institution must have internal guidelines to do so. 19 Now, one question that Elliot has often 20 asked and I think quite appropriately is once a 21 conflict of interest is actually identified as 22 being a significant financial interest that could 71 1 reasonably appear to be affected by the research, 2 how would that be managed?" And there are some 3 suggestions that are not exclusive remedies, but 4 that are suggestions in the regulations and they 5 range from publicly disclosing the financial 6 interest that is complicating to actually requiring 7 that the investigator if he or she wants to proceed 8 with the study actually sever their financial 9 relationship or divest themselves of the financial 10 relationship. But there are a number of 11 intermediate steps that could also be kind of 12 intermediate sanctions, as it were, that could be 13 applied in order to manage the conflict. 14 NSF itself has a conflict of interest or 15 financial disclosure rules that largely track the 16 PHS standards, but they only apply to NSF-funded 17 research. I won t go into the complications here, 18 they are arcane and quite obscure and actually, in 19 the end, probably not to important because the NSF 20 requirements are largely the same, although not 21 entirely, as the PHS requirements. 22 On the FDA requirements, however, are the 72 1 other large source of background regulations on 2 these issues and they apply to a pharmaceutical 3 company, a device manufacturer, or any other party 4 that has submitted a marketing application and is 5 therefore an applicant to the FDA for approval. 6 Because the financial relationships that are 7 required to be reported by the FDA are submitted -- 8 are collected by the sponsor during the course of 9 the research, but submitted at the time of 10 application, they are largely retrospected in 11 nature rather than the prospective application of 12 the PHS, NIH, and NSF guidelines. 13 Clinical investigators under the FDA 14 regulations do not report their financial 15 relationship directly to the FDA. They report them 16 to the sponsor who in turn is responsible for 17 collecting the information and then redisclosing it 18 to the FDA. 19 For every clinical investigator in a 20 covered clinical study, there are definitions in 21 the FDA relations as to what must be reported and 22 those are not consistent, they are not consistent 73 1 with the PHS and NSF requirements in terms of the 2 definition of the financial relationship. 3 In fact, they basically would -- like the 4 PHS requirements that definition of a financial 5 relationship that must be disclosed actually 6 excludes the compensation to the researcher that 7 flows from the research itself that is in question, 8 but it includes in the other compensation from the 9 sponsor that is worth more than essentially $25,000 10 per year. It also includes any ownership or other 11 financial interest in the sponsor held by the 12 clinical investigator that exceeds an approximately 13 $50,000 during the time that the investigator is 14 conducting the study or within a year after the 15 completion of the study. Okay. 16 And, again, it is the sponsor the 17 applicant, the FDA of applicant that submits this 18 information to the FDA, not the clinical researcher 19 or himself or herself. 20 Now, what are the differences, the basic 21 differences between the PHS and the FDA 22 requirements? Note that the dollar thresholds are 74 1 higher in the FDA regulations. That PHS 2 requirements focus on conflicts that reasonably 3 appear to affect the research. Or, actually that s 4 not accurate. They reasonably appear to be 5 affected by the research. Whereas FDA requirements 6 focus on conflicts essentially relating between the 7 relationship between the investigator and the 8 research sponsor. And one gets then to the issue 9 of the goals. 10 It looks as though one of the primary 11 goals, and perhaps the primary goal, of the FDA 12 regulations is essentially to assure that there is 13 not undo financial relationship or inappropriate 14 financial relationship between the researcher and 15 the sponsor leaving the sponsor and/or the 16 researcher to misinterpret data or aggressively 17 interpret data in favor of the approval of the 18 application. Also note that disclosure to the FDA 19 is retrospective at the time of application, but 20 PHS requirements are prospective. 21 And, finally, another thing that's 22 embedded in here is that PHS requirements only 75 1 apply again to PHS-funded research whereas FDA 2 regulations apply to all research that is submitted 3 as part of an FDA application and therefore to 4 privately funded research. But that means in the 5 end that there is a range of activity that is not 6 funded by PHS, not funded by NSF, and that is not 7 submitted as part of an application to the FDA 8 witch is privately funded research that is subject 9 to none of these requirements. Okay. 10 In additional there is law that governs 11 the financial relationships or conflicts of 12 interest held by IRB members themselves. There are 13 some state laws that are applicable here. I won t 14 go into them but they, in many cases, are either 15 consistent with or can even be more restrictive 16 than the FDA and PHS regulations. 17 There is obviously and the common rule is 18 one of the primary sources of law for IRBs 19 including on this particular issue as are FDA 20 regulations. 21 Basically the HHS and the FDA regulations 22 prohibit the participation of a IRB member when the 76 1 IRB member's review of the project is reviewing a 2 project in which the IRB member has a conflicting 3 interest. Although importantly there is absolutely 4 no definition in any of the state rules that I know 5 of, or the federal rules regarding what is a 6 conflicting interest. There is no threshold amount 7 as at least we have in the PHS and the NSF and the 8 FDA regulations. 9 Now, since there is no definition of what 10 is a conflict and what s not what s a conflicting 11 financial relationship or a troubling financial 12 relationship, how ever one describes it, then 13 institutions are free to develop their own 14 definitions. But they clearly, according to the 15 regulations, need to document and enforce the 16 policies that they adopt. And the recommendation 17 or actually more than recommendation, the 18 requirement in the regulations that there be an 19 institutional official who is given the 20 responsibility for monitoring this, or that there 21 is a system for monitoring this. 22 There are clearly some conflicting roles 77 1 here in terms of duties, because especially if an 2 IRB member is actually a PI in a study then 3 obviously a dual role can also cause a nonfinancial 4 conflict, or even a financial conflict, which is 5 also apparently prohibited by the various federal 6 IRB requirements. 7 This needs to be considered obviously by 8 institutions in selecting IRB members when they 9 frequently have conflicts. In other words they are 10 often PI's in studies and this is obviously 11 something that should be avoided. And it's a 12 problem that's even more severe if the IRBs chair 13 is in fact a PI himself or herself. 14 There is some guidance from OHRP on this 15 issue which basically is a strong recommendation 16 that when an IRB member has a conflicting interest, 17 which the inn is not defined, that they leave the 18 room when they IRB votes, that the departure from 19 the room is noted in the IRB minutes and then there 20 are a few others as well. But the important point 21 here is that there is no definition in these regs 22 as to what is a conflicting interest of an IRB 78 1 member and what isn't. 2 So, basically, I'll tell you what most 3 institutions actually do, at least in my experience 4 and perhaps members of the committee could add to 5 this, but actually most institutions because there 6 is no particular definition of conflicting 7 interest, most institutions that have strict 8 research policies actually have a zero tolerance 9 for conflicting interests when it comes to IRB 10 members and say that if there is any financial 11 relationship to the study or even non-financial 12 relationship to the study at issue the IRB member 13 should recuse himself or herself. Okay. 14 So that in the end is the background that 15 we have here. We have PHS requirements. We have 16 NSF requirements close to the PHS and then we have 17 FDA requirements. They deal with the conflicting 18 relationships both of the researchers and of the 19 IRB members but they do not -- there are gaps in 20 the coverage and obviously there is no definition 21 here in the restriction on what has been termed an 22 institutional financial relationship to the 79 1 research or rising perhaps to the level depending 2 on the case of an institutional conflict of 3 interest. 4 Now, because of that, or perhaps as a 5 result of that, there have been these concerns 6 raised which led to in fact to the conference to 7 the various publications on these issues, the 8 conference in August of 2000 at NIH, to the various 9 publications on these issues, to the attention from 10 the New England Journal, and in its amassed 11 editorials on this issue and related issues, and, 12 finally, the draft interim guidance was issued late 13 last year I believe it was issued and the comments 14 were received through March; although hopefully 15 they will accept our comments that would be late 16 filed as not to untimely how. 17 This draft interim guidance basically is 18 an attempt -- appears to be an attempt by the 19 Department to really craft some guidelines that 20 would try to fill some of these gaps and try to 21 develop a best practices -- a series of best 22 practices recommendations for how these conflicts 80 1 can be identified, managed, financial relationships 2 can be identified and classed either as a troubling 3 financial relationship or as an actual conflict of 4 interest. 5 I am not going to go through all of the 6 draft interim guidance that are available on the 7 web, and I know that many of you have already read 8 it, but let me just go through a few of the 9 highlights of the draft interim guidance. 10 The draft interim guidance basically 11 endorses the idea that there would be a conflict of 12 interest process or an actual conflict of interest 13 committee or designated official that would be 14 essentially an adjunct to the operation to the IRB 15 itself. So that the IRB itself is not faced with 16 the task of not only protecting human subjects in 17 terms of assuring their informed consent, but also 18 indulging in -- I shouldn t say indulging in -- 19 engaging in -- because I don't think it's much of 20 an indulgence -- engaging in the -- maybe a plenary 21 indulging or something, but in the religious sense 22 -- 81 1 [Laughter.] 2 MR. BARNES: -- but it s clearly a task 3 but so that the IRB would not be faced with the 4 very onerous task for which it is not -- it members 5 are really not particularly well-qualified and 6 don't really have the expertise of deciding what is 7 a conflict, what is not conflict, what is a 8 financial interest, what is not a financial 9 interest, or what exactly a stock ownership or 10 future springing right in a patent would or would 11 not be in terms of a conflict of interest in the 12 research. 13 The guidance also importantly identifies 14 and contemplates the policies for the disclosure of 15 and the management of institutional conflicts of 16 interest in which the actual research institution 17 -- the place at which the research is conducted 18 would have an interest, a financial relationship to 19 the product or device on being tested or the 20 company that owns that product or device. 21 There are suggestions for education and 22 training of IRB staff members and investigators on 82 1 these issues. And also importantly the draft 2 introduces the idea which was oft expressed in the 3 August 2000 conference that in fact when financial 4 relationships are identified that are relevant to 5 the research that there should be some level of 6 disclosure to patients, or financial research 7 subjects, in the conformed consent process. 8 So I would in the end probably -- and 9 others may have different interpretations of these 10 draft interim guidance but there essentially are 11 three features of the draft interim guidance that 12 have perhaps been most troubling to some on both 13 sides of the issue; those who think that the draft 14 guidance goes too far, and those who think that the 15 draft guidance doesn't nearly go far enough. And 16 that would be the identification of a conflict of 17 interest process that was separate from the IRB, 18 but an adjunct to the IRB number one. 19 Number two would be the idea of there 20 being institutional conflicts of interest that 21 would have to be revealed or financial 22 relationships that would have to be revealed and 83 1 actively managed when they rise to the level of a 2 possible conflict of interest. And number three 3 would be the idea of disclosure of these financial 4 relationships to research subjects to potential and 5 actual research subjects. 6 Now, there were comments received -- many 7 comments received by the Department through the 8 period and I believe all of these are posted on the 9 web so that anyone can see the various comments 10 that were received. I tried to, in a sense of a 11 religious cosmology, to limit my bullet points to 12 12, but my best efforts at this were in fact 13 thwarted by my colleagues who insisted that other 14 things be added. 15 So in fact we have for the 12 disciples. 16 We have Mathias and Paul and perhaps Timothy added 17 on, but anyway, let me go through the basic 18 comments that were received on these issues. 19 The one basic comment is that the draft 20 guidance is to directive and is not compliant with 21 the Administrative Procedure Act, that it would 22 essentially, once issued, have the effect of 84 1 regulation, but would not have been issued through 2 the regulatory process. 3 Another set of comments said, please wait 4 until the private associations have acted on these 5 issues. And in fact the AAMC has appointed a 6 committee recently and has essentially a two-year 7 process for developing policies and procedures for 8 it s own members on these issues. 9 There were requests for additional 10 consultation with stakeholders. There was the 11 general comment that the roles of the IRB and the 12 COI committee or entity or not clear in the 13 guidance and that related set of comments were that 14 IRBs are already over burden and perhaps they 15 should not even be an adjunct to the IRB process. 16 They should simply be a separate conflict of 17 interest process. There were other comments that 18 the COI function should not be vested in the 19 committee, but should be vested in an institutional 20 official like a Dean, Provost or Administrator. 21 There were particularly a series of 22 comments that criticized the idea of identification 85 1 and on disclosure requirements for institutional 2 conflicts of interest. The basic comment from the 3 different commenters was that the draft interim 4 guidance was going too far into uncharted territory 5 on this issue. 6 There were other comments that research- 7 related compensation, that is compensation that 8 flows either to the institution and/or to the 9 researcher in as part of the actual research study 10 should itself be subject to financial disclosure 11 and to analysis in the conflict of interest process 12 which is a radical departure from the existing 13 requirements of FDA, PHS and NSF. 14 Other comments received that the 15 disclosure of these identified financial interests 16 to subjects is undefined; there's no practical 17 experience that we have a and little data in the 18 area; that much attention is needed to a conflict 19 of interest process in the so-called "independent 20 IRBs" and also the contract research organizations 21 that are not particularly -- that may work with 22 institutions but are, in fact, not subject to 86 1 institutional oversight and regulation. 2 There was a general comment that was 3 received or a few general comments that the draft 4 guidance was too complicated, that it promoted 5 bureaucracy and ran the risk of actually stifling 6 human subjects research. That's perhaps the 7 tipping point that Jonathan was referring to 8 earlier. 9 There were also comments that in fact 10 there was no need for draft interim guidance in 11 this area. That there were only a few bad apples 12 that have been identified in the media that 13 anecdotes should not drive -- anecdotes of bad 14 research practice should not drive policy in the 15 area. 16 Other comments that I think would be 17 obvious from our presentation so far is that the 18 PHS, FDA and NSF disclosure requirements should 19 definitely be standardize, and by regulation if 20 necessary, and she'd be extended, I should point 21 out, to all research regardless of source of 22 funding. 87 1 Another set up comments that conflict of 2 interest is not simply financial, but also 3 implicates issues of personal procedure, academic 4 advancement, et cetera. The other comments that 5 the draft guidance in fact had unclear goals or 6 even possibly conflicting goals is the goal to 7 avoid COI or to manage COI and is in fact the 8 government putting forward the position that there 9 is and ought to be a zero tolerance for identified 10 conflict of interest. 11 And, finally, what is the goal of the COI 12 process itself? Is it to ensure research 13 integrity? That is, integrity in the 14 interpretation analysis and presentation of the 15 data, or is it to protect subjects from 16 unscrupulous researchers, or even for those 17 researchers who motivations may very well be mixed 18 and whose subconscious motivations may enter into 19 the equation because of their conflicting duties. 20 These are the -- in general, the comments 21 that were received in the process. So we got 22 together the working group of this committee and we 88 1 developed a process by which we thought we could 2 try to come up with a consensus which certainly 3 does not reflect the individual opinions of the 4 members of the working group, but is proposed only; 5 but does represent, I think, a kind of nipping and 6 tucking and pushing and pulling in very polite ways 7 during the process among the members of this 8 working group. 9 The working group was charged at our last 10 meeting of this committee. We reviewed the draft 11 interim guidance and we also reviewed all of the 12 comments that were received in the process of the 13 draft interim guidance by the Department. We had a 14 couple of conference calls with roundtable 15 discussions to identify issues and map out some 16 strategy proceedings and to share some of our 17 insights and reflections on this. 18 There was a day-long face-to-face meeting 19 in Washington at the Department on March 21st in 20 which the members of the working group really 21 engaged in a full-day discussion, not only of the 22 draft guidance, but also of an agenda for conflicts 89 1 of interest for the committee that may actually -- 2 although embedded in our proposed comments, would 3 actually go beyond the draft interim guidance and 4 go into the future on these issues. 5 We put together a draft which was 6 circulated last week and then there were comments 7 that were delivered during the week last week by e- 8 mail. The draft was revised and what you have in 9 front of you is the revised draft and the redline 10 version so that you can compare the previous draft, 11 the penultimate draft, to the ultimate draft 12 hopefully preceding this committee's ratification 13 of the draft so that we can actually make it or 14 something resembling it into a committee comment -- 15 a formal comment to the Department. 16 Now, let me go through the third part, and 17 the final part of this presentation, which is, to 18 kind of outline and review the basic highlights of 19 the proposed commentary put together by the working 20 group. 21 We were called to task by Elliot who is a 22 philosopher and a theologian who basically required 90 1 that we identify our goals and that identification 2 of goals and objectives be front and center in all 3 of our duties and he really kept us honest in this 4 process, and we identified a few goals and 5 objectives which are hopefully complementary but in 6 fact they are different goals. 7 One is to ensure the integrity of the 8 informed consent process to make sure that 9 researchers are not compromising the research of 10 the informed consent process because of their 11 possibly conflicting duties or conflicting 12 relationships to research sponsors or to government 13 funding agencies. 14 The second goal is to promote research by 15 assuring research integrity. That is, to make sure 16 that financial relationships that researchers or 17 institutions have to the research sponsors or to 18 products or investments that may reasonably be 19 expected to be affected by the research, that that 20 does not influence the interpretation, the 21 analysis, the presentation of data. 22 And then a kind of subheading under that 91 1 is to make sure that data is not actively or even 2 passively misinterpreted and to make sure that 3 there is a rigorous adherence, no misprision of 4 research and professional duties of researchers 5 and of institutions. 6 In general, what the -- and please if the 7 working group members have different opinions about 8 this, then please jump in. We basically thought in 9 response to especially to the comments that we 10 received, we thought that OHRP and the department 11 should actually proceed with these guidelines -- 12 should not hold back from them, but should proceed 13 in a careful and stepwise manner. 14 We thought that there was a continual need 15 once the draft interim guidance was finalized as in 16 fact guidance rather then draft interim guidance, 17 that those guidelines be periodically and perhaps 18 frequently, especially at the beginning, revisited, 19 reviewed and their effects evaluated. 20 We also thought that as the private 21 associations had develop their guidelines over next 22 couple of years that the best features that emerge 92 1 from that development should in fact be folded 2 into, be adopted selectively by the department in 3 additional iterations of the interim guidance. 4 In terms of -- then I will go to the 5 subheadings here -- in terms of defining conflicts 6 of interest, we did make it clear, I think, in our 7 draft, and it is clear especially in the revised 8 draft that you have before you, that financial 9 disclosure is not the same and financial 10 relationships are not the same as conflicting 11 financial relationships. And that a financial 12 disclosure process does not mean that there are 13 actual conflicts of interest that are identified 14 and that different categories have to be kept 15 separate. And basically what emerged from the -- I 16 think, by a kind of group thing among the working 17 group members, was the idea that there should be a 18 financial disclosure process, that financial 19 relationships that emerge that really are related 20 to the research, that those should be identified as 21 some category, whether they are called relevant 22 financial relationships, complicating financial 93 1 relationships, or troubling financial relationships 2 depends very much for your perspective on those 3 financial relationships, but in fact there is that 4 category and then a subset of those relevant 5 troubling or complicating financial relationships 6 would actually rise to the level of being 7 identified actively as an actual conflict of 8 interest in the research or even as a possible 9 conflict of interest in the research. 10 We also thought that it was important in a 11 financial disclosure process that confidential 12 reality for researchers was definitely needed. And 13 we thought that there had not been enough attention 14 really paid to that issue. Confidentiality in that 15 if researchers do not feel comparable that the 16 process is going to be a confidential process 17 especially in these interim beginning stages before 18 a troubling financial relationship or an actual 19 conflict is even identified that they would not be 20 willing perhaps to fully disclose, it would act as 21 a business to fully disclose, and it would also be 22 in the end, if there is not confidentiality 94 1 actually be a deterrent for researchers who have 2 financial investments of any kind to participate in 3 research in close cases. 4 We also thought that even where there is a 5 financial relationship that is -- and this is a 6 departure, I will tell you, from the draft interim 7 guidance that where there is a financial 8 relationship that is disclosed that is even related 9 to the research, that there ought to be some 10 threshold levels that there are some levels beneath 11 which one share of stock or ten shares of stock in 12 a company that is also sponsoring a research simply 13 is so trivial, that for issues of convenience, of 14 effectiveness of regulation, and for identification 15 of actual or possible conflicts that things falling 16 below those thresholds should not, in fact, be 17 identified as complicating, troubling, or relevant 18 financial relationships. So we did believe that 19 there should be de minimus exceptions in the 20 process of financial disclosure. 21 We preferred the PHS standards if we had 22 to about standards that were in place now. We 95 1 thought that those were obviously more restrictive 2 than the FDA standards, and we would encourage the 3 Department on either through the draft interim 4 guidance in terms of suggested best practices or in 5 the end in terms of actual regulations to 6 standardize these requirements and let the PHS 7 standards prevail; the $10,000 and/or 5 percent 8 ownership interest standard prevail as opposed to 9 the FDA standard. 10 We also thought, and this went further 11 than the draft interim guidance that this ought to 12 be applied to all research not simply to that 13 research that falls under the PHS, NSF, and FDA 14 regulations. 15 We thought that research compensation 16 should be analyzed itself as part of the conflict 17 of interest process to make sure that the money 18 that is changing hands in the research endeavor 19 would in that particular study itself in terms of 20 the researchers and also the institution should be 21 transparent in the conflict of interest process. 22 And that the conflict of interest analysis should 96 1 not just apply to honoraria and trips and 2 investments and that sort of thing. 3 We also recognized that in certain 4 illnesses that there was a reason even for 5 financial relationships that exceeded the PHS 6 standards that there was a reason to have an 7 exception or a series of exceptions for compelling 8 in necessary circumstances in which individuals, 9 physicians and others, but especially physicians, 10 who -- and if I don't say this right, please tell 11 me, who in fact are the primary individuals who 12 treat particular diseases when they develop these 13 devices or interventions or therapies themselves 14 and they may be in fact, especially in the early 15 stages of research, in the very best position to 16 test those devices and to test those product so 17 that the highest degree of safety for patients is 18 assured. And that was strictly thought in the 19 early stages of research and there were thoughts 20 that there should be some exceptions, actually to 21 allow such research to proceed, but obviously with 22 conflict management safeguards. And we can talk 97 1 about what those might be. 2 In terms of the conflict of interest 3 process, we thought that IRBs clearly were already 4 over burdened with what they already have to do 5 simply in terms of the analysis of protection of 6 human subjects research and particular with the 7 inundation of IRBs by adverse events reports that 8 have phenomenon that has occurred especially in the 9 last couple of years. 10 We endorse the idea of the creation of an 11 adjunct conflict of interest financial disclosure 12 process with a conflict of interest committee 13 reporting to the IRB existing to receive and 14 analyze financial disclosure and then identify 15 those discloses financial interests that would rise 16 to the level of relevant, troubling, complicating 17 financial interests or a possible conflict of 18 interest, or even actual conflicts of interest. 19 We thought that the COI analyses should 20 precede the IRB review and should in fact be 21 required, that the participation of the researcher 22 and the institution in that conflict of interest 98 1 analysis process should be required as a precedent, 2 as a condition precedent to the submission of the 3 research application to the IRB so that when the 4 IRB receives the research application it has 5 digested information about these issues; 6 information that has been digested with firm 7 recommendations by the conflict of interest entity 8 or committee. 9 We thought that this should be integrated 10 at appropriate with existing conflict of interest 11 mechanisms and the financial disclose the process 12 that are ready should exist as a general compliance 13 mechanism in most institutions that are connected 14 with research and that exists as a background issue 15 -- as a background compliance issue not for 16 research particularly, but for all of the other 17 compliance reasons for conflict of interest process 18 in all of our hospitals, et cetera. 19 Now, unfortunately, I'm not sure that you 20 can see this, but I am going to try and walk you 21 through this what this handy pointer. 22 This was one iteration and if it looks 99 1 like a mess, I apologize for that, but it was the 2 best that a poor lawyer could do in regard to an 3 organization chart. This is the basic idea and 4 this is only one possible iteration of what a 5 conflict of interest process might look like. 6 Okay. 7 Basically, you have a PI, you have the 8 institution, and you have the IRB members reporting 9 their disclosure forms to a COI committee or a 10 designated official of the institution, or the 11 independent IRB or of the CRO who is responsible 12 for receiving this information and analyzing it. 13 Please note that IRB members if there is a 14 conflict then although they should obviously 15 participate in the conflict of interest disclosure 16 process they are generally expected to recuse 17 themselves from the process with the idea being 18 that IRB members themselves should be like Caesar's 19 wife, above suspicion. Okay. 20 Now, once financial interests are 21 disclosed their basically or two and if one adopts 22 the idea or embraces the idea that we had that 100 1 there should be some thresholds for financial 2 interests, that would once disclosed would rise to 3 be level of troubling, complicating, or a possible 4 conflict, then one would adopt a two-part analysis. 5 One is that those for financial interest that fall 6 under the threshold or in fact that just simply 7 don't exist at all because they don t -- they are 8 not in fact a relevant financial relationship, as 9 opposed to those that come in that are disclosed 10 that are relevant to the research and that are over 11 the threshold. 12 Let's follow the simple case first which 13 is, for those that under the threshold or financial 14 interests that are disclosed that really aren't a 15 conflict, then one would go to -- the COI would in 16 fact consider the -- what does that even say? I 17 can t even read it from up here? Can you see what 18 it says Judy? 19 Exactly the COI committee -- thank you -- 20 would make recommendations and would consider the 21 issues and obviously would make the recommendations 22 but it would be under the threshold -- unless there 101 1 were compelling circumstances in which a financial 2 interest that fell even under the threshold would 3 rise to the level of being a possible or troubling 4 financial relationship. 5 This will be reported to the IRB which 6 either would approve the research in its normal 7 course of business or disapprove the research; and 8 if it approved the research, then there would be no 9 disclosure because there would be no troubling 10 financial relationship that had been disclosed. 11 If in fact the financial relationship 12 disclosed were over the threshold amount or even 13 under the threshold but were identified as being 14 particularly complicating or troubling, then the 15 COI process or committee would consider this, it 16 would make its recommendations. 17 If it thought that something disclosed 18 over the threshold was in fact not a conflict, and 19 one can imagine some situations in which that might 20 be the case, then it would go over to this process. 21 If there were a conflict that were identified, then 22 it could discuss that conflict or that troubling 102 1 financial relationship and can make its 2 recommendations about management or control of the 3 conflict to the IRB. 4 It may decide, however, that a financial 5 relationship is so troubling that the conflict in 6 fact should really mean that is the conflict is not 7 divested or pruned away by the research or 8 institution that the research actually should be 9 aborted; that the research should not proceed. 10 Okay. 11 If, in fact, however, there were conflict 12 management strategies that were identified that 13 were regarded as appropriate, then the 14 recommendation would flow to the IRB which would 15 either consider the issue and either approve the 16 research or disapprove research and then, if it 17 approved the research, it could order a couple of 18 different things. It could order various conflict 19 management strategies, and those were outlined as 20 examples in the existing PHS regulations, for 21 example, to have outside parties be the external 22 data monitors, have outside parties actually 103 1 observe the informed consent process, make the 2 researcher place his or her investments in the 3 blind trusts. There are many different things they 4 could be done to manage a conflict. 5 And then there also would be in the IRB's 6 consideration of the informed consent process and 7 the informed consent form, there would be a 8 generic, what we would call a generic disclosure 9 made to patients. I will get back to that. 10 But the generic disclosure would not, in 11 fact, contain under this scenario, the actual 12 amount of the investment, the identity of the stock 13 interest, the identity of the patent, but would be 14 a generic disclosure that would say to patients we 15 have a conflict of interest process, the conflict 16 of interest process has worked in this process, 17 there have been complicating financial 18 relationships identified. There have been steps 19 taken and recommendations made that it must be 20 followed by the researcher and the institution to 21 manage and control those conflicts, and if you want 22 more information, please go to be research 104 1 administrator or the physician who is in charge of 2 the research and they are required to give you 3 additional specific information about these issues. 4 And we'll get in a minute to why we 5 adopted the issue of generic disclosures as opposed 6 to specific and complete detailed disclosure in 7 this case. 8 These disclosures and these financial 9 relationships would then go to the research subject 10 or the patient. The patient, if he or she chose to 11 ask additional questions, then those questions must 12 be answered, under our recommendation, truthfully 13 and completely by the institution and/or the 14 research administrator and/or the clinical 15 researcher. 16 And the disclosure could consist of a 17 disclosure of the actual financial relationship, 18 depending on what the patient asked about, a 19 disclosure of the particular financial relationship 20 and all of its particulars, a discussion of what in 21 fact, the general COI guidelines and practices are 22 of the institution and/or the researcher and the 105 1 IRB, and might consist of a detailed discussion of 2 the conflict management strategies that were 3 adopted as apart of the research approval process, 4 which takes us up there. Okay. 5 So this is only one scenario, not 6 exclusive, but one scenario that we tried to 7 identify, and, I think, I hope it captures the 8 general thought of the working group. 9 Institutional conflict of interest. We 10 supported the draft interim guidance response to 11 this. We thought that it was essential especially 12 given the troubling financial relationships that 13 have been reported, albeit in anecdotal cases, that 14 there be attention finally to the issue of 15 institutional investments or financial 16 relationships in the process of research, and not 17 just to private sponsors, but also to public 18 agencies, or not-for-profit agencies that fund 19 research. 20 We noted the increased incidence of these 21 institutional investments in, or financial 22 relationships in research, and particularly given 106 1 that, for example, you know, several of the 2 hospitals, particularly in the Boston area had even 3 entered into plenary agreements with pharmaceutical 4 companies that pharmaceutical companies have 5 intimate relationships with the clinical research 6 in these medical centers in Boston. The last one 7 reported was the Beth Israel Deacons in Boston 8 which has recently entered into such an arrangement 9 with a particular pharmaceutical company. I point 10 that out by way of example, not because I know or 11 would say anything about on Deacons . 12 We noted the attenuated influence -- or 13 the pharmaceutical company -- on IRB members who 14 are affiliated with the research, this could take 15 the form of people who sit on IRB who themselves 16 may have complicating or complicated relationships 17 and duties because they may in fact be responsible 18 for the financial integrity of the institution 19 itself. So if they sit on the IRB, then there are 20 some issues perhaps with the way in which they make 21 decisions when research compensation is flowing to 22 the institution itself. 107 1 We noted the NBAC recommendation with 2 regard to the 50/50 split recommendation between 3 the affiliated and unaffiliated members of the IRB. 4 We had doubt about the efficacy of that and the 5 practicality of doing that given the difficulty and 6 even getting anybody to be an unaffiliated member 7 to sit through IRB meeting these days. But we 8 understood and appreciated the goals and we 9 supported the idea of having additional 10 unaffiliated members if that's possible. 11 Finally disclosing conflict of interest to 12 research subjects. We noted that there is little 13 data on best practices. That what was needed here 14 was real information for patients, not information 15 that is simply thrown at patients or research 16 subjects willy-nilly with lots of facts and details 17 but in and undigested form. Because we did not 18 think that that contributed to a meaningful 19 informed consent process for patients. 20 And we certainly did not think -- and I 21 bring this up because I think there were many 22 people at the August 2000 conference who did think 108 1 that we did not think that simply disclosing 2 financial relationships to patients substituted for 3 an effective conflict management process by the 4 institution and by the researcher himself or 5 herself. 6 We thought that those duties existed 7 independent of, and had to be really respected and 8 enforced by institutions independent of simple 9 disclosure to patients, as tough that's the only 10 answer to this problem. 11 The goal here was that if a real conflict 12 exists, their information should be reasonably 13 available to be subject or potential subjects. We 14 thought that patients should be given things, 15 information that is understandable to them. 16 It was generally thought that generic 17 disclosure, once there have been a troubling 18 financial relationship identified, would give the 19 patient enough information to let them know that 20 there were financial relationships identified that 21 were relevant, that there was a conflict management 22 process in place, that there were processes and 109 1 systems within the institution or the research to 2 manage those conflicts, and then to allow the 3 subject as the subject is interested to pursue and 4 to get full disclosure of whatever relevant 5 information on these issues he or she wants. 6 Here is one example of a generic 7 disclosure to patients that is floated in the -- 8 and I have no idea what Mercy Hospital is, it just 9 sounded like a good name in line with my 10 theological approach. I guess I was trained too 11 well as a child. So here is Mercy Hospital 12 disclosing to a patient or a potential research 13 subject that there was a financial relationship 14 disclosed, that it was a relevant or troubling 15 financial relationship, that there is a conflict 16 management process in place, and if the subject 17 wants additional information then the research 18 subject may ask about it and will receive it. 19 And obviously this means that there is a 20 duty on the part of the researcher and the 21 institution to the answer these questions 22 truthfully and fully. 110 1 Education and compliance. We obviously 2 said that once the policies are adopted that 3 compliance mechanisms that are in place either 4 research compliance mechanisms, or general 5 compliance mechanisms at institutions, really need 6 or medical staffs or whoever or whatever body has a 7 compliance process in place needs to audit whatever 8 process that is adopted by the institution to make 9 sure that it's respected enforced. And obviously 10 compliance cannot occur without education of key 11 staff, and that's in line with many of the 12 initiatives that Dr. Koski talked about earlier, to 13 require education of staff in a number of areas 14 regarding research compliance. 15 So in conclusion, the working group 16 generally supported the concept of an interim 17 guidance document carefully crafted and subject to 18 periodic review, evaluation, and revision. We did 19 not think that the Department should hold off on 20 this issue, but we do think there is reason to 21 proceed in a careful and step-wise fashion with 22 evaluation at appropriate points and with 111 1 integration of private association guidelines as 2 those guidelines issued. 3 We also thought that one of the really 4 animating reasons for proceeding with the draft 5 interim guidance is for the pressing need to 6 bolster public confidence in the integrity of the 7 research enterprise itself. 8 And, with that, I will conclude and I 9 apologize for running a little over on time. 10 [Pause.] 11 CHAIRPERSON MARSHALL: We are doing well 12 on time because of Dr. Koski is not going to need 13 45 minutes for his declaration of Helsinki update, 14 so I just wanted to let you all know that and 15 reassure you that we will have time for discussion. 16 Mark, thank you very much. That was a 17 stellar report. You and your committee just did a 18 fabulous job. 19 What I would like to do in terms of 20 sequence is to give Adil -- who is a member of the 21 committee, and has its own comment that he would 22 like to make -- time to do that then I would like 112 1 for us to take a 15-minute break and come back for 2 discussion. 3 So, Adil. 4 DR. SHAMOO: Thank you, Mary Faith. 5 I have a written statement I want to 6 distribute copies of it. I have enough for 7 everybody. 8 I concur, as you know, during the 9 discussion with a great deal of what -- and I think 10 Mark has done a great job. However, I do have a 11 different spin on it. 12 I would like to express my own views 13 regarding the discussions on conflict of interest 14 policy. The draft NHRPAC policy on conflict of 15 interest rests solely on IRBs and their 16 institutions. The proposed policy is well 17 intentioned but not workable within the current 18 system. The structure of IRBs and its relationship 19 to their institution makes these policies 20 ineffective. 21 In order to restore public trust in our 22 research institutions, it is vital that an 113 1 effective and viable conflict of interest policy be 2 put in place. The campaign waged by universities, 3 their lobbying organizations, their apologists, and 4 supporters is shameless, self-serving, and 5 arrogant. It is shameless because they do not want 6 anyone to produce an effective and viable policy on 7 conflict of interest. It is arrogant because they 8 demand that a federal agency withdraw the weak and 9 mild draft proposed guidance. 10 These are the same research institutions 11 and their supporters who claim that there is only 12 anecdotal evidence with regard to the issue of 13 human subjects that requires new reforms. To my 14 knowledge, these institutions have never called for 15 a study to find out the data on violations of 16 federal rules. 17 These are the same research institutions 18 in ten years of research with nearly seventy 19 million Americans as human subjects reported only 20 eight deaths to the former OPRR. When more surely 21 occurred. This is in violation of the federal 22 reporting requirements and can in no way be 114 1 construed as anecdotal evidence. No one with any 2 common sense believes that such a number is 3 correct. On the contrary, the estimates would 4 indicate that hundreds if not thousands of 5 reportable deaths go unreported. 6 These are the same research institutions 7 in the same ten years reported a mere 300-400 8 adverse events. And these are not, again, 9 anecdotal evidence. 10 On the contrary, the same type of 11 statistical estimates would indicate that tens of 12 thousands of adverse events go unreported. These 13 are the same research institutions that were 14 investigated on site 41 times by OPRR resulting in: 15 51 percent suspensions/terminations; 34 percent 16 violations in informed consent; and 27 percent 17 requiring re-review. 18 These data are from official records of 19 the federal government. These startling data were 20 obtained by OPRR without ever looking at the 21 medical records of human subjects. Could we 22 imagine what the results would have been if medical 115 1 records were audited? This is in addition to 2 countless reports in the media regarding 3 allegations of flagrant violations of ethical 4 standards including issues of conflict of interest. 5 These same institutions also keep most of 6 their IRB membership and their minutes closed from 7 public scrutiny. These research institutions and 8 their supporters or their lobbying organizations 9 want the public to trust them. They tell us that: 10 they will not engage in research where their 11 researchers and universities will make millions of 12 dollars of profit and their stocks or equity value 13 goes up or down depending on positive outcome from 14 clinical trials conducted in their institutions. 15 Human subjects and the public are supposed 16 to put their trust in these same institutions 17 without any checks and balances. 18 More specifically, my recommendations are: 19 1. The conflict of interest policy should 20 be made within the context of the overall system 21 and oversight of human research protections. 22 As I have stated at the first meeting, we 116 1 need to start addressing the overall problem rather 2 than piecemeal enacting a policy on conflict of 3 interest policy without reworking the overall 4 system avoids the issue and may result in 5 unintended loopholes. This approach was 6 recommended by NBAC. 7 2. IRBs are the gatekeepers for the 8 protection of all human subjects. Unfortunately, 9 IRBs as currently constituted are structurally and 10 functionally flawed. They are riddled with 11 conflict of interest simply because they are 12 employees of the same research institutions. These 13 are the same IRBs that approve the projects leading 14 to the negative events I cited earlier. 15 Moreover, research institutions can change 16 the composition of IRBs at any moment. They can 17 fire and hire the administrator at will. And they 18 can eliminate an inconvenient IRB. So also has 19 NBAC recommended that 50 percent of IRB membership 20 should come from the community. I think we should 21 follow the NBAC s recommendation. 22 3. Conflict of interest should be 117 1 disclosed to human subjects. Human subjects carry 2 the ultimate burden of risk for drug testing. It 3 is not sufficient for the so-called institutional 4 conflict of interest committee to just simply state 5 that they looked at and it has been managed. And 6 we are told that if the patient asks then the 7 investigator should inform the subject of the 8 nature of the conflict orally. 9 This is unacceptable because it lacks 10 specificity and accountability. All significant 11 conflicts of interest whether for the investigator 12 or the institution should be disclosed in writing 13 to the patient and/or patient s ombudsman. 14 Concerns for the privacy of the investigator or the 15 institution are secondary to the evaluation of 16 safety of the study by the subject. 17 4. Severe sanctions should be levied for 18 infractions on requirement for conflict of 19 interests disclosures such as: cause for firing, 20 rescinding of IRB approval for the implicated 21 research and other lesser sanctions. 22 5. Once the conflict of interest 118 1 committee has determined that a study should not go 2 forward, the IRB should never be able to overrule 3 the decision of the COI committee. 4 Finally, at the last meeting of this 5 committee, I was challenged on my statement that 6 some physicians are paid up to $20,000 per patient 7 as a bonus. I was wrong on the upper limit. 8 During the deliberation of the conflict of interest 9 workgroup a colleague with first-hand knowledge in 10 this area informed us that the upper limit is even 11 higher. A I quote: 12 "Investigators have received stipends in 13 the range of $5-30,0O0 per subject for 14 participating in clinical research trials. 15 These stipends may be offered on top of 16 reimbursement for the hospital charges for 17 the procedure, blood chemistries, nursing 18 support and technical assistance charges. 19 Thank you, Madam Chairman. 20 CHAIRPERSON MARSHALL: Thank you, Adil. 21 I would like for us to break now for 15 22 minutes. And we will restart promptly. 119 1 Let me ask Greg, I would perhaps like to 2 have our comment period on the financial 3 relationships paper and then make sure we give you 4 adequate time at the end for your Declaration of 5 Helsinki update. 6 DR. KOSKI: Yes, Madam Chair, I would say 7 just looking at the schedule, my report, the update 8 on the Declaration of Helsinki, probably would not 9 take more than 15 minute and I would encourage that 10 the time that we have available before lunch be 11 directed primarily toward discussion of the 12 financial relationships issues. 13 Thank you. 14 CHAIRPERSON MARSHALL: Thank you. So we 15 plan then on 12 to 12:15 for the Declaration of 16 Helsinki update. And let me just ask those of you 17 -- everyone in the room, committee members, ex 18 officio members, public members to think about your 19 comments that he would like to make now. We want 20 to be fair we want everyone to have a chance to 21 speak who would like to speak. So I would like for 22 them to be concise and on point. And I will hold 120 1 you to that. 2 We will see you back here promptly at 11, 3 thank you. 4 [At 10:50 a.m., a recess was taken.] 5 CHAIRPERSON MARSHALL: A little less than 6 an hour before Dr. Koski has the floor for his 7 update on the Declaration of Helsinki. What I 8 would like to do first is give the members of the 9 committee an opportunity to ask Mark and other 10 members of the working group about questions of 11 fact or interpretation relative to the presentation 12 and then move into the discussion. 13 I also do want to make one observation and 14 that is about Adil s statement. That this is not a 15 NHRPAC policy, NHRPAC does not set policy, NHRPAC 16 gives advice to those who by our charge ask for it. 17 So I just want to clarify that. And I am sure you 18 understand that and didn't mean that, Adil, I just 19 wanted to make that observation. 20 We will give the floor first to Mark as 21 the workgroup leader and then please just raise 22 your hands and I will take your name. 121 1 MR. BARNES: Just a brief comment on 2 Adil s statement which we appreciated very much and 3 it certainly is consistent with many of the 4 positions that Adil articulated very eloquently 5 during our discussions of the workgroup in the 6 workgroup deliberations. But I do want to point 7 out really the following: that there were other 8 people on the committee who felt strongly in other 9 directions from Adil and the committee -- I should 10 say working group process really tried to reach a 11 basic consensus about these issues, to try to in a 12 concerted way, in a way that kind of respected all 13 points of view to move the ball forward in 14 significant ways. 15 And, in fact, I mean, if one looks at what 16 the proposed commentary of NHRPAC would be under 17 the working group proposal as opposed to the world 18 as it is now there really are some very significant 19 departures that we re recommending. We're 20 recommending that all research be covered, you 21 know, either through this draft interim guidance 22 although it could only be in the form of suggested 122 1 practices instead of regulation; that's a different 2 story. 3 We're recommending that institutional 4 conflicts of interest be identified and disclosed. 5 We're recommending disclosure that it, we're 6 recommending generic disclosure to patients of 7 troubling financial interest, and that if patients 8 have questions they can get all the information. 9 So these are really significant although obviously, 10 you know, Adil's points of view are very strongly 11 felt. In fact, I do want to just for the committee 12 to know and the public to know that his point of 13 view really did push this process forward and many 14 of his points or the general thrust of his points 15 and of other people's points are included in the 16 document as it is. 17 CHAIRPERSON MARSHALL: Thank you, Mark. I 18 have Abbey, Alan, Bob, Denise, Greg and Susan. 19 MS. MEYERS: First of all, it's just a 20 wonderful job you've done, and as I was reading it 21 I was saying, I know that you had to make a lot of 22 compromises and you did a wonderful job in finding 123 1 those compromises. So I have, I think, just three 2 comments. 3 First, it's wonderful that you put in the 4 paragraph on page 6 about compelling and necessary 5 exceptions. Because for scientists who are 6 studying rare diseases, for example, rare genetic 7 diseases that might affect 300 or 600 people in the 8 whole country, once they publish, they become known 9 as the United States expert on the disease. And so 10 if they're going to try to develop something and 11 always in the beginning at least, it's without a 12 commercial sponsor, they get the IND and then every 13 child in the country is treated under their IND. 14 So there could be conflict of interest 15 there that can t be eliminated. So it is important 16 that in those cases that they be managed. But it 17 seemed to me in the last sentence you talk about 18 consulting with cardiac surgeons, and orthopaedic 19 surgery groups, but there are also others like the 20 inborn areas of metabolism those types of 21 professional groups. 22 The next thing is page 10 on the paragraph 124 1 that you've drafted up about Mercy Hospital. You 2 know in a normal informed consent document it says 3 that at any point you can decide not to continue in 4 the study. And if you decide to drop out it will 5 not be held against you and your future care at 6 this hospital won't be put in jeopardy. That needs 7 to be added to this sentence. Because, first of 8 all, if there is a sentence about conflict of 9 interest and a patient wants to ask, they're going 10 to be number one embarrassed, because it is their 11 doctor and, of course, they trust him. 12 But number two, they're going to wonder if 13 they ask if it'll be held against them. So they 14 have to be assured that there is not going to be 15 any punishment for asking. 16 And the third thing is that I want to 17 reiterate my unwaiving support for 50 percent 18 membership of IRBs coming from the community. I 19 don't think that there is an institution in this 20 country who could possibly say they can't get 21 volunteers from the community. 22 I run a charity and I have to get people 125 1 come up to be on committees, to decide, for 2 example, which patient deserves to get free drugs 3 because they have no insurance and they can't 4 afford it. And I have a waiting list of people 5 trying to get on those committee not only from the 6 retired community, but from young mothers, who if I 7 do something to help them with their daycare, 8 they'd love to come up there and just do it. And 9 they love it and they wouldn't miss a meeting. 10 So I think that its just an excuse saying 11 it's impossible, we can't do it. If you find a way 12 to do it you can do it and it should be done 13 because IRB should not be composed of employees of 14 the institution. 15 CHAIRPERSON MARSHALL: Thank you, Abbey. 16 Greg has a quick comment on point and then I have 17 Alan. 18 DR. KOSKI: Thank you. 19 I think it is important as we enter into 20 the discussion to mention that as part of our 21 overall remodeling of the system that I described 22 earlier which is very much underway already, Adil, 126 1 we emphasized the need to, what I call, "get the I 2 out of the IRB." Okay. Which doesn't mean to take 3 the IRBs out of institutions necessarily, but 4 rather to defuse the institutional interest in the 5 outcome of the human research review and protection 6 process which can be accomplished in many ways. 7 And in many instances we are already 8 beginning to see individual institutions join 9 together with broader community groups or through 10 private foundations a host of different 11 organizational structures that actually move us 12 from the current model in which it's often very 13 difficult, as has been pointed out, to separate the 14 institutional interest from the IRB process. 15 So I think as we look forward toward the 16 future let's think a little beyond the current 17 structure. Because we need to think out of the box 18 in order to accommodate the changes that are 19 coming, and, in fact, in many places they are 20 already instituted. 21 CHAIRPERSON MARSHALL: Thank you, Greg. I 22 second that. 127 1 I think that the National Breast Cancer 2 Coalition and their work and training their members 3 to serve on IRBs is a wonderful model and that we 4 should be moving in that direction. 5 I have been remiss in not making some 6 procedural and organizational statements in terms 7 of how we might proceed as a committee and we are 8 setting some precedence for ourselves here. I 9 don't want us to feel rushed or constrained by 10 other people's time, agenda and need. I want the 11 committee to have its time to do good work and to 12 put out a good product. So, I would propose that 13 in terms of moving forward with the working group's 14 draft report to us, that we have a conversation 15 today. Obviously we we will not finish that 16 conversation today. Mark's presentation will be 17 put on the web. The draft document will be put on 18 the web. He will take comments from the public and 19 others about it. 20 We will continue the conversation among 21 ourselves as a committee and look forward to our 22 July meeting where we might as a committee put 128 1 forward a document that we have achieved consensus 2 on. So, I just wanted you to frame your remarks 3 knowing that there will be ample opportunity in the 4 future to weigh in if you don t get a chance today. 5 Alan. 6 DR. FLEISCHMAN: Mark, I had two questions 7 which would help me understand some of the, I 8 think, major thrusts of this report. One is, and 9 this is kind of half a question, half a comment 10 about the process of the evaluation of the 11 financial relationships and the potential conflicts 12 of interest. 13 It seems to me that that process should be 14 independent of any research initiated and that it 15 ought to be a general process in the institution in 16 which all physicians and research scientists are 17 asked by such financial relationships having 18 nothing to do with their independent assessments as 19 to whether there are potential or real conflicts. 20 At which point then, when an investigator comes 21 forward with a proposal, he would not need or she 22 will not need at that moment in time to add in more 129 1 information about their financial relationships to 2 industry, because that would already be on record. 3 And the conflict of interest process would be 4 evaluating what is on record in the institution; 5 making a recommendation about either management or 6 lack of any kind of conflict. 7 For me that s an important safeguard in 8 this process which allows for the conflict of 9 interest officer or committee to make judgments far 10 more broadly than relative to just this research 11 project. And I wonder whether that's imbedded in 12 here, intended in here or not intended. That's one 13 question. Should I give the second one or go with 14 that? 15 CHAIRPERSON MARSHALL: Yes. And please 16 be mindful that I have a list of about five other 17 people who need to speak as well. 18 DR. FLEISCHMAN: So I should give my 19 second one? 20 CHAIRPERSON MARSHALL: Please do. 21 DR. FLEISCHMAN: Okay. I think Mercy 22 Hospital is well intended in its paragraph, but I'm 130 1 not convinced of this approach and I'd like you to 2 share with us more of the thinking, of the working 3 group, as to why we ought not disclose something 4 about this conflict which has been determined 5 rather than just kind of a flag that says, we did 6 it, we fixed it, if you're interested call us." 7 DR. BARNES: Let me try to answer these 8 two questions and if other members of the working 9 group have different opinions or views then, please 10 voice them. 11 Most institutions that receive -- whether 12 they are private institutions, private corporations 13 not-for-profits, or hospitals, academic 14 institutions have a conflict of interest process 15 which usually requires, which is an annual form 16 that is filled out by all employee and medical 17 staff members. The problem is that in that form 18 there are certain generic or particular disclosures 19 that have to be made. But very few hospitals, very 20 few institutions, in my experience, you know, in 21 counseling hospitals on compliance processes and 22 medical schools actually have a requirement that 131 1 for example every single financial interest be 2 disclosed. 3 They do not require that all investment 4 interest be disclosed. They are not his nearly as 5 vigorous as, for example, the federal employment 6 guidelines in requiring that we all had to fill out 7 for what passes for us as federal employment as -- 8 [Laughter.] 9 DR. BARNES: -- which I think falls more on 10 the issue on the realm of good works, but I guess 11 that is employment too. 12 It s not nearly that detailed and so, in 13 fact, I agree with you and I think the working 14 group contemplated that the conflict of interest 15 process for research would operate in relation to 16 and informed by the general conflict of interest 17 process within institutions. But that conflict of 18 interest process in most institutions does not 19 actually require, for example, that every financial 20 relationship be disclosed and therefore what we 21 would be searching for and seeking that the 22 researchers and the institutions disclose and the 132 1 institutions and the IRB members disclose in the 2 conflict of interest disclosure process would be 3 those financial relationships that in particular 4 could be reasonably expected to be affected by the 5 research under the PHS as thresholds. 6 So certainly one could develop a COI 7 process for research and one ought to with the 8 background of the general COI process and informed 9 by all of the disclosures that are made in the 10 general COI process, but I think that's not -- 11 that's still not going to be enough under most 12 institutional compliance programs to vindicate the 13 goal here. So that is the answer perhaps to your 14 first question. Okay. Fair? 15 DR. FLEISCHMAN: I don't agree with the 16 approach, but I think that's a fair answer. 17 [Laughter.] 18 DR. BARNES: Okay. On the second issue, I 19 call your attention to the paragraph in terms of 20 the thinking, in my attempt to sort of encapsulate 21 the thinking, I call your attention to the 22 penultimate paragraph of the section that is 133 1 marked, "disclosing relevant financial 2 relationships and conflict of interest to research 3 subjects." And this is in regard to the so-called 4 "Mercy Hospital disclosure." 5 CHAIRPERSON MARSHALL: Can you tell us 6 what page you're on, Mark? 7 DR. BARNES: Actually it is page 11 at the 8 bottom, okay. 9 Basically there was one minority view 10 which was certainly articulated well by Adil which 11 is there should be complete transparency of all the 12 information. On the other hand there were other -- 13 DR. SHAMOO: All significant -- 14 DR. BARNES: All significant, yes. That s 15 right. All relationships that rose to the level of 16 troubling or significant. 17 Number one, if a financial interest is 18 identified and is relevant and is over the 19 threshold and is relevant and is troubling or a 20 possible conflict, then the goal of the conflicts 21 management process must be to reduce the level of 22 risk or influence of the conflict to a level that 134 1 is underneath that is below the level of 2 significant risk or material risk to the patient. 3 So that is the goal of the conflict 4 management process. So there is already that 5 process in place and that process cannot be, we 6 thought could not be substituted for by simple 7 disclosure to patients. And what that means is, 8 that if that process is operating whereby the 9 conflict once identified is reduced by the 10 management strategy to something that is less than 11 a significant risk to the research subject, then 12 one must use a comparative analysis in 13 understanding that if something -- that if any 14 risk, for example, an adverse effect is below the 15 level of significant that too is not disclosed to 16 research subjects in the standard informed consent 17 process. 18 Only significant risks material risks are 19 disclosed. So, in fact, we're using a comparative 20 analysis about risks and what risks are disclosed 21 that already the conflict of interest process has 22 reduced that below the level at which the regular 135 1 sets of risk are disclosed. But we're not 2 satisfying ourselves with that because we're going 3 beyond that in this situation, largely because the 4 quantification of risk in this area is a new 5 process. So we're saying that where the patient 6 has questions, the research subject or potential 7 research subject has questions, then they deserve 8 to be able to -- to know that they can ask those 9 questions, to ask those questions, and to get full 10 disclosure once they asked those questions. 11 Number two. We fear, and at least I speak 12 for myself, I don't know what everybody else fears, 13 but I fear that if we have simple disclosure that 14 that will be to patients of anything that is in the 15 level of significance. That will be a default 16 position that will rapidly kick in by IRBs and by 17 COI committees or entities so that they will simply 18 default and say, it's being disclosed so why 19 operationally should we engage in this tight 20 attention to the conflict of interest management 21 process. 22 Number three, informed consent forms float 136 1 all over the hospital. They are readily available 2 to almost anybody. They're looked at by the IRB 3 they're approved by everybody. Is ita fair to 4 researchers, is it the kind of incentive we want to 5 set up so that their individual financial interests 6 -- forget about the institution for a second, 7 because I have less concern about the institution's 8 financial disclosures. Do we want to impose the 9 burden on them that their personal financial 10 information is actually printed and distributed 11 willy-nilly around a medical center? I don't think 12 so. 13 And so those were the things that would 14 deter people from engaging in research. It's not 15 going to mean that all research is going to stop, 16 it's going to mean in close cases that there could 17 be some self deferrals from engaging in the 18 research process because of financial disclosure. 19 So those were the, I think, the animating reasons 20 for our reasoning on that point. I don't know if 21 you all have different opinions. 22 CHAIRPERSON MARSHALL: Thank you, Mark. 137 1 I have Bob, Denyse, Greg, Susan, Felice, 2 Jonathan and Margaret. Bob. 3 DR. R. LEVINE: I would like to first say 4 something about the proposition of having half of 5 the members of the institutional review board be 6 unaffiliated with the institution. As I followed 7 the debate on this, I find it curious that the most 8 forceful advocates for that are the most forceful 9 opponents for having all of the members not 10 affiliated. There have been proposals about 11 turning everything over to private corporations 12 like Western IRB or Philadelphia Area Clinical 13 Trials. And the concern has been that they are too 14 far removed from the daily realities of the 15 institution. 16 I also want to say that when Greg says 17 that we've got to get the I out of the IRB, I 18 think that has to be considered very carefully. 19 Right now I think the discussion is 20 dominated by an I called interest and interest in 21 the sense of financial. It is very important to 22 keep in mind that these institutions have very 138 1 powerful interest in not being exposed publicly as 2 being evil or exploitative. and they are making 3 enormous investments in that. I think it's very 4 important to have members of the institution who 5 experience that institutional commitment to not be 6 added to the hit list along with Rush and Duke and 7 so on. That let's try not to dilute that too much. 8 A couple of other brief comments. First, 9 I m concerned, I think it's okay to express an 10 awareness of the fact that the desire for fame, 11 prestige, and academic advancement maybe for the 12 typical academic a much more powerful incentive 13 than any amount of money that any corporation might 14 pay. 15 However, I don't think we can go much 16 further than to acknowledge that. It would get a 17 little silly if we started putting on consent forms 18 that if this all goes well here I might get tenure, 19 you know. 20 A third comment is on the proposal to have 21 the conflict of interest determination made before 22 the IRB reviews the protocol. You did, Mark, call 139 1 attention to all the other things that are done by 2 committees other then the IRB, ranging from bio- 3 safety, radiation, DSMP s and so on. I think it is 4 important not to create an inflexible requirement 5 about what comes first. In general, many of these 6 things occur in parallel. And any requirement that 7 something must be accomplished before the next 8 step, imposes some delays in the project that would 9 probably be unwelcome and probably in many cases 10 would act to the detriment of the research 11 subjects. 12 And finally, Adil Shamoo was asked at the 13 last meeting to provide documentation for the upper 14 level he estimated for payments to doctors for 15 individual research subjects. He gave us 16 documents. He said it was in the Medical College 17 of Georgia case, a statement that was corrected by 18 Sidney Wolfe later in the day. 19 Now, he s coming in with different 20 documentation. We are told that a colleague with 21 first-hand knowledge in this area informed us, 22 blah, blah, blah. Some of us don t consider that 140 1 documentation. I can tell that a colleague who 2 knows all about such matters has told me that Greg 3 is a bad guy. You probably want something more 4 substantial than that. Thank you. 5 CHAIRPERSON MARSHALL: Denyse. 6 DR. THORNLEY-BROWN: I just have two 7 questions. First of all, did the working committee 8 make any recommendations about the composition of 9 the conflict of interest committee? So, for 10 example, by analogy to the IRB having members of 11 the community in the committee would this be 12 something that they would address? And the second 13 thing is, any recommendations or comments regarding 14 monitoring conflicts of interest that develop 15 during the course of research. So, for example, if 16 a study is having problems with recruitment, the 17 sponsor may want to put in some incentives to try 18 to increase recruitment. What would be done to 19 evaluate that? 20 DR. BARNES: Brief responses to that. 21 First of all, I think that we actually did not or 22 perhaps we should have gotten more deeply into the 141 1 issue of the composition of the COI committee or 2 the identity of the institutional official. I 3 think it was our general feeling that those who sit 4 on the conflict of interest committee should be 5 removed enough from the situation so that there is 6 a fiduciary duty that can be meaningfully exercised 7 so that they are not, for example, they don't have 8 conflicting interests themselves in judging 9 conflict of interest, but, in fact, I think that we 10 did not spend really any significant amount of time 11 in discussing those issues. Do you all agree with 12 that? 13 DR. CHODOSH: I think that what we were 14 talking about is that it is not clear that there is 15 one ideal way to approach this, and that we were 16 looking at the possibilities of having people 17 develop workable situations in which indeed the 18 conflict of interest committee can't have 19 conflicts. Now, how that is going to work out in 20 institutions or independent situations is really 21 not clear at this point, and for us to specify that 22 at this point would have really been pushing the 142 1 situation and that's not what we intended. 2 What we intended was that there be a 3 mechanism developed within any one who s doing 4 research of this kind to do this job appropriately. 5 Now, appropriately has a lot of leeway to it but we 6 are talking about, you can't have a conflict of 7 interest committee that has a conflict of interest. 8 And if you think of it that way we have a better 9 chance of developing something worthwhile. 10 DR. BARNES: In answer to the second 11 question that you had, in fact I think that we can 12 -- it certainly is our intention and it is required 13 under the existing guidelines that do exist that 14 information be updated. That as new financial 15 interests emerge that would implicate the research 16 that those in fact that there is an affirmative 17 duty of the researcher and the institution to 18 disclose those to the conflict of interest in the 19 conflict of interest process which would then 20 proceed along the lines that we set forth. But we 21 can clarify that in the final draft. 22 CHAIRPERSON MARSHALL: Thank you. Susan. 143 1 DR. KORNETSKY: I promised to bring up the 2 practical and I think that's what I'm going to do. 3 First of all, I definitely want to support the 4 separation of the conflict of interest committee 5 from the IRB and I think that that's a large change 6 -- a big change from the first one. I think that 7 is very, very important to want to totally support 8 that. 9 Having said that just a couple of issues. 10 First of all, I think that one of my questions is 11 the top of your chart you had that the IRB member's 12 disclosures to conflict of interest committee and I 13 will ask the practical question of whether you are 14 thinking about that for every individual protocol, 15 every individual time, because I think that will 16 also add a blockage or a time commitment to that. 17 Bob took the words out of my mouth about 18 the idea of having this go before the committee. 19 In actuality some of the committees that you've 20 listed there, there is a parallel process. It is 21 important that all of that get accomplished before 22 any human subject is enrolled and it's probably up 144 1 to the institution to decide how that all can get 2 done. 3 I do want to support Adil's comment that 4 -- his last comment that once the conflict of 5 interest committee has determined that a study 6 should not go forward, the IRB should never be able 7 to overrule that. I think that that is mixing the 8 message of keeping the IRB sort of process 9 separate. 10 The other comment about membership from 11 the community in Abbey s comments, I do believe and 12 support that there should be more community 13 representation on the committee. I am definitely 14 for that. But I think it's also important to 15 remember that we don't want to water down the sort 16 of the expertise of the committee. And so although 17 there may be and perhaps I m unaware, a waiting 18 list or individuals who want to serve on the 19 committee you also want professionals and those are 20 much more difficult to find to serve on committees. 21 So I want to support community involvement 22 but I think your definition of "community" and sort 145 1 of taking the "I" out of institutional, there s a 2 practical problem there. 3 I do support a more general type of 4 statement for the informed consent, I think having 5 dealt with informed consents and subjects, I think 6 that it is very important that they have the 7 opportunity to ask questions and generally in 8 support. I think that is a compromise. 9 I'm also to recognize and to support the 10 institutions can go further than this. I think 11 this is, you know, again has to be a minimum 12 standard and I know there are institutions that may 13 and will want to go further than this. Thank you. 14 CHAIRPERSON MARSHALL: Thank you. Robert. 15 DR. RICH: I'd like to say that by and 16 large I congratulate the working group on a fine 17 product. As a signatory one of the letters that 18 you received from one of the associations that 19 dissented from the draft interim guidance, however, 20 I want to respond with the comment that I think 21 that I can endorse everything that's basically in 22 this letter with the exception of the last 146 1 paragraph on page 3 which suggests -- with maybe 2 the central paragraph suggesting going forward with 3 the issuance of formal guidance. 4 I think it's really important to 5 understand how seriously the professional 6 associations that have been engaged in this process 7 have taken it. And that the letters that you 8 received from such organizations as the AAU and 9 Koger and AAMC, and FASSUP, among others were also 10 the results of a deliberative process; and I can 11 assure you are the result of a lot of thinking 12 about whether or not a formal draft interim 13 guidance regardless of just how one frames it is 14 really appropriate at that time these organizations 15 are trying very hard to wrestle with most difficult 16 and important issues. 17 I think that if the draft interim guidance 18 had been issued from other than a government 19 regulatory agency that perhaps would not be the 20 same sensitivity to the word guidance as there is 21 when organizations that have been so frequently 22 found guidance translating to -- translating to 147 1 regulation literally in the twinkling an eye, and 2 with very little in the way of informed discussion. 3 I would say that OHRP is enjoying a 4 remarkably collegial relationship with these 5 organizations and I think that it's a very 6 productive relationship at the present time. It is 7 to be advantaged, I believe, by a process of 8 discourse and deliberation and not by a process 9 that jumps ahead of what is a very active engaged 10 process going on particularly by the AAMC and the 11 AAU for which I don't speak. I speak for FASSUP. 12 Having said that, a couple of other 13 specific comments -- 14 CHAIRPERSON MARSHALL: Can I interject 15 here? I do want to say that I am troubled by your 16 use of the word "the letters that you received." 17 Those other letters that we received -- 18 DR. RICH: I'm sorry I should clarify -- 19 CHAIRPERSON MARSHALL: And you sit on this 20 committee, yes, wearing a FASSUP hat. But you also 21 where a committee hat, and I want us to be mindful, 22 all of us, of our responsibilities as members of 148 1 this committee and of our responsibilities in 2 protecting the interest of human subjects. That is 3 our primary responsibility. So I am just throwing 4 that out there and then we do need to move alone 5 quickly. So each of the next people who speak 6 please be concise. 7 DR. RICH: I have no confusion about those 8 issues. I thank you for making the clarification. 9 But I truly am not confused about them, I can 10 assure you. 11 I would like to point out that I think 12 there are important problems that the issue of 13 thresholds raised and I am particularly glad that 14 the working group brought up the problem of 15 researcher compensation into something that Adil is 16 obviously very much concerned about. But I think 17 that even a few hundreds of dollars to a young 18 physician sometimes in direct compensation to a 19 researcher is very different from even tens of 20 thousands of dollars in research support to an 21 established investigator. 22 So dollars in an investigator's pocket, 149 1 and I would point out, as most of you know, that 2 the vast majority of clinical trials are done 3 outside of academic medical centers and are really 4 in a sense becoming a business or becoming a part 5 of the way in which practitioners actually support 6 themselves. And so the issue -- I think we cannot 7 turn away from the issue of researcher 8 compensation. 9 I'd like to also echo the comment that 10 Abbey made about the importance of exceptions with 11 regard to the involvement of investigators and 12 extend it from rare diseases to simply the 13 recognition that in many cases the inventor of new 14 technologies and the inventor of new devices is the 15 world's expert and at least at the very earliest 16 phases of translation into practice, it is 17 unworkable to prohibit that individual from 18 actually participating in it. Because otherwise 19 the discovery or the invention or the devise will 20 not be translated into practice. 21 CHAIRPERSON MARSHALL: Thank you. 22 DR. RICH: And finally, one last very 150 1 brief point. On community representation I think 2 that Susan made an important point. I would simply 3 say that the most important thing that the IRB does 4 is protect human subjects and that involves risk 5 assessment and that certainly involves the 6 professional expertise of a substantial number of 7 members of the committee. 8 CHAIRPERSON MARSHALL: Thank you. Felice. 9 DR. F. LEVINE: Thank you. I think what I 10 will do is just bullet a number of topics that I 11 hope we discuss more over the months ahead as 12 opposed to -- 13 CHAIRPERSON MARSHALL: Let's be specific 14 to this paper, okay. 15 DR. F. LEVINE: Yeah, I will. I will. 16 CHAIRPERSON MARSHALL: Okay. Thank you. 17 DR. F. LEVINE: No, on this issue, I mean, 18 as opposed to explicating what might be additional 19 questions under each. I thought one of the best 20 and most elegant parts of this is coming to terms 21 with the difference between financial relationships 22 and bias in conflicts or conflicts of interest. 151 1 Which raised for me the larger issue of when I 2 first read this, I saw this as focusing on 3 financial interest and clinical trials. And so it 4 raise for me the broader issue of the relationship 5 between financial interests or financial 6 relationships of potential conflicts and other 7 forms of bias in conflicts of interest and how 8 narrow or how broad we want to go in thinking about 9 the general conflicts of interest issue. 10 Also I read this as focusing specifically 11 on clinical trials and clinical interventions 12 although you had said on all the reports, as in a 13 number of spots, that this should meaningfully 14 reach to all research. And the nature of the 15 compensation that we have to have about the 16 differences between different forms of research is 17 one of my bullets. 18 I think that this issue that's come up in 19 a number of questions and in a number of statements 20 and in your own presentation about the separation 21 of the conflict of interest review and the IRB 22 review is extraordinarily important, and I am 152 1 concerned about the integration of the two. 2 Whether they are indeed two separate parts of very 3 reasonable processes. 4 One it speaks, of course, to our primary 5 role with respect to human subjects protection and 6 another which speaks to larger questions with 7 respect to the integrity of research that may or 8 may not raise issues of human subjects 9 protection's. So I am not sure the two need to 10 converge. I think there are some issues of 11 cumbersomeness if they do. 12 I have some concerns about -- and I think 13 I'd like us to have fuller discussion about the 14 issue of public disclosure. There's kind of the 15 micro issue of how it affects individual patients 16 or subjects and then there's the macro issue of how 17 it affects that ratcheting up issue of both 18 research, research integrity, and the broader 19 community of research subjects. And I think short 20 of publishing everybody's tax returns there are 21 ways of publicly disclosing what might be conflicts 22 or potential relational issues that are informative 153 1 about the research and are formative about the 2 research or without necessarily raising a flag. 3 And I think we need further discussion about that. 4 Which I guess brings me to a broader 5 issue, I hope, over the next months that we have 6 additional discussion with other of the federal 7 agencies that have developed their statements about 8 how the fit would -- especially if we go broader 9 than clinical, how the fit between those conflicts 10 of interest rules and any alterations that might be 11 recommended with fit. And especially the Office of 12 Research Integrity that has played a very primary 13 role in this issue. 14 In that regard, I also think a broad 15 number of scientific societies have developed 16 statements with respect to conflicts of interest, 17 less than I would see happen, and it might be 18 useful to collect those, assess those, and see the 19 fit between some of the guidance to researchers and 20 scientists in this area and how that fits with also 21 their guidance with respect to human subjects 22 protection. 154 1 CHAIRPERSON MARSHALL: Thank you, Felice. 2 Jonathan. 3 DR. MORENO: First a question for Mark or 4 any of the lawyers who happen to be at the table. 5 And actually Alan's previous question helped me a 6 lot and saved me a couple of minutes. This is with 7 respect to the status of an OHRP guidance I think I 8 understand what that means, but just for the 9 record, in the first instance a guidance from any 10 federal regulatory agency. A guidance is 11 exhoratory; is that correct? That is to say short 12 of articulated and recorded as regulation and 13 policy? 14 DR. BARNES: Two answers to your question, 15 one in general answer and one is a specific answer 16 about what we're recommending in this proposed 17 letter. In general, the federal guidance that does 18 not have the status of actual regulation and has 19 not gone through the process of the Administrative 20 Procedure Act is basically information that is 21 provided to regulated persons or entities in order 22 to give them examples of the best practices in the 155 1 area. 2 The legal effect of that adherence of the 3 institution's or person's adherence, a covered 4 person's adherence to those best practices would be 5 a essentially to provide that person with the kind 6 of safe harbor so that if they engage in those 7 practices that are recommended, then they would not 8 be subject to sanction for having done so okay. 9 It does not me, however, that they can do 10 something other than the guidance and they could 11 still not be subject to regulatory sanctions but if 12 they did adhere it would be a kind of safe harbor. 13 In regard to what we recommend, I call 14 your attention to -- and this was Elliot's 15 insistence and it really was appropriate and I 16 think everybody on the working group appreciated 17 it. On page four, the third full paragraph, Elliot 18 was very careful that we recommend to the 19 Department in the draft interim guidance that there 20 be a very clear distinction between those things 21 that must be done which are actual legal duties 22 under the existing regulations, those things they 156 1 should be done, in which there is a moral duty to 2 do them, and those things which might be done or 3 could be done as examples of the fulfillment of 4 either the moral and/or the ethical duties. 5 And we really -- I think that the rhetoric 6 of the guidance is not clear in the use of the 7 conditionals and the operatives and all that, but 8 it needs to be, and that was our recommendation. 9 DR. MORENO: Very good. 10 The non to valued logic comes in handy 11 when you're doing this kind of thing. 12 That having been said, and I gather this 13 goes to Dr. Rich's comment as well, under certain 14 circumstances an enterprising plaintiff's attorney 15 could, with respect to a grievance against a 16 noncovered party, identify a guidance as what an 17 element in a standard of care? Would you say? 18 DR. BARNES: Yes, Jonathan, that's right. 19 I mean, that would be. And the tighter the degree 20 the more that the should use or must use in the 21 guidance then the more persuasive that will be as 22 the articulation of the standard of care. 157 1 DR. MORENO: Thank you. 2 Finally, one last point. Or really a kind 3 of rhetorical question or maybe a wishful thinking. 4 I thought I heard, a few minutes ago, Adil and Mark 5 and perhaps as well the other members of the 6 working group agree that what we are talking about 7 here is significant conflicts of interest, not all 8 prima facie troubling conflicts of interest, is 9 that right? 10 That being the case and without being too 11 hopeful about this depending on how we filled out 12 the content of a troubling conflict of interest, 13 where we set the bar, and perhaps what levels 14 financial levels were set and so for there might be 15 room here for some consensus. I'm not sure I'm 16 right about that but clearly that's an area we need 17 to look at, it seems to me, based on what I heard 18 before that that seems to be an area we need to 19 look at more closely. 20 DR. BARNES: I think that I speak for the 21 working group when I say that the -- that we felt 22 there should be thresholds and that where the 158 1 financial relationship that is reported is directly 2 relevant to the research, but exceeds the 3 threshold, there is a presumption that that is a 4 troubling financial relationship. One could adjust 5 the thresholds either downward of upward depending 6 on, you know, as a point of consensus or 7 negotiation or whatever but that I think was the 8 general feeling. 9 DR. MORENO: So the issue here might not 10 be disclosure, that is to say, the full hangout 11 route advocated by Adil or the partial hangout 12 route advocated by others. But it might rather be 13 how we understand what we mean by the term 14 "significant." 15 Let me say one last thing. I think that 16 anything that we say about how any modification of 17 the rules or introduction of the new rules could 18 affect the conduct of research both from the point 19 of view of the potential subjects, the 20 investigators themselves, or the institutions is 21 wholly speculative. We have no idea how a change 22 in the rules would affect what happens. 159 1 And I, for example, believe that it would 2 have relatively little effect on the potential pool 3 of subjects to have even a very detailed 4 disclosure, but might cause my colleagues in the 5 medical community a lot of cirrus in the beginning 6 depending on how it actually worked out. 7 DR. BARNES: One brief response to that 8 is, that not only the disclosure point, but on the 9 other points about adopting the PHS guidelines 10 across the board and disclosing institutional 11 conflicts of interest over financial relationships 12 as part as of the process, I can tell you that my 13 personal experience in advising clients who are 14 medical institutions is that adhering to those 15 self-imposed guidelines has not created mass 16 confusion on anxiety. In fact, the use of 17 thresholds across the board to all research is 18 actually a late anxiety because at least it is 19 introduced regularity you know and predictability 20 into the process. 21 CHAIRPERSON MARSHALL: Margaret, you have 22 the last question before we open the floor to our 160 1 ex-officio members. 2 3 DR. BORWHAT: I just wanted to concur with 4 Abbey and her statements that advocates and 5 community representatives are readily available to 6 work on IRBs and I'm not sure that much of an 7 outreach has been made to gain community 8 membership. 9 I also had a comment on the generic 10 financial disclosure. I think we're definitely, 11 with this type of disclosure, shifting the burden 12 to the patient and I'm not sure that that's where 13 it should be. And I think the essential elements 14 similar to the informed consent as it relates to 15 risk in the medical procedures, we ve comprised 16 essential elements that are a part of the informed 17 consent. And I'm not sure that we can't come to 18 some sort of working document with the same type of 19 essential elements for financial disclosure. 20 And at the very least with all the changes 21 in the health care system and the different and 22 very complicated financial arrangements that are 161 1 taking place, it at least would be an exercise of 2 what is going on out there and how it appears to 3 the public and to the potential participants. 4 CHAIRPERSON MARSHALL: Thank you, 5 Margaret. 6 I was remiss, I had Greg last on my list 7 and then we open the floor to our ex officio 8 members. 9 DR. KOSKI: Thank you, Mary Faith. Just a 10 couple of points. The working group noted that of 11 those regulations that are currently out there, the 12 FDA has a set of retrospective regulations that 13 really address only the validity of the data, 14 that's their intent. The PHS and the NSF 15 regulations are prospective, but they are intended 16 to protect the objectivity of science. What's 17 lacking is a set of specific guidelines or 18 regulations for the protection of human subjects. 19 The draft interim guidance that was posted 20 on the web site to stimulate public discussion is 21 crafted specifically in the context of the common 22 rule for the protection of human subjects, the 162 1 purpose being to stimulate the discussion leading 2 to a broad federal government policy for dealing 3 with these issues in the context of protection of 4 human subjects. 5 I think it is very important to not lose 6 sight of that. And I would say that with respect 7 to the recommendation that we need to watch the 8 confidentiality of the investigators as well, I 9 would agree with that in broad terms, however, when 10 it comes down to human research I think that an 11 investigator who is going to engage in research 12 while maintaining a financial relationship that 13 poses a problem has an obligation to subjugate 14 one's own claims to confidentiality to the 15 protection of the individual subjects in that 16 instance. So I think that would need to be 17 qualified. 18 Having said that, I think it's critically 19 important in this concept of managing the conflict 20 of interest that we don't send anything to an IRB 21 that isn't a problem. There is enough that goes 22 there anyway, so in your flowchart that would 163 1 direct certain items that basically have been 2 deemed through a robust process for analyzing and 3 managing conflicts of interest, you come up with 4 something that's not a problem. Well, that s not 5 something that an IRB needs to know about. The 6 only thing, it seems to me, that an IRB should be 7 dealing with are those issues that pertain to 8 specific research projects in which there is an 9 interest that could compromise the rights, the 10 interest, the well-being of the research subjects, 11 that's the only thing they need to know about and 12 that's what their role should be. 13 Finally, I would just like to address the 14 issue that Bob brought up about FASSUP an AAU and 15 Koger, I would say not only do we enjoy a 16 collaborative relationship with those 17 organizations, we relish that, and indeed have 18 worked closely with them. I regret, actually, that 19 in the letters that came from those organizations 20 there was a characterization of what was put up to 21 stimulate public discussion as a guidance. Because 22 I think it unnecessarily sort of stimulates angst 164 1 because indeed this was a draft document that came 2 from a public process that was put their only to 3 stimulate discussion. And indeed I think anyone 4 who has been the following this recognizes that 5 there is no rush in this instance to do something 6 prematurely, but there is a need to move 7 expeditiously toward addressing this issue. 8 And I want to acknowledge openly the fact 9 that all of these organizations are doing what 10 they're supposed to be doing. We have the AAU 11 effort been made by Bill Danforth, FASSUP has 12 issued policy statements on this. The work that 13 already many of the academic institutions, the one 14 group that was headed up by Joe Martin at Harvard, 15 another group that's being headed up by Mayo 16 Clinic, Bill Wood. I think this is all wonderful. 17 It's a demonstration of the commitment that they 18 have toward resolving these issues. 19 And as I said in the beginning of -- or at 20 the end of my opening remarks this morning, we are 21 destined to do this right together and that means 22 we are going to continue the process. But make no 165 1 mistake about it, it must move forward and it must 2 move forward in a timely fashion, because it is not 3 something that we have time to waste. 4 Every time there is another incident in 5 the papers that puts another slam to the body of 6 science we all suffer from that. So let's keep it 7 moving, that's all I ask. 8 CHAIRPERSON MARSHALL: Yes, very nice. 9 Thank you, Greg. 10 Let me open the floor to our ex officio 11 members. If you could tell us when you ask your 12 question or make your remarks who you are and what 13 agency you represent. 14 DR. RUBIN: Philip Rubin, from the 15 National Science Foundation and I really appreciate 16 particularly Greg s comments at the end. And I 17 would like to respectfully disagree in part with a 18 portion of them and get back to the issue of 19 practice. What we've been seeing recently, I agree 20 that things need to move ahead and I agree with 21 pretty much almost everything Greg said, but we 22 have been saying that guidelines are being 166 1 interpreted as regulations, inappropriately 2 interpreted as regulations and we need to somehow 3 counter that, that that's not how they are 4 intended. So that's the practiced effect and we're 5 seeing it coming up more and more and more. And on 6 that issue I would also suggest that if you're 7 going to harmonize the PHS with NSF we're real 8 happy about the way things are working; you're 9 apparently not so you're going to bring us 10 potentially aboard. 11 We have a very good conflict of interest 12 policy and we strongly support it. It's the 13 guiding principle of everything the protection of 14 participants in research that's our guiding 15 principle and I think you should consult with our 16 general counsel Paul Rudolph and Anita Eisenberg 17 and engage them in the process a little bit more 18 actively to make sure that any potential 19 harmonization doesn't adversely pull our 20 nonclinical research into that domain, and then get 21 more stuff bogged down, adversely, I think, 22 affecting the clinical stuff. Because what's going 167 1 to happen is that the IRBs are going to start 2 seeing COI's from a whole bunch of stuff that they 3 should not see, dealing the processes which we 4 don't want to do. 5 We are really looking at trying to protect 6 the participants not bogging down the process so 7 that it gets so crippled that the larger goal is 8 missed. Thank you. 9 CHAIRPERSON MARSHALL: Thank you. 10 MR. MATHER: John Mather, with the VA. 11 I'm not sure if I'm not going to be just a bit 12 redundant here given what Philip said and Jonathan 13 was asking. I do think that it's an important 14 thing to be clear on the word "guidance." I'm 15 reminded of Humpty Dumpty, who was asked by Alice, 16 you know, what do you mean a word and he says, I 17 mean it what it means to mean" in essence. And I 18 think it's very important, there's a difference 19 between a set of ethical principles and the Belmont 20 Report which just about everybody uses, but that's 21 far from being a regulation or put in sort of a 22 mandated guidance and the other end of it being 168 1 taking a set of principles which maybe the FDA may 2 have to do given the way their construct is to put 3 it in fact into regulation. 4 For us in the VA where approximately 20 to 5 25 percent of our money comes from the NIH meaning 6 PHS it will certainly be a driving force whatever 7 is written into this guidance. I don't know where 8 I have a solution to it. I think there is a need 9 to push ahead. I think there is a need to push it 10 out there, but I think there is a very clear need 11 to be very clear on what this word "guidance" 12 means. 13 CHAIRPERSON MARSHALL: Thank you. And I 14 think Greg would like to respond to that. And I do 15 just want to say that we acknowledge and I have 16 certainly heard this overwhelming message regarding 17 what guidance means and what the implications of it 18 are. So thank you very much for saying that. We 19 hear you. 20 DR. KOSKI: Indeed I will reiterate that. 21 I want to also point out that the working group, it 22 was an HHS working group by and large that crafted 169 1 the draft interim guidance, struggled with what to 2 call this kind of thing in the context of the 3 Secretary's announcement that the Department would 4 issue guidance, but that it seemed pretty immature 5 to issue guidance that would be precluding of the 6 broader discussion, particularly of some of the 7 longer term issues. And around institutional 8 relationships in particular because that is new 9 territory. And we actually considered using the 10 words, "points to consider." As an alternative we 11 ultimately didn't use that because it had been used 12 in a specific sort of context of by FDA. And it 13 turned out to be the easiest way to get a draft 14 there was to call it this interim guidance that we 15 felt was an appropriate thing, and, of course, it 16 was just a draft document. 17 Going forward I think, you know, clearly 18 it is something that we want to be very sensitive 19 to. I'm proud to say we have not issued a new 20 guidance since I've been in my position, but we 21 want to, again, keep it moving forward. 22 It may well be that crafting it in some 170 1 way as a points-to-consider document or other 2 terminology that would be useful to the community. 3 That's what we want to do is to have something that 4 is useful to the community that helps us move 5 towards the shared goals that we have. And I think 6 those comments were very helpful from the 7 organizations that sent them in, and we look 8 forward to that. We also endorse the notion of 9 having another follow-up conference to, again bring 10 together the stakeholders to further this 11 discussion. So we look forward to all of that and 12 I know that all was intended it in a most 13 constructive fashion. 14 CHAIRPERSON MARSHALL: Robert. 15 DR. RICH: A very brief comment. I think 16 if we simply called it "framing the issues" instead 17 of "draft interim guidance" there would not have 18 been this controversy. I think that's what in 19 actual fact most of the content is simply framing 20 the issues. And certainly the content of Mark's 21 working group was framing the issues and not 22 presuming the answers. And I think that that's 171 1 where we are right now is framing the issues. 2 CHAIRPERSON MARSHALL: Let me ask whether 3 there are ex officio members or members of the 4 public who have comments? Okay. 5 I am going to give Greg and Abbey briefly, 6 briefly a response to that and then please go ahead 7 and stand in line because the floor is yours. 8 DR. KOSKI: Bob, I would just say we don't 9 consider it a controversy we consider it a 10 dialogue. 11 DR. MEYERS: I don't think you should be 12 framing the issues. You know, I spent ten years on 13 the recombinant DNA Advisory Committee and the Gene 14 Therapy Subcommittee where everybody had to conform 15 to points to consider, and they didn't conform and 16 we ended up a tragedy out of all that. 17 I think we need something here that says 18 here are the rules. If you don't obey the rules, 19 you're not going to be able to do research. And I 20 think that the opposition of the societies makes 21 institutions look very bad, makes IRBs look like 22 institutional protection committees instead of 172 1 patient protection committees. 2 CHAIRPERSON MARSHALL: Thank you. 3 4 MS. LEE: I m Bonnie Lee from the Food and 5 Drug Administration. Without applying the 6 financial disclosure guidance to IRB staff, that is 7 completely missing from yours. And I m not 8 advocating that it be added, but I think there 9 needs to be some conscious consideration as to 10 whether you would want this to apply to IRB staff, 11 if it were to apply to IRB staff, how, for example 12 would you want similar disclosures in the informed 13 consent form if IRB staff had some significant 14 financial interest, or would you want them to 15 somehow not be involved in some way in those 16 meetings at which it was reviewed. That would be 17 very helpful. 18 Also from FDA's perspective we tend to be 19 very clear as to when we require something it s a 20 regulation. We follow good guidance practices when 21 we issue guidance to solicit public comment and 22 perhaps that's another thing you need to consider 173 1 as well if you really want is to apply in all 2 cases. As a requirement, at least from our 3 perspective that would require some regulatory 4 change. 5 If this is intended, however, for good 6 practices and advice then that becomes some form of 7 a guidance document, and that's another judgment 8 that clearly I think you need to consider. Thank 9 you. 10 CHAIRPERSON MARSHALL: Abbey has a 11 question for you. 12 DR. MEYERS: FDA's requirement on conflict 13 of interest it's like -- it's the most amazing 14 thing I've ever seen. It basically says that the 15 scientist who is being paid by the company has to 16 reveal to the company whether he has a financial 17 interest in this product or owns stock in the 18 company or whatever. And then they put it in the 19 file and they keep it in that file until they 20 submit the new drug application. 21 So the conflict of interest is hidden from 22 view until the whole process is finished. And 174 1 after all the research is done they still keep it 2 in the file. They don't give FDA the file unless 3 you ask for the file. 4 So a person could have a tremendous 5 conflict of interest and it never sees daylight. 6 Now how did this come about, why is it this, this 7 way? 8 MS. LEE: I'm not an expert on that rule, 9 but my understanding is that the whole purpose 10 behind it is that when the financial interests 11 reach a certain threshold amount that is reported 12 to us along in the marketing application. We can 13 look at that significant interest if there is one 14 disclosed, look at the data associated with that 15 interest and make a determination as to whether we 16 need to look at the conduct of the particular 17 study, for example, more carefully, to see if in 18 fact it honestly reflects the research that took 19 place. 20 It's a very different purpose in our 21 regulations than what you're trying to accomplish 22 here. And so I think to look at those regulations 175 1 as a way of protecting subjects wold probably be 2 inappropriate. That was not their intent. It's 3 done retrospectively as you say. 4 5 CHAIRPERSON MARSHALL: Bob and then Susan. 6 DR. R. LEVINE: The discussion this 7 morning on the subtle nuances and the distinctions 8 between guidance and regulations doesn't address 9 one major problem and that is that there is a 10 perception out there that OHRP might act very 11 forcefully on things that are not even guidance. 12 Things that were never articulated until an 13 institution was suspended. 14 One case in point is the Virginia 15 Commonwealth incident where everyone out there 16 thinks that the reason that research was suspended 17 there was enforcement of a policy that no one had 18 ever heard of before, the secondary research. What 19 I think one problem is that OHRP and its 20 predecessor never get clear about what were simply 21 observations and what was the reason they suspended 22 an institution. 176 1 But another thing is that you have to be 2 aware of the fact that there is extreme sensitivity 3 out their that anything that's posted as a even a 4 solicitation of comment that OHRP is likely to fan 5 the flames of paranoia that exists out their. 6 Thank you. 7 DR. KOSKI: Having been an IRB chair for a 8 decade, I'm sensitive to that. Thank you very 9 much. 10 MR. MATHER: I just want to come back on 11 one thing that has been troubling me since it's 12 been said and that's that this has been an exercise 13 in framing the issues. To me it's more than that 14 that's been going on here. I think we're trying to 15 frame some organizational principles that will have 16 a little bit of teeth in them than just say, well, 17 let's frame the issues folks, and let's have a nice 18 little chitchat about them. 19 To me I sense as a need to move this thing 20 a little bit further and whether you call it best 21 practices or quasi-regs or something, maybe the 22 term "organizing principles" or "organizational 177 1 principles" gets away from sort of going one way or 2 the other. I think we need some best practices. 3 We need some frameworks that can be put out there 4 and say, you know, folks, take them or leave them, 5 but these are some organizing principles and the 6 ways in which you can do this. And, in fact, you 7 know, it will be helpful to you. 8 CHAIRPERSON MARSHALL: Anyone from the 9 public or I know Susan s hand is up, but I want to 10 make sure the folks from the public have a chance 11 to speak. 12 MS. CHAMBERS: Hello. My name is Cheryl 13 Chambers and I live in Richmond, Virginia. Three 14 weeks ago I got the Seattle Times and on the front 15 cover is a picture of my sister. I was a donor for 16 her for two bone marrow transplants and she's 17 holding my new baby girl that I had to go out there 18 for the second transplant with the new baby. 19 We were not informed about the fatalities 20 of the consent on the consent forms. My sister 21 chose the T-cell depletion. We had undue 22 influence, as you all said, to do this. I remember 178 1 sitting in the protocol meetings and saying, if you 2 had cancer, which transplant would you use? And 3 they all assured us that the T-cell transplants had 4 the highest success rate. 5 We could have gone anywhere in the country 6 and we went to the Fred Hutchinson Center because 7 it had the highest success rate in the world at 8 that time. My sister lived in Alabama and I lived 9 in Virginia. I left two teenagers and a husband 10 and went there for four months both times a total 11 of eight months. When she signed this T-cell 12 depletion thing it was a fatal thing because at the 13 time they already had nine patients in the program 14 all nine relapsed due to the T-cell depletion. She 15 signed her life away. 16 It was not stopped then. The doctors 17 doing the T-cell depletion had stock in a biotech 18 company. This company was sold for $294 million. 19 These doctors became multimillionaires because of 20 my sister. It wasn't stopped in 1985 and '86 after 21 she died and '87. It continued on and 10 more 22 patients were given this protocol even though other 179 1 doctors in the hospital said, "please stop this, 2 please stop this," and all 20 patients died. 3 I want something to be done about this. 4 As a sibling I cannot sue in the state of 5 Washington, so I m here to plead my case. These 6 are real people I had to photo albums of both 7 transplants and other patients there that died 8 because of this. 9 Also the financial investment, I think 10 when you show this little form that you had on the 11 chart, if you leave it down to the patients to make 12 the final questions. When you get patients there, 13 all of us had education; I have a master's in math, 14 it doesn't help trying to digest all of these 15 abbreviations you all use up here sometimes. But I 16 feel I was educated my sister Becky Wright's 17 husband owned the only drug store in the little 18 country town in Alabama. 19 His brother was a pharmacist and his dad 20 was a doctor there in the town for 62 years. We 21 felt like we were educated, we knew what we were 22 doing, but when someone is sick you can't sit there 180 1 and say, do you have any financial investment in 2 this? If you do let us know; ask any questions 3 about it; your mind is not in that framework to do. 4 What I would like to see done is all have 5 financial disclosure immediately. In the world 6 today and the federal workers that we have here, 7 you have to give your financial disclosures in 8 everything that you do. My husband is a minister 9 and we get audited just about every single year and 10 we have to put down everything that we own. Why 11 can't these hospital's doctors have to do that and 12 the hospital institutions have to do the same 13 thing. 14 The Fred Hutchison Center get $143 million 15 for federal dollars every single year. Why can't 16 they have this disclosure written up? I appreciate 17 all the work that you've done and thank you for 18 having me here today. 19 [Applause.] 20 CHAIRPERSON MARSHALL: We appreciate you 21 very much. Thank you for coming. 22 Do you have any specific questions that 181 1 you would like to ask besides making your comments? 2 Ma am in the back. 3 AUDIENCE PARTICIPANT: [Off mic.] No, 4 just work as hard as you are right now. I would 5 like to see some regulations and not just 6 guidelines and not just issues. 7 CHAIRPERSON MARSHALL: Come up to the 8 microphone so that we can record your comments 9 please. 10 AUDIENCE PARTICIPANT: Would you have her 11 repeat her name. 12 CHAIRPERSON MARSHALL: Yes. Could you 13 repeat your name? 14 MS. CHAMBERS: My name is Cheryl Chambers, 15 I'm there in Richmond, Virginia. 16 I would like to see not only guidelines or 17 issues, I would like to see some regulations. 18 There are some review boards out there at all the 19 hospitals advisory review boards, almost all the 20 hospitals we've investigated since this, do not 21 allow their doctors to own stock in the companies. 22 At the Fred Hutchison Center nothing has been said 182 1 about this. They continue to become 2 multimillionaires. They won't even admit to how 3 much stock they own. 4 One of the Nobel Prize winners that did 5 this project donated his money from the Nobel Prize 6 to the hospital, but he won't admit how much stock 7 he still owns. 8 For these 20 patients to die once you 9 start a program you cannot get out of it because 10 they start a total body chemotherapy and radiation 11 and once you start that, you have to have the 12 transplants or you will die. 13 My sister went through agony, I went 14 through agony. I had both kinds of transplants. 15 They never brought this up where you're doing 16 direct medical research. They said, oh, a 17 transplant you're going to have two or three holes 18 in your hip. The second transplant was like that I 19 had very few bruising and very little pain. The T- 20 cell depletion, and I would like someone to 21 investigate this, I had 22 holes placed in my back, 22 I had pressure bandages and tied to the bed when I 183 1 first woke up. I couldn't sit down for over a 2 month and I don't know whether they took out more 3 bone marrow than necessary to do their testing or 4 procedures or whatever they were doing with this 5 DNA biotech company. 6 Once it got done we didn't mind dealing 7 with it because I knew my sister would probably 8 have a good chance of living. She did and all this 9 time we bragged on the Fred Hutchison Center, the 10 Swedish hospital there, we sent patients out there 11 because the work out there is extraordinary. It 12 was just for these few doctors and other doctors 13 tried their best to get it stopped and it took year 14 after year after year to get it stopped. And I 15 want to thank the investigators for finding this 16 all out for us. Thank you. 17 CHAIRPERSON MARSHALL: Thank you very 18 much. 19 Abbey and then Greg has asked to speak. 20 Any other members of the public or our ex officio 21 membership who would like to say something before 22 we close for lunch? 184 1 DR. MEYERS: It's just that this is 2 another body slam to research. These kinds of 3 revelations I think that the institutional 4 community doesn't understand that if it wouldn't 5 look good on 60 Minutes it shouldn't be done. And 6 that should be the measurement that you've got. 7 And something like this Fred Hutchison Center, this 8 series of newspaper articles, its been 9 extraordinary. But it just comes from the heels of 10 how many other institutions with their revelations. 11 That's why we can't wait, we have to put something 12 in place as soon as possible. 13 CHAIRPERSON MARSHALL: Judy. 14 DR. SEIGEL: I would just like to comment 15 on a couple of things. I think within the workings 16 of the committee one of the primary things that our 17 working group that we discussed was really not 18 necessarily only the financial relationships but to 19 focus back on the protection of human subject. And 20 I think probably what's happened over years and 21 years is maybe that has not been the focus of the 22 primary deliberations. 185 1 And so I think as we really came through 2 our deliberations, what I think this guidance may 3 do is focus people back on what the issue is. It's 4 not necessarily how much stock you have someplace, 5 it's does the existence of that relationship in any 6 way compromise the protection of this patient? I 7 think that's really what we were trying to focus on 8 in bringing everything back to what is the 9 question, and the question is what is the 10 protection of human subjects. 11 I think to a point earlier, actually I 12 think Margaret you expressed the focusing on the 13 informed consent process not to document. I think 14 that was another very large discussion that we had 15 which is: what is the process? Do we really know 16 what the process is? Is the process really 17 executed with the attempt to protect the human 18 subjects or to dump information? And you're right, 19 there are elements of informed consent. If you try 20 actually to find them in most informed consents 21 even those of us who actually are involved in 22 writing them, it becomes very difficult. 186 1 And so as we were discussing this the 2 issue is, again, I think one of the points that 3 Mark brought up, is it to eliminate conflict of 4 interest, to manage conflict of interest, and what 5 is it that a patient subject needs to know that 6 will help them make that decision as they are 7 trying to digest all of the rest. So I think that 8 was really the other main thing which is, how do 9 you tell someone what exists so it can help them 10 make their decision and protect themselves. 11 DR. MEYERS: Do you think the Mercy 12 Hospital paragraph is the right way to do it? 13 DR. SEIGEL: I think what we try to do is 14 give a stab at it, because, again, I think we get 15 to that part actually quite late in the day. I 16 think it was the intent to basically tell the 17 patient or subject that in fact there is a process 18 going on that is intended to protect your rights. 19 Now, maybe that paragraph is not the be 20 all and the end all, but the intent of that 21 paragraph is to tell the patient to synthesize what 22 is going on in the background a little bit. It was 187 1 an intent really to give a little bit of hopefully 2 information about what's going on in the 3 background. 4 Now, again the discussion that I think is 5 still up is, what is the end of that and are their 6 other ways to actually give some more detail? But 7 mostly it was to frame for the patient the fact 8 that there is this whole thing going on in the 9 background. 10 CHAIRPERSON MARSHALL: This is your lunch 11 time that your cutting into. But it is an 12 important discussion so I don't want to preclude it 13 will cut short. Sandy. 14 DR. CHODOSH: I think a major issue that 15 we have to face at some point by this committee or 16 somewhere is, what is the informed consent form? 17 And, finally, we have to decide if we intended to 18 be a contract or whether we intended to be informed 19 consent, and we have not decided that. And if you 20 read most informed consent forms they are so full 21 of junk legalese, et cetera, that even the 22 investigators don't understand that I think that 188 1 that is just a wrong way for us to have gone and in 2 trying to put something more into this, we were 3 trying to put something into it which would allow 4 the subject to understand what is going on and what 5 is being done, but not overwhelm them again with 6 all this junk. 7 Frankly, most of it is not to their 8 interest at all and we have to get away from the 9 informed consent form and back to the process and 10 then we would resolved some of these issues. 11 CHAIRPERSON MARSHALL: Thank you, Sandy, 12 well said. Alan. 13 DR. FLEISCHMAN: I think a response to 14 both the comments that have been made and some of 15 the concerns around the table, unpacking with some 16 examples, examples that may even have some bases in 17 reality, how this process that we're proposing my 18 actually prevent harm to research subjects if it 19 worked well. That might be very compelling in the 20 argument. Because I think some of the concern 21 that's been voiced is that the subjects are not 22 going to be knowledgeable enough, based on the 189 1 Mercy Hospital paragraph, to ask the right 2 questions. And then, of course, there's also the 3 concern about who they're asking and whether 4 they'll get the right answers. 5 So I think if we could be reassured 6 through specific example, exploration, at least for 7 this observer it would be a much more compelling 8 case. 9 CHAIRPERSON MARSHALL: And, Alan, I do 10 believe that you made room for that and actually 11 proposed that the academic societies and others 12 helped flesh those out. 13 DR. R. LEVINE: Alan Fleischman has made 14 a very interesting and important proposal. I want 15 to suggest that it might be a useful exercise for 16 us to have a long consent form put on the table in 17 front of us and to have people around the table say 18 what they want to take out. Because that's the way 19 you're going to flesh out the positions of those 20 people who insist, no, it's got to stay in. But if 21 we can find a way to take out all of what Sandy 22 quite properly calls "junk," we would have done a 190 1 great service to the community. 2 CHAIRPERSON MARSHALL: Greg. 3 DR. KOSKI: Thank you. Bob, that's an 4 interesting suggestion. I will sort of give you 5 some previews that in fact we were anticipating 6 putting a discussion of the consent process on the 7 agenda for the next meeting so we might get a 8 chance to go through that exercise. Yes. 9 DR. R. LEVINE: I'm not talking about the 10 process, I'm talking about the form. The form is 11 not informed consent. 12 DR. KOSKI: I understand that, certainly. 13 However, the form is part of the consent process 14 and I think the exercise that you suggest is one 15 that would be very interesting. But let me go back 16 to that main topic here. 17 Alan, you asked for examples. I can think 18 of few examples that could be more compelling than 19 the story then we just heard from Ms. Chambers. I 20 think that it gives an example of where the process 21 can clearly go awry. 22 Now whether or not in such a situation 191 1 anyone ever does anything wrong is almost 2 irrelevant in some respects, because, you know, the 3 perception, the damage that can be done to the 4 scientific process and the public trust in that 5 process results regardless of whether or not. So 6 the harms a very real. So we need to be sensitive 7 to that. 8 In the draft interim guidance that's up, 9 there are some specific examples that are given of 10 where in a human research study an individual 11 investigator, okay, is most likely perhaps to -- 12 not inclusive -- but most likely to do harm or at 13 least be in a position to do harm. Such as in the 14 identification, recruitment, and enrollment of 15 patients in the trial as part of the consent 16 process, such as actually adjudicating an adverse 17 event to make a determination as to whether or not 18 that event was in some way related to the actual 19 test article. 20 Participation in a safety monitoring board 21 would similarly be inappropriate. We can easily 22 identify certain areas where if an individual has a 192 1 conflict of interest, they probably should not do 2 those things, because they could still participate 3 perhaps in other ways without doing damage to 4 either an individual themselves or the process. 5 I want to go very much on record as saying 6 I don't think there's anything wrong at all with 7 our research institutions or with companies making 8 money as a result of their discoveries. I don't 9 think there's anything wrong with an investigator 10 getting lots of grants or other kinds of financial 11 compensation for the work that they do. That's all 12 fine, but we can't do those things at the cost to 13 the individual research subjects. 14 Now, many institutions in this country 15 have already adopted policies, many of them have 16 been in place for decades, hey, that simply say we 17 recognized this is a problem so we're not going to 18 do it. Okay. 19 And I can tell you some of those are among 20 the most successful research organizations in this 21 country. It's not as though it impairs the 22 research process. In fact, I would say quite the 193 1 contrary, I think it promotes the research process 2 because you don't end up in a position of having to 3 apologize for a perception or for for actual harms 4 that are done in the long run. 5 I've already personally gone on record, at 6 least twice, publicly, saying that I simply don't 7 believe that an investigator in a study should hold 8 equity interest in a company that they are doing 9 the research for. That's one of the instances. 10 And you talked about 5 percent, well, if you can do 11 the math. Let's say your 5 percent in a start-up 12 company, okay, is 10,000 shares worth 50 cents a 13 share. Well you've got $5,000 up there. 14 If it works and that turns into 10,000 15 shares valued at $80 a share, which is not an 16 unrealistic prospect, you're looking at nearly a 17 million dollars. Okay. 18 So in those instances the stakes are so 19 great, okay, that it seems to me that we simply 20 can't allow that. But, of course, that's a 21 personal opinion and I've stated it very clearly. 22 As I said though, that does not mean that 194 1 the individual investigator need give up the 2 financial rewards that can come with discovery. 3 Indeed investigators may spend 10, 15 years 4 developing something that ultimately goes on to 5 become a successful product. Should they be not 6 denied the benefits of having created and carry 7 that work forward? No, I don't think so. But, 8 they can enjoy that without participating in those 9 roles that could lead -- put them in a conflicted 10 position and indeed could ultimately, whether 11 anything goes wrong or not, undermine the trust and 12 the integrity in the research that ultimately leads 13 to the success of the product. 14 And, again, we see many institutions 15 simply say now, and investigators, we're going to 16 have someone else do this research because if it 17 works we don't want there to be any question about 18 the fact that it worked because it was done by 19 people who didn't care whether or not it worked. 20 And I think that's an important place to end up in 21 all of this discussion, which is going to go on for 22 a time. 195 1 Let me reassure everyone that neither 2 OHRP, this is not an OHRP initiative, of course, 3 but neither OHRP nor the Department, nor, would I 4 say, the federal government in general, has any 5 interest in rushing this to forego foregone 6 conclusions. We want this to be a constructive 7 dialogue, and as I said before, we will all benefit 8 from the outcome. Thank you. 9 CHAIRPERSON MARSHALL: Thank you, Greg. 10 Kate. 11 MS. GOTTFRIED: Well, we are just about 12 ready to wrap up and I just wanted to say one 13 thing, first of all of to the group overall, that I 14 think that the workgroup did a phenomenal job. I 15 am so impressed with the work that has been 16 accomplished. 17 [Applause.] 18 MS. GOTTFRIED: And I want to especially 19 thank Mark Barnes for reflecting what was said 20 during the day the 21st and all the work up until 21 that point. Because I think we re all overly 22 impressed with the presentation. 196 1 Having said that, I want to say one other 2 comment based on what was described to us with 3 respect to the scenario at the Fred Hutchinson 4 Center. And that is, we did talk at the workgroup 5 committee meeting about where the onus is with 6 respect to disclosure. That issue did come up, we 7 thought about it, and I want to reinforce for my 8 own prospective and my own work in a variety of 9 capacities that the onus cannot be simply put on 10 the patient. That we have to come up with the 11 system that's mindful and considerate of the fact 12 that patients can be compromised because of the 13 situation that they're in; the ordinary patient can 14 certainly be compromised; the above average patient 15 can easily be compromised and that to insist that 16 the patient consider and deliberate based on an 17 informed consent and then ask the appropriate 18 questions is in fact a very large burden and 19 responsibility that I think we have to come to some 20 sort of understanding as to how to reconcile the 21 issue. 22 CHAIRPERSON MARSHALL: Thank you, Kate. 197 1 Those were wonderful last words for us to wind up 2 this session. And we will be back promptly at 1:30 3 to begin the discussion on genetics. Thank you 4 all. 5 [Whereupon, at 12:35 p.m., the meeting was 6 recessed to be reconvened this same day at 1:30 7 p.m.] 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 198 1 A F T E R N O O N S E S S I O N 2 [Time noted: 1:45 p.m.] 3 CHAIRPERSON MARSHALL: It is time to 4 reconvene. 5 Welcome all of you who have joined us who 6 weren't here for our very productive morning. 7 Greg is reminding me to let you know that 8 we have not foregone to Helsinki discussion, we 9 will have it later on this afternoon. There will 10 be ample time for it. And thank you, Greg, for 11 being so gracious as to allow us to be flexible 12 with the schedule. 13 It's my distinct pleasure to have Francis 14 Collins join us today. And he is going to do a 15 yeoman's duty, I think we're putting him to work. 16 Dr. Collins, as you know, is the director 17 of the Human Genome Research Institute at the NIH. 18 He is going to begin our discussion by laying out 19 for us a framework of current issues in genetics 20 research that he thinks bear the committee's 21 attention. And then he is graciously going to 22 moderate our panel discussion that will follow on 199 1 the question of whether family members or third 2 parties should themselves be subjects of a 3 protocol, and if so, whether informed consent can 4 be -- should be obtained by an investigator to 5 retain private information about family members or 6 third parties. 7 So we look forward to as fruitful an 8 afternoon as we had a morning. And, Dr. Collins, 9 the floor is yours. 10 DR. COLLINS: Thank you very much. I am 11 really pleased to have a chance to come and meet 12 with this committee because I have great hopes for 13 what you're going to accomplish in the coming 14 months. 15 My point, to cut the chase of this 16 presentation, is to say to you that I believe there 17 are a number of areas of pressing importance in 18 genetics research where there is considerable 19 uncertainty on the part of IRBs researchers and 20 members of the public about exactly how we ought to 21 proceed. And that while those things have been 22 getting discussed and various conclusions have been 200 1 drawn in an ad hoc bases, there really has not been 2 the kind of gathering that we have here this 3 afternoon, to consider those issues by a group that 4 has been charged to take them on and to make 5 recommendations that will have a profound 6 consequence for the future of the way that research 7 is carried out. 8 And so if you read USA Today and you 9 noticed that I said today was a very important 10 meeting. I meant it. This is a very important 11 meeting. I will not come to you with a lot of 12 answers. I have, like most people, some opinions, 13 but I think most of the issues that I want to raise 14 with you are not those for which easy answers can 15 be obtained. Just the same, I believe that 16 together we can find our way through this pathway 17 in a fashion that encourages research but protects 18 the interests of those who participate in research 19 which is, of course, our most important charge. 20 What I want to do in this presentation is 21 to give you a quick snapshot of the rate at which 22 genetics and genomic research has progressed over 201 1 the course of the last two or three years, 2 especially, and to point out a number of ways in 3 which research involving genetics has changed its 4 character as a consequence of the ability to do 5 things that previously we just didn't know how to 6 do. 7 And then I want to pose for you five areas 8 of where I believe there is considerable need for 9 clarity and clarification, all of which I hope our 10 areas that this committee might be able to make 11 some useful contributions to. One of them will, in 12 fact, be this issue of obtaining consent from 13 family members in pedigree research, but I'm not 14 going to dwell too heavily on that because that 15 will be the subject for the panel which follows 16 after my presentation. And you have a number of 17 distinguished folks prepared to talk explicitly 18 about the issues and then we'll have a chance for 19 discussion amongst the committee and after that 20 public members from what I understand from your 21 chairperson. 22 So I don't want to preempt that by going 202 1 too heavily into that topic, but I will touch upon 2 it. So without further adieu certainly genomic and 3 genetics is getting more into the public 4 consciousness than it used to be. There are so 5 many cartoons out there that you could do a whole 6 talk just based on them, and I think that's good. 7 Because it used to be pretty hard to find these. 8 [Laughter.] 9 DR. COLLINS: And now we're overwhelmed 10 and here's one from a couple of months ago. Well, 11 why are we doing the genome project anyway? It's 12 important to remember the reasons that have led us 13 to this particular juncture. And while my computer 14 is trying to find the next image -- there it is. 15 We are after all engaged in this effort to 16 try to understand medical conditions. Genomic may 17 tell us a lot about other things but the major 18 motivation for the genome project was a medical 19 one, and, in fact, we are making considerable 20 headway in many directions in that regard. For 21 single gene disorders like cystic fibrosis where 22 the genetics component is very powerful we have 203 1 essentially identified most of the disorders that 2 are inherited in that fashion to the gene level 3 albeit, of course, that's just the beginning of the 4 effort to try to use that information for 5 therapeutic purposes. 6 And we are making headway in the middle 7 category here of conditions like adult onset 8 diabetes that are partly environmental and partly 9 hereditary and where the hereditary influence are 10 much messier than they are for something like CF. 11 And even for infectious diseases, we are certainly 12 learning that hereditary factors can help us a lot 13 in understanding what happens after an exposure and 14 using the information to develop new ideas about 15 therapies is one of the more exciting developments 16 in the treatment of infectious disease. 17 So genetics is about all disorders, but to 18 have this come true, to have those yellow 19 components of these pie charts and the red 20 components understood, we're going to need a lot 21 more research than we currently have had, and hence 22 the importance of considering how that research 204 1 ought to be done. 2 The genome project has been underway now 3 for 11 years in the U.S. The NIH is the agency but 4 this is an interimational effort involving many 5 countries and many laboratories that I have had the 6 privilege to lead. And over the course of the last 7 couple of years, a great deal of progress has been. 8 But it didn't just start a couple of years ago. 9 The projects focused its first five or six years on 10 developing maps of chromosomes, genetic and 11 physical maps, which were themselves of enormous 12 utility in terms of mapping disease genes to their 13 appropriate location on chromosomes. And then we 14 were able thanks to advances in technology and 15 particularly to the creative juices of a host of 16 genome center directors to move forward this 17 timetable for sequencing the genome which 18 originally had been targeted for 2005. 19 In fact, in March of '99 when the largest 20 genome centers got together to discuss the 21 possibilities, we had finished about 15 percent of 22 the genome, as you can see here in this cartoon of 205 1 the various human chromosomes most of the territory 2 you'll note here was untouched at that point. But 3 thanks to a very significant ramp up that was 4 organized at that point, and a lot of investment 5 from the NIH and the DOE and our partners 6 interimationally, it was possible in the space of 7 15 months to go from that to that. And if you just 8 notice the differences there, that's an awful lot 9 of territory that got covered, sequencing a 10 thousand base pairs a second, seven days a week, 24 11 hours a day to get to that point. 12 So there was a big announcement last 13 summer about that, and we were all pretty excited. 14 But the really interesting parts of this 15 scientifically were not just to derive the letters 16 of the code but to try to understand with they 17 mean. And in that regard just a month ago in this 18 issue of Nature we published not only the methods 19 that were used to sequence 95 percent or so of the 20 human genome but also an initial analysis of what 21 could be learned from the sequence itself. 22 The cover was carefully chosen by the 206 1 international sequencing consortium to depict what 2 this was really all about. Which is it's about 3 DNA, but in fact if you look carefully this cover 4 is made up of a mosaic of the faces of individuals 5 from all over the world. This is the genome of all 6 of us. With this is our shared inheritance. We 7 are 99.9 percent the same at the DNA level and the 8 cover is supposed to convey that. And I think 9 perhaps for today's discussion it's an appropriate 10 symbol of the future in that we want to understand 11 this molecule DNA, we want to understand its role 12 in health and disease, but to do so will involve 13 the participation of folks from all over the world 14 as our full partners in that effort and we need to 15 be very thoughtful about how we are setting up that 16 partnership. 17 Just for fun in this mosaic of individuals 18 most of whom come from various places and are not 19 people whose faces you would recognize, we did hide 20 in here a picture of Watson and Kirk [ph] -- 21 [Laughter.] 22 DR. COLLINS: -- just to make it a little 207 1 more interesting. And having encountered a number 2 of people who have wasted a lot of time trying to 3 find this, I will reveal the secret for those of 4 you in the room so you don't have to do this. It's 5 right down there, and if you look very carefully in 6 that little part of the double helix sure enough 7 there is the famous photograph from 1953 of Watson 8 and Creek standing on either side of their model of 9 the double helix. 10 So we did learn a lot from this analysis. 11 I could go on, and I have on occasion, about the 12 number of surprises that came out of this discovery 13 process of looking at the sequence. Here are just 14 a few of the cool things we learned about the 15 genome that we really didn't expect; the number of 16 genes in the genome coming in at only about 31,000 17 give or take 10 percent or so. It's certainly a 18 lot less than what had been expected, making you 19 wonder, are we as complicated as we thought? 20 Well, we certainly are. And so clearly 21 our degree of complexity must have some other 22 basis, one of which seems to be that our genes can 208 1 make more proteins per gene than other critters. 2 We can make about three different proteins from 3 each gene on the average. There also turns out to 4 be the case that our proteins are more complex in 5 what they can do than what you might find in the 6 similar proteins from worms or flies. 7 So we seemed to have recovered our sense 8 of pride here, although this gene count was an 9 affront to many people, I think we've overcome the 10 initial hit. 11 We also discovered that we had genes in 12 our genome that seemed to have crossed over all 13 sorts of the boundaries that weren't supposedly 14 crossable. That it came from bacteria without 15 going to the usual evolutionary steps. This didn't 16 happen last week, these are genes that arrived 17 there tens or even 100 million years ago. But it's 18 surprising to find that they are there and they're 19 actually quite beneficial, they're doing us some 20 good. 21 We learned the male mutation rate is twice 22 that of females by a very careful analysis of the 209 1 genome sequence, which if you are a male might be 2 bad news because here now responsible for two- 3 thirds of genetic disease. On the other hand, if 4 you want to look at it the other way, you're 5 responsible for two-thirds of evolutionary 6 progress. So you can decide. 7 [Laughter.] 8 DR. COLLINS: And we also studied the 9 junk, or so its been called, and maybe we should 10 stop calling it that, and discovered that we can 11 learn a prodigious amount about where our genome 12 came from my looking at the repetitive sequences, 13 which is roughly 50 percent of the genome, and we 14 learned that at least one large class of such 15 repetitive elements must, in fact, have a function 16 after all by the way in which it has been 17 selectively retained in various parts of the 18 genome. And that was a big surprise. 19 So I could go on and on about this but we 20 learned a heck of a lot about this. But not only 21 do we study the genome sequence that's 99.9 percent 22 the same, another paper in the same issue described 210 1 the discovery of 1 1/2-million places of the genome 2 where there are common variations between 3 individuals. That catalog of human variations is 4 going to be an absolutely critical resource for 5 trying to nail down the hereditary contributions, 6 the common polygenic conditions, things like 7 diabetes, heart disease, Alzheimer's disease, 8 schizophrenia, the common cancers, as multiple 9 sclerosis, virtually anything you can think of that 10 runs in families, and that's most diseases, but 11 doesn't have a nice clean mendelian inheritance 12 pattern. Those things are going to be now much 13 more approachable because of having this catalogue. 14 So the way in which we hope this would 15 turn its attention now from a basic science 16 enterprise into one which has increasing clinical 17 applications might be diagramed as you see here, 18 starting at the left and moving to the right, this 19 is what one would expect to see happening for 20 disease gene after disease gene in the course of 21 the next 10 or 20 years. 22 We have the tools, we believe, to identify 211 1 the genes that are contributing to virtually any 2 disease that has a hereditary component using what 3 the human genome project has produced but it will 4 require a great deal of careful pedigree research 5 to do so, because you don't know the significance 6 of a particular variant until you've studied it in 7 individuals with a condition and people who don't 8 have that condition. Otherwise it's just a 9 candidate change in the DNA. 10 Human research really will not go very far 11 without that very big risk clinical effort which 12 will involve lots and lots of families and 13 individuals and lots of clinical researchers. And 14 that is one of the things really need to talk about 15 today in terms of how to catalogue that. Otherwise 16 the arrow that you see here will not progress very 17 rapidly. 18 Once you've identified a variant that 19 plays a role as a risk factor in disease and then 20 following that central arrow there, you have a 21 diagnostic that might allow you to make a 22 prediction about who else is at-risk but not yet 212 1 affected by the disorder. If that's all you're 2 doing is providing a risk estimate without an 3 intervention that may not be of great interest to a 4 lie of people, although some will still want to 5 know. It would be more impressive, of course, if 6 you had a preventive option to offer. 7 Now, already in some circumstances we are 8 at that point. For colon cancer, for instance, if 9 you're in a family that has lots and lots of colon 10 cancer we have identified a number of the genes 11 that are involved in those fairly strongly 12 hereditary forms. You could find out if you decide 13 you wish to be tested and go through the 14 appropriate protocol whether you're at risk or not. 15 Then, if you are, then begin a program of 16 colonoscopy starting at an early age in order to 17 pick up that polyp while it's still easily removed 18 and perhaps spare you from a terrible outcome of 19 metastatic disease down the road. 20 That kind of preventive strategy is 21 currently available only for a small number of 22 conditions. Which is why we are not yet in the 213 1 circumstance of offering this kind of diagnostic 2 genetic testing to lots and lots of people for lots 3 and lots of conditions. But it will be coming 4 along with the increasing recognition both of what 5 the hereditary factors are and of what 6 interventions might have value. 7 Pharmacogenomics which I'm sure we'll hear 8 about a little later on from the panel is also on 9 this list. It's a particular kind of diagnostic 10 where in this instance you're not predicting the 11 risk of future illness, you're predicting the risk 12 of responsiveness to a drug that's being given for 13 a particular condition. And there is strong 14 evidence in many conditions that that is at least 15 in part influenced by heredity. And if you knew 16 ahead of time that this is the person who isn't 17 going to respond well to that drug, or who might 18 even have an unfortunate side effect, you could 19 spare them the experience of being treated 20 ineffectively for a condition where some other 21 treatment is already available. 22 So the field of pharmacogenomics has grown 214 1 very rapidly out of essentially of nonexistence 2 three or four years ago to a very, very important 3 topic both in academia and in the pharmaceutical 4 industry with many people predicting that this 5 approach will come into fruition for drugs that are 6 already on the market in perhaps the next five to 7 seven years. 8 Of course the ultimate outcome that one 9 hopes to see from all this as far as consequences 10 is the therapeutic one and that might be a 11 circumstance where they gene is used as the drug; 12 that's what gene therapy essentially is. Or that 13 you use the understanding of the gene to develop a 14 sufficiently precise molecular analysis of the 15 problem to allow you to design a drug that goes 16 right to the heart of the problem. 17 If you read in the press last week 18 accompanying a number of reports in the New England 19 Journal about this drug called Glivax which was 20 previously call STI571. It's a very good early 21 example of a drug designed specifically based on 22 molecular understanding of a problem. In that case 215 1 adult leukemia which appears to be enormously 2 promising in terms of its success rate in providing 3 benefit to affected patients. 4 So this is the pathway that we'd like to 5 travel, but at every one of these branches we will 6 not make progress without vigorous clinical 7 research involving large numbers of individuals, 8 and hence, the critical importance of getting that 9 part right and all the more reason why we should be 10 talking about it today. 11 Not only will we be studying a lot of 12 individuals, we will be studying lots of genes in 13 those individuals and methodologies for studying 14 how gene expression, getting turned on or off gets 15 affected by health or disease, has been moving very 16 rapidly with things like microarrays and you see an 17 example of that. So the whole approach to try and 18 understand illness has taken a turn in the 19 direction of high throughput methods that we could 20 not have anticipated a few years ago. 21 Again, my hope would be that if this moves 22 forward the way it should, that the use of 216 1 information about genes to develop truly effective 2 drug will be considerably accelerated. And this 3 particular issue of Time magazine from a couple 4 months ago is a whole special issue on that topic 5 where the DNA you see here in the bottle is not 6 really the drug, it's the information that used to 7 develop the drug. And I think the field is 8 extremely promising there and that's why every 9 pharmaceutical company is basically targeting this 10 as the way in which they hope to develop the next 11 generation of pharmaceuticals. 12 Well, how is this all going to come to 13 pass? Let s sort of look at the contrast between 14 the way genetic research might have been done by 15 many of us perhaps 15 years ago and the way in 16 which it is starting to be done now. 17 Fifteen years ago most genetic research 18 was done on conditions that were fairly, highly 19 heritable, because they were the ones you had some 20 hopes of making progress on so the pedigree over 21 here would likely be a dominant or a recessive 22 condition. 217 1 The investigator who is doing the research 2 might very well be the same person who is examining 3 those individuals in the clinic and in some 4 instances even be their physician. Although we all 5 recognize there are problems with that the 6 particular equivalence. 7 That investigator would be generating 8 clinical records and would be carrying out DNA 9 testing and perhaps analyzing tissue. But it would 10 all be connected in this fairly small sphere of 11 activity. 12 This is all changing with the challenge 13 now to be to try to understand the genetics of 14 complex disorders where the genes play a weaker 15 role individually your only way of success is to 16 study much larger numbers of individuals. 17 And so increasing repositories are coming 18 into the fore. That means much larger numbers of 19 subjects, larger numbers of tissues perhaps, 20 clinical records, DNA test results frequently 21 finding their way into some central data 22 repository, and the possibility then of many 218 1 investigators tapping into that to try to answer 2 important research questions. A very different 3 kind of scenario than the rather circumscribed one 4 that was more familiar fifteen years ago. 5 And yet much of what we have been 6 following as far as guidelines that IRBs attempt to 7 adhere to, is really more focused on the old way 8 than on the new way. And most of the issues that I 9 want to put in front of you relate to what happens 10 when we make this transition and are we ready for 11 it. 12 So we want research to improve human 13 health. We all agree based on the principles 14 established and remarkable that they were and how 15 well they've stood up in the Belmont report that 16 respect and beneficients and justice are the goals 17 of all of these various efforts to try to implement 18 responsible clinical research involving human 19 participants. 20 How do we do that? Well, I think our 21 language is important and this is probably a topic 22 that's come up to this group before. The whole 219 1 issue of human subject is becoming a bit 2 controversial. And the more some of us have talked 3 about that and discussed it, particularly with 4 members of the public, I think that more were 5 coming to a conclusion that this term is probably 6 conveying a significance that is unfortunate. 7 Subjects in general in sort of the classic sense 8 are those who are subjects to somebody. They are 9 the subjects and somebody else is the king or the 10 queen. Is that the relationship that we really 11 want to put forward by our language as we talk 12 about people participating in research? 13 I think many of us would argue that really 14 isn't the very good fit and this is not a specific 15 opinion of mine. And this is not an attempt to be 16 politically correct. I think it's an attempt to 17 try to convey with our language what we really mean 18 about the role of participants in research. 19 And so recognizing that I'll probably make 20 the mistake all afternoon and continue to use this 21 term, I'm going to advocate that we shouldn't and 22 that instead it would be appropriate to begin to 220 1 move into a language that utilizes an alternative 2 term of research participant to convey the fact 3 that both the clinician and the individual being 4 who is being involved in the research are both co- 5 participants in the enterprise, and that there is 6 more of a horizontal relationship than a vertical 7 one. Okay. 8 Having to put particular plug in, let me 9 go on to point out a couple of the things that are 10 shifting in their emphasis in research as a 11 consequence of moving from the so-called old way to 12 the so-called new way. Research protocols perhaps 13 in the time gone past had a clear goal at the 14 outset. We're trying to identify the gene for a 15 particular mendelian disorder. Whereas 16 increasingly now we're contemplating large genetic 17 epidemiological studies where one may not know what 18 studies you might want to on those materials in 19 five or ten years. And that raises the question of 20 what is the ethical way to obtain consent for such 21 studies, one of the issues which I'll come back to. 22 This is one form of shifting emphasis. 221 1 Another is that I think in the past, much of the 2 IRB oversight and certainly much of the informed 3 consent process related to physical risks. 4 Genetics have certainly presented relatively little 5 in the way of physical risk when you're talking 6 about pedigree studies. Obviously that's not true 7 in circumstances such as gene therapy where we've 8 all been awakened to the great risk there of 9 potential consequences of that sort of 10 intervention. 11 But for pedigree studies where you're 12 trying to map gene disease susceptibility to 13 physical risks tend to be quite minor. But the 14 psychosocial risks which aren't as well, in 15 general, covered in previous versions of the 16 informed consent discussion process loom much 17 larger. And that's another part of the shift here 18 that I think we're seeing over the last 15 years. 19 A the third shift, perhaps not to be over 20 emphasized but it's certainly there, is that when 21 it comes to genetics research much of this was 22 considered to be rather academic and was carried 222 1 out in academic centers. And that's certainly not 2 the case anymore and we have a vast amount of 3 genetic research now going on in the private sector 4 with legitimate concerns about whether the 5 appropriate protections for participants are 6 equivalently there in those settings as they might 7 be in academic settings, and, hence, the importance 8 of facing up to that issue. 9 So those are three areas of shifting 10 emphasis. Now, I want to sort of spend the rest of 11 my time talking about five issues. And I could 12 have chosen, I suppose, a different set of five. 13 I had interesting discussions leading up 14 to this meeting with a number of folks and 15 particularly with my own staff members Kathy Hudson 16 and Elizabeth Thompson, both of whom are here about 17 where we thought the highest priority ought to be 18 paid amongst a long list of possible topics with 19 regards to trying to beef up the understanding and 20 the implementation of appropriate oversight of 21 participation in research by human individuals. 22 And we came up with these five. And, again, I 223 1 could easily be talked into the notion that we left 2 something off or that maybe one of these isn't as a 3 important as the rest. 4 Let's begin though with the first one 5 which is the topic of the panel discussion that 6 will follow, and which has been very much, I think, 7 on the minds of many folks involved in genetic 8 research studies. Since this first came to a great 9 deal of attention as a consequence of a particular 10 instance where Mr. Richard Curtain who is here with 11 us today in the process of uncovering something 12 that was going on with a research study carried out 13 on his twin son and daughter became quite concerned 14 that his privacy was being invaded by the 15 investigator, an investigator at VCU, without his 16 having been asked for his consent. 17 And I need to give Mr. Curtain a great 18 deal of credit for raising this issue to the 19 consciousness of a lot of folks who I think 20 intended to discount this as been worthy of serious 21 consideration. It is certainly now a topic of 22 great serious consideration and we will spend much 224 1 of this afternoon on it. But I must say, it's a 2 very thorny one because we have a collusion here, 3 as often is the case in ethical dilemmas, between 4 two things that are good. 5 It is good to do research to try to 6 uncover the causes of disease and to try to come up 7 with better methods of understanding and treating 8 those conditions. But, it is also good to protect 9 the privacy of individuals and not to carry out 10 research on their identifiable private information 11 without their consent. And there are certainly 12 folks in this room, I suspect, who are deeply 13 concerned about how we could achieve both of those 14 goods simultaneously. Recognizing that pedigree 15 research has depended, for a long time, on the 16 ability to collect information about the family 17 history of the proband and we have traditionally 18 not gone to the extent of looking to see whether 19 other family members are willing to be consented 20 for this purpose or not. 21 I think now we have to face that issue 22 square on and I hope this committee will do so in 225 1 the follow-up deliberations after today. 2 I think Mr. Curtain is right that we have 3 made an assumption in the past that's not really 4 consistent with other ethical principles and that's 5 why this is such an important issue to consider. 6 So a couple of background points and maybe 7 this will help illuminate a bit the panel 8 discussion. Again, although I've said "human 9 subject" may not be a good term, it is a term that 10 is certainly written in the regs. And so in the 11 definition of a human subject, it means a living 12 individual about whom an investigator conducting 13 research obtains: (1) data through intervention or 14 interaction with the individual or identifiable 15 private information. 16 So you can certainly say in the 17 circumstance where the proband reports information 18 about their sibling or their parent which is 19 identifiable in that they are giving you in the 20 most extreme case that person's name and address or 21 phone number, and it's information that that 22 individual would consider private and would not 226 1 feel would be appropriate to be shared outside of a 2 very small group of family members, then you could 3 make the case that that converts that individual to 4 a human subject by the nature of this definition. 5 I'm sure we will debate that a bit in the 6 panel, but that certainly is a case that has been 7 made. 8 Now, if that is in fact the case then the 9 regs would say that consent either has to be 10 exempted -- and I'm not going to go into the 11 exemption because I think it's fairly difficult to 12 make a case that exemption fits in that sort of 13 circumstance, although perhaps some of the panel 14 members would like to raise that. But perhaps more 15 feasibly one might consider the IRB in a position 16 to waive consent for those family members. But 17 there are very clear statements in the regs about 18 what is required for such a waiver. And there are 19 the four criteria probably familiar to most of you 20 who have read the regs reread the regs, and reread 21 t regs, they are these four criteria. 22 That research is no more than minimal 227 1 risk; that waiver does not adversely affect rights 2 and welfare; that the research is not practicable 3 without the waiver; and that whenever appropriate 4 -- and that's an interesting clause -- subjects are 5 provided with information after participation. 6 So one of the things we should talk about 7 in the panel is whether in fact family members 8 about whom information is being obtained from a 9 proband fit the circumstance of this waiver. 10 Just one observation, certainly the great 11 concern here, or much of the concern relates to 12 whether private identifiable information obtained 13 as part of this research might end up doing damage 14 to that individual. And the damage could certainly 15 occur if that information leaked out into the hands 16 of other third parties particularly those involved 17 in employment decisions or other areas where that 18 individual might be discriminated or injured as a 19 consequence of that information becoming available 20 through the researcher's work. 21 It seems at a minimum that if one were to 22 consider a waiver of this sort it would require 228 1 very strong confidentiality and privacy protections 2 provided by the researcher. And then if IRBs were 3 to take tis route in trying to decide whether 4 family members needed to provide consent at a 5 minimum, they would have to be assured that 6 researcher has paid close attention to putting up 7 appropriate firewalls to prevent the leakage of 8 information of this sort and breaching the 9 confidentiality and privacy of participants. 10 Now, whether, in fact, if that kind of 11 firewall is there that would be sufficient to say 12 that this is a possible pathway out of the dilemma 13 is something this committee which I think this 14 committee will have to wrestle with. It is 15 certainly one possible way to look at the issues 16 but not the only one. 17 Now, in trying to delivering about what 18 kind of pathway out of this dilemma might be 19 identified there are a number of considerations or 20 questions that might be asked. First of all, this 21 is a process, pedigree research, which is been 22 going on for some time. I think it could be argued 229 1 without appropriate consideration of the possible 2 risks to family members who have not given consent. 3 I must say, I think our whole thinking process 4 about carrying out research on human participants 5 has been maturing over quite a long period of time. 6 And this is another example of a circumstance where 7 I suspect 20 years ago most people would not have 8 thought that this was a legitimate cause for 9 concern, and now I think with our consciousness 10 raised by a variety of issues, it is very much 11 appropriate to consider it. 12 But we ought to ask the question, is there 13 evidence that there have been harms carried out in 14 the past? Mr. Curtain may feel that his 15 circumstance was one of those. Are there others 16 that we have not heard about? Is there a way of 17 collecting this information? Is there a research 18 opportunity here? They're probably is. 19 Clearly we need a greater opportunity then 20 has happened in the last year or so for public 21 input about this issue in terms of what the level 22 of public concern is. 230 1 A second point that I would like to raise 2 to your attention because I think it hasn't 3 received much attention so far, is that ironically 4 in certain instances, insisting that there be 5 consent from family members, might actually create 6 harms for the proband. In circumstances, for 7 instance, where the Proband does not wish other 8 family members to know they're participating in 9 research. 10 In Huntington's disease, for instance, 11 individuals who participated in the phase of 12 carrying out presymptomatic testing once there was 13 actually a gene and you didn't need to have family 14 members available for linkage purposes, that 15 individual could find out their risk. And, of 16 course, we didn't want to do that as part of 17 clinical practice of medicine until it had been 18 carefully studied in research. Many of the 19 individuals participating in that kind of genetic 20 testing protocol for Huntington's disease were 21 quite adamant that they did not want their family 22 members to know that they were undergoing such 231 1 research, because they felt that they would in some 2 ways upset the dynamics of the family by revealing 3 that they were interested in this information and 4 they would be probably quizzed fairly strongly by 5 other family members about the results which they 6 would not want to necessarily disclose. For their 7 purposes their privacy was very important that the 8 information not be made available to other family 9 members. So that creates a certain dilemma. 10 This dilemma becomes even more acute I 11 suppose in circumstances where you're talking about 12 not necessarily genetic research but for perhaps 13 situations of domestic violence, for instance, 14 where the mere fact that the individual is 15 participating in a research project on that topic, 16 if revealed to other close family or household 17 members, might in fact place them at some risk of 18 retaliation. 19 So one cannot assume that this is simply a 20 matter of saying oh, heck, we had better just put 21 the resources into it and go out and find all the 22 family members and get their consent even though 232 1 it's going to be onerous it's the right thing to 2 do. In some instances it may not be the right 3 thing to do. It may actually, in the scheme of 4 things, create a greater harm rather than a lesser 5 one. And that needs to be thought about. 6 In terms of consistency, it's certainly 7 true now that when you carry out pedigree studies 8 where you do have consent of a number of the 9 individuals in the pedigree. There may be 10 instances in which you reveal the genotype of 11 someone who has not given their consent simply by 12 where they're positioned in the pedigree. 13 If you know that the grandfather and the 14 grandchild are carrying a Huntington's disease 15 mutation, you have revealed that the individual in 16 between them must also, even if that person was 17 opposed to the research, and not willing to 18 participate, it is a natural consequence of the way 19 that genetics works. And so one can't be 20 unrealistic about the fact that even if every 21 effort was made to get consent from all the family 22 members who would like to give it, by carrying out 233 1 the research you may still reveal genotypic 2 information on individuals who did not want to 3 participate, but, who, because of their family 4 relationships had their genotypes revealed. 5 And, of course, there is the question 6 about how far in the pedigree do you go? Are we 7 talking first-degree relative, second-degree, third 8 degree? In many pedigree studies you would like to 9 have information about cousins sometimes distant 10 cousins if you're trying to track down a particular 11 inheritance pattern. How far do you go in that 12 process? 13 I know in the panel discussion we'll deal 14 with these issues and a number of other ones, but I 15 thought he would be good to put these in front of 16 you. 17 Again, I am not here today to propose a 18 solution to this. I am here to advocate as SACGT 19 has already done in their letter to the Surgeon 20 General that it is really important for NHRPAC to 21 take this particular task on and to try to come up 22 with a well-thought-through set of recommendations. 234 1 Because IRBs are understandably left in the lurch 2 at the moment with a very unclear situation where 3 none of the current guidelines seem to be all that 4 well-written for the circumstance, and they are 5 seeking guidance and need it and need it soon. 6 Okay. The next issue I want you to think 7 about is this community consultational question. 8 And this is a bit of an expansion question about do 9 you need consent from family members? Well, if 10 you're studying an identified population or 11 identifiable population, you could consider that 12 that entire population becomes your family members 13 and do they also need to be involved in the process 14 of designing and implementing the research? 15 This has been discussed considerably over 16 the last three or four years in a number of 17 gatherings. And I think we've made some 18 substantial headway, but I would not stay there is 19 a consensus about exactly what ought to be 20 considered by IRBs that are reviewing such 21 protocols. After all, research involving 22 identifiable population's may potentially create a 235 1 risk of stigma that extends beyond the individual 2 to the whole group. 3 There is a research study going on in 4 Baltimore looking at schizophrenia where they have 5 specifically decided to look at Ashkenazi Jewish 6 individuals because of the fact that that's a 7 founder population, where, in general, genetic 8 research studies have a somewhat greater chance of 9 success because of a limited number of alleles that 10 would be expected to be found at a susceptibility 11 loca. 12 This is not to say that schizophrenia is 13 more common in Ashkenazi Jews. There is no 14 evidence that it is. But only to say that a 15 research study might be more likely to succeed 16 there. And for the same reason researchers are 17 frequently going out and looking at Mennonites or 18 Amish of people who live in Iceland or other places 19 where you'd expect there to be a limited founder 20 pool. But there is a great potential for 21 misunderstanding, as there already has been, for 22 the BRCA1 gene, for instance, which is referred to 236 1 in some press reports as the Jewish breast cancer 2 gene which is completely turning it on its head 3 misunderstanding of what's actually happened. But 4 there is a risk there. 5 So should the community be involved in 6 research, design an implementation is a question 7 that many people have been asking and many people 8 do feel the answer is yes. But it's very difficult 9 to see how to exactly how to codify this. And I'm 10 not sure how much we should try to codify it too 11 explicitly; after all in many communities it's not 12 clear who to consult with. In other communities it 13 is somewhat more clear but in many it's not so 14 obvious and how do you do this in a fashion that is 15 genuinely respectful of the fact that communities 16 themselves have a lot of diverse opinions. 17 An example of an early study in which this 18 what a major issue was the study done here in the 19 Washington area about three or four years ago 20 looking at the risks associated with BRCA1 BRCA2 21 mutations in ashkenazi individuals by collecting 22 DNA samples and family histories from over 5,000 237 1 such individuals in this area. 2 In order to set that study up and do it 3 responsibly, the investigators conferred 4 extensively with members -- leaders of the Jewish 5 community before setting up the study and designing 6 its follow-up. And I think that was a very useful 7 learning experience, not to say we got it perfectly 8 right, but I think it was a good example of a 9 genuine involvement by the community in the 10 process. And yet, one could argue that that was a 11 community that was particularly well motivated and 12 perhaps the leadership was easier to identify than 13 it would be in many other kinds of studies focused 14 on different populations. 15 Again, I think IRBs are left somewhat in 16 the lurch here without clear guidelines about this 17 kind of community involvement and what is expected 18 of an investigator who is studying an identified 19 population, and it would be very timely to give 20 this matter some consideration. 21 Stored tissue research. Well, goodness, 22 there has certainly been a lot of discussion, many 238 1 conferences, many articles written, many speeches 2 given, a few arguments that came almost two blows, 3 and I wouldn't say that at this point we've 4 completely reached the consensus. Although I think 5 we've come a long way. In that regard, the old 6 days of tissue collection might have looked a bit 7 like this here, another good cartoon from the 8 recent transition of cartoonist into scientific 9 topics. 10 But you probably have noticed that tissue 11 collection is also becoming big business. There 12 are a number of for-profit organizations and 13 perhaps another not-for-profit that are getting 14 going now to collect very large numbers of tissue 15 samples in order to make them available to both 16 academics and private companies to try to draw 17 correlations between phenotypes and genotypes and 18 how does that all fit together here? 19 Many groups have made recommendations on 20 the topic of tissue samples, but I would say it's 21 still the case that researchers and IRBs are 22 somewhat confused. NBAC, of course, weighed in, in 239 1 a very definitive and extensive way on this, but 2 those recommendations had not sort of gotten thrown 3 over the transom to the IRBs in a fashion that I 4 think they are fully ready to implement and 5 incorporate. That would be very useful thing for 6 this committee to consider. 7 A fourth issue, blanket consent; is it 8 ethical to ask individuals to give open-ended 9 consent for use of their biological specimens for 10 all possible purposes for an indefinite period of 11 time? 12 There are many instances where that could 13 be quite useful for research. If you're simply 14 concerned about facilitating research having such 15 repositories where you have a very large amount of 16 clinical information, perhaps the possibility of 17 longitudinal data and following up the individuals 18 in such studies and carte blanche to do whatever 19 kind of genotyping you'd like to try to correlate a 20 particular clinical situation with a particular DNA 21 spelling would be in many people's view a wonderful 22 circumstance for getting a lot of important 240 1 conclusions drawn quickly. And you could argue 2 that as long as the participant had the chance to 3 understand all of those things and decided to give 4 their consent to such open-ended use of there 5 biological specimens, who are we to say that they 6 shouldn't do so. 7 On the other hand I think there are many 8 people who feel that that kind of open-ended 9 consent really doesn't meet the standard that we 10 expect when we use the words "informed consent." 11 How could you be informed about a host of 12 possible future uses that the investigator doesn't 13 really have the ability to enumerate. And in that 14 circumstance, maybe we need to do better. 15 So the alternatives for consent for such 16 large genetic epidemiological studies, and there 17 are many of them getting underway, and I think they 18 are going to be extremely important for the future 19 of genomic and genetics and the medical 20 applications thereof. One can, of course, 21 anonymize the specimens. But in the process you 22 undoubtedly run the risk of losing clinical 241 1 information because if you're truly anonymizing the 2 specimens you may have to strip off enough clinical 3 information that nobody could actually track that 4 back to the individual, and, of course, in the 5 process, it makes it very difficult although not 6 quite impossible to incorporate ongoing 7 longitudinal information about clinical follow-up. 8 There is the middle ground here were you 9 obtain a relatively narrow individual consent for 10 initial uses. And then maintain contact with the 11 participant and recontact them for future uses that 12 did not fall within the original consent. And then 13 there is the blankets consent that I've already 14 mentioned. 15 I think many folks would like to see this 16 migrate in the direction of the middle option here 17 without being quite sure how to set that up. And 18 it would be very useful to have a statement -- 19 recommendation from this committee about whether, 20 in fact, blanket consent is considered ethical in 21 some circumstances and if so what would they look 22 like? Because investigators I think are truly 242 1 interested in trying to have some guidance here and 2 IRBs are as well. 3 This is going to come up a lot. I've 4 talked in the last three or four months to at least 5 four different groups that are proposing to carry 6 out very large genetic epidemiological studies 7 where they basically want to test every hypothesis. 8 And it would be most convenient for them to carry 9 out blanket consent that they want to know. Is 10 that something that is legitimate? Their IRBs want 11 to know too, is that something that can be done 12 without violating basic principles of what informed 13 consent is all about? 14 Finally, disclosure of research results. 15 This is an issue also that I think is somewhat 16 controversial. Under what circumstances should 17 research results that may have very little meaning 18 at the sort of immediate stage of carrying out the 19 project be disclosed to patients or to 20 participants, rather, and under what circumstances 21 is it legitimate not to do so, providing that, of 22 course, the investigator has informed the 243 1 participant up front that that information is not 2 going to be made available. 3 There is a bit of the controversy, NBAC 4 coming in on this says that disclosure of research 5 results to subjects represents an exceptional 6 circumstance. If you look at the currently under 7 review regulations provided by the Secretary in 8 response to the mandate from HPPA to have such 9 privacy regulations, and these are currently under 10 review, it suggests that the individual does have 11 rights of access to inspect protected health 12 information which would include a lot of research 13 information, except when access would violate CLIA, 14 that is that the results were carried out in a non- 15 CLIA-approved lab or research that includes 16 treatment in progress as in a double-blind study, 17 for instance, where it would perhaps invalidate the 18 study. 19 So there's a bit of a discordance here 20 between these views. A number of folks have 21 weighed in on this without passing judgment on 22 whether these particular criteria are the right 244 1 ones. Here are certainly five that have been put 2 forward that it is reasonable to disclose research 3 results: first, if the finding is scientifically 4 valid and confirmed, and that will often not be the 5 case of course. 6 If you're carrying out a linkage study and 7 you have a lot of genotypes who knows at the moment 8 when you do those first genotype's what they mean? 9 It takes a lot of follow-up before you 10 have anything that you could say has validity and 11 has been confirmed. Clearly based on other parts 12 of the law, if you're giving results that are going 13 to in anyway influence clinical decisionmaking they 14 should be obtained in a CLIA-approved lab, and so 15 since most research labs are not CLIA-approved then 16 you have a bit of a collision here. 17 The findings have significant implications 18 for the subject's health that would certainly 19 increase your sense of responsibility and 20 disclosure. A course of action readily available, 21 that is, it is not only clinical valid but 22 clinically useful would greatly increase the 245 1 mandate to disclose and, of course, the ability to 2 provide caring counseling so you're just dumping 3 valid information into people's laps. 4 But this is an area also that needs 5 considerable attention and I think at the moment 6 many IRBs are not clear. When they get an informed 7 consent form that says, "the results obtained in 8 this research study are not going to be made 9 available to you the participant." Is it okay to 10 go along with that, or is that in violation of some 11 other principles as have been recently enunciated 12 in the Secretary's regs. 13 A fifth issue then on your already very 14 full plate, finally, I would say, for all of these 15 the IRB guidebook, which is what IRBs are currently 16 trying to work with, was last updated in 1993. 17 Going through and glancing over it we encountered a 18 number of howlers that really give you pause about 19 whether anyone could find appropriate answers to 20 the kinds of question that are being asked today. 21 There's virtually nothing in there, for 22 instance, about studies on genetic alterations that 246 1 might confer a predictive risk of future illness. 2 It just sort of wasn't much talked about in 1993. 3 So immediately I would suggest there is a need to 4 take the guidebook and update it, but, of course, 5 the most effective updating would be predicated 6 upon some consensus for the five problems that I've 7 posed in front of you, and probably a few others as 8 well, and that is going to be a difficult and time- 9 consuming enterprise. 10 I must say, finally, in conclusion here, 11 we have a problem in front of us here about privacy 12 and particularly public concern about genetics. I 13 am personally delighted that this committee has 14 come into being; personally delighted that Greg 15 Koski has come here to oversee this effort with a 16 very approach he has taken; and counting on all of 17 you to help us see our way out of this thicket and 18 offering myself and my staff in anyway that we can 19 be of use to you in helping you come up with some 20 consensus ideas about how to do these two good 21 things: do wonderful research that's going to 22 advantage human health as quickly as possible but 247 1 also protect the interests of the human 2 participants without whom none of this will happen. 3 Thank you very much. 4 [Applause.] 5 CHAIRPERSON MARSHALL: Bob, did you have a 6 comment or -- Bob Levine? 7 DR. R. LEVINE: Yes. Thank you. A very 8 good, comprehensive look at the field given the 9 time constraints. I just what to make a couple of 10 short comments. First, the word "subject" as in 11 research subject is under attack I think 12 unnecessarily. People who are attacking it says 13 that it is used because it talks about subjects 14 like subjected is to the king. 15 Actually, the first use of this word in 16 medical matters was it was used to introduce a 17 person who was going to be discussed at teaching 18 rounds. And the word "subject" is in the sense of 19 the topic for conversation. 20 If we shift to participant as many people 21 are arguing for, you're still going to have to 22 invent new language to figure out whit could have 248 1 been participants have to file financial 2 disclosures. Which ones will become co-authors? 3 Which ones are responsible for informed consent? 4 And you're going to end up back where you started 5 anyway. 6 Another comment I want to make is an 7 attempt to make current policy conform to the 8 regulations definition of human subject. That was 9 a faulty definition the day it was written. Many 10 of the definitions in the regulations are based on 11 the recommendations of the National Commission for 12 the Protection of Human Research Subjects. That 13 one was not. And I think instead of changing 14 policy to conform to this faulty definition, we 15 ought to write a definition that's valid. 16 One final point. Francis, you're very 17 concerned about forcing everything to fit under the 18 rubric of informed consent. And you rightly ask, 19 how could one be informed of all possible future 20 contingencies? 21 Historically tbe requirement for consent 22 that was introduced into the field of research 249 1 ethics is in the first sentence of the Nuremberg 2 code and it calls for voluntary consent. And while 3 you might not be fully informed about everything 4 that will happen in the future, you could say, I've 5 thought about it and it's my judgment that I'm 6 willing to have my tissue used for various purposes 7 into the foreseeable or even unforeseeable future. 8 Curiously that term "informed consent" was 9 introduced into our lexicon in an Amicus brief 10 filed by the American College of Surgeons, and they 11 were actually opposing the concept. But the judge 12 was interested in it and since that time "voluntary 13 consent" has been called "informed consent." 14 Thank you. 15 CHAIRPERSON MARSHALL: Thank you, Bob. 16 DR. MORENO: Can I get one word in 17 edgewise, Mary Faith? 18 CHAIRPERSON MARSHALL: Yes, please do, 19 while we're -- 20 DR. MORENO: Actually, as Bob knows from 21 hearing me talk about this before, the term 22 "informed consent" was actually introduced in the 250 1 context of an Atomic Energy Commission letter that 2 was written in a classified conversation in 1947 in 3 a research context that had to do with the use of 4 radioisotopes. So, in fact, the term "informed 5 consent" does come up in a research context, not in 6 the clinical context so far as we know. And the 7 first documented instance, I think that's 8 historically important. 9 Nonetheless, I too was thinking, when 10 Francis was talking, about the fact that we do have 11 this rich history of the use of the concept or the 12 notion of voluntary consent. And I think that's 13 one we ought not to forget perhaps in future 14 discussions. 15 DR. R. LEVINE: Jonathan, I ll concede the 16 point. 17 [Laughter.] 18 DR. R. LEVINE: However, I said, 19 "introduced into the general lexicon." One of the 20 problems with the conversation that you're 21 reporting on now is that it was classified as top- 22 secret. 251 1 [Laughter.] 2 DR. MORENO: Actually, it wasn't 3 classified as top-secret but it was classified. 4 [Laughter.] 5 DR. MORENO: Do you want to split another 6 hair? 7 [Laughter.] 8 CHAIRPERSON MARSHALL: Abbey. 9 Oh, I'm sorry. Mary Kay. 10 DR. PELIAS: I think we're going to spend 11 a lot of time talking about language as we try to 12 get to the bottom of these genetics problems. And 13 while we're quibbling about subjects and 14 participants I'd like to remind everybody that we 15 have a few words in the world of genetics research 16 including "ProBand." Also we use the word 17 "informant" who is the individual who gives us 18 information and who may be the mother of the 19 ProBand who first came to clinical attention and we 20 have family members usually with people that we 21 talk about in terms of the immediate family of the 22 ProBand, and we have collateral relatives. So we 252 1 have a lot of language already floating around that 2 means a lot in the world of genetics research and 3 may be appropriately applied to ideas of subjects 4 and participants. 5 CHAIRPERSON MARSHALL: Thank you. I 6 really don t want to get into a discussion because 7 we need to move along. Abbey, just a brief 8 comment. 9 DR. MEYERS: If it looks like a duck and 10 it walks like a duck, it s a duck. And once you 11 start using those kinds of words, you're going -- 12 ordinary people will not understand it. They are 13 not genetic professionals. So if we just talk 14 about people and persons, I think we ll keep it on 15 a level that I think people understand. 16 But in this one question, this burning 17 question that s in front of us, I m absolutely at a 18 loss. It s gone through my mind, you know, for 19 several weeks. When I go into see a new doctor he 20 takes a medical history, hands me a piece of paper 21 and he wants to know what all of my relatives had 22 kidney, liver, you name it, it's there. If we say 253 1 that this issue of the secondary consent is 2 important, then we will stop local doctors even 3 from asking you what your relatives have and that's 4 just totally unacceptable. 5 Now, I really want to know from Francis 6 what do you recommend? 7 CHAIRPERSON MARSHALL: I think that this 8 discussion is a little bit premature. I would like 9 to hold off until we have heard from our panel and 10 then we will open the floor up for discussion. 11 So, in terms of speaking to and of 12 persons, I would like to introduce to you Jeff 13 Botkins, from the Department of Pediatrics at the 14 University of Utah. He is going to make a 15 presentation using the computer. But we also have 16 other members of the panel, and perhaps once Jeff 17 is through the entire panel could convene here and 18 Dr. Collins is going to moderate it. 19 Terri Arledge with GalaxoSmithKlein. 20 Sharon Terry who is vice president for Consumers of 21 Genetic Alliance and president of PXE 22 International, and Terri Seargent who is a consumer 254 1 advocate with the Alpha One Association. 2 So, Jeff, when you're done, if all of you 3 could then convene up here and Francis will 4 moderate the panel and I d ask each panel member to 5 please remember that you have 15 minutes. We are 6 already slightly over time and we want to have 7 enough time for a fruitful discussion later. So 8 please do not go over time. 9 DR. BOTKINS: Good. Thank you, Mary 10 Faith. 11 It's a privilege to be here. I come to 12 this discussion as somebody who has been involved 13 in pedigree research for about the last five or six 14 years also an IRB member and somebody who's been 15 interested in the ethical, legal, and social issues 16 for a number of years as well. 17 And as you'll see from my analysis of the 18 issues that I'll present to you, I think for the 19 most part IRBs can make reasonable judgments on 20 these issues largely within the framework of 21 contemporary regulations. I think that there may 22 be a little bitter shoe-horning necessary but, for 255 1 the most part, I think the regulations have served 2 us well for the last 20 years and from my 3 perspective there doesn't need to be a fundamental 4 change in order to address these new issues. 5 As Dr. Collins had outlined, the issues 6 are pretty straightforward. And I think that many 7 of you may have seen an article I had published a 8 number months ago that was in the packet. And what 9 I'm going to do is just touch on the analysis that 10 I outlined in the article pretty quickly and then 11 move on to additional concerns and some 12 clarifications that have arisen since that 13 publication. 14 So really the issues are when do family 15 members and social contact become subjects 16 themselves? And then the second level analysis, if 17 you determine that they are subjects, when is it 18 necessary to obtain consent? And I think the key 19 issue from the investigative standpoint really is 20 the consent issue. Do we really have to go out and 21 get consent to enroll these folks in our projects? 22 And of course this issue tends to come up 256 1 primarily in the genetics context but it's relevant 2 to any other context in which were asking one 3 individual about potentially private information 4 about others, whether that's students or faculty or 5 employees et cetera. 6 Definition of human subjects I think it's 7 been touched on a couple times today already, 8 identifiable private information readily 9 ascertained by the investigator and those are the 10 key concepts that my comments are going to hinge 11 on. 12 So an individual is a human subject for 13 the purpose of the regulations when individuals are 14 readily identifiable, again, to the investigator 15 and the information required constitutes private 16 information. 17 When are family members not readily 18 identifiable? I think at least a couple of 19 circumstances. Obviously anonymous primary subject 20 and no unique identifiers on family members. A 21 second situation where you may have an identifiable 22 source, but the family data has been unlinked in 257 1 some fashion perhaps an epidemiologic study. And 2 then, thirdly, family members are identified by 3 family relationship alone to an identifiable 4 subject. And I think this may be an issue for some 5 discussion in controversy. Does Jeff Botkin sister 6 constitute a unique identifier for my sister or 7 does it not? My claim is that in fact it does not 8 without additional information about the specific 9 identity of my sister. 10 When are family members readily 11 identifiable straightforward when unique 12 identifiers are obtained such as full names and 13 addresses and I think there may be ambiguous 14 circumstances like initials or first initials and 15 birth dates, et cetera, that may be t subject of 16 some discussion. But I think from my perspective 17 this aspect is straightforward. 18 So the implications are detailed health 19 information can be acquired on family members as 20 long as the information is not linked with unique 21 identifiers. 22 Now, what constitutes private information? 258 1 This really has been the focus of considerable 2 discussion in this arena. My claim here is only 3 slightly more specific than what is within the 4 regulations themselves. And my claim being that 5 information over which individuals usually want and 6 can maintain control. And I think that does 7 include health information and things like 8 reproductive history and legal history. 9 I would make the distinction between types 10 of personal information that are readily accessible 11 by casual social contacts, age, employment, family 12 structure. Now these are issues that of course 13 sometime people are sensitive about, but I would 14 still draw a distinction between private 15 information and information that is generally 16 available within our normal social interactions. 17 So the implications, again, family members 18 are not human subjects if they identifiable, but no 19 private information is retained. Family members 20 are human subjects if there are unique identifiers 21 and private information is retained. 22 So once one has made a determination of 259 1 whether the secondary subjects or family members 2 social context, et cetera, are human subjects then 3 the second level of analysis is relevant and that 4 is, do we have to get consent from these folks and 5 can we waive it? Dr. Collins had already talked 6 about or outlined these four criteria that are part 7 of the regulations. And I'm going to focus on 8 number one and number 3, specifically. 9 You folks here are probably well aware of 10 the definition of "minimal risk." So here's the 11 key question: does the recording of health 12 information on secondary subjects pose more than 13 minimal risk? And you need to consider both the 14 probability of a breach of privacy and the 15 magnitude of harm should that breach occur. 16 So I would say there's a couple factors in 17 the magnitude of harm. One is whether the health 18 information is existing or not. And much of the 19 discussion around genetic information has focused 20 on research protocols in which new information is 21 generated about the future health risks of an 22 individual, say BRCA1, testing protocol, for 260 1 example, heritor colon cancer risk, et cetera, in 2 which new health information is being generated by 3 the protocol. 4 That's clearly not the circumstance here 5 in that we're dealing with existing health 6 information. You're already relating information 7 that is obviously known to the family members about 8 that individual. I would make a distinction, 9 however, about whether the information is what I've 10 termed "highly sensitive" or perhaps not exactly 11 merely sensitive but at a somewhat lower level of 12 sensitivity in suggesting that there are few 13 aspects of research that may be focusing on sets of 14 information that individuals might consider more 15 problematic because they are elements of social 16 stigma involved should there be a breach in 17 privacy. And I've listed the mental health 18 conditions and I would say that that should not be 19 taken as an all-inclusive or absolute condition but 20 certainly some mental health conditions I think 21 still are associated with significant stigma and 22 discrimination. 261 1 Issues like sexual orientation, criminal 2 records, substance abuse records, et cetera, are 3 the kinds of things that I think may constitute 4 more than minimal risk in the conduct of this kind 5 of research. 6 So those are the recording of information 7 on secondary subjects more then minimal risk -- 8 issue and I think the second aspect the magnitude 9 is the probability. And the IRB needs obviously to 10 look at the data management protocol for the 11 proposal in front of it. What's the protocol 12 that's being developed for the management of this 13 kind of information? How well have interviewer and 14 data management personnel been trained? And data 15 security measures. 16 And I think from a perspective in my 17 experience the risk posed to privacy is at a 18 personal level rather than at a database level. 19 And I think the risk of people hacking into 20 databases or getting into locked cabins is 21 relatively remote. The possibility of individuals 22 who are the interviewers coming across a juicy 262 1 tidbit of information that is shared among 2 colleagues, I think is where the real risk arises. 3 And this was illustrated with some of our 4 research protocols in which a member of the kindred 5 we were working with was a graduate student at the 6 university as it turned out. Our interviewers were 7 graduate students at the university. 8 The second project we were looking at 9 genetic testing and the local Ashkenazi jewish 10 community and many of those individuals are faculty 11 members at the university. So I think it's those 12 sort of personal contacts that may end up being a 13 greater risk to privacy in this context than data 14 security measures, per se. 15 So my conclusion is recording of health 16 information on family members poses minimal risk if 17 health information is not highly sensitive and if 18 there are careful protocols and strong data 19 security measures in place. 20 The practicability of research without the 21 waiver, I think a lot of folks are reasonably 22 concerned that significant additional burdens of 263 1 informed consent will not make research projects 2 feasible. I think the question in this context is 3 not, can this research project be carried out 4 without a waiver if the project has not been 5 adequately developed to address these issues. 6 But rather, I think the appropriate 7 question is, could this line of research not be 8 pursued if consent was a requirement. 9 And I think along with this investigators 10 and funding agencies clearly need to plan for 11 appropriate support for consent where necessary. 12 And I think this is a new trend in the last five to 13 ten years that funding agencies need to be aware of 14 and need to evaluate protocols appropriately for 15 data management. 16 So conclusions, from my perspective, are 17 family members human subjects? Yes, if unique 18 identifiers are associated with individual data and 19 information consists of the kinds of things that 20 we're typically interested in, health status, 21 health history, et cetera. 22 If family members are human subjects, can 264 1 consent be waived? Yes. It's minimal risk and 2 which I would consider not highly sensitive data. 3 And you have strong data security measures in 4 place. And then the other three criteria would 5 have to be addressed as well. 6 Now clarification that's emerged in this 7 debate the I've heard. First of all, the analysis 8 that I presented would require consent from only 9 selected family members. So only those individuals 10 on whom you are retaining private information that 11 are relevant. Those family members who you haven't 12 obtained any particularly interesting information, 13 they're healthy, then it's not clear to me that 14 consent needs to be obtained from those 15 individuals. 16 Secondly, this analysis is not relevant to 17 take a family history in clinical medicine. I 18 think there are privacy concerns with taking a 19 family history in clinical medicine, but these are 20 not -- this is not the place to debate or be 21 concerned about those. I think a justification for 22 family history in that context is quite different 265 1 and I don't see any reason why that should be 2 impinged by this current debate. 3 Thirdly, and this is something that Dr. 4 Collins had already mentioned, some family history 5 data can be extremely sensitive. Have to find some 6 better terms here -- history of child sexual abuse, 7 for example. How would one do research on that in 8 pursuing the alleged abuser for consent is not an 9 appropriate way to proceed. And so however the 10 guidelines are developed, there would have to be 11 obvious attention to this kind of circumstance. 12 Additional problems. Temporary retention 13 of private information on subjects before consent 14 is obtained. Now, I think very important to 15 emphasize that the way that I've approached this 16 argument is to identify subjects only after you've 17 obtained the private information. So, in a sense, 18 it's backwards from our traditional approach which 19 is to obtain consent before you pose the risk to 20 the individuals. 21 Now, the alternative here is to get 22 consent on everybody before you even start to ask 266 1 questions about family history. Now, I find that 2 to be entirely impracticable, and that wouldn't be 3 shut down research. And so this, from my 4 perspective, is indeed a compromise, but one that 5 has to be directly addressed. 6 Secondly, next ask the family members. 7 That can be ascertained indirectly from testing the 8 family members and Dr. Collins already noted this 9 difficulty. You test one individual and you know 10 the parent from the affected kindred is affected 11 also. Does the fact that you know that information 12 and know the identify of that individual all of a 13 sudden make them a subject? And this is really a 14 tough nut to crack if you try to think about the 15 consent implications in that circumstance. 16 And then, thirdly, deletion of data when 17 subjects decline participation. A smaller point, 18 but still one that needs to be addressed. You've 19 identified a subject. You think consent is 20 required. They don't consent to participate with 21 you. What is necessary from your perspective at 22 that point. Simply remove the identifiers from 267 1 that individual or does all the data and 2 identifiers need to be expunged from the database, 3 et cetera. 4 A smaller point, but I think one that's 5 been floating in genetics for a while about what 6 constitutes withdrawal from research in pedigree 7 studies. 8 This was raised by Dr. Walter Nance and 9 also our research group at Utah with this debate. 10 And the question is: Can we ask family members to 11 assume some responsibility for guarding the privacy 12 of family members? And I think folks have 13 appropriately pointed out that people can refuse to 14 participate at any time they would like and can 15 refuse to answer questions about their family 16 members. It may add some additional layer of 17 protection to reinforce to those individuals, but 18 they probably shouldn't be telling you things that 19 they think the family member might object to. 20 Now, I don't think that's a solution to 21 this problem, but it's worth considering as 22 potentially an additional layer of protection. 268 1 And then lastly, just some research 2 strategies to consider. Obviously development of 3 careful protocols anticipate this problem from the 4 beginning. And I think for those genetic studies 5 that are involved in identifying so-called 6 interesting families are then subsequent more 7 detailed analysis. It's not clear to me, at least, 8 that many of those initial projects need to be done 9 with identifier. 10 As you interview a large number of 11 individuals and you've now identified a kindred or 12 two or three that you think may be valuable for 13 research, then you can focus your resources, obtain 14 consent from those individuals within the family, 15 and obtain their medical history. And I think 16 obviously a significant advantage of this approach 17 is that you're going to get a much better history. 18 As folks have noted, the accuracy of secondhand 19 information on health status is poor. And so as 20 you talk only to primary subjects about the health 21 status of their family members, that can only be an 22 initial stage of research because the quality of 269 1 that information in many circumstances is not very 2 good. 3 So by talking to the secondary subjects 4 directly, not only do you address the consent 5 issues, but obviously you get first-hand higher 6 quality health data than you would otherwise. 7 And then lastly, the broad survey is 8 designed to create a database resource for research 9 which is in part how this whole issue arose. You 10 should seriously consider avoiding highly sensitive 11 questions of the kind that I've outlined and that 12 may make the database less valuable for the conduct 13 of research, but may help get around some of these 14 difficult issues by not including data items that 15 would be considered greater than minimal risk. 16 So in a whole, I think from my 17 perspective, these are legitimate issues that raise 18 a number of complex questions, but I think it 19 really does offer an opportunity to think through 20 these issues and potentially to significantly 21 enhance the quality of research in this arena 22 without really creating significant roadblocks to 270 1 the conduct of this work. 2 So thank you. 3 DR. COLLINS: Thanks, Jeff, for staying 4 precisely on time. That's much appreciated. 5 I think we should hold the discussion 6 until all the panel has presented because I think 7 we'll see a number of these issues raised from 8 different perspectives by all four. And we do have 9 time then for considerable opportunity for 10 discussion. 11 The next presentation is Terri Arledge. 12 Clearly the private sector is increasingly involved 13 in genetic research, both in pharmacogenetics and 14 the effort to identify susceptibility risks that 15 will lead you to new ideas about therapies and so 16 it's highly appropriate to have one of our 17 presenters, in this case, Terri, who comes from 18 GalaxoSmithKline. All of us are still trying to 19 figure out how to say that since it's a fairly 20 recent merger between Galaxo Wellcome and 21 SmithKline Beecham to come and give a perspective 22 from the private sector about that is important 271 1 issue. 2 It looks like we're ready to go. Terri. 3 DR. ARLEDGE: Good afternoon. My name is 4 Terri Arledge. I'm the U.S. department head of 5 drug development genetics at GalaxoSmithKline. 6 Today I want to talk to you about the 7 pursuit of better medicines through genetic 8 research and I want to thank you for inviting me. 9 The overview of the presentation that I'm 10 going to be giving today in the next 15 minutes, 11 what I want to do is talk about the genetic 12 research goals and initiatives at GSK. I'm also 13 going to touch on a multi-industry group, 14 pharmacogenetics working group that's addressing, 15 ethical, legal and regulatory issues with genetic 16 research and to drug response. We call that 17 pharmacogenetics. 18 And I will present GSK's perspective on 19 family consent and suggested points to be 20 considered. 21 What are the key genetic research goals at 22 GSK? First we want to identify susceptibility 272 1 genes for common diseases. These would be common 2 diseases with large unmet needs. The objective is, 3 once we identify the susceptibility gene is to 4 better understand the disease, hopefully identify 5 new targets, and come up with better therapies. 6 We want to use the results of the genetic 7 research to discover new medicines. We want to 8 improve the safety and efficacy of medicines by 9 understanding the genetic basis for both positive 10 and negative drug response in individuals. 11 Now, this is on both our marketed 12 compounds and drugs that are in development at this 13 point. And we want to promote education and 14 informed discussion about genetic research. 15 Now, we have a genetics counselor on staff 16 who acts as an interface with our patient groups 17 and health care providers. We also have personnel 18 who are involved in the ethical, legal, and social 19 issues discussions involving our genetic research. 20 Now, there are really two key initiatives 21 in genetic research at Galaxo Wellcome. 22 First we've got understanding drug 273 1 response which is the area that I work in. Where 2 the objective is to correlate genetic markers with 3 safety and efficacy outcomes and target treatments 4 appropriately for the right patients. We get the 5 right medicine to the right patient. 6 The other initiative is to better 7 understand the disease. And this is the area where 8 we're looking at disease susceptibility genes in 9 order to build or better understand the disease, 10 come up with new targets, and develop new 11 therapies. 12 Our clinical genetics networks have been 13 set up to look for disease susceptibility genes. 14 These are large, interimational studies among 15 academic institutions, genome screening centers, 16 and genetic epidemiology centers. 17 The clinicians and the genetic 18 epidemiologists have come together to develop 19 protocols with well-characterized, standardized 20 patient assessment criteria. 21 The investigator collects a detailed 22 family history, clinical information, and DNA from 274 1 affected and unaffected siblings and parents. 2 Informed consent is gathered from all study 3 participants and the information, the data and the 4 blood sample, or DNA sample are coated with a 5 patient code number prior to leaving the 6 investigational site. 7 Again, what we want to do is identify 8 susceptibility genes, look for new targets, look 9 for better therapies. 10 Examples of some of the common diseases 11 that we're looking at right now include asthma, 12 depression, COPD, early onset heart disease, and 13 osteoarthritis. 14 Now, pharmacogenetic research is the type 15 of research that I'm involved in. What we are 16 looking at is how genetic differences among 17 patients influence your response to medications. 18 In some of our drug development trials, GSK has 19 included pharmacogenetic research. Participation 20 in the pharmacogenetic research portion of the 21 trial is voluntary. 22 Patients who are in the main clinical 275 1 protocol do not have to participate in 2 pharmacogenetics. If they choose to, they sign a 3 separate informed consent, they give us a DNA 4 sample, that's coded with the subject trial 5 identification number, only the investigator, the 6 physician at the site, can actually link a number 7 to a patient name. And that information is used -- 8 we use that information to correlate drug response 9 with genetific information. And that's from pooled 10 data, either pooled across the study or pooled 11 across multiple studies. 12 Now, the SNP map is also offering us a new 13 avenue of research in pharmacogenetics. Basically 14 what we think will happen is because the SNPs are 15 fairly frequently and evenly distributed along the 16 genome, they make for good landmarks for what we're 17 looking for. 18 What we are anticipating is that we'll end 19 up with a section of the SNP profile in which we've 20 got patients without a side effect and patients 21 with a side effect. And they end up with a SNP 22 print that is predictive of the specific side 276 1 effect. 2 Now, we would use this information to 3 build the medicine response test so that health 4 care providers are able to choose the right 5 medication for their patients using this further 6 information that we can provide. 7 I also want to touch on the 8 pharmacogenetic working group. This is a multi- 9 industry group. It involves 12 pharmaceutical 10 companies that have gotten together to advance the 11 understanding and development of pharmacogenetics 12 by openly addressing and disseminating information 13 on noncompetitive topics such as ethical, legal, 14 and regulatory issues. 15 The first output, the first example of 16 what they've been doing is that they define the 17 terminology we use in pharmacogenetic research. So 18 they came up with standard definitions for coded, 19 de-identified, anonymized, and anonymous. If we 20 are all using the same terminology, it makes it 21 much easier for ethics committees, IRBs, 22 regulators, sponsors, investigators, and patients 277 1 to understand what it is we want to do with the 2 samples and the data. 3 Now, these standard terminology have been 4 accepted by the NIH pharmacogenetic working group. 5 Their follow-up activities include 6 sponsoring symposia, preparing publications, 7 interfacing with U.S. and European regulators, and 8 addressing elements of pharmacogenetic research 9 protocols and consents. 10 Now, I do want to -- now that you have 11 background on what we're doing and why, I did want 12 to try and go through a few things that I would 13 like the committee and others to consider when they 14 are discussing this issue. One is, is there a 15 distinction among different types of research? Are 16 there different social, ethical issues associated 17 with genetic testing or genetic research on a 18 monogenic disease versus looking for disease 19 susceptibility genes for common illnesses or 20 looking at pharmacogenetics. 21 Additionally, as has been mentioned 22 before, there are implications for study 278 1 participants. Requiring family consent might 2 impede study participation. And we also want to 3 look at the implications for the feasibility 4 research. And while it's inappropriate to say that 5 costs are inconvenience, it's at all a justifiable 6 reason for trampling on anyone's rights. We do 7 need to make certain that when we implement family 8 consent that it's done in a way that doesn't 9 completely shut off important research. 10 Some of the points that we would like to 11 be considered during the discussion and debate is 12 the scientific rationale for collecting family 13 history. Is there strong scientific rationale? 14 Is there justification for the degree of 15 detail that's been collected? Is there some degree 16 of confidence that the subject is a credible source 17 of family history? Has the researcher implemented 18 safeguards in data collection environment, data 19 access, and release of data and results? 20 Now, we think that informed consent is 21 critical to ensuring that patient's rights and 22 welfare are protected. And we think it's the 279 1 responsibility of sponsors, ethics committees, 2 investigators, everyone involved in clinical 3 research and in all types of research to ensure the 4 integrity of the consent process. 5 We would, however, make a few 6 recommendations to be considered during the 7 discussions. We think that responsibility for 8 assessing family consent issues should remain with 9 local investigators, ethics committees, and 10 research sponsors. And that what is valuable would 11 be educational and guidance materials developed for 12 use by researchers, ethics committees and sponsors. 13 Thank you. 14 [Applause.] 15 DR. COLLINS: Thank you very much, Terri. 16 We now have the opportunity to listen to a 17 couple of perspectives from notable consumers. And 18 I think that's highly appropriate for this 19 particular discussion. For some reason three- 20 quarters of the people on this panel have Terri as 21 their first or last name which may lead to some 22 confusion -- 280 1 [Laughter.] 2 DR. COLLINS: -- but I'll try not to fall 3 into that trap. 4 The next presenter is Sharon Terry who -- 5 as the co-founder of the pseudoxanthoma elasticum 6 interimational effort which is a consumer group 7 studying this disorder called PXE -- has played a 8 significant role for that disorder, but in a much 9 larger way with the genetic alliance has been one 10 of the true leaders in the enterprise to try to 11 raise consciousness about the issues that surround 12 families that are struggling with genetic disease 13 and at the same time trying to encourage research. 14 And so Sharon brings a great deal of experience to 15 this issue. And as soon as we get the computer to 16 work we will get to hear about that. 17 While we're waiting, I meant to say in my 18 presentation, there is a trans-NIH group that has 19 recently formed to look at this question about 20 obtaining consent from family members in pedigree 21 research because it is of great interest to the NIH 22 to see how this plays out. That group is being co- 281 1 chaired by Jim Hanson and Sarah Carr who are both 2 here today and I'm sure would be glad to say more 3 about what the goals of the group are. It's 4 relatively early in its existence, but it is 5 another entry into this area that hopefully will be 6 collecting useful data to inform the discussion. 7 How are we coming. It's a big file. 8 Sharon Terry. 9 MS. TERRY: Thank you. Today I'm going to 10 give you briefly a consumer perspective on informed 11 consent and third-party issues. I'm going to begin 12 by speaking about my perspective which is informed 13 by my experience. I'm the parent of two affected 14 children. As Francis mentioned, my husband and I 15 learned about five years ago that our kids had a 16 rare genetic disorder and learned some rather 17 devastating things a couple days before Christmas 18 and so went through all the typical things that 19 parents do in this situation. 20 I'm also a participant in research. Two 21 days after our kids were diagnosed, our blood was 22 drawn without informed consent. 282 1 I'm also a researcher. I've done a great 2 deal of research on this disorder leading to back- 3 to-back papers in nature genetics last year and 4 also filing an application for a patent on the PXE 5 gene. 6 I have a masters degree in religious 7 studies. I am truly a consumer and come to this 8 entirely as a consumer and not as a scientist. 9 I'm the administrator for PXE 10 Interimational, we have 2,000 affected individuals 11 registered, 50 offices worldwide. I run a 17-lab 12 research consortium. And I'm a board member for 13 the genetic alliance which is a coalition of over 14 300 lay advocacy groups working to promote healthy 15 lives for people with genetic diseases. 16 In 1995 Elizabeth and Terry were diagnosed 17 with PXE. I do have informed consent to use this 18 picture. 19 [Laughter.] 20 MS. TERRY: And they do charge me a 21 royalty every time I use it. 22 [Laughter.] 283 1 MS. TERRY: We went through all the 2 typical things that parents do being overwhelmed 3 with what this disease meant to us and our family 4 and our children. But then decided to face this 5 head on and look at what we could do to advance 6 research on the disorder. 7 We realized quickly that there was a 8 scientific and political reality and that is that 9 gene discovery and genome sequencing have no 10 meaning unless correlated with real people. So all 11 the wonderful hype and excitement around sequencing 12 the genome is important, but until we get the 13 correlations we need, they won't be as useful as we 14 need them to be. 15 Talk a little bit about informed consent. 16 I see that really as a seesaw balancing on ethical, 17 legal, and social issues. And a number of 18 continuums being really critical in considering the 19 risks. And those continuums we have talked a 20 little bit about earlier, the type of research, the 21 length of research, common versus rare diseases, 22 the morbidity of the disease, the mortality, the 284 1 perceived stigma, familial awareness about the 2 disease and the community climate. 3 And until we really start to look at the 4 nuances of those balances and those risks and 5 benefits, I don't think we can make any kinds of 6 assumptions in general about informed consent. 7 When our parents deliver genetic 8 information to us as offspring that all of our 9 information comes from our parents, and we don't 10 ask our parents if we can give that information to 11 our offspring. And so in some sense genetics and 12 genetic information presents a whole new scenario 13 and new understanding of family. 14 I didn't ask my parents if I could give 15 their genes. I assume that that, of course, would 16 be fine. And so I believe also inherent in that is 17 something of their medical history and my medical 18 histories being passed to our children. And I 19 think it redefines family in a new way for us as 20 people and as something that we need to discuss as 21 a society. 22 Informed decisionmaking we think begins 285 1 with the individual and we've heard a little today 2 about some other pieces of that and I propose to 3 make that fairly concrete and say that the 4 individual resides within a family and there isn't 5 anyway to divorce informed decisionmaking for an 6 individual from the family. Even if the person is 7 alienated from the family, genetics ties them to 8 the family. 9 I further would recommend that we always 10 look at that within the context of community. I 11 think informed decisionmaking is very different for 12 different communities. I think marginalized 13 communities and disenfranchised communities have a 14 very different experience of research. I think the 15 community context is critical for understanding 16 what is appropriate and what is not. 17 And within that community sometimes 18 resides the research enterprise and sometimes 19 outside that community and the same goes for the 20 health care enterprise. And I think we need to 21 look at where do those circles overlap, acknowledge 22 where they overlap, acknowledge where they don't 286 1 overlap, and accept that we need to work within 2 those parameters. 3 I don't think there's anything wrong with 4 pushing the envelope, pushing the edges, but I 5 think that we at least in the genetic alliance, the 6 300 or more groups that we speak with regularly 7 have worked really well with researchers when we've 8 said, "here is our agenda, and there is your 9 agenda, and here is where they overlap and here's 10 where we can live together and really acknowledging 11 that quite honestly." 12 I brought an epidemiological study in 13 which in some sense has been used as a model for a 14 number of other groups. The study is looking at 15 600 individuals with PXE both for natural history 16 and also for characterization of the phenotype now 17 that we have the genotype. It's an IRB-approved 18 questionnaire even though we are not federally 19 funded, so we didn't need to do that. We felt it 20 was very important. We have a consent and assent 21 process for adolescents. Again, I underline the 22 word "process" it's a fairly lengthy process. It's 287 1 really critical that it's a process and not just a 2 form. And it does have a form at the end. But it 3 has been really well established in terms of being 4 a process. 5 Information about relatives is obtained 6 without identifiers. And informants contact 7 relatives. So if individuals identify -- say to me 8 that they have relatives who have PXE, I ask them 9 to go and speak to the relatives. I don't contact 10 the relatives myself. 11 I think there's a number of myths that we 12 need to consider when we're talking about informed 13 consent for third parties and those myths, I think, 14 are that privacy is possible. 15 In this world now, I don't think privacy 16 is possible. I think the critical issue is 17 confidentiality. I think misuse of information is 18 a much more critical issue than actually keeping 19 information private. I think you will hear, after 20 me, Terri Seargent's story and see that misuse of 21 information is a much more critical issue. Those 22 people who work in IT will tell us privacy is not 288 1 something we can be too concerned about anymore in 2 the sense of retaining it. What I want to see is 3 legislation that helps us to know that our 4 information will not be misused. That would be the 5 critical piece for this. 6 It's a myth that samples can be stripped 7 of identifiers, even totally anonymized samples are 8 still samples of DNA and DNA is probably the 9 ultimate identifier. So in another age, ten years 10 from now, we'll be laughing at ourselves for having 11 this discussion and using these words. 12 Humans are subjects. I also take a great 13 deal of issue with the word "subjects" nd I'd go a 14 little farther than Francis even and not only using 15 the king and queen analogy, but maybe to address 16 yours, you Bob, if you had been invited to be a 17 part of this committee as a subject of the 18 committee, you would not feel as good as being a 19 participant of the committee. So for those of us 20 who are people involved in research, we much prefer 21 to be called participants in research and to work 22 with the researchers. 289 1 It's a myth that voluntary informed 2 consent is attainable. And to a greater or lesser 3 degree, again, all those scales and continuums come 4 into play when you're being faced with a research 5 issue as a family, as a person, you are not really 6 making voluntary informed consent. I liken it to 7 having a rope hung out and you're falling, do you 8 grab the rope or not? That's an easy answer. And 9 it isn't really making a voluntary decision. 10 Now, I also do agree that even, for 11 example, when my blood was taken without my 12 informed consent, was there a great deal of risk to 13 me? No. But I think we need to continually look 14 at what does it mean to consent somebody especially 15 when they're vulnerable and not just vulnerable 16 according to the kind of end back sorts of 17 parameters of vulnerable populations, pregnant 18 women, children, that sort of thing, but also 19 what's the degree of morbidity and mortality in 20 their disease, what is the chronic effect on the 21 family, that sort of thing. 22 Genetics is about the individual -- have 290 1 talked a little about that. I think genetics is 2 really about the family and the community and it 3 makes it a much more complex issue for us than a 4 simple visit to the doctor. 5 It's a myth that research is altruistic 6 and you discussed that at length this morning. I 7 don't mind that research costs something, that 8 drugs cost money to develop; but, again, I like it 9 when we say, quite honestly, this is my agenda and 10 that's your agenda and here's where they overlap 11 and we live quite well within that overlap. So I 12 think it's a myth to continually say though that 13 it's an altruistic endeavor. 14 And it's also a myth that the public is 15 going to learn truths about genetic research via 16 the media. 17 [Laughter.] 18 MS. TERRY: The media is going to teach us 19 a lot of things and most of it won't be the truth 20 about genetics. So I think that we have a lot of 21 work to do to make sure the real information is out 22 there and informed consent can be truly had in 291 1 terms of the whole population. 2 I would propose a number of guidelines 3 that we have culturally sensitive research. That 4 research has to be done in a context and that 5 includes all kinds of communities everywhere, not 6 just middle-class white Americans. So I think it's 7 a critical issue that we should look at. 8 That we convey non-coercive hope and not 9 hype. I think that also we can go on about that 10 that a lot of times research conveys a great deal 11 of hype and that's not a fair way to even look at 12 consenting anyone. 13 I think we should contact the informant 14 only. The informant, again, being like Mary Kay 15 said, perhaps the mother of a child who comes to 16 clinic or perhaps the person themselves. The 17 contact should remain with the informant only. 18 The informant can extend that contact if 19 they so desire. Informed consent process should 20 occur for all who are contacted. So once a person 21 is contacted, they are now a participant in 22 research and there should be informed consent. And 292 1 we should have state-of-the-art data protections 2 and our IT people are certainly working on that, 3 but they should continually be addressed and 4 improved. 5 I think the bottom line is that together 6 we can balance the requirements, the research, and 7 the needs of the individuals in the context of the 8 family. 9 Thank you. 10 [Applause.] 11 DR. COLLINS: Thank you, Sharon, that was 12 great and all said very clear. 13 The final presentation of the panel is 14 from Terri Seargent who represents a somewhat 15 different consumer perspective having gone through 16 the experience of learning that genetic information 17 can in fact be used against you and Terri has been 18 very willing to share that experience in other 19 settings. We are fortunate she is willing to do so 20 today. 21 Terri. 22 MS. SEARGENT: Good afternoon. You'll 293 1 have to look at me, let me make a presentation. 2 Sorry. 3 I would like to take a moment to than the 4 committee for addressing this very important 5 subject and seriously considering all the issues 6 involved and for inviting me here today to tell my 7 story. 8 Although I have never taken part in a 9 research study, my story is an example of the 10 devastation which did happen due to the misuse of 11 personal medical information. 12 I was introduced to the implications of a 13 genetic disorder twice in my life. The first time 14 was when my 37-year-old brother died of a genetic 15 disease called Alpha1. The second time was ten 16 years later when I was diagnosed with the same 17 disease, Alpha1; and fired from my job because of 18 it. 19 Alpha1 is a hereditary, chronic, usually 20 fatal, recessive disorder in which a low 21 concentration of Alpha1 antitrypsin is associated 22 with slowly, progressive, severe lung disease that 294 1 manifests itself in the third to fourth decade of 2 life. Twenty million people carry the Alpha1 gene. 3 In April 1999, I went to the doctor for 4 what I believed was allergy problems. In 5 disclosing my family history I told the doctor that 6 my brother had died from Alpha1 at age 37. A test 7 was immediately ordered to see if I too might have 8 the disorder. 9 When the test came back showing that I do 10 have the defective gene my doctor told me about the 11 replacement therapy that would keep my symptoms at 12 bay and protect my lungs against infections. He 13 also told me that the treatment would allow me to 14 continue to live a productive life and not 15 drastically deteriorate the way my brother did. 16 After watching my brother die a horrible 17 death from Alpha1, I opted for the treatment. To 18 me there was no alternative. It was a way to keep 19 from dying. That decision cost me my job and my 20 family our middle-class lifestyle. 21 I was employed for three and a quarter 22 years where my annual salary reviews were excellent 295 1 and I had salary increases of 60 percent. The 2 company was partially self-insured. 3 In September 1999, the in-house plant 4 administrator, who is also the human resource 5 director, and accounting manager had requested and 6 received a letter of necessity from my doctor 7 stating the diagnosis, treatment, and longevity of 8 treatment. 9 She did the initial investigation into the 10 prescribed treatment and found out that the cost of 11 the drug alone would be approximately $48,000 a 12 year. 13 In November 1999, she disclosed to the 14 president of the company that I had a, quote, 15 "blood disorder and was facing expensive 16 treatments." end quote, as reported by her in her 17 EEOC affidavit. 18 After another great review and salary 19 increase in November, by the president and vice 20 president, I was unexpectedly told my services were 21 no longer needed, five days before Christmas. 22 After I was identified as someone with 296 1 Alpha1 a genetic disease, I realized the 2 seriousness of my disorder. Not only could it take 3 a life, it could, and did take my job and ability 4 to make a living. And now I'm uninsurable. 5 When I lost my job, I lost all my life 6 insurance and disability insurance. The only way I 7 will ever get them back is if I get a job in a 8 company large enough where health questions are not 9 asked on insurance forms. 10 My family and I have been devastated by 11 the loss of my job. In less than ten minutes we 12 went from being a secure middle-class family to 13 financially scraping by and not knowing whether or 14 not I could afford to continue my life-sustaining 15 treatments. 16 Fortunately, in October 2000, I secured 17 employment with Alphanet Incorporated and have 18 health insurance benefits that I pay a partial 19 premium. My salary is considerably less than what 20 I was making, the health insurance coverage is not 21 as good, and I have to pay twice the amount of out- 22 of-pocket expenses. 297 1 We have exhausted all of our savings and 2 retirement trying to keep our family afloat during 3 this time and to adjust to a minimal lifestyle. 4 In March 2000, I filed a claim with the 5 Equal Employment Opportunity Commission charging my 6 employer with genetic discrimination. I had to 7 file under one of the three prongs of the Americans 8 with Disabilities Act. I filed under the second 9 prong that is regarded as disabled. 10 Even though I do not consider myself 11 disabled, nor am I considered disabled by the 12 government, and have not developed any disabling 13 symptoms, the only way to be able to file with the 14 EEOC was to declare my genetic condition a 15 disability. 16 On November 20, 2000, the EEOC rendered a 17 decision that I was discriminated against due to 18 the cost of my treatment under the guidelines of 19 the Americans with Disabilities Act. 20 My hope is that that decision will give 21 direction to those who have been unjustly 22 discharged or harassed due to information obtained 298 1 about their genetic disorder. 2 Our government is spending millions of 3 dollars funding scientists to map human genes to 4 find ways to cure disorders and disease so that we 5 can have a long, quality life. But what good is 6 all this money and effort if no one is willing to 7 take part in research, get tested, or receive 8 treatment for the fix out of fear that the 9 information may get into the wrong hands causing 10 them to lose their job or not be able to obtain 11 health, life, or disability insurance. 12 Medical privacy in genetic discrimination 13 is a real threat to real people. The Council for 14 Responsible Genetics a national bioethics advocacy 15 organization has documented more than 200 reports 16 of genetic discrimination. 17 A 1995 Georgetown University study found 18 that three out of 332 families belonging to genetic 19 disease support groups, 22 percent said they had 20 been refused health insurance. And 13 percent said 21 that they had been fired from their jobs because of 22 perceived risks attributed to their genetic status. 299 1 In the Alpha1 community alone, there are 2 several reports of misuse of private medical 3 information. A young, single mother was identified 4 accidentally when she had a pre-op X-ray for foot 5 surgery. She was harassed at work until she left 6 and took an other job. 7 An infant that was born with an unrelated 8 problem had to have corrective surgery. His liver 9 became very slightly enlarged after the surgery 10 because of the medications he was taking. 11 Consequently the orders were read wrong and an AAT 12 deficiency test was done and surprisingly he was a 13 ZZ. He is now a toddler with no symptoms. His 14 diagnosis will haunt him and his ability to obtain 15 health insurance in the future if protections are 16 not put in place. 17 An asymptomatic Alpha was identified 18 through family members that were also ZZ. This 19 Alpha is in her mid-50s with normal lung function 20 and has been denied life insurance over and over. 21 This is a very typical and reoccurring 22 problem in the Alpha1 community. Due to Alpha1 300 1 being a genetic condition, family members are too 2 quick, out of caring, to give names and relations 3 to doctors and researchers. 4 A 28-year-old daughter of an Alpha 5 personally told me she refused to get tested and 6 will not discuss it because she is afraid she will 7 lose her job and her insurance. 8 A family of four siblings, three of which 9 had tested positive as ZZ Alphas could not talk 10 their older sister into getting tested. In fact, 11 the fear of anyone thinking that she too could have 12 this deadly genetic disorder caused her not to have 13 any contact with her siblings for years to protect 14 her privacy. 15 When symptoms began to show at age 62, she 16 finally agreed to be tested. The damage to her 17 lungs is so significant that she needs a lung 18 transplant. If she would have gotten tested 19 earlier and started a replacement therapy, she may 20 have averted the need for the transplant. 21 It is because of this same fear that more 22 people are not coming forward to tell their story. 301 1 To protect their privacy and their standard of 2 living, people are making choices based on fear and 3 knowledge that at this time there is no protection 4 to safeguard them against devastating consequences. 5 My story epitomizes that devastation. 6 I think what concerns me most with what 7 happened to me is that I lost control over my 8 private medical information. And because of this, 9 it was used against me. I no longer have the 10 freedom to make personal choices. I felt violated 11 and stripped of all security. Not from something I 12 had done wrong, but because I have a genetic 13 disorder, a chance at birth, and I wanted to choose 14 to live. But since it costs a lot of money, 15 someone else whom apparently has no concern for my 16 life chose for me. 17 This is all anyone is asking for, respect 18 each person's right to privacy and allow them to 19 make their own choices on how their private 20 information is given and used. 21 I'm here today because I want research to 22 flourish and personally understand the benefits of 302 1 genetic testing. So we must go the distance to 2 eliminate the fears so that participation in the 3 research and the testing can be the life-giving 4 benefit that you so desperately want and I so 5 desperately need. 6 Thank you for allowing me to share my 7 story and my concerns, and Godspeed in research. 8 [Applause.] 9 DR. COLLINS: Thank you, Terri, for a very 10 powerful statement. And a reminder of just how 11 critical it is that we do protect this kind of 12 information from breaches of confidentiality that 13 can have very real risks. That's a very important 14 part of our conversation. 15 Mary Faith, should we take a break? 16 CHAIRPERSON MARSHALL: About ten minutes. 17 DR. COLLINS: Okay. It's suggested that 18 we take a ten-minute break and then we will 19 reconvene and get into the discussion. 20 [Brief recess taken at 3:30 p.m.] 21 CHAIRPERSON MARSHALL: What we would like 22 to do during out discussion period is to ask -- 303 1 we're going to designate until 4:30 as time for the 2 committee and our ex officio members to interact 3 with the panel and then open the time up at 4:30 -- 4 between 4:30 and 5:15 p.m. for public comment. 5 There are two people who specifically are 6 here to make public comments. So when the public 7 commentary period begins, perhaps we could hear 8 first from Mr. Levinson and then secondly from Mr. 9 Curtain. That would be great. 10 So let us move back to perhaps -- I'm 11 going to ask Francis if he will moderate this 12 session. But just remind everyone who has 13 something to say to remember that there's always 14 and also someone else who has something to say. 15 Please don't repeat what someone else has said, and 16 please don't be long-winded in the sense of asking 17 questions that go on forever. Thank you. 18 DR. MORENO: The first question is for 19 Francis and it's a scientific question, and the 20 second one is for anybody. 21 I attended a meeting of the Howard Hughes 22 a few weeks ago which you also attended on the 304 1 structural biology. And I was impressed that what 2 the smartest people in the world are working on is 3 what is now being called proteonomics. That is to 4 say, rather than genomic, it visualizing and 5 mapping the protein. 6 Where does proteonomics fit in your four 7 pathways of genetic medicine? That's my first 8 question and I reserve the right to ask a second. 9 DR. COLLINS: Well, sure. In fact, there 10 seems to be a great deal of press attention to 11 proteomyces right now perhaps because people feel 12 that genomic is now passe. Boy that happened 13 quickly, didn't it. 14 [Laughter.] 15 DR. COLLINS: Never mind that we still 16 have to finish the job of getting the sequence in 17 finished form; never mind that there are all these 18 other genomes to be sequenced; never mind that we 19 don't understand how genes turn on and off very 20 well. Proteomyces is basically to study the 21 protein products of the genes recognizing that 22 they're the ones that do the work and certainly 305 1 we've been doing that for a long time, one protein 2 at a time. But what is new here is the idea of 3 doing this at large scale. 4 It is much more difficult to define a 5 protium project in the same precise terms that we 6 did a genome project. It's much more open-ended. 7 You want to understand how many proteins there are, 8 what kind of modifications they have, what other 9 proteins they touch, where they live in the cell, 10 all of this. And while there is undoubtedly going 11 to be a good deal of focus on this in both the 12 private and the public domain, it seems unlikely at 13 the moment that there will be the same kind of very 14 goal-driven, milestone-driven effort that 15 characterized the genome. 16 I would say in my diagram proteomyces 17 falls into that step of understanding the biology 18 of the disease after you have pinpointed the 19 variants that contribute to hereditary risk, how 20 does that work, usually means you've got to get 21 into proteins. And to the degree that we can do 22 that rapidly and in a global high throughput way, 306 1 we'll get there quicker. But I don't think it is a 2 brand-new arrow on the diagram. 3 DR. MORENO: My second question is for 4 anybody on the panel or in the room. You mentioned 5 the community consultation, shall I say, model? We 6 have one other experience with community 7 consultation in human subjects research in this 8 country, namely in the emergency room. Not very 9 much experience, perhaps. Do we have any 10 information about how that's gone, how that's 11 worked, when it's been used, and do we have any 12 better understanding about what community 13 consultation means now than we did five years ago? 14 DR. KOSKI: No. 15 [Laughter.] 16 DR. COLLINS: If I can without it being 17 inappropriate -- oh, Greg, go ahead. 18 DR. KOSKI: Yeah. Just to respond a 19 little split way. It's very interesting that 20 actually I can't remember now whether it was the 21 genome institute or NCI, they held a have I think 22 it was the first public consultation conference 307 1 here at this very center -- 2 DR. COLLINS: NIGMS. 3 DR. KOSKI: Oh, is that where it was. 4 DR. COLLINS: In collaboration with 5 genome; yes. 6 DR. KOSKI: One of those places. And it 7 was very interesting. I think the take-home 8 message from it was that the public in fact has an 9 awful lot more interest in a lot of this stuff and 10 an interest in being involved in it than we may 11 have actually given them credit for. There was an 12 enormous amount of interest and so that's a good 13 thing. I think the experience though from the 14 emergency waiver of informed consent and the 15 community consultation there that we really have 16 very little experience. 17 I'm only aware of, I think, two projects 18 that have been approved under that provision in the 19 last three or four years since it was initially 20 approved. And everyone has struggled with, what is 21 the definition of community? So we are still -- we 22 have a long way to go there and I think that that 308 1 may be something worth further discussion in the 2 future. 3 DR. COLLINS: Could I take the moderator's 4 prerogative here and ask that we try to focus as 5 much as possible the discussion on the issue of 6 family member consent since I think that was the 7 intention of the organizers of this afternoon's 8 conversation is to try to dig a little more deeply 9 into that topic and not try to cover all of the 10 issues that relate to genetic. 11 So, Abbey, is that where you're going? 12 MS. MEYERS: Yes. 13 DR. COLLINS: Okay. Go. 14 MS. MEYERS: Well, from everything that we 15 heard this afternoon, what we heard about was 16 discrimination. But I'm sure that, for example, 17 your boss didn't know what Alpha1 antitrypsin 18 deficiency was and that it was a genetic disease. 19 They only knew that they had a $40,000 bill in 20 front of them. That's what they care about. 21 So I'm trying to think whether, you know, 22 to solve this problem do we need a genetic 309 1 discrimination law or do we need a medical 2 confidentiality law? If we had national health 3 insurance it would solve the whole thing and nobody 4 would get fired for having expensive diseases. 5 But, you know, what do you see as a way to solve 6 this problem? 7 MS. SEARGENT: In my situation, if he had 8 not received that information, he would never have 9 known the costs. That's the point. 10 DR. COLLINS: Mary Kay. 11 DR. PELIAS: I'd like to raise a question 12 about what actually constitutes private information 13 under the definitions in the federal regulations. 14 Jeff and I have been around about this a couple of 15 times already and I have been unable to satisfy 16 myself with the definition of private information 17 with regard to genetics as private information as 18 defined in the regulations. 19 I find myself thinking that if we're going 20 to allow the individual to define what is private 21 and what is not, then perhaps we should say that 22 all information generated from individuals that are 310 1 given to us in genetic studies by individuals 2 should be regarded as private and be protected in 3 that way. 4 To make the point a little bit clearer, I 5 think when we gather family history information in 6 genetics, we find that some families are very open 7 in discussing whatever malady that is in the family 8 with regard to genetics and they don't feel 9 stigmatized by discussing, for example, severe 10 mental illness. Other families on the other hand, 11 are very close and very guarded about discussing 12 the same disease that is in their family. 13 So, as I've been talking about this, I 14 think that maybe we have a sliding scale that goes 15 everywhere from personal information to very, very 16 private information and that depends on who is 17 defining it. So, if we're going to continue to 18 collect information -- genetic information -- from 19 families, should we operate from the premise that 20 all information that we collect is private and 21 should we then focus on establishing standards for 22 maintaining confidentiality, very stiff standards 311 1 for maintaining confidentiality of all genetic 2 information so that we can continue to do our jobs, 3 and at the same time protect the individuals who 4 are the foundations of all of our genetic studies. 5 DR. COLLINS: I think that's an 6 interesting suggestion. And maybe, Jeff, since you 7 particularly addressed that a bit in your 8 presentation, I'll just add a query to Mary Kay's. 9 In your presentation you talked about both the 10 magnitude of the risk and the likelihood of the 11 risk as though the real issue is the product of 12 those two. Maybe what Mary Kay is saying is that 13 if the likelihood can be made very low, likelihood 14 of disclosure, that even if the magnitude could be 15 quite high if it happened, the product of the two 16 is still a small enough number that you might call 17 that minimal. 18 I hope I'm not overdoing the mathematics 19 here. 20 How does this play out in your mind 21 because you thought about this a lot? 22 DR. BOTKIN: Well, I think from my 312 1 perspective we're working with very little research 2 in this arena to actually document what the risks 3 may be. And so a lot of it ends up being intuitive 4 level, ad hoc, sort of arguments about what 5 constitutes privacy and what constitutes minimal 6 risk, et cetera. You know, from my perspective I 7 would be willing to concede that if in fact the 8 risks were extremely low and documented to be such, 9 then it would be minimal risk irrespective of the 10 degree of harm that might accrue from a breach of 11 that -- from a breach of confidentiality. But I 12 think getting to any firm conclusion that in fact 13 documented risk was that low will be quite 14 difficult. 15 The other thing that I think has to be 16 part of the public policy debate is simply people's 17 sensitivity about that. And if you ask members of 18 the public about acquiring these kinds of -- this 19 kind of information and retain that within a 20 research enterprise, folks may not be willing to 21 accept that as appropriate conduct of research 22 whether or not there's a risk of further disclosure 313 1 and harm. And I think it gets to the issue of what 2 do we care about with breaches of privacy? Is it 3 the secondary harms that may result from that, or 4 are there wrongs as part of the simple sharing of 5 information whether or not it's disclosed further? 6 I think that needs to be a significant part of the 7 public policy debate here. Do we really care about 8 secondary effects or is it simply acquiring the 9 information to begin with that people are 10 understandably concerned about. 11 And I think the second aspect of that gets 12 to the issue of privacy and minimal risk and how 13 one defines those. And I think with the conduct of 14 any kind of research, if you were to ask each 15 subject what they would consider minimal risk, you 16 will get a wide range of answers. 17 And so I think the approach has been for 18 the IRB to make a determination based presumably on 19 some sort of reasonable person standard about what 20 for the population ought to constitute the 21 definition of these terms rather than make it a 22 subjective term that has to be addressed in the 314 1 context of each subject that may be enrolled. 2 So I'm willing to accept a public policy 3 process that makes that determination based on some 4 reasonable person standard for those reasons. 5 DR. COLLINS: Mark Barnes and then Bob 6 Levine. 7 MR. BARNES: A couple of brief points. 8 One is that this issue of the family member medical 9 information that's embedded in the research record 10 is not only a research issue, it is also an issue 11 of those people who are undergoing genetic 12 counseling and testing right now for together 13 purposes. And, you know, the hospitals every day 14 and physicians face the issue of when a person who 15 is the patient signs a release for their medical 16 records and copy is made of the medical records is 17 all of the information about their family members 18 included in the record that is sent out to the 19 third party. 20 So I just want to make it clear that, you 21 know, this is not just a research issue. This is a 22 medical records and medical privacy and 315 1 confidentiality issue generically. 2 Second point is that there are precedents 3 to this. Because, for example, in the case of 4 newborn screening for HIV disease, in fact, it is 5 not the newborn's HIV status that is revealed in 6 the newborn's record, it is the mother's HIV status 7 that's revealed in the record. And, so, there 8 certainly are differences between HIV infection on 9 the one hand and many different types of genetic 10 testing on the other, but there are ways in which 11 we have dealt with those issues before, largely by 12 deciding on a case-by-case basis to redact medical 13 records to redact those portions of medical records 14 before we send the records out to a third party, 15 again, on a case-by-case basis really trying to 16 understand exactly who the party is to whom we're 17 sending the information. 18 Finally, on the issue of sort of a related 19 point, but different, on the issue of health 20 insurance. I understand the point that in your 21 case that the sort of exciting clause was the 22 release of your genetic information, but in fact 316 1 whether you had a -- your employer had a self- 2 insured ERISA plan or whether your employer had an 3 actual group health insurance plan that he or she 4 purchased from an insurance company. The fact is, 5 even if they had not received that information 6 about you, about the genetic information, then they 7 would have, at the end of the year, when the time 8 came to renew their premium and they had a risk- 9 rated premium, they would definitely have been 10 given the information that they had one employee, 11 and the employee probably would have been 12 identified by name, who had a medical expense that 13 exceeded by -- you know, by a factor of ten what 14 the average medical claim history was for the 15 average employee in that employment situation. 16 So that they would have probably, if they 17 were motivated by cost considerations, then I 18 venture to say as a hypothesis that you would have 19 been singled out anyway, simply through cost, and 20 that's regardless of whether you had a genetic 21 condition of a metastatic breast cancer or AIDS or 22 HIV or anything else. 317 1 MS. SEARGENT: What you're talking about, 2 Mark, that has been discussed a lot over the last 3 year and a half. And two points. First of all, it 4 is against the law for an insurance company to put 5 a name to any of that situation. So it's a small 6 company, they could have figured it out. But it 7 could not be a name that was passed. I did want to 8 make that point. 9 Secondly, in this case scenario, in mine, 10 there were other people that had very large costs 11 through that one year. The point was, he knew the 12 longevity and that was another situation. I mean, 13 his own father-in-law had cancer. They removed him 14 from the policy a year before and just took him on 15 his own. So there is -- things happen, but he knew 16 the longevity of it and that is a major point. 17 DR. COLLINS: Yes, Bob. 18 DR. R. LEVINE: Thank you. I just wanted 19 to make a point about the use of risk probability 20 and magnitude language in the definition of "risk". 21 I'm the one that wrote that definition, of risk, 22 not of minimal risk. And I just want to say 318 1 something about what was intended when the National 2 Commission recommended this. It was not intended 3 to be a mathematical algorithm that if you 4 multiplied the probability by the magnitude, if you 5 came out with a low number you're okay. What it 6 really was, was an exhortation to the IRB to keep 7 in mind that they had to consider both probability 8 and magnitude. 9 The third component that I put in that 10 made it into the commission's recommendations, but 11 did not make the cut in the regulations was that 12 one should also consider the nature of the risks. 13 And you've given us a good illustration of one 14 subset of the issue of nature when you identified 15 sensitive information such as information that 16 could expose you to prosecution or serious 17 prejudicial behavior. I think that's an extremely 18 important one. 19 There are some things that don't make you 20 die often, but can create enormous problems in your 21 life as we've heard from Terri Seargent. 22 On minimal risk my argument to the 319 1 National Commission was that this was a stupid 2 idea. And, you know, they were really distorting a 3 lot of concepts there and this has been adequately 4 addressed by many of my colleagues, most notably 5 Loretta Kobelman. 6 I do want to say though that one of the 7 problems with the definition of minimal risk is 8 that it's not only measured in terms of what would 9 occur in the daily life of the subjects, but also 10 what would be -- what would happen in a routine 11 medical examination. And as Abbey Meyers has 12 pointed out so clearly, in a routine history in a 13 doctor's office they ask a lot of questions that 14 are far more sensitive than any geneticist would 15 ask. And you've also heard about how available 16 that is to insurance companies and so on. So one 17 might say in effect that if we can really take in 18 account what happens in a routine medical 19 examination very nearly all epidemiology and 20 genetics pedigree work is minimal risk. And I 21 don't think that's what you want to say. 22 Finally, Mark Barnes talked about 320 1 redaction of records. People who create medical 2 records know that that is very nearly impossible. 3 And in the cases where the court has required that 4 you turn over research records to someone who 5 appeals for them, they have usually made as part of 6 their decision that it's the obligation of the one 7 who requires the records to pay for the redaction. 8 Thank you. 9 DR. COLLINS: Thanks. Moving to this side 10 of the table, we have Felice and then Adil and then 11 Denise. Felice. 12 DR. F. LEVINE: Thank you. This was a 13 riveting panel from everyone. The Terri's, 14 Francis, Jeff. It was just terrific. 15 I want to focus and ask a question in the 16 context of human participant protection and 17 research. Although other issues have come up that 18 I think are important about privacy and protection 19 of health related records and information. 20 And that is, the hardest issue that I 21 think among the many hard issues, the hardest that 22 I think we face is the notion of human participants 321 1 other than those engaged in the research to be 2 classified as human participants, secondary 3 parties, tertiary parties, and each of you 4 struggled with that issue in a way. And this is -- 5 although it pertains to the particular context of 6 the gene research we're talking about, this really 7 has much broader implications for many other forms 8 of research that I think Jeff outlined in his 9 presentation. 10 And I guess I'm wondering and want to ask, 11 given the liabilities of defining, as human 12 participants, secondary and tertiary parties not 13 engaged in the research and communities, were the 14 investment put in innovative protection of these 15 data, methods not only of confidentiality, but also 16 of not just redacting, which I recognize has 17 problems, but even separation of files with ways of 18 running analytic procedures from a research point 19 of view that never even physically has the link and 20 other methodologies that I think in the social and 21 behavioral sciences I won't say are everyday 22 commonplace methods, but certainly exist in our 322 1 scientific capacity to do. Would that go a long 2 way to keeping the best of ethical practices and 3 the protection of human participants without the 4 downsides of defining such a range of individuals 5 as human participants? 6 DR. COLLINS: Who wants to respond? 7 Terri. 8 DR. ARLEDGE: Well, let me respond from an 9 industry perspective. We already have a number of 10 those firewalls and data safety provisions in place 11 to ensure that we -- but, keep in mind, it doesn't 12 come without a cost. Because everything that we 13 design has to be GLP, GCP appropriate and if we've 14 not identified samples, we can no longer make any 15 kind of regulatory claims. So even if we find 16 something, it's not clear that we could go to the 17 FDA, we could go to the EMEA and make a regulatory 18 claim. 19 So it's possible. We certainly have it in 20 place. It is not inexpensive. But it is what 21 we're doing. It has certain costs associated with 22 it. We certainly have it in place, it is not 323 1 inexpensive, but it is what we're doing. It has 2 certain costs associated with it, both resource, 3 monetary, and what we loose the ability to -- like 4 I said, to make a regulatory claim. 5 DR. F. LEVINE: If I could just clarify. 6 That it isn't that I was necessarily suggesting 7 that extreme was at all levels of risk necessary or 8 appropriate, but what I was postulating is the 9 spectrum of strategies that could be used short of 10 defining individuals that are not human 11 participants in any realistic way, human 12 participants, in order to ensure that private 13 information about them isn't vulnerable. 14 MS. TERRY: I think I totally agree with 15 that and see that the continuum that I named plus 16 now the continuum trying to define who is a 17 participant and who is not do lend us to say, let's 18 put our resources elsewhere. And the issue of 19 protecting information is going to be much more 20 critical. 21 I think the other thing I tried to say too 22 was that we are not going to be able to make 324 1 blanket statements for all of the U.S., for all 2 families, for all communities. We have said that 3 over and over in many ways. And that if we could 4 start to look in communities and this is where I 5 think a community IRB with community members on the 6 IRB makes a real difference in terms of assessing 7 for those individuals. 8 Sometimes people ask me, how many people 9 have refused to be part of my epidemiological 10 study. It's 900 fields that people fill out. 11 People told me, no one will fill this out. Well, I 12 got back 600 out of 1,000. That's pretty good. 13 And not one person refused. Because it's done in 14 the context of a community. And it's all over the 15 world, but we have a community of persons who 16 understand the values that we're espousing, and the 17 protections. It's a double-blinded thing, the 18 codes are removed and only I have the key to 19 anything. 20 DR. BOTKIN: And I do think this is a 21 wonderful opportunity to rethink research 22 methodology with families and try to come up with 325 1 some new creative ways that may limit the risk. 2 Along with that, I would say, that one of 3 the risks we run in this whole enterprise is 4 creating an aura around genetic information that 5 isn't justified. And to the extent that genetic 6 information becomes exceptional, then, in fact, we 7 may create the sort of shame and stigma and 8 discrimination that we are trying to protect people 9 against, but fostering that social attitude in the 10 process. I do see that as a problem. 11 Medical information in 12 general, but I think it probably goes along with, 13 the more secretive we are about things, then the 14 more people may feel ashamed by events that they 15 can't control when disclosed. 16 DR. SHAMOO: I have a quick comment and a 17 question for Mark. Medical records are protected 18 by state and federal law, a little bit federal law, 19 but mostly state. But research records is the 20 property of the principal investigator in most 21 cases, that's my understanding. So the research 22 records you can do whatever you want with it, so 326 1 far. 2 The question is, we talked about an 3 anonymization or delinking, and my question is, is 4 it temporary or permanent and whether it is 5 permanent or temporary, are we talking about 6 destroying the fingerprint, the DNA fingerprint 7 itself, so that it cannot identify the person or 8 even destroying the tissue or just destroying it -- 9 there is still a file cabinet there, somebody -- 10 and it has happened to me. I was in a research 11 committee was trying to appoint me to something, 12 and I got the job, they were supposed to, and I had 13 access to the search committee's minutes so I saw 14 all the pros and cons of what they said about me. 15 [Laughter.] 16 DR. SHAMOO: So they have ways of -- and I 17 went to the guy who said the negative comments, of 18 course, he wasn't very happy. 19 [Laughter.] 20 DR. SHAMOO: Did you really say that? But 21 anyway, if I didn't get the job, of course, I would 22 have never seen those records. So, what's your 327 1 answer? Is it temporary; permanent; and what type? 2 DR. COLLINS: Well, I would be interested 3 in Terri Arledge's response because I gather there 4 has been a discussion in this working group about 5 these definitions. Certainly the numerous 6 conversations about stored tissue disagreed to some 7 degree about the definitions. But I think most 8 came to the general consensus that if you're saying 9 "anonymized" you mean that it is irreversibly 10 delinked, that that tissue cannot be connected with 11 any individual by anybody who currently lives on 12 the planet. 13 Now, I will take the point that was made 14 by one of the earlier speakers that that is perhaps 15 a bit of a fiction in that DNA itself is capable of 16 identification. If you have something to compare 17 it to and you're seeking a match, we do that in 18 forensics all the time. 19 A current assumption is that that would be 20 impractical to do in most situations because we 21 don't have databases about everybody's DNA to make 22 that comparison and to be able to draw the 328 1 identities. But that may be only a matter of time 2 before that opportunity looms ever larger. In 3 which case, to call something truly anonymized may 4 no longer be possible. At least at this moment in 5 time "anonymized" means irreversibly delinked in 6 most people's parlance. Is that how you did it as 7 well? 8 DR. ARLEDGE: Yes. That is how the 9 pharmacogenetics working group has defined this. 10 And to give you an example, we bring in samples, 11 for example, undercoded. And that would mean that 12 they're coded with the individual subject 13 participation number. Only the investigator at the 14 site can link a number with a name. 15 We do some limited research, very 16 restricted research while it's coded, and then we 17 make them deidentified or, excuse me, anonymized 18 which means we renumber the samples and the data 19 and we destroy the mapping file. That means 20 they're anonymized. 21 If we had a third party retain the mapping 22 file that linked the two numbers, that would be de- 329 1 identified. Sort of subtle, but we do not destroy 2 the actual forensic results. So it could be 3 tracked back to someone if you had another DNA 4 sample to compare it against. 5 DR. THORNLEY-BROWN: I just wanted to get 6 the panel's opinion about recruiting the secondary 7 subjects. I mean, one of -- can you hear me? 8 One of the reasons why get pedigree data 9 is in order to study some of the relatives of these 10 people. 11 I know, Sharon Terry, you mentioned that 12 you believe that only the informant should be 13 contacted. Did other people on the -- that seemed 14 a little bit impractical. Do other people on the 15 panel have comments? 16 MS. TERRY: I can make a further comment. 17 Because of the shortness of the talk, I couldn't go 18 into some nuances which are that, again, because 19 it's a real community, I keep all the identifiers. 20 No researcher ever sees any data on anyone except 21 what I give them in terms of DNA samples and 22 phenotype information that's coded. 330 1 In various instances it is much more 2 practical for Uncle John to call me and say: could 3 you call my sister, she really would love to hear 4 from you. And I do. So within the context of what 5 I see as a community within the values of that 6 community, I think it works very well for me to 7 approach other people. If we're going to make 8 absolutely blanket statements about protecting 9 people, then I think we have to say the informant 10 is the person we'll work with and we'll try to go 11 through the informant to get to other subjects. 12 But I think in community contexts, and I'm 13 working now with an African-American community with 14 a native American community and it's working for 15 them to come to the researchers as they need to 16 rather than just going through the informant. But 17 I don't think we can make blanket statements about 18 these things. 19 DR. THORNLEY-BROWN: You're talking about 20 a very specifically defined community. I'm 21 thinking of other diseases, people with 22 hypertension and kidney disease, with diabetes, 331 1 diseases that maybe subclinical, et cetera. The 2 community isn't as well defined. 3 DR. ARLEDGE: If I can give you some 4 experience that we've gone through because we are 5 looking at these common diseases. We're looking at 6 cardiovascular disease and asthma and COPD and OA. 7 And the community is not well-defined. We are 8 still making preliminary contact with the families 9 through the proband or through the informant. And 10 unless they tell the investigator it's okay for 11 them to go ahead, the proband is the one that goes 12 back to the family and asks them to participate or 13 asks them to contact the investigator. 14 DR. COLLINS: I'm involved in a study 15 that's looking at prostate cancer in African- 16 Americans and this is a challenging effort to try 17 to enlist the participation of the families that 18 are affected because of a number of issues. 19 Prostate cancer is still, in many of those 20 families, a subject that's not talked about. It is 21 certainly a community that has considerable 22 concerns about research in general for which 332 1 Tuskegee is still very much on their minds. 2 And in that instance, in general the 3 proband who is seen by a urologist is asked about 4 family history. If the family history appears 5 fairly dramatic with multiple affected males, then 6 that proband is asked to be the messenger to the 7 rest of the family about an interest in 8 participating. But then you do end up with the 9 investigator which in this case is the community- 10 based -- often a urologist, often who is part of 11 the same community contacting the other affected 12 males directly after gaining permission to do so 13 from the proband; and developing a relationship 14 with them that is also associated with their 15 specific informed consent. 16 What you don't end up doing in general is 17 having consent from everybody in the family, either 18 because of geographic lack of availability, or 19 because they're not affected, or because they're 20 not interested. 21 That's, I think, a fairly typical kind of 22 scenario for the way a lot of this research goes. 333 1 You start with an involved proband and then you see 2 where it takes you. 3 Mary Kay. 4 DR. PELIAS: I've been intrigued for quite 5 a while now about this verb "to anonymize." And I 6 would like to put a question to the committee and 7 to the panel about where the ultimate authority 8 lies for stripping identifiers from samples, 9 especially samples that we are collecting now and 10 prospectively for future studies. 11 Retrospective sample collection, that's 12 one thing altogether. But I have contended that 13 it's important to recognize that the person who 14 donates the samples may have some interest and 15 should therefore at least retain or elect not to 16 retain identifiers attached to those samples with 17 the option for future feedback. And I think this 18 is something that we need to address as we're going 19 through this business about consent, exactly how 20 far can consent go and can it be a blanket consent 21 and so on and so forth? 22 DR. COLLINS: Now, those are very good 334 1 questions and it touches on the issue of under what 2 circumstances does an investigator carrying out a 3 genetic research protocol actually find themselves 4 carrying the responsibility to recontact research 5 participants because the finding is of such 6 importance clinically that not to do so is to place 7 those individuals at-risk. 8 I didn't put that on my list of areas to 9 look at. But it is clearly one of the ones that's 10 on some people's minds and pretty soon I'll 11 probably need some additional guidance because I 12 don't think there's any real consensus there. 13 Susan. 14 MS. KORNETSKY: Thank you. This is more 15 just a comment than a question and perhaps for Greg 16 and the OHRP office to direct it to. 17 I appreciate your article and actually as 18 someone sitting on an IRB trying to instruct an IRB 19 what to do when we actually get involved with these 20 issues, I appreciate your article and your 21 presentation. 22 Two of the things that you mention, I 335 1 think we all recognize now where we haven't in the 2 past that involving secondary family members can be 3 research subjects. And then we move on to the 4 discussion about waiver of informed consent which 5 you point out in your article. 6 You correctly point out that the first and 7 the third, the minimal risk and the practicability 8 are the difficult ones to get over. My question -- 9 my issue about minimal risk, we have often heard or 10 IRBs have been told that genetic research should 11 not be considered minimal risk. 12 And I guess the issue is, does this mean 13 that the research prior to steps being taken is 14 minimal risk? Or does this mean that there can be 15 steps taken so an IRB can consider it minimal risk? 16 And this comes up not only with genetics, but with 17 other types of questionnaires. And there's been 18 some inconsistency and perhaps when we do come up 19 with some guidelines OHRP can help us understand 20 how to interpret that minimal risk. 21 The third thing is the practicability. 22 And you had made a statement that it's not 336 1 necessarily the particular research project, but 2 can any research project be done? And both of 3 these things have been a little bit inconsistent 4 with at least the way IRBs have been operating. So 5 I guess my plea is that given this discussion, that 6 there also be some interpretation of the 7 regulations and that also that this applies to 8 other research as well, not only genetic research, 9 it has implications for that. 10 DR. BOTKIN: Excellent question and I 11 guess I would just make a couple of brief comments. 12 I wouldn't accept the distinction between genetic 13 and nongenetic conditions in terms of minimal risk. 14 I think it hinges on other aspects of the 15 information and how sensitive is it, how is it 16 regarded within society, et cetera. And it so 17 happens that some genetic conditions fit that bill 18 pretty well, but a lot of nongenetic conditions do 19 as well. So I wouldn't be so concerned about that 20 aspect. 21 I think the general question for debate is 22 whether information, per se, and Dr. Collins had 337 1 pointed out, we're moving into the sort of 2 psychosocial realm rather than physical risks. Are 3 there distinctions to be made between different 4 kinds of information that will confer substantially 5 greater risks for some types of information versus 6 others, or is that entirely a subjective call. 7 I think that kind of line drawing is 8 something, of course that I attempted to do and 9 folks have disagreed with where those lines are 10 drawn. But I think the general task is an 11 important one. And I think the practicability one, 12 I would just echo a welcome for further discussion 13 of that particular problem. 14 And my presentation here may have been a 15 little starker than what I actually believe. I 16 think the question is, can nobody do research 17 without the waiver? But, you know, does it create 18 such a substantial barrier that it is unreasonable 19 in balancing that with the potential benefits of 20 the projects. 21 MS. KORNETSKY: I agree with your 22 interpretations. The point I want to bring up is 338 1 that this hasn't always been the IRB's 2 understanding of those interpretations. 3 DR. COLLINS: Sandy. 4 DR. CHODOSH: I'm having some trouble, 5 Terri -- this Terri, with what she is doing. 6 Because this is a little bit different than some of 7 the other situations. This is FDA-related research 8 in which you are tagging a separate consent form 9 onto a regular consent form that has to do with the 10 actual drug trial. That information of the regular 11 drug trial obviously must be linked to what you're 12 doing in terms of the other work or else what 13 you're trying to do can't be done. 14 That linkage to FDA-related information 15 which goes to the FDA and which the FDA can now 16 review and research on site and subpoena records 17 that although confidentiality is always relative, I 18 wonder about whether that linkage is really 19 described very well. 20 I had a problem actually with your folks 21 in England when you were Glaxo discussing this in 22 that they couldn't give me a good answer. I said, 339 1 well, you can't just use the specimen of the DNA 2 without the history and what happens with the 3 study. So why are you telling me this is a 4 separate consent form? It's not. So we didn't do 5 that part follow-on the study. And I wonder what 6 you're thinking is. This is not a simple -- it's 7 more complicated than usual genetic research. 8 DR. ARLEDGE: Well, I agree with you, it's 9 very complex and we periodically go back and review 10 our processes, work with outside ethicists to try 11 and ensure that what we're doing is the best that 12 we can do to protect confidentiality. So I'll 13 start with that general thought and then I'll go 14 down tot specifics. Basically when we're doing 15 what we call "coded research" which is 16 pharmacogenetic research where the DNA sample and 17 the results are coded with the subject number, and, 18 again, only the investigator can relate that to a 19 patient. We restrict ourselves to looking 20 specifically at candidate genes involved in the 21 drug target or drug metabolism. 22 Now, we don't return these results. So 340 1 the results do not end up back in the patient's 2 medical record. We ask that the site ensure that 3 they don't even write down that the patient was in 4 the pharmacogenetic research in their medical 5 record. That information is kept just in the study 6 file and they signed an informed consent document. 7 Now, when we produce tables it is just 8 aggregate data. 9 DR. CHODOSH: What you're describing would 10 be illegal in the VA. I don't know about the rest 11 of the world. But consent forms must be part of 12 the medical record. 13 DR. ARLEDGE: When IRBs have raised that 14 issue, and that's actually been fairly infrequent. 15 There have only been two or three that have raised 16 that issue. We have told them that they need to 17 follow the process that they have established, but 18 it needs to be clear in the consent form what it is 19 that they're doing and that the information will be 20 in the patient's medical record. 21 Now, we have argued that this is purely 22 research. It has nothing to do with medical 341 1 treatment or diagnosis. We do not look at 2 candidate genes that have clinical relevance. And, 3 therefore, this information does not need to be in 4 somebody's medical record. But it's up to the IRB. 5 DR. CHODOSH: I'm sorry, this is double- 6 talk. Because you're looking for things that have 7 clinical relevance and therefore to say it doesn't 8 happen, you know, is a little disturbing to me, you 9 know. How far back -- if this were not FDA- 10 related, I would say that you probably have a much 11 better chance at ensuring a higher level of 12 confidentiality than you could in this situation. 13 I really am concerned about this. 14 DR. ARLEDGE: When I say "clinical 15 relevance" I do mean that we're not looking at 16 specific genes that are associated with disease, 17 Huntington's, BRCA, those kinds of things. So if 18 that will help you any with the clinical relevance. 19 20 The other thing is, a lot of this 21 information is so new that we are just in the 22 hypothesis generation phase and we need to confirm 342 1 it, replicate these findings in order for it to 2 truly be clinically relevant. But even if we 3 replicate it, remember, we're not a CLEO associate 4 and not a CLEO-approved lab. This is all research 5 results. 6 DR. KOSKI: Thank you. While this has 7 been a very interesting discussion of a number of 8 different points, I'm a little concerned that we 9 still seem to be talking around the central issue 10 here. With medical records we have well- 11 established procedures that we've used for years 12 that determine when and how it's appropriate to 13 allow access to medical records for research 14 purposes with waiver of consent, what appropriate 15 safeguards are and so on. 16 The real question that we are here to talk 17 about right now is how do we apply that in a 18 situation where we have one individual who has 19 volunteered to participate in research who has 20 access to information that would not otherwise be 21 available that is of some concern to other 22 individuals with whom they have relationships where 343 1 that information may have been obtained under 2 certain expectations of privacy. Okay. 3 When is it permissible, okay, to have that 4 individual disclose that information that has been 5 given to them under some expectation of privacy for 6 use in research, and when is it permissible for us 7 to allow a waiver of the informed consent for those 8 individuals about whom that information is being 9 disclosed. These are the real questions that we 10 have to get to. And at the risk of sounding like 11 some kind of a slave driver here, I think it's 12 important that we try to focus the discussion on 13 this central issue. Because if we -- the 14 complexity of how do we deal with archive samples, 15 how do we deal with, you know, this and that, we're 16 going to miss the real meaty matter that we have to 17 deal with right now. 18 So I would ask you, please, if you could, 19 try to focus a little bit on that. 20 MS. MEYERS: Well, I'm going to try again, 21 but I think it's hard to get people to understand. 22 A few months ago we had medical 344 1 confidentiality regulations were published and the 2 Secretary has suspended them. If we had guaranteed 3 legal confidentiality of medical records that 4 anything that we say about ourselves or our 5 relatives would be confidential and nobody -- it 6 wouldn't hurt anybody. If I told you that my uncle 7 had schizophrenia, my mother had -- you know, it 8 doesn't matter if nobody can get into my medical 9 records. Even if I give that away for research, if 10 you're showing a family three that is not 11 personally identifiable to me, then it wouldn't 12 matter what my relatives have. All you would have 13 is data on a family tree. 14 DR. F. LEVINE: Perhaps I was oblique, but 15 I thought that was exactly what I was saying or 16 suggesting or implying with my question and that is 17 that unless a human participant is engaged in that 18 research all of those secondary, tertiary, and 19 community parties are not human participants and 20 thus are not necessarily fall under any framework 21 of consent. That the human participants is that 22 individual who has consented to be in that 345 1 research. 2 If that person is sitting with a medical 3 record in their drawer of their mother and chooses 4 to hand it over, then that person perhaps is 5 engaged in a criminal act himself or herself or 6 something by turning over something that, you know, 7 some private information. But to respond to a 8 series of questions doesn't -- about parties that 9 one is connected to whether familial based or other 10 forms of networks, I think leads us down a slippery 11 slope. Or I guess I was asking the panel, and I 12 thought I got a pretty good response from the 13 panel, it's potentially leading us down a slippery 14 slope to anthropomorphize those individuals as 15 human participants and I thought the responses were 16 reasonably clear. I say as a devil's advocate. 17 DR. KOSKI: Well, I think we've seen the 18 definition, it's the legal definition if you are 19 within the regulations of human subject which is, 20 of course, what the regulations talk about. As 21 being an individual about whom an investigator 22 obtains private, identifiable information. And, 346 1 so, you know, I think that this has been the 2 interpretation that way it's been applied. 3 Bob, I know, you may have again some 4 further insight on this. But I guess what I'm 5 striving for in my comments is to try to get some 6 real clarity here that can be used in a pragmatic 7 way as to development of sensible policy guidance 8 on this issue. 9 DR. COLLINS: Well, it seems as if a 10 number of the panelists have been trying to respond 11 to that in the sense that it does seem that there 12 may be considerable opportunity to utilize the 13 waiver guidelines to fit this situation. But that 14 the real challenge is to figure out when do they 15 fit and when do they not? When are you in a 16 circumstance where that family member is being 17 exposed to a greater than minimal risk as however 18 we now decide we want to define that. But I think 19 there has been some sense that the waiver pathway 20 might be the most appropriate way to deal with the 21 issue in that it does require the IRB to think 22 about it, to look at the details of the situation, 347 1 to consider what is the information that's being 2 collected from family members, and how much of a 3 risk does it pose to them, and what kind of 4 confidentiality practices are being applied to this 5 particular circumstance. So, not to overstate what 6 may not be a consensus at all, but I think I heard 7 a little bit of that in some of the responses. 8 Bob seems anxious to respond, and then we 9 have Mark, and then we should go to the public 10 testimony. 11 DR. R. LEVINE: I want to say that I do 12 not think the waiver is the way to go. 13 [Laughter.] 14 DR. R. LEVINE: I think that it's a bad 15 definition. It's a definition that was written 16 without skill. And it has create a category of 17 secondary research subjects that is not part of the 18 ethics or e-thoughts of any research group. And 19 now what we are trying to do is to make up for this 20 poorly crafted definition by trying to squeeze it 21 in under a waiver. And what we ought to just say 22 is, research subjects are people that we actually 348 1 engage personally. And, also, part two of that 2 definition was not intended to pick up people -- 3 relatives that you ask about their relatives. It 4 was intended to pick up such things as use of data 5 sets, secondary use of data sets for research 6 purposes. 7 I think what we really need is to rewrite 8 that definition so that it's coherent. 9 DR. SIEGEL: I think I'm struggling with 10 the same thing. I'm reading 21 C.F.R. Parts 50 and 11 56 which define a human subject differently than 12 4546. 21.50 and 56 define a human subject means an 13 individual who is or who becomes a participant in 14 research either as a recipient of the test article 15 or as a control. And where I guess I've been 16 having a problem during this whole conversation is, 17 much of the research that I've been involved with 18 for the past 20 years has actually involved the 19 collection of information from our research 20 participants on family issues. And depending on 21 the type of research. 22 So, for instance, my own specialty was 349 1 psychiatric research, we collected a lot of 2 information. Because, again, along with looking at 3 drug response, you're also looking at predictors, 4 you're also looking at a lot of things. 5 Now, I guess where I'm having -- this 6 discussion has never made its way onto that side of 7 the fence. It's always on the genetic side and I 8 guess that's been my -- if it's an issue, shouldn't 9 it be an issue or not. And, again, we get into a 10 regulatory definitional difference that sort of 11 gets us all confused again; or me anyway. 12 DR. KOSKI: Yeah, I think it's very 13 important to recognize that the definition under 14 Title 21 is specifically crafted to deal with the 15 type of research that FDA regulates, and, indeed, 16 much of the research that we're talking about here, 17 particularly that which would involve social and 18 behavioral sciences, there is no test article. And 19 so we need to think differently about that 20 definition. But, I think the important point here 21 is that if in fact there is a consensus that the 22 regulatory definition was poorly written 350 1 misunderstood, or whatever, in the first place, 2 then we ought to get down to the hard business of 3 saying what it ought to be instead. And this 4 sounds like real progress. 5 MR. BARNES: Just a brief comment. There 6 actually are a host of other duties here which are 7 not addressed in law at all, which is that for 8 research participants or subjects who actually 9 acquire genetic information on their relatives and 10 their family members, they have no legal duty in 11 regard to disclosure or maintenance of the 12 confidentiality of that information in the way that 13 all laws are drafted now. 14 For everybody else there are at least kind 15 of plenary ethical, legal, professional duties to 16 keep information private. But for those who -- but 17 for recent participants who are actually given 18 information by researchers about their family 19 members, there is no duty to keep that information 20 confidential because they're not a licensed 21 professional, they haven't signed a contract or 22 anything else, which raises a host of issues about 351 1 whether in fact research participants should 2 themselves have duties of confidentiality. 3 DR. KOSKI: If I may just quickly respond 4 to that. While there may be no legal duty, okay, 5 many would argue that the very nature of privacy 6 and confidentiality and intimate relationships 7 would mean that there is a moral duty to preserve 8 the sanctity, if you will, of the relationship in 9 which private information is disclosed to another 10 person. 11 After all, the only way that we can 12 interact with people and get to know them is to 13 share some information about ourselves in one way 14 or another, and we do that within the context of a 15 relationship that sets the bounds around how that 16 information is going to be used. 17 So that while there is no legal 18 responsibility, I think that we would be remiss not 19 to recognize the important moral responsibility and 20 make sure that as we go forward we're respectful of 21 that with how we interpret and apply these things. 22 MR. BARNES: And just one thing to that, 352 1 you -- more intact family than I do in regard to 2 people protecting one another. 3 [Laughter.] 4 CHAIRPERSON MARSHALL: Was that a howler, 5 Dr. Collins? Have we achieved the level of howler 6 yet? 7 [Laughter.] 8 CHAIRPERSON MARSHALL: Can we open the 9 floor up to the public. Mr. Levinson. 10 You need to use the microphone please, 11 because we are recording. 12 DR. LEVINSON: -- for the United States 13 for the Interimational Society of Psychiatric 14 Genetics. My name and e-mail address are listed 15 there for anyone who needs them. 16 I represent a group of investigators -- 17 senior investigators in one of the fields which is 18 most heavily involved in genetic research and in 19 complex disorders, and one of the fields which has 20 the most critical need to use family history 21 information in the course of the research. It's 22 difficult to explain in the course of a few minutes 353 1 that are available today why that need is present. 2 I would be happy to do that at another time and our 3 task force would be happy to work with or assist 4 this committee in any way that would be helpful. 5 We have been working on this issue for 6 nine months and we have developed a certain 7 understanding of it, although we feel that more 8 data are needed. 9 Let me just briefly discuss some of our 10 concerns about these issues and I hope to have more 11 opportunities to work with some of you later. 12 This started with the, quote, "VCU" case. 13 I would like to point out that from the perspective 14 of those of us who work everyday in this field, 15 that was an unusual protocol in a number of ways. 16 It involved the research registry of twins, 17 something that most studies do not involve. It 18 collected a highly diverse set of personal and 19 family history data, not focused on a particular 20 health problem of each subject. Very different 21 from what we do everyday. 22 As some OHRP staff have pointed out, there 354 1 was a wide variety of potentially identifying 2 information about relative in that database which 3 created special problems and risks with which I 4 tend to agree, although I haven't investigated it 5 in detail. And there were serious questions, 6 apparently, of an adequate IRB oversight of the 7 rationale for the protocol and its procedures. 8 In most human subjects, in most human 9 genetics protocols, by contrast, the subject 10 suffers from a serious disorder, whether its a 11 common disorder or a rare disorder, psychiatric, or 12 other, or non-psychiatric, the subject has a 13 compelling interest in research on that specific 14 disorder; very limited family history information 15 is typically collected in the protocols I know 16 about. 17 The information is about only directly 18 relevant disorders, it's limited in scope, it's 19 known by the subject from many shared family 20 experiences over a long period of time, and is 21 really part of the subject's own health history 22 because the disorder is at least probably genetic. 355 1 This creates very serious questions about 2 whether this is information that is truly the 3 relative's private information, or whether it's 4 experience that in a sense both the subject and the 5 relative have some control over. And I think that 6 that's one reason why, for the past 20 years, very 7 few IRBs have considered family history procedures 8 when appropriately limited and appropriately 9 focused to be a violation of the relative's rights 10 or to be something that the relative has to consent 11 to. These are the real circumstances we deal with. 12 The regulation defines "private information" in 13 terms of a, quote, "reasonable person's 14 expectations." And the fact is that most adults 15 accept that their adult relatives have some 16 autonomy in making decisions about disclosing very 17 limited family history which has a direct relevance 18 to their own personal health risks. Whether that's 19 to a doctor, or with far greater confidentiality 20 protections, to a researcher. 21 On the other hand, this is clearly a 22 controversial issue. Reasonable people have 356 1 different feelings about it. Health information 2 seems intuitively private. And it may be difficult 3 to achieve a total consensus at any point about the 4 definition of private information. 5 Nevertheless, IRB practice, since 1981, 6 since these regulations were promulgated, has 7 recognized the scientific need for family and for 8 history information for certain types of studies. 9 Researchers have generally been permitted to record 10 family history information on a very confidential 11 basis or in some cases information has been 12 considered private and waiver of consent has been 13 considered justified. It's buried usually the 14 first, sometimes the second. 15 It seems to me from experience as a 16 researcher and an IRB member in the past that IRBs 17 have considered the risks to be minimal. Members 18 of my task force who have collected tens of 19 thousands of subjects don't know of a case or 20 breach of confidentiality in family history 21 information by researchers. No such breach 22 occurred even in the VCU case whose procedures we 357 1 questioned; and none of the participants in the 2 recent forum on third-party risks that was held at 3 VCU knew of such a case. 4 So although there may be such cases -- and 5 I'd be prepared to admit there may be ones we don't 6 know about -- they must be rare. And if they're 7 rare, researchers are apparently doing a far better 8 job in protecting confidentiality than the health 9 industry is. And that's one reason why IRBs tend 10 to feel that what we're doing is not unreasonable. 11 Although I'm not saying that every 12 researcher has been reasonable or that every IRB 13 has been reasonable, in general we've done a pretty 14 good job. 15 A few other points, that I think are of 16 historical relevance, it's very difficult to 17 predict the harm that would befall a specific human 18 being if their information were violated. We 19 really disagree seriously with Dr. Botkin's lines. 20 You know, you may think that a heart attack is not 21 a very sensitive condition. But if you're an 22 airline pilot, you're going to lose your job. If 358 1 you're an associate professor at Penn, you're not. 2 If you have depression you have no problem 3 telling your Chairman at the University of 4 Pennsylvania that you have depression. If you're 5 an airline pilot, you can be on an antidepressant, 6 but you better not have a heart attack. It's very 7 difficult to predict. What we need to do is 8 protect all information. Not to claim that IRB 9 members can sit and decide who would be hurt by 10 breaches. We have to prevent breaches of 11 confidentiality. We've done a good job, perhaps we 12 can do a better job. And I think the discussion is 13 well worth it. 14 We were disturbed by some of the 15 statements that were made the OHRP representative 16 who spoke at the VCU third-party risks forum. Some 17 examples were that a relative may expect that 18 information that is given to perhaps the subject 19 will not be repeated. The example that was given 20 was, what if a husband tells his wife that he has 21 HIV infection or perhaps a genetic disorder in 22 order that they can discuss health decisions or 359 1 childbearing decisions together. 2 And the statement was made that the 3 subject may be violating the relatives -- the 4 husband may be -- the wife may be violating his 5 wife's privacy rights if she discloses that 6 information to a researcher. 7 Well, you know, I think that really 8 depends on the situation. I think that's a very 9 dangerous position to take and a somewhat 10 ideological one in my view. What if that wife 11 decides to enroll in a prospective study of what 12 happens to women who perhaps have had risk factors 13 for HIV and she wants to be in that study? In 14 order to be in it, she has to describe what her 15 risk was. Well, I'm married to someone who tells 16 me he has HIV and I had sex with him. Does she 17 need her husband's permission to enter that study 18 about her own health risks or to tell the study why 19 she is at risk? 20 What if they divorce and she has medical 21 decision authority over their child? Their child 22 develops that genetic disorder, she wants to enroll 360 1 him in a genetic study, the researcher says, tell 2 us a bit about him and his history? The father's 3 diagnosis is part of that child's health history. 4 Does the wife have to have her ex-husband's 5 permission to tell a researcher, we have a family 6 history of that disease, we would like to be in 7 your study. 8 I'm not sure, but I don't think so, but I 9 think that we should take seriously whether all of 10 this family history information in focused, 11 directly relevant studies to the subject's health 12 risks is really private to the relative, or may, in 13 fact, be the subject's own health information. 14 By the approach that's just been 15 described, that was ascribed to the conference, no 16 family history inquiry would be possible about 17 identifiable relatives by the position that this 18 representative took. Because virtually all health 19 information will be defined as private, so all the 20 relatives would be subjects and because the wife's 21 action is being interpreted as a violation of the 22 husband's rights, you can't waive consent because 361 1 there's a violation of rights involved which 2 invalidates that part of the regulations. 3 So we would be totally invalidating 4 something that IRBs have been routinely allowing 5 for 20 years, since the regulations were 6 promulgated. That is a major change. But it was 7 asserted at the conference that this was not a 8 change. 9 I respectfully submit that this 10 interpretation of the regulations by some OHRP 11 staff represents a substantial change in 12 interpretation of the regulations. And, in fact, 13 could be defined as a change in the regulation. 14 What are the alternatives to that 15 approach? Well, Dr. Botkin has pointed out that in 16 many studies identifiability of relatives can be 17 reduced or the definition of identifiability may be 18 such that many studies are not really identifying 19 the relatives in a unique way. 20 I would mention, though, it's very 21 difficult to pick a reasonable change in these 22 regulations based on one's information about a few 362 1 types of research because there's always another 2 type that would be totally paralyzed by that exact 3 same approach. 4 What if you're using genealogical 5 information? You have to identify people. At some 6 point the scientific and public community have to 7 decide whether researchers can be trusted to 8 maintain certain information confidential when they 9 really need it, and IRBs have to decide when we 10 really need it and when we don't. 11 We could define some family history 12 information as the subject's health history, not as 13 the relative's private information which I believe 14 is reasonable in certain kinds of studies, perhaps 15 not in others. Or we could define it as private, 16 but say that the people's rights -- the relatives' 17 rights are not being violated depending on the 18 nature of the information and its real relevance to 19 the subject; not a blanket permission to collect 20 whatever we want from subjects about the relatives 21 who -- I don't think any of us believe is 22 justified. 363 1 The interpretations that were presented by 2 OHRP staff at VCU are really inconsistent with the 3 regulation's original intent, with their actual 4 wording, and with 20 years of IRB decisions. The 5 basic principal of the Belmont report is 6 "magnificence," maximized benefits/minimized risks. 7 Are we reducing the potential benefits of research 8 without reducing risks? And the reason I'm raising 9 this question today is that we are already 10 beginning to see IRBs change their behavior based 11 on the following. 12 I think there's a serious question of 13 whether in this issue I think in a sincere way and 14 in the interest of addressing a serious issue OHRP 15 staff may in fact be overstepping their authority 16 in the short term. 17 IRBs alone have the authority to interpret 18 federal regs. It's a very fundamental principal of 19 our system based on the Neuremburg codes and based 20 on 45 C.F.R. 46. Centralized authority was held to 21 be dangerous and undesirable. There is not 22 supposed to be a centralized agency telling IRBs 364 1 exactly how to interpret regulations other than 2 procedural issues and gross negligence. 3 Is OHRP in its current approach of this 4 issue in effect imposing new interpretations on 5 IRBs? I think there's some evidence that this may 6 be happening, but I don't have enough data about it 7 right now to give chapter and verse. NIMH staff 8 are trying to look into this and find out exactly 9 what's happened in different cases. But what I do 10 know is that IRBs are starting to fear OHRP 11 intervention around this issue. After all, VCU 12 lost its multiple project assurance and it cost 13 them millions of dollars and a delay of one year of 14 many research projects. 15 While those actions may have been 16 justified at VCU, I mean, I wasn't there, I didn't 17 investigate it. IRBs now feel from a variety of 18 stories they've heard about other cases that if 19 they don't vote on family history issues the way 20 OHRP wants, they may get the university in trouble. 21 That is exactly what our regulations were written 22 to prevent. A central agency is not supposed to 365 1 dictate to IRBs, nor this committee, exactly how to 2 interpret regs. IRBs must accept that 3 responsibility. 4 What we can do is try to develop more 5 information, more consensus, more discussion. If 6 we really need a change, we should change the regs 7 in a public and, you know, legitimate legal way so 8 that there is some consensus. 9 Our recommendations to this advisory 10 committee is that in the short run we do believe 11 that OHRP should issue clarifying guidelines to 12 IRBs to remind them what their formal obligation is 13 on other regulations which apparently the VCU IRB, 14 for one, did not follow, and maybe many IRBs are 15 not following. 16 They have to determine in any protocol 17 that obtains information about third parties what 18 is being collected from whom, about whom, by what 19 procedure, with what kind of identifying 20 information, and very critically, what's the 21 rationale. There's a real question in the VCU 22 case, was there a good scientific rationale for 366 1 what was done? There may not have been. And 2 that's an IRB responsibility. 3 Part of the relatives really human 4 subjects based on what regulations, and if so, was 5 waiver of consent justified? I have 30 more 6 seconds. 7 Secondly, we believe that IRBs should be 8 informed in the short run that the regulations have 9 not changed. They should be reminded in writing. 10 There has been no change in 45 C.F.R. 46. They 11 alone retain the authority to interpret these 12 regulations. And I would hope that OHRP staff 13 would decide to refrain from any actions that have 14 been interpreted as imposing interpretations of the 15 regulations, on IRBs in areas where there is a long 16 established interpretation in place and where there 17 is no compelling reason to force a change. 18 There is no evidence of great harm to 19 subjects. There is no evidence of any breach of 20 confidentiality. So we could obstruct very 21 important research without helping relatives or 22 subjects. We have time for a deliberate and broad 367 1 discussion involving diverse groups and individuals 2 about what really needs to be done and what doesn't 3 need to be done in this area. 4 We also would like scientific groups, our 5 own, American Society of Human Genetics, advocacy 6 groups and others to begin work and we urge to 7 begin work on their own standards and curricula for 8 what would be reasonable procedures and training 9 for staff in this area, both when there's family 10 history information needed, how should it be 11 collected, and how do you train staff to maintain 12 our high standard of protection of privacy of that 13 information. 14 I believe that if those kinds of 15 guidelines and standards are developed and put in 16 writing, they can serve as a gold standard for IRBs 17 to compare to protocols and to help them make 18 decisions in their own local and community 19 contexts. I think in the long run it will not be 20 necessary to dictate those interpretations 21 centrally. I think a reasonable consensus will 22 develop. It may involve clarification of 368 1 regulations in the future. It may involve 2 producing some new regulations. But I think that 3 consensus will be helpful. Thank you. 4 CHAIRPERSON MARSHALL: I would like the 5 panel members to come back if they could. We are 6 engaging the panel. And the panel is going to have 7 the first opportunity to respond to Mr. Levinson. 8 I'm asking the panel members, anyone on 9 the panel, would you like to respond to Mr. 10 Levinson? Dr. Levinson. Thank you. 11 Abbey. 12 MS. MEYERS: I'm not sure if he was right. 13 Some expert here will be able to say whether he's 14 right that local people -- it's more or less like 15 the State of Kansas passed a law that evolution 16 won't be taught in Kansas because local people have 17 the right to make local laws. 18 Is it true that the federal government 19 doesn't have the right to tell IRBs what to do? 20 CHAIRPERSON MARSHALL: I'm moderating this 21 panel. Thank you. I have Bob, I have Adil, I have 22 Greg. And I want to say that I want this 369 1 discussion to be limited and to remember what our 2 focus is this afternoon. And I do not want this to 3 degenerate into a discussion about what happened at 4 VCU and parsing out the federal regulations. So 5 let's try and keep it focused on protecting human 6 subjects and on the secondary or the family 7 secondary subject issue. Thank you. 8 Bob would like to respond to that on 9 point. Greg would like to respond to that on point 10 and then I have Adil. 11 DR. R. LEVINE: As much as I agree with 12 Dr. Levinson, I have to say that there's nothing in 13 the regulations that says that only the IRB can 14 make these decisions. I will say though that in 15 the background to the regulations, particularly in 16 the introductory chapter of the National 17 Commission's report on IRBs, it presented a very 18 strong argument for why the centerpiece of 19 decisionmaking about a particular research project 20 should be made by an IRB that is in the locale in 21 which the -- or preferably in the institution -- in 22 which the research is going to be carried out. 370 1 It had a lot to do not only with 2 interpreting local standards, and it was assumed 3 that there could be important differences across 4 different communities, but it also had to do with 5 the capacity to educate and also to be aware of the 6 players that do this work within the institution. 7 You would hate to say this in regulations, but the 8 National Commission reflected its awareness that 9 some people are more inclined to be respectful of 10 human subjects' rights and welfare than others. 11 And the colleagues of the individuals within the 12 institution were most likely to be aware of which. 13 Thank you. 14 CHAIRPERSON MARSHALL: Thank you. Greg. 15 DR. KOSKI: I would just say that with 16 respect to the local issue, there certainly may be 17 instances in which a local IRB simply abrogates its 18 responsibility to effectively protect the 19 participants in the research. And in an instance 20 such as that, and we could all come up with 21 examples, I believe it's important to recognize 22 that there is a responsibility to make sure that 371 1 they're doing what they're supposed to be doing in 2 a faithful manner. And to a certain extent, I 3 think it falls to -- in some instances -- what may 4 be application of a prevailing community standard 5 of decency and appropriateness and those are 6 difficult issues. 7 But I can assure you that in the event 8 that a local IRB failed to exercise in a 9 responsible manner it's responsibility to protect 10 human subjects our office would do what was 11 necessary to correct the action of that local IRB. 12 CHAIRPERSON MARSHALL: Adil and then Mr. 13 Curtain. 14 DR. SHAMOO: [Off mic.] -- for someone -- 15 for advocacy -- Dr. Levinson. I hope I did not 16 understand you that medical psychiatric information 17 did not contribute. You had a few cutsie examples 18 of how discrimination occurred, heart attack, about 19 the airline pilot, or at your own university if it 20 is depression, the chairman wouldn't mind. But as 21 you well know there is a wholesale discrimination 22 toward the mentally ill in health care, in jobs, in 372 1 all aspects of life, and I have a son who has 2 schizophrenia, he's 30 years old. He is the last 3 one to be hired, and the first one to be fired. 4 And furthermore somehow you have neither 5 heard us nor listened to us and to all the 6 newspaper reports and other that there are 7 wholesale violations of 45 C.F.R. 46 and that's why 8 you see there has been in ten years 21 suspension/ 9 terminations, 12 of them or at least ten of them 10 entire institutions were suspended. You probably 11 will not hear until in the morning that we have 12 eight deaths reported in ten years to OPRR. You 13 could tell me with 70 million Americans we have 14 eight deaths only. So there are wholesale 15 violations and every regulatory agency has the 16 right to insure compliance by the local, whatever 17 system is in place. And in this case it's the IRB. 18 CHAIRPERSON MARSHALL: Thank you. And I 19 would like to close the discussion on that narrow 20 construal of what we are about this afternoon and 21 refocus us on the issue of family members and 22 others and the privacy of their information and 373 1 adequate protection of human subject. Mr. Curtain. 2 MR. CURTAIN: No, VCU, right, Dr. 3 Marshall? 4 In his opening remarks Dr. Collins listed 5 five issue areas. And one common theme that I saw 6 discussed through all five of those areas was, and 7 this is almost a quote, the IRBs are confused. 8 This is just unacceptable. The IRBs are 9 the advocate. They have to function as the 10 advocate for the research subject. I guess earlier 11 this morning you discussed the business about 12 research, principal investigators, being 13 altruistic. We all know that they all aren't. 14 Okay. 15 And when that occurs, even when it doesn't 16 occur, who is going to be there for the research 17 subject if not the IRB. 18 I disagree strongly with Dr. Botkin, and 19 we've discussed this by e-mail, and his position 20 that he thinks that the IRBs are basically okay and 21 they just need some changing at the margins. I 22 think the word he used was "shoe-horning" them into 374 1 the common rule. 2 From my personal experience, from what 3 I've read in the paper, from reading the Inspector 4 General's report for Health and Human Services, I 5 don't see how anybody can say that this system is 6 not broken. It needs to be changed. You cannot 7 have an IRB sitting at an institution where the 8 guys on the IRB go out to lunch and then after 9 lunch they come back and approve one another's 10 projects. And this happens. I know it happens. 11 You know, Dr. Koski's office has proven that it's 12 happened. The IRB system has to change. They have 13 to be the ones who look out after the research 14 subjects. 15 And I don't mind being called a research 16 subject because people within a research project 17 are kind of at the mercy of the principal 18 investigator. We aren't equal. If that's what the 19 word "participant" kind of suggests, we're kidding 20 ourselves. Some people -- as Ms. Terry and the 21 lady who spoke earlier, you know, she has become so 22 knowledgeable about this that she probably is a co- 375 1 equal of the principal investigator and she may be 2 a true participant. That's a very, very rare 3 situation. 4 We are subjects. We are at a 5 disadvantage, and we need somebody to level the 6 playing field. 7 Thank you. 8 CHAIRPERSON MARSHALL: Can I ask you if 9 you had a suggestion for the committee in terms of 10 how to go about leveling that playing field? What 11 would it be? 12 MR. CURTAIN: Yes, ma'am. I would 13 envision -- and this costs money, I understand that 14 -- I would suggest a regional IRB structure where, 15 for instance, you would have a Philadelphia IRB. 16 You wouldn't have an IRB at Penn in this medical 17 school and that research institution. You would 18 have a regional IRB for that area, there would be a 19 professional staff there full-time who was 20 constantly -- who is expert in the rules, the 21 regulations, knowing what's going on in Dr. Koski's 22 office and then you would bring in ad hoc groups of 376 1 researchers and community people maybe from that 2 are to serve on an ad hoc IRB. You form it, they 3 do their business, they disband and they go away. 4 The projects they're working on are coded so that 5 they don't know that, gee, this is really the guy 6 in the cubicle next to me, you know, or the lab 7 next to me. This is his project. That would be my 8 suggestion. 9 You need some kind of a full-time staff, 10 you need training, and it's expensive, yes, but 11 what you've got isn't working. As I've said 12 before, if you folks don't fix it, Congress is 13 going to fix it Because that entire code of 14 federal regulations that's out there, people who 15 work for the federal government like me, we just 16 didn't get up one day and decide to write a right. 17 Every regulation in that book shelf was written in 18 reaction to some kind of an abuse. Something had 19 gone wrong. And things in your community have gone 20 wrong. And if you don't fix it, and fix it soon, 21 there's going to be another book in the Code of 22 Federal Regulations telling you how you're going to 377 1 do your business. 2 CHAIRPERSON MARSHALL: I'm sorry that Mr. 3 Rich isn't here to hear your perspective and point 4 of view on this issue. 5 Members of the panel, would anyone -- does 6 anyone have any words for Mr. Curtain? 7 DR. COLLINS: Mr. Curtain, I think you've 8 raised our consciousness on a number of issues. 9 Let me ask you a more explicit question than what 10 Dr. Marshall did which is specifically related to 11 the issue of family members from whom information 12 is collected by the proband as was the case in the 13 study that you found you were a participant in 14 without expecting to be. 15 In a very explicit sort of circumstance 16 such as this, what would you say, based upon your 17 own experience, should have been done in that 18 instance in order to facilitate that research and 19 do you see it as an approach that could be 20 extrapolated to other types of pedigree research 21 which many people in this room are very concerned 22 about not losing as a consequence of some overly 378 1 onerous process. 2 MR. CURTAIN: Dr. Marshall, I'm going to 3 have to talk just a little bit about these here. 4 This, by the way, is the questionnaire that started 5 it all. When I received this questionnaire, the 6 first thing I did was write to the principal 7 investigator. I didn't go running to OPRR at the 8 time. I wrote to the principal investigator. I 9 said -- I suggested, just take off the column that 10 has "mother, father, and siblings" and when you 11 send a package to the twin just, you know, Xerox a 12 few extra copies and ask the twin to distribute 13 them. Not a real satisfactory response. Kind of a 14 pat on the head, you know, you're nice, we'll take 15 care of the science, okay, that type of thing. 16 [Laughter.] 17 MR. CURTAIN: I wrote to the Chairman of 18 the IRB and he ignored me, so I wrote to the head 19 of the medical college. He ignored me. And then, 20 you know, it was like three months later, I says, 21 this isn't going anywhere, so I'll try the Office 22 of Protection and Research Risks. I'm certainly 379 1 not suggesting that pedigree research has to be 2 revised in total. 3 All I'm saying is, if you've got an IRB 4 there who can look at something like this and say, 5 hey, Dr. X, this is not the way to approach this 6 subject. The twin is there. 7 The thing went to my address and I still 8 want to know and VCU still hasn't answered this, 9 how did they know that my daughter was at our 10 current address when it's a different address than 11 her birth records. I want to know how they tracked 12 her down at that address? Nobody will answer that 13 question. 14 So all I'm -- now I've lost my train of 15 thought. I'm having a senior moment here. 16 [Laughter.] 17 MR. CURTAIN: I'm not asking that the 18 pedigree research be done away with, but when it's 19 such an obviously easy thing, I mean, the immediate 20 family. Give me a break. 21 CHAIRPERSON MARSHALL: Abbey has a 22 question for you. 380 1 MS. MEYERS: You've heard us talk about 2 what the impact of what you -- you've brought this 3 to our attention and what the impact would be. For 4 example, when you go to see a new doctor, and he 5 asks you what diseases are in your family, you 6 wouldn't be able to answer that question. Do you 7 want that to happen? Do you think it should? 8 MR. CURTAIN: That's a red herring. I 9 don't even want to discuss that. Really. That has 10 nothing to do with this issue. To compare my 11 doctor with some principal investigator at some 12 university 100 miles away whom I have never met who 13 is going to take this information and instead of 14 putting it in a folder with my name on it and stick 15 it in his office filing cabinet, instead of that, 16 this principal investigator is going to dump it all 17 into a computer database and then this principal 18 investigator tells me, hey, don't worry. This 19 stuff is really secure in my database. I had to be 20 the one to tell the principal investigator, no, 21 it's not. It's subject to a federal subpoena. And 22 then she -- oh, she, right. You know, this is just 381 1 a red herring, this discussion comparing that 2 individual with my family. 3 MS. MEYERS: So what you're talking about 4 you want only to apply to research? It shouldn't 5 really affect everyday medicines? 6 MR. CURTAIN: Absolutely. Absolutely. 7 If my daughter's gynecologist thinks that 8 he needs this information about me to promote the 9 health of my daughter, hey, I'll go and tell them 10 all about my abnormal genitalia -- 11 [Laughter.] 12 MR. CURTAIN: My low sperm count. You 13 know, I'll be the first one there to give them the 14 information. 15 CHAIRPERSON MARSHALL: Does anyone else on 16 the committee have any remarks or questions for Mr. 17 Curtain? 18 [No response.] 19 CHAIRPERSON MARSHALL: Thank you very much 20 for being with us today. We appreciate it. 21 We are running behind and I'm mindful of 22 that. We are running about 15 minutes behind. So 382 1 what I would like to do is this -- 2 Dr. Collins has just posed a very 3 interesting question to me. Has the committee 4 already discussed who has the authority to rewrite 5 the regulations? And the answer to that is, every 6 agency. Right. That we have not discussed that in 7 particular. 8 DR. COLLINS: I raised the question 9 because I thought I heard Bob Levine saying, we are 10 making a mistake by trying to take regulations that 11 maybe were not as artfully crafted as he would have 12 liked and were written some time ago and trying to 13 force the current circumstance through that 14 particular filter and perhaps we ought to be 15 bolder. And I guess I was inquiring whether that 16 was a realistic option. 17 CHAIRPERSON MARSHALL: I'm just going to 18 very quickly qualify and remind everyone that 19 within our purview is to give advice. So I think 20 the committee is clear in terms of what its 21 authority and what its role is. Bob, if you can 22 respond on point and then I would like to bring 383 1 some closure to this session and give Dr. Koski the 2 opportunity to talk about the Declaration of 3 Helsinki and to bring some closure to that as well. 4 DR. R. LEVINE: I think that if we don't 5 have the authority to recommend that regulations be 6 revised, and there are plenty of examples of errors 7 in the regulations that beg for revision, and we 8 recently saw the entire Subpart B revised after a 9 delay of about two and a half years which I don't 10 understand, but if we can't recommend revision in 11 regulations then we really shouldn't even be 12 discussing them. 13 CHAIRPERSON MARSHALL: We certainly can 14 recommend them. And, you know, I think that in the 15 various contexts of the subjects that we look at, 16 we can and we will. And I know that we have 17 discussed in the committee the fact that in 18 relation to children we may find out that there are 19 regs that are outdated or that need parsing out in 20 some way, shape, or form, and that we may find that 21 in the genetics area as well. And I imagine as our 22 work unfolds we'll find it in other areas. 384 1 So I could envision a scenario in the 2 future when we might make some wholesale 3 recommendations for changes in the regulations. 4 Whether we do that subject-by-subject, or whether 5 we do that en masse at some point in time is 6 something that we as a committee need to consider. 7 And that's a question that I have raised to the 8 respective chairmen and chairpersons of the working 9 groups. And we need to consider that, how we're 10 going to proceed along those very lines as a 11 committee. 12 I'd like to bring some closure today to 13 our charge. And perhaps to think about a plan. 14 Dr. Collins has provided us with five sort of very 15 nicely articulate issues that bear explanation and 16 he has suggested that we focus in terms of a fast 17 track component to a larger effort, more narrowly 18 on the issue of family members and privacy issues 19 and who constitutes a research subject or a 20 research participant within the context of genetic 21 research. We've had other issues brought up as 22 well, so I imagine that we have a list of probably 385 1 six or seven things that the committee could 2 consider. 3 So it looks to me as though we have 4 certainly an agenda, or beginning of an agenda for 5 our working group and what the committee's pleasure 6 is in terms of proceeding. Does the notion of 7 asking our working group to look at the issue of 8 family members and research and how one defines a 9 research subject within the context of genetics 10 research and then moving on to the other issues 11 that have been articulated, is the committee in 12 agreement with moving ahead that way? 13 DR. CHODOSH: I would just say that it 14 would be a waste -- not a waste of time, but a 15 partial job done if we don't extend it beyond 16 genetics. There are just enough situations out 17 there that are very similar and really should be 18 resolved if we can, at once. 19 CHAIRPERSON MARSHALL: Bob has a response 20 to that. I'm seeing a lot of nods around the table 21 that we might actually have consensus on something. 22 DR. R. LEVINE: What I want to respond to 386 1 is I've heard several propositions this afternoon 2 that the definition of a research subject should 3 mean one thing for the FDA and a different thing 4 for the public health service, and another thing 5 for genetics. I think that the government has 6 repeatedly got itself into trouble by stipulating 7 definitions or words that are in common usage and 8 have their own definitions in the dictionary. 9 That's why so many of us who think we're talking 10 about the same thing really aren't. 11 I think it would be a good idea to have 12 one good definition of the term research subject 13 and use it through all of the regulations and in 14 all of the letters we write to each other about the 15 regulations. 16 CHAIRPERSON MARSHALL: Thank you. 17 Mary Kay, do you have an interest in this 18 workgroup and in being our leader? 19 DR. PELIAS: I'm willing to explore it. 20 Yes, I am. 21 CHAIRPERSON MARSHALL: Thank you very 22 much. Are there other committee members? Kate, 387 1 yes. 2 MS. GOTTFRIED: I just had a request 3 with respect to the workgroup. I don't know if we 4 want to do it right this minute, but to clarify to 5 some extent what the charge to this workgroup would 6 be. Because at this point it's pretty broad. 7 CHAIRPERSON MARSHALL: Here is my plan. I 8 would like to get a list of people who are 9 interested; members of the committee who are 10 interested in working on the workgroup. We have a 11 nice list that Dr. Collins has articulated for us 12 and what I would ask the workgroup to do, over 13 night is to give us at least a brief list, perhaps 14 in the morning when we're recapping our first day, 15 of what they would conceive our charge to be. 16 I think we've gotten some very concrete 17 suggestions and we could begin with those. And 18 members who are interested in sitting on a working 19 group can flesh those out overnight. We would be 20 interested in hearing about them in the morning. 21 Dr. Collins. 22 DR. COLLINS: In the way that you operate, 388 1 would this working group potentially also include 2 other members from outside the committee in order 3 to flesh out the expertise for some of these areas? 4 CHAIRPERSON MARSHALL: Thank you very 5 much. And I didn't slip him five dollars under the 6 table to -- 7 [Laughter.] 8 CHAIRPERSON MARSHALL: -- there's no 9 underhanded financial relationship here. 10 Yes. And we will take Dr. Collins up on 11 his generous offer of assistance. 12 [Laughter.] 13 CHAIRPERSON MARSHALL: Thank you very 14 much. I said it publicly. You can't retract that 15 now. 16 And I think we would very much like to 17 engage the public and others who may have a real 18 interest in helping us work our way through these 19 thorny issues, some of which are very fundamental 20 in terms of their definitions and how we conceive 21 of the problems. 22 Yes. Kate. 389 1 MS. GOTTFRIED: Just a footnote that 2 that would be analogous to some of the other groups 3 that we already have in existence such as the 4 children's workgroup. And I think it's a very 5 important recommendation and it's worked 6 exceedingly well thus far. So we would be remiss 7 not to do so and I think we do need to expand it to 8 include the public as well. 9 On another note, I just want to remind 10 everyone that the NIH has a TNBC group which has a 11 workgroup. And they also are looking at this issue 12 specifically within the NIH. And Sarah Carr and 13 Dr. Jim Hanson so that, Mary Kay, with respect to 14 your charge, you could have an exchange with this 15 group as well, invite information and exchange and 16 work forward towards coming to some more or 17 obtaining further information. 18 CHAIRPERSON MARSHALL: And those of you 19 who are members of the committee or who are ex 20 officio members or who are public members, if you 21 have an interest in participating in this working 22 group, then you should let Mary Kay know, and we 390 1 will be appointing a working group once we've had 2 time to receive input from all of the people who 3 should be heard from. 4 Dr. Koski. The floor is yours and thank 5 you for being so patient with us today. 6 DR. KOSKI: Thank you very much, Mary 7 Faith. I'll try to make this quick and give you an 8 update on the have sort of the status, if you will, 9 of the ongoing discussion of the revisions of the 10 Declaration of Helsinki. You know, we discussed 11 this at our first meeting of NHRPAC. The 12 Declaration of Helsinki was originally issued by 13 the world medical association in, I believe, 1964, 14 close, somewhere around there. And it certainly 15 has been a valued set of guidelines for the ethical 16 conduct of human research for nearly four decades 17 now. 18 The declaration has been revised from 19 time-to-time, as you know, most recently in October 20 of 2000 and the October 2000 revisions included 21 some respositive statements with respect to 22 conflict of interests and so on, but there were 391 1 several provisions which have been considered 2 controversial as well. 3 In particular, four of those included the 4 assertion of privacy of the Declaration of Helsinki 5 over all other codes and regulations for the 6 conduct of research, the broad proscription of 7 placebo controlled trials, as it's been viewed, as 8 well as a requirement for the provision of best- 9 proven therapy upon completion of the clinical 10 trial, and finally, a failure to sort of recognize 11 the very broad scope of human research in its 12 entirety which extends well beyond the actual 13 conduct of treatment-oriented clinical trials. 14 Now, all of these points were discussed at 15 some length at the last NHRPAC meeting. We had a 16 wonderful presentation by Dr. Dixie Snider from the 17 CDC and a very useful discussion. And we emerged 18 from that meeting with a broad agreement that 19 certainly we would all recognize that it would be 20 unethical to withhold known effective therapy in a 21 placebo control arm for trial, and which doing so 22 would result in serious morbidity or mortality. 392 1 But at the same time, there is a need to 2 recognize and sort of clarify the interpretation 3 and scope of the application of the declaration 4 when extended beyond the particular focus or the 5 rather narrow focus of the treatment-oriented 6 clinical trials. 7 Now, upon the advice of NHRPAC, we 8 convened a federal-wide working group that actually 9 was headed up again by Dr. Stuart Nightingale who 10 has been extremely useful and it included 11 representatives from not only the HHS agencies, but 12 also other government agencies as well under the 13 auspices of the human subjects research 14 subcontract. That group has been working, but it's 15 not done. It still has some distance to go. We 16 are nowhere near the adoption of a government-wide 17 policy on this. 18 But back in February, I think, the World 19 Medical Organization in cooperation with the 20 European Forum on Good Clinical Practice and the 21 University of Pretoria decided to hold an 22 interimational conference on the interpretation and 393 1 application of the revised Declaration of Helsinki. 2 And this meeting actually occurred a couple of 3 weeks ago I think now, in Pretoria, South Africa 4 where delegates from -- I think it must have been 5 around 40 countries from around the world, I don't 6 know the exact number, but it was clearly a broad 7 interimational group that came together in a 8 serious collegial, collaborative environment to 9 openly discuss the declaration. And we have 10 several people in the room here, I think, if 11 they're still left, who actually participated in 12 that conference. 13 On behalf of the Department of Health and 14 Human Services, I delivered a prepared statement 15 copies of which are out at the table. If you 16 haven't already seen it, I believe it's been in the 17 news as well, so that you perhaps have had a chance 18 to read it. And it addressed those very issues 19 that I mentioned earlier. 20 And I guess I would report to you that 21 from that meeting I believe it was the sense of 22 everyone -- or almost everyone -- almost unanimous 394 1 across the board from all of the countries that 2 indeed there was a need for further clarification 3 and interpretation of the declaration, possible 4 change, but that this was something that was going 5 to require ongoing discussion and dialogue. So 6 that no formal policy recommendations were made, a 7 statement from the organizers of the committee will 8 be issued. I haven't seen it yet. I don't know, 9 Bob, if you have seen it as yet. But this is the 10 expectation. 11 There was a statement that was drafted by 12 the committee and the organizers, and I believe 13 that we should see this forthcoming soon. And it 14 commits the delegates who were at the meeting as 15 well as other willing participants. The World 16 Medical Association providing leadership in the 17 area, working together with CIOMS, and other 18 interimational organizations, including Global 19 Forum on Bioethics to continue this discussion and 20 reconvene in about a year with a lot of work done 21 in the interim. At which time I would expect to 22 see some finalization, if you will, of the actual 395 1 recommendations. 2 So I think that in the meantime it's 3 important that certainly the Department of Health 4 and Human Services and perhaps a more government- 5 wide basis, let our institutional review boards 6 know that there is no change in policy. That 7 indeed, you know, the investigators as well as the 8 IRBs need to understand this. Clearly every 9 experimental design needs to have appropriate 10 control groups justified not only on scientific 11 grounds, but on ethical grounds. And, you know, 12 clearly the protection of the rights and the 13 interest and the welfare of the human subjects must 14 be a priority. 15 So, the working group that we have 16 established will continue its work. We will 17 continue the dialogue with other interimational 18 groups and look forward to that and know that we 19 will emerge from this process with something that 20 will serve us all well in the long run. So thank 21 you. 22 CHAIRPERSON MARSHALL: I really don't want 396 1 to open a discussion on this because it is an 2 update. So if you have concerns or questions you 3 could direct them to Dr. Koski. And I am concerned 4 for the welfare and the well-being of our guests 5 and our committee members. So I would like to 6 thank you, Dr. Collins, so very much for giving us 7 a framework within which to think, and for being so 8 generous of your time today and for moderating the 9 panel. 10 Thank you very much. 11 [Applause.] 12 CHAIRPERSON MARSHALL: And I would like to 13 thank our other panelists, Terri Seargent, Sharon 14 Terry, and Terri Arledge, and Jeff Botkin who is no 15 longer here for giving us the breadth of vision 16 that we need in order to move forward in thinking 17 about these very complex problems. For sharing 18 your personal stories with us, and for informing 19 our values and our thinking as we move ahead. So, 20 thank you so much. We really appreciate it. 21 [Applause.] 22 CHAIRPERSON MARSHALL: And we will see you 397 1 tomorrow morning. Thank you, Mr. Curtain, for 2 being here. 3 [Whereupon, at 5:35 p.m., the meeting was 4 recessed to be reconvened on Tuesday, April 10, 5 2001 at 8:30 a.m.] 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22