1 UNITED STATES OF AMERICA + + + + + DEPARTMENT OF HEALTH AND HUMAN SERVICES + + + + + SECRETARY'S ADVISORY COMMITTEE ON HUMAN RESEARCH PROTECTION + + + + + MEETING + + + + + FRIDAY, MARCH 30, 2007 The Advisory Committee met in the North Ballroom in the Sheraton National Hotel, 900 South Orme Street, Arlington, Virginia, at 8:30 a.m., Samuel Tilden, M.D., J.D., L.L.M., Chairman, presiding. MEMBERS PRESENT: SAMUEL TILDEN, M.D., J.D., L.L.M., Chair BERNARD A. SCHWETZ, Ph.D., D.V.M., Executive Secretary CATHERINE SLATINSHEK, M.A., Executive Director JEFFREY BOTKIN, M.D., M.P.H., Member MYRON GENEL, M.D., Member LISA LEIDEN, Ph.D. Member PATRICIA A. MARSHALL, Ph.D. Member DANIEL K. NELSON, M.S., CIP Member NEIL R. POWE, M.D., M.P.H., M.B.A., Member JAMES H. POWELL, M.D., Member FRANCINE C. ROMERO, Ph.D., MPH Member DAVID H. STRAUSS, M.D. Member 2 EX OFFICIO MEMBERS PRESENT: KATHRYN LYNN CATES, M.D. U.S. Department of Veterans Affairs SALLY FLANZER, Ph.D. Agency for Healthcare Research and Quality DENISE H. GEOLOT, Ph.D., R.N., F.A.A.N. HRSA SARA GOLDKIND Food and Drug Administration PETER T. KIRCHNER, M.D. Department of Energy WARREN E. LUX, M.D. Environmental Protection Agency AMY PATTERSON, M.D. National Institutes of Health JOAN PORTER, D.P.A., M.P.H. Department of Veterans Affairs JEFFREY W. RODAMAR Department of Education SANDRA SCHNEIDER, Ph.D. National Science Foundation LINDA TOLLEFSON, D.V.M., M.P.H. Food and Drug Administration 3 ALSO PRESENT: KELLY BOOHER Office of Human Research Protections MICHAEL CAROME Office of Human Research Protections JULIA GOREY Office of Human Research Protections JULIE KANESHIRO Office of Human Research Protections KEVIN PROHASKA Office of Human Research Protections IRENE STITH-COLEMAN Office of Human Research Protections 4 C-O-N-T-E-N-T-S AGENDA ITEM PAGE Remarks SACHRP Chair 4 Remark John Agwunobi, M.D. Assistant Secretary for Health 5 Discussion on Conflict of Interest Among IRB Members Leslie Wolf, J.D. 42 Marjorie Speers 57 Ernest Prentice, PhD 68 5 1 P-R-O-C-E-E-D-I-N-G-S 2 8:40 a.m. 3 CHAIRMAN TILDEN: Good morning, 4 and I'm happy to welcome everyone back for the 5 second day of our SACHRP meeting. As you 6 know, yesterday, we had presentations by our 7 SubCommittees, Subpart A and Subpart C 8 SubCommittees and a panel discussion on issues 9 relating to impaired decision making in 10 research and today our agenda includes panels 11 for certification and training and also 12 conflicts of interest for IRB members. 13 But first, we are really pleased 14 and honored to have Dr. John Agwunobi here. 15 Dr. Agwunobi is Assistant Secretary for 16 Health. He's our boss and of course, he's 17 responsible for OHRP and SACHRP. John is an 18 infectious individual with a tremendous amount 19 of enthusiasm and interest in what SACHRP is 20 about and what SACHRP does and we're glad to 21 have him here to make some remarks for us 22 today. 6 1 DR. AGWUNOBI: Thank you, Mr. 2 Chairman. I'll start, if I may, by correcting 3 you just a little. According to the rules and 4 regulations, I'm not the boss of you. You are 5 an independent advisory body that is supposed 6 to tell me what to do. It's not supposed to 7 go the other way around. 8 CHAIRMAN TILDEN: Don't tell that 9 to too many Committee members, because you'll 10 be getting those midnight telephone calls. 11 DR. AGWUNOBI: I am once again, 12 honored to be here. I always try to attend 13 these meetings. I have to admit with some 14 disclosure here, that I don't attend every 15 Advisory Committee's meetings. This is the 16 only one that I come to regularly and on a 17 continuing basis and it's because I have a 18 very special interest in the work that you do. 19 It's also, I think, because I 20 believe very much so that it is work that 21 affects more than just your office, Bern. 22 It's work that effects every part of the 7 1 Department of Health and Human Services. All 2 of the agencies are affected by your work. 3 It's work that affects every university in 4 every area of research across our nation. 5 Other departments are affected by your work. 6 It's very important work. 7 I recognize today that we have -- 8 this is the first time that I've gotten to sit 9 next to our new Chair, although he is not new 10 to the Advisory Group. He clearly is, I 11 think, able and up to the task. He and I and 12 Bern and the previous chair, there he is right 13 here, just a little breakfast meeting without 14 breakfast in which we discussed the very 15 exciting things that lie in front of you. I 16 was briefed on some of the work that you are 17 doing but actually was very excited by some of 18 the work that you potentially might be doing 19 n the future. 20 I know that there are three new 21 members today and they've been introduced to 22 me just prior to our sitting down. I hope to 8 1 get to know them intimately. I hope that they 2 learn that I am -- that I want to be a friend 3 of this group. Both at the group level and at 4 the individual level, I seek personal counsel 5 on how I might be of assistance to each of you 6 and to the Advisory Group as a whole. 7 Because there are new members 8 here, let me, if I may, just highlight a few 9 issues that relate to the charter, issues that 10 I think are important, issues that I review as 11 I come before you each time you meet. As most 12 of you are aware, the SACHRP is tasked with 13 advising the Secretary. Now, when you do so, 14 Secretary Michael Leavitt, you advise the 15 entire Administration. His job is to transmit 16 up and across the entire Administration the 17 advice and the guidance that we receive from 18 all of our Advisory Committees. 19 My job, as the Assistant Secretary 20 for Health, is to make sure that your voice is 21 being heard by the Secretary. My job is to 22 facilitate the communication between you and 9 1 the rest of the Administration. But it is my 2 boss that you advise, I need to make that 3 point very clear. 4 The charter specifically states 5 that there will be a special emphasis on a 6 number of key issues. These include the work 7 that's being done by your SubCommittees, 8 including research involving special 9 populations, I'm a pediatrician, and these 10 special populations include fortunately, 11 pleasingly to me, neonates and children and 12 that's being done under Subpart D. The 13 current requirements for research involving 14 prisoners as subjects are also being covered 15 by your SubCommittees. Issues involving the 16 concept of accreditation of research 17 protection programs is also an important part 18 of your charter. 19 Now, there are many other things 20 that you work on and indeed, the charter 21 allows you to be somewhat creative as you try 22 to identify areas that aren't specifically 10 1 named within the charter but clearly fall 2 under your purview, and we mentioned a few 3 earlier today. The notion of reaching out and 4 involving minorities in research and assuring 5 that they're protected during research, 6 potentially the notions related to the work of 7 protecting subjects in emergency settings, 8 that clearly is an important part as well. 9 But I understand you're already 10 working on what I think is a critical area 11 which is the area of impaired decision making 12 in research and I applaud your willingness to 13 take that on. It is very complicated, as you 14 know, very nuanced and yet, very, very 15 important. I understand that you've heard 16 from a number of panel experts yesterday and 17 that others will come to speak before you 18 today. The issues of conflict of interest and 19 how that might affect the human subject in 20 research are essential. They're very timely. 21 They're being talked about across a number of 22 different agencies and within academic 11 1 settings. And I applaud your willingness to 2 take on that issue and we look forward to any 3 recommendations that might come out of those 4 discussions. 5 I understand that another panel 6 later this afternoon or today is going to be 7 speaking about the issues involving training 8 of investigators. All too often the 9 regulatory infrastructure of our governments, 10 not just federal but across the system, we 11 tend to look at the aftermath of events. I'm 12 quite pleased that increasingly there's an 13 understanding that government should be 14 involved in trying to prevent bad things and 15 in trying to promote good things before events 16 occur. 17 This notion that we might reach 18 out to researchers and teach them how to 19 protect their human subjects even before they 20 fully engage in the career or in a career of 21 research, that we might reach into schools and 22 into training programs, and get to not just 12 1 individuals who will go on to become PI's and 2 full time researchers, but the entire system 3 of clinicians and practitioners and 4 scientists, that we might train everybody in 5 how to look out for and protect human 6 subjects, these are all very important. 7 Now, I recognize and I'm going to 8 try and pre-empt a question that I understand 9 may be out there, but we can -- we will have 10 a question and answer session in just a 11 second. I also recognize that one of my jobs 12 in addition to facilitating the transmission 13 of your recommendations and your advice to the 14 Secretary and beyond, that one of my jobs is 15 to try and make sure that I provide you 16 feedback on what happens with your 17 recommendations and whether they result in, 18 try and show you that your work is changing 19 the world, that your work does affect policy 20 and does affect the thinking within any given 21 administration. I recognize that there have 22 been recommendations, a flurry. In fact, Bern 13 1 and I were talking about the fact that SACHRP 2 is probably one of the most productive 3 Advisory Committees in the entire system as it 4 relates to its work, its recommendations, the 5 product that it pushes back into the 6 Administration and into the larger community 7 and I may have failed in that. I'm told that 8 there are some recommendations that are as old 9 as two years old and that no feedback has been 10 received to SACHRP, at the level of SACHRP as 11 to what the impact of those recommendations 12 has been on the system, what the response of 13 the Secretary or others might be to those 14 recommendations, and I commit to working with 15 Bern to get a list of the recommendations that 16 have kind of gone out and for which nothing 17 has come back, and to try and see where it is 18 and what are the formal thoughts and 19 recommendations of the system to give you some 20 feedback on those recommendations. I commit 21 to doing that for new recommendations as well, 22 obviously. 14 1 I have given the Chair my personal 2 cell phone number and asked him to consider 3 using it whenever he has a specific question 4 or a concern or whenever SACHRP has a specific 5 question or concern and I'm not present. He's 6 promised me that he won't call me between the 7 hours of 2:00 and 5:00 a.m. He recognizes 8 that I might be asleep at that time but I 9 would urge all of you, if you have any 10 questions at any time, reach out to your 11 Chair. Have your Chair grab me. I work for 12 you and hence, my correction at the beginning 13 of the meeting. 14 I really do. My job is to keep 15 you happy, keep you satisfied, keep you 16 productive, facilitate the transmission of 17 your work into the system and to provide 18 feedback from the system to you on the results 19 of those recommendations. I commit to trying 20 with each passing month to do it better than 21 in prior. 22 Let me stop there, if I may, Mr. 15 1 Chair. Might I ask your colleagues if they 2 have any question? 3 CHAIRMAN TILDEN: Certainly. 4 DR. AGWUNOBI: Before I do, I 5 would just like to, once again, welcome the 6 three new members of the Committee and thank 7 the three of you for being willing to join 8 your colleagues on this advisory group. It's 9 a very important group and I think you'll 10 realize that as you do your work, that it 11 affects lives. It affects real people. 12 Having said that, are there any questions for 13 me? 14 DR. GENEL: Dr. Agwunobi, Myron 15 Genel, the last subject that you speak of is 16 a subject that I raised yesterday morning, and 17 that is regarding the fate of the 18 recommendations on the Privacy Rule or HIPAA 19 that were made by SACHRP almost three years 20 ago, actually. And which I found to be very 21 compelling. The last statement, the last 22 paragraph of the letter from the Chairman at 16 1 that time, Ernie Prentice, I think speaks for 2 it and it says, "SACHRP is concerned that in 3 some areas the application of HIPAA to human 4 subject research has unnecessarily complicated 5 research activities, including IRB review and 6 oversight". And I think in terms of the great 7 interest and evidence based medicine and other 8 activities of this sort, I think it's 9 critically important that this be harmonized 10 with the Privacy Rule. 11 DR. AGWUNOBI: Thank you, sir. 12 The Secretary has identified 10 key issues 13 that he is going to work on during the 14 remainder of his term. When I say he's going 15 to work on, I mean he's going to personally 16 engage in 10 key issues between now and the 17 end of the Administration; however, there are 18 many other issues that he works on, on a day- 19 to-day basis but these 10 issues he plans on 20 championing. 21 One of those issues, I believe 22 it's Number 7, and they're not listed in 17 1 priority, is called personalized healthcare. 2 It's a poorly descriptive term, an area that 3 he believes is critical to the future and 4 relates in large part to your comment. It 5 involves his understanding that advances in 6 genomics and proteomics, that advances in 7 science have gotten us to the place now where 8 there is a very real and present potential for 9 us to be able to take current advances in 10 science and begin to translate them into what 11 he calls personalized medicine, personalized 12 healthcare; the notion that we might be able 13 to make -- we might be able to diagnose 14 illness or a really high propensity to develop 15 illness in people prior to them actually 16 exhibiting any symptoms based on their unique 17 genomic profiles and the like. 18 It talks about the fact that we 19 might be able to customize medicines, to treat 20 the individual as opposed to treating groups 21 of individuals, that we might be able to 22 actually design therapeutics to meet not just 18 1 the disease in an individual, but how it 2 uniquely interacts with that individual's 3 genetics. The notion that we might be able to 4 -- he talks in this area about the fact that 5 we need to lay the tracks today to assure that 6 we acquire that vision quickly. And I bring 7 all of that up to say, he's identified three 8 or four barriers that he wants this 9 Administration to try and overcome in order to 10 further the goal of personalized healthcare. 11 One of those barriers, I won't 12 bore you all with all four but one of those 13 barriers is his sense, I will bore you with 14 two. One of those barriers is his sense that 15 we have to advance -- we have to bring 16 together the advances of science and the vast 17 amount of data that is being generated, both 18 individual genetic data and larger population 19 based data. We need to be able to make that 20 accessible and so that it can be translated 21 into therapeutics and into diagnostics through 22 the use of expanded interoperable health 19 1 information technology, including taking -- 2 getting to a point where we have an electronic 3 medical record that contains your genetics, 4 your genomics, your proteo -- the unique, the 5 unique data that is you. The science now 6 allows us to describe people not just in terms 7 of words and sentences but also in terms of 8 proteins and genes, and there's this potential 9 that the electronic medical record might 10 contain your genetic makeup. 11 Now, the second barrier -- so he 12 wants to advance health IT. The second 13 barrier is that he recognizes that if we're 14 going to do this, clearly privacy and HIPAA 15 specifically needs to be looked at, needs to 16 be reviewed to see if it's a hindrance, to see 17 if there are ways that it can be used to 18 promote this initiative, while also making 19 sure that its tenants, the notion of privacy, 20 are protected and that people trust the 21 systems that are built. 22 So there is ongoing review of this 20 1 very issue and I promise to take a good look 2 at where exactly is the response -- is the -- 3 how exactly did the recommendations effect 4 where we are and as we move forward, what 5 might our response be to them? A long answer, 6 you'll forgive me. It basically says, I don't 7 know what the answer is now, but I'm going to 8 go find out. 9 DR. GENEL: If I may just comment 10 that in order to utilize this information, 11 it's going to be necessary to generate the 12 research that demonstrates its applicability 13 and I think the real stumbling block, I think 14 that I'm hearing from people doing this type 15 of research is in fact, the fact that they are 16 hamstrung by some of these privacy rules in 17 terms of generating the information that's 18 going to make this -- these new discoveries 19 useful in a personalized way. 20 DR. AGWUNOBI: I completely 21 concur. I would just state the obvious, which 22 is that as we talk about protecting human 21 1 subjects, you know better than I that 2 protecting their privacy is an important part 3 of that obligation, is an important part of 4 that notion and finding balance is key. 5 If there are no questions from the 6 group, I'm willing to answer any questions 7 from the audience as well if there are any. 8 Mr. Chairman, I -- 9 DR. POWELL: I do have a question. 10 In a previous meeting of SACHRP we talked 11 about and you mentioned research in prisoners. 12 And we discussed that and had a report from 13 the Committee. In addition in a recent 14 meeting at a National Medical Association they 15 talked about electronic medical records and 16 tracking health and one of the issues was how 17 well the health of prisoners are being tracked 18 and that there may not be a system in place to 19 do that very well. 20 And one of the concerns that I 21 have about not being able to do -- not having 22 some kind of -- the need to get more guidance 22 1 on health in prisoners because when prisoners 2 get out, they become a part of the community 3 and they take whatever ailments or diseases 4 with them into the community. I wonder about 5 that as a priority for HHS. 6 DR. AGWUNOBI: Thanks. It's a 7 great question and it allows me to highlight 8 at least one other of the Secretary's 9 priorities. In addition to this review of 10 HIPAA to see where it can be improved in terms 11 of not only its ability to protect privacy but 12 also to try and remove any barriers that might 13 exist in the field of -- in the fields of 14 research, advancing research. As I mentioned, 15 the Secretary is also, as a stand-alone 16 priority, going to be focusing on trying to 17 encourage, push, cajole, nurture, do 18 everything he can to further the vision of the 19 ubiquitous use of interoperable health 20 information technology using common standards. 21 Indeed, the President in August of 22 last year, wrote an Executive Order that 23 1 mandated that the Federal Government begin 2 moving in that direction, including getting 3 Veterans Affairs, the Federal Employee Health 4 Benefits Program, TriCare from the Military 5 and at least -- and Medicare, and Medicare a 6 big player, getting them all to commit to 7 moving towards a common set of standards that 8 they all share, the goal being that ultimately 9 it should be interoperable. That if you have 10 a health record in one of those systems, that 11 it will be transmitted across others. 12 The recent discussions related to 13 Walter Reed are going to force, I think, the 14 military and the VA system to move rapidly 15 towards that even quicker. There's a notion 16 that both -- as you know, prisoners sit across 17 both federal systems, state and in some cases 18 local systems, jails, and there's a sense that 19 we also need to move -- this movement towards 20 interoperable health records in that setting 21 as well. 22 We're committed, and this 24 1 Secretary is committed to getting us beyond 2 the point of no return in this journey toward 3 interoperable health information technology 4 across this system before he leaves. He's 5 already traveling the country, he's visited 6 almost every state and is getting great 7 excitement from industry, employers who 8 purchase health insurance as they realize that 9 this is the way to go, but also from managed 10 care, from hospitals, and from physicians. 11 The AMA and others have signed on to this 12 notion of expanding and pushing forward 13 interoperable health information technology. 14 But, sir, it's going to take 15 awhile. There's a realization that there's so 16 many different standards today, that driving 17 them gradually without forcing people which 18 probably would be the wrong way to go, given 19 that people have already invested in one 20 system, their own hard earned dollars, trying 21 to evolve the system towards the standard is 22 where we're going as opposed to a situation 25 1 where if you happen not to be there today, too 2 bad, we're moving tomorrow, is this notion 3 that we need to evolve towards it. 4 I've come to learn, for example, 5 that there are at least 10 or 11 in big 6 mainstream health -- electronic medical 7 records, there are at least 10 or 11 different 8 ways of just describing the name of an 9 individual. The field in the health 10 information record for just the name has so 11 many variations, Agwunobi, John O., John O. 12 Agwunobi, J. Agwunobi, Agwunobi, J. I mean, 13 there are just so many permutations and 14 driving just that field, that one field to a 15 common standard is one of the initial 16 initiatives. How can we get it so that people 17 are described using a common standard in 18 health electronic records. 19 There is a new commission that's 20 been started by the Secretary through another 21 advisory group called the American Health 22 Information Community, AHIC which has 26 1 developed a certifying commission called the 2 Certifying Commission for Health IT, that 3 actually now is going out and reviewing all of 4 the health IT systems, not just electronic 5 medical records, but data bases and others, 6 and is reviewing them all and endorsing a 7 group, certifying a group of those health 8 information systems that it believes are the 9 beginnings of a push towards a common standard 10 that are compatible with each other and will 11 help us move in a current direction. 12 And we're right now urging 13 researchers, practices, hospitals, prison 14 healthcare -- correctional health care systems 15 and others, to as they evolve their systems, 16 only purchase, only invest in systems that 17 have that certification stamped on them and 18 that body is continuing to do its work. It's 19 reviewing systems even as we speak. 20 Long answer, long journey. Sir. 21 DR. BOTKIN: I think SACHRP has 22 done a good job of identifying and working on 27 1 cutting edge or important issues as SACHRP has 2 perceived them to be in human subject 3 protection, but I wonder whether there might 4 be an opportunity for more communication from 5 your office or from the Secretary's office to 6 articulate its priorities as it looks over the 7 research landscape to say, "There's some 8 critical issues and we would love to have 9 SACHRP's assessment of this set of issues". 10 DR. AGWUNOBI: It's a wonderful 11 thought and you'll forgive me for not having 12 done it already. I will send to you a list of 13 the 10 -- my only caution is that even as we 14 list the 10, I would urge you to recognize 15 that everything else that we do is still 16 important. We're obligated in law and quite 17 frankly, in our hearts to not put anything 18 down, even as we get the Secretary to focus in 19 on these 10 things. 20 I'll send a list to each of you 21 through your Chair that describes where we're 22 going. The include things like -- and I won't 28 1 try and list them all, but they include things 2 like Medicaid -- I can't remember the exact 3 term but it basically relates to the notion 4 that we need to improve Medicaid. It's 5 threatening states. It's growing too rapidly. 6 It's not meeting all of its stated goals and 7 there's a notion that state -- we need to 8 encourage states to innovate. It's not a 9 federal initiative. It's our role in 10 supporting states as they innovate Medicaid. 11 Another is pandemic influenza 12 preparedness specifically because it has both 13 global and local implications. Yet another is 14 this notion of emergency preparedness on the 15 larger front, hurricanes, bioterroism, 9/11, 16 those kinds of things. How can we better 17 prepare communities for the next disaster 18 wherever it might come from? 19 A fourth is the issue of 20 personalized healthcare. A fifth -- there's 21 a whole bunch of them. Primary -- I'm sorry, 22 prevention, specifically the obesity epidemic, 29 1 and how the Secretary and the President and 2 the entire Department might engage to further 3 what's already happening at the grass roots 4 effort to try and give it leadership and to 5 try and move it forward. That's yet another 6 priority and there's a whole bunch and I'll 7 send it onto you. It's a great thought and I 8 will share everything with you in great 9 detail. 10 There's one global health 11 initiative in there as well related to helping 12 under-served nations with vulnerable 13 populations. Sir. 14 DR. POWE: You brought up the 15 issue of ethnic minorities and I am aware of 16 a recent report that the Institute of Medicine 17 did on -- for the NIH on its disparities 18 initiatives and I was just interested in what 19 other things the Department has going on to 20 address health disparities. 21 DR. AGWUNOBI: Every agency of the 22 Department of Health and Human Services has an 30 1 Office of Minority Health with a Director. In 2 some it's much more -- it's larger and better 3 formed in the lager agencies -- in some of the 4 smaller -- like CDC and FDA. In some of the 5 smaller agencies like AHRQ and others it's 6 smaller and much more focused on the mission 7 of that agency. 8 I, in my shop also have the 9 Department's Office of Minority Health run by 10 Deputy Assistant Secretary Garth Graham. And 11 its job is to coordinate the work of all of 12 the other agencies and to take the President's 13 and the Secretary's initiatives and try and 14 translate them into action across the nation. 15 I think it's quite clear that as a department, 16 we're doing a lot of work towards trying to 17 eliminate health care disparities and indeed, 18 there's some evidence that our work, perhaps 19 not as a department but as a nation, that as 20 a nation our work is making a difference. 21 I was encouraged to hear that just 22 last year for the very first time we 31 1 eliminated the -- let me restart. 2 As you all know, there are a few 3 indicators, health indicators, that are used 4 as proxy measures for the larger issues of 5 health across our nation, one being infant 6 mortality in which there continues to be a 7 very significant healthcare disparity between 8 minority groups and non-minority groups. 9 Another is -- infant mortality, by the way, 10 the reason that's important is because it's an 11 indicator not just of child health, it's 12 children who die before the age of one, but 13 it's also an indicator of maternal health and 14 an indicator of systems infrastructure, of 15 access to that infrastructure across a 16 community. 17 Another very symbolic and another 18 proxy measure is infant immunizations. It 19 effects -- it's a measure not just of infant 20 health but also of access to care. It's a 21 proxy for the ability of the system to reach 22 out to its communities and provide services. 32 1 It's a measure of the notion of prioritizing 2 prevention within any given community. And I 3 learned, now, back to my point, I learned that 4 just last year for the first time ever we have 5 statistically at least, community to community 6 there might be variation, but from a 7 statistical standpoint, we have eliminated the 8 racial and ethnic health disparity that 9 existed across racial groups in terms of 10 infant immunization for the three main 11 antigens. There no longer is that longstanding 12 gap between African American and non-African 13 American population that existed for the last 14 30, 40 years in terms of immunization. 15 Something happened and over the 16 last few years we've managed to eliminate 17 completely the disparity that existed. 18 Children, whether they're Black, White or 19 Native American or Latino are based 20 statistically, now are at the same place. Now 21 we need to continue driving up the 22 immunization rates for all children but it was 33 1 a sense to me that, you know, sometimes we 2 make a difference. Sometimes our work 3 actually -- we can do this. We can drive out 4 and eliminate -- I know David, my colleague 5 David Satcher took some criticism when he made 6 that the target but in truth, we've shown that 7 you can eliminate disparities that are based 8 on racial and ethnic groups. 9 Now, I say that and now I give you 10 the bad news. The bad news is that in the 11 vast majority of public health issues of great 12 significance, there continues to be and in 13 some case worsening, especially between Latino 14 American men and the rest of our communities, 15 in some case, worsening disparities. I'm 16 particularly worried about the HIV/AIDS 17 epidemic that is burning through Native -- I'm 18 sorry, African America. I'm particularly 19 worried about the methamphetamine epidemic 20 that is burning through Native America. There 21 are disparities that are clear and apparent. 22 In Latino populations, we're not 34 1 going a good job with access to health 2 insurance, with health insurance. Those 3 populations, the gap is widening when you 4 compare them to other populations on that 5 measure. 6 The point is, that in spite of the 7 fact that we're doing a lot of good work, we 8 need to do more and I know that it also exists 9 in the area of research and I hope that later 10 today as you talk about how to get -- or 11 rather not today but across the course of the 12 Committee's work, that as you talk about how 13 to enroll more minorities safely and in a way 14 that keeps them protected into research 15 protocols, that we learn from them and build 16 those into our programs as well. 17 I would just remind everyone, 18 today I wear the uniform of the -- proudly of 19 the Public Health Service. I see a few of the 20 officers in the hall, in the back here, 21 somebody behind me, there's a Rear Admiral 22 right there, wearing the uniform of the US 35 1 Public Health Service and we do so proudly 2 because of the work that we've done over the 3 last 200 years, since 1798 in the US Public 4 Health Service Commission Corps. 5 However, the US Public Health 6 Service which is a proud agency that it is, 7 that proud entity that it is, conducted the 8 Tuskegee experiments on syphilis in African 9 Americans in Southeast -- in the Southeast. 10 We did it and I highlight that to say that 11 protecting human subjects has come a long way 12 clearly but that your advice to us is always 13 going to be held, in my mind, as being very 14 important. And inasmuch as you can direct us, 15 I'll always take it very, very seriously. Mr. 16 Chair. 17 CHAIRMAN TILDEN: Dr. Agwunobi, I 18 think we might have one question from the 19 audience, if you wouldn't mind taking that, 20 then I think -- then we'll probably end this 21 part of the meeting. 22 DR. AGWUNOBI: Thank you. Good to 36 1 see you again. 2 DR. GYI: Thank you for your 3 accessibility. My name is Felix Gyi and I'm 4 a recovering SACHRP member. 5 DR. AGWUNOBI: Thank you for your 6 service. 7 DR. GYI: I wondered if I might 8 get your thoughts on a couple of topics that 9 you've raised today. One is on the arrival, 10 if you will, at that standardization that you 11 talked about, the excellence in human subject 12 protection and both the questions relate to 13 that one topic. We have a number of programs 14 that are well-established like accreditation 15 to help us demonstrate our commitment to 16 excellence and human subject protection that 17 I'm not sure has gotten the full force of the 18 regulatory endorsement if you will. 19 Inasmuch as it is a voluntary 20 program it would be helpful to have some 21 recognition of its value much like other 22 certification programs. 37 1 The second point is, as a co-chair 2 with my distinguished colleague, Dan Nelson on 3 SACHRP on a Committee looking at the 4 regulations, one of the areas that we keep 5 running into is the lack of harmonization 6 between the agencies. And so every time we 7 talk about some measure of improvement, we run 8 into this notion that it would take some time 9 to try and make it available across all 10 agencies and so that lack of harmonization 11 serves as an impediment to what this group is 12 trying to do. 13 I wonder if you might comment on 14 those two. 15 DR. AGWUNOBI: Yes. If there was 16 complete harmony between the public health 17 service agencies, I wouldn't have a job. As 18 the Assistant Secretary for Health, in 19 addition to supporting many offices include 20 OHRP that do this work, and transmitting 21 messages from our Administration into the 22 community and from the community -- probably 38 1 more importantly, from the community into our 2 Administration, one of my other jobs is to 3 help coordinate the work of the public health 4 service agencies. Now, I recognize that your 5 question goes a little beyond public health 6 service agencies, it probably includes CMS, 7 which is not one of the public health service 8 agencies, and not under my purview but CDC, 9 NIH, FDA, AHRQ, SAMHSA, Indian Health, those 10 are the agencies that my job is to kind of 11 coordinate their work, make sure that they 12 aren't working in cross -- at cross purposes 13 with each other and make sure that when there 14 are systemwide initiatives that they all 15 embrace and move in the same direction towards 16 those systemwide initiatives, the 10 17 priorities of the Secretary you know, things 18 that effect us all. 19 We are currently, I can't speak to 20 what the end point will be but I can tell you 21 that Bern and others are currently -- have 22 brought the agencies together to discuss 39 1 definitions and certain standardized 2 interpretations of the regulations as they 3 apply to the agencies. You'd be surprised at 4 how much -- and how wide the spectrum of -- 5 the continuum of interpretations are, even 6 within agencies, not to speak of across 7 agencies. And we're hoping to drive towards 8 a common set of understandings by bringing the 9 agencies together. We've had them in dialogue 10 for a little while now, and hopefully we're 11 driving to some conclusion in the not too 12 distant future on that front. I've no doubt 13 you'll be briefed when the group -- when the 14 agencies finish their work at that level. 15 But I have no doubt because 16 there's always drift over time, that I'll 17 always be engaged in trying to keep the 18 agencies at a certain place, at a certain 19 point. There's always -- you know, over 20 administrations and within any given 21 administration, because of changes in 22 leadership, changes in thought, changes in 40 1 interpretation at the legal level, at the 2 regulatory level, at the scientific level 3 there's always some drift that occurs over 4 time. When you have so many fairly autonomous 5 agencies that way we do, each with their own 6 distinct mission, FDA, CDC, NIH, distinct 7 missions, they're all wonderful organizations 8 but there is some drift that occurs and my job 9 is whenever that drift is identified, is to 10 try and bring people back to the table, get 11 them to reagree upon a consensus set of 12 standards, a consensus set of interpretations 13 and then move them, nurture them across, over 14 time, as close to that agreement as I possibly 15 can. 16 If SACHRP identifies specific 17 issues where they believe there are 18 impediments, your word, to progress related to 19 the agencies, I get paid to try and help 20 resolve those issues. You pay me, the 21 taxpayer pays me to try and take on -- that is 22 actually specifically the kinds of things that 41 1 are written into my job description, I'm 2 supposed to take on. 3 So I would urge the Chair and 4 Bern, where you identify impediments to 5 progress, that sit within agencies because of 6 differences across agencies, I urge you to 7 bring that to my attention so that I might try 8 to resolve it. And if you have something 9 specific you want them to feed to me, you 10 know, you're still always a family member. 11 CHAIRMAN TILDEN: I have his card. 12 DR. AGWUNOBI: All right, Mr. 13 Chair, with your leave, with your permission, 14 I'll go off and do some other work. 15 CHAIRMAN TILDEN: Well, I just 16 want to thank you very much, coming here and 17 spending the time you do with the Committee is 18 invigorating. I think it gives us a sense and 19 perspective of the work we're doing and that 20 there's an ear in the agency and someone who's 21 very interested in what we do and hears us. 22 So thank you very much and I look forward to 42 1 having you here again. 2 DR. AGWUNOBI: Thank you, sir. 3 (Applause) 4 CHAIRMAN TILDEN: Wow. I feel 5 like we could just adjourn now in some 6 respects. My mind is spinning here with all 7 that. So, anyway, from here, we can move on 8 into our program and with some new sense of 9 mission. So today, we're going to begin our 10 discussion this morning session on conflict of 11 interest on IRB members. And we have a 12 distinguished group of individuals to lead 13 this discussion and present us information in 14 this area. 15 So this morning we'll -- excuse 16 me, I'm going to stop for just a second. It 17 was brought to my attention earlier that we 18 didn't approve the minutes from the last 19 SACHRP meeting and I'd like to just take a 20 minute and entertain a motion to approve those 21 minutes. 22 DR. LEIDEN: I move that we 43 1 approve the minutes from the last meeting. 2 CHAIRMAN TILDEN: Second? 3 DR. POWELL: Second. 4 CHAIRMAN TILDEN: Okay, all if 5 favor, aye, okay, so the minutes stand 6 approved from the meeting from November, I 7 believe, of `06. 8 DISCUSSION ON CONFLICTS OF INTEREST AMONG 9 IRB MEMBERS 10 CHAIRMAN TILDEN: Okay. Now, 11 getting back to our discussion group. I'd 12 like to introduce our first speaker today 13 which is Dr. Leslie Wolf. She's Assistant 14 Adjunct Professor in the Program of Medical 15 Ethics Incentive for Age Promotion at UCSF. 16 She teaches and conducts research related to 17 research ethics. Formerly she was Greenwell 18 Fellow in bioethics and health policy. 19 She serves on the Committee on 20 Human Research and the GCRC Advisory Committee 21 at UCSF and is published in the area of IRB 22 conflicts of interest and she's here today to 44 1 give us her thoughts on that. 2 MS. WOLF: Good morning. It's a 3 pleasure to be here this morning. What I'm 4 going to be doing is presenting the results of 5 a study I conducted in IRB conflicts of 6 interest. I'll tell you to start why I 7 focused on this issue in this study. 8 Obviously, the regulations require IRBs to 9 address conflicts of interest and more 10 importantly, I think because IRBs are 11 responsible for protecting human subjects that 12 we want the process to have integrity. That 13 we have independence and we're assured of that 14 process. 15 And there have been a number of 16 concerns that have been raised in recent years 17 more tangentially to IRBs, you know, the more 18 the focus has been on researcher conflicts of 19 interest, but in some of the discussion, 20 people have also looked at the IRBs' role and 21 there have been some concerns expressed that 22 IRBs may favor approval, in part because of 45 1 their makeup. That the members typically are 2 researchers themselves and therefore, may be 3 more predisposed to approving research and 4 also they're primarily reviewing their 5 colleague's work. And so you may be inclined 6 to be less critical because they're your 7 colleagues or you may be thinking, "As an 8 investigator myself, I might be kinder this 9 time in hopes that I will get a kinder review 10 in the future". And they may have other 11 relationships that might effect their ability 12 to provide independent review, as well as some 13 concerns about institutional interest that may 14 compromise IRB independence. 15 We -- because there's little 16 literature on this and the regulations 17 themselves don't describe what a conflict of 18 interest is, for example, there's not as much 19 guidance there, we wanted to see what do IRBs 20 themselves do here. So we analyzed policies 21 for IRBs at 121 US medical schools that 22 receive NIH funding. We actually ended up 46 1 with an n of 124 because we went to websites 2 and one of the medical schools listed several 3 IRBs that were referred so we included all of 4 those in our study. 5 What we did is we went to the 6 websites, we downloaded the policies. To make 7 sure that we got the most recent policy and 8 that we didn't just miss something in our 9 search, we also contacted IRB representatives 10 and asked them to confirm that either we had 11 the right document or to point us to the 12 appropriate document. And then our two team 13 members independently reviewed the policies on 14 our research questions and then reached a 15 consensus to make sure that we were 16 interpreting correctly. 17 An important note is that we 18 excluded general conflict of interest 19 policies. Many universities will have a 20 general conflict of interest policy that 21 applies for when they're buying pens and 22 computers and everything else that goes along. 47 1 We felt that those really didn't address the 2 specific issues of IRB review and so we set 3 those aside even though they may actually 4 apply to many of the members. 5 Primary research questions were 6 first of all, do IRBs have written policies 7 regarding their own conflicts of interest. If 8 they did, we then looked, how do they define 9 conflicts of interest? Do they systematically 10 collect information about conflicts of 11 interest? To whom do the policies apply and 12 then what happens if there's a conflict? And 13 I'm going to focus in my presentation 14 primarily on our findings, a little bit about 15 implications but I'm going to sort of leave 16 out the recommendations that were included in 17 the paper that we ultimately wrote. 18 So for the question do IRBs have 19 written policies, we found that 74 percent of 20 the IRBs in our study have written policies 21 regarding IRB conflicts of interest which 22 means, obviously, 26 percent didn't. So a 48 1 good quarter of IRBs had no written policy. 2 They relied solely on the regulations. And we 3 also found substantial variation within the 4 IRBs, so that some of them were very simple, 5 it was just a statement and we included that, 6 and some were really detailed. 7 Of those that had written 8 policies, 79 percent actually defined 9 conflicts of interest within those policies. 10 So you have a substantial minority that didn't 11 go beyond just saying it's a conflicting 12 interest like the regulations do. We looked 13 more closely at what does that include; 75 14 percent of the IRBs with written policies 15 included project involvement. So if a member 16 is serving as the PI, a co-investigator or a 17 consultant for example on a project, they have 18 a conflict of interest. 19 The next largest number was for 20 financial interest which has gotten a lot of 21 attention in other areas in terms of conflicts 22 of interest. About half included personal or 49 1 professional relationships so if you are in a 2 supervisor or a supervisee relationship, if 3 you are a co-investigator on a project with 4 somebody, not on this particular project, but 5 that might be something that's considered a 6 conflict of interest. And a very small number 7 included personal beliefs. And there it 8 described it as if it were something that 9 would otherwise be permissible under the 10 regulations, but no matter what the 11 investigator did, you would not approve it, 12 that that might be a conflict of interest, but 13 that was quite rare. 14 Just because it has been sort of 15 the focus of the discussion of conflicts of 16 interest, not because I think it's more 17 important, we did also look how do they 18 describe financial conflicts of interest and 19 to raise it here. Twenty percent of the IRBs 20 that describe this as a conflict, said any 21 financial interest. So from the first penny 22 that that would be a conflict of interest. 50 1 Most of the IRBs discussed a 2 significant financial interest, which comes 3 from the PHS' regulations and what is true for 4 investigators, and most of them, as you can 5 see, really use that PHS definition which is 6 greater than $10,000.00 in payments whether it 7 be for honorarium, contract, whatever form or 8 in equity. But we found a couple of 9 exceptions or really one, where it was greater 10 than $25,000.00 in money or $50,000.00 in 11 equity with no explanation for why they're 12 changing that number. 13 And then there were a number that 14 were undefined and we sort of assumed but it's 15 not clear that by significant financial 16 interest they were referring to the Public 17 Health Service definition. But 27 percent, 18 again, didn't define what a financial conflict 19 of interest, so it's not clear, you know, is 20 it the first penny, is it $10,000.00 or some 21 other amount. 22 When we asked how many IRBs 51 1 systematically collect this information so 2 that they know about their members' conflicts, 3 we found very few actually do this 4 systematically, 20 percent. Some of the IRBs 5 actually limited it only to investigators who 6 conduct research. So members who are, you 7 know, outside members or maybe just clinical 8 personnel wouldn't have to fill out that 9 information, although presumably they may also 10 have conflicts of interest. Two of them only 11 collected it for the chairs. One collected it 12 for staff and in all of these but one, the 13 focus was only on financial conflicts, in 14 part, I think because they're already 15 collecting it from the investigator's side of 16 things. 17 One did require disclosure of 18 personal relationships that the member felt 19 was a conflict of interest that should exclude 20 them from review. We then looked to whom do 21 they apply? We found all the policies applied 22 to IRB chairs and members which sort of we 52 1 would expect. We also looked for other 2 differences and we found 15 percent applied 3 them to IRB staff, and 20 percent to ad hoc 4 reviewers and consultants. So if you don't 5 have the experience on your membership and you 6 need to bring somebody else, it would apply to 7 them. And interestingly, we found a couple 8 that applied it to guests or somebody who is 9 visiting the IRB meeting, but they didn't also 10 apply it to staff or consultants who might be 11 there more regularly. 12 And then we looked at, okay, you 13 have a conflict of interest, what do you do 14 about it? We focused first on the reviewer 15 role and we found only about a quarter of the 16 IRBs discussed what to do if, as a reviewer 17 you have a conflict of interest. And that 18 broke out with about half of those prohibiting 19 serving as a reviewer explicitly, just saying, 20 "You can't do it", and the other half dealt 21 with it saying, "If you have a conflict, let 22 us know when we send out your big thick 53 1 packet, let us know so we can reassign you". 2 So essentially, the same thing but just a 3 different way of handling it. 4 One IRB discussed it for 5 consultants, but again, didn't discuss it for 6 members, which you would think would be the 7 more common experience. And three IRBs might 8 permit serving as a reviewer. For example, 9 one IRB said if you disclose the conflict, you 10 can still serve as a reviewer. 11 Other things that happened is 75 12 percent of the IRBs say you need to leave the 13 room if you have a conflict of interest for 14 the protocol discussion and about half, 51 15 percent of the IRBs specify as it states in 16 the regulations, you may stay and answer the 17 questions. And so, you know, you answer the 18 questions about the protocol if it's your 19 protocol, and then leave and the members 20 continue with their discussion. 21 But again, we find a few and I 22 should emphasize only a few IRBs that may 54 1 permit the member to stay in the room. So one 2 of them made it voluntary, some distinguished 3 by types of conflicts so they indicate that if 4 you are from the same division, for example, 5 you may have a conflict of interest and then 6 say but it's not a conflict that we need a 7 response for, so by different categories. And 8 some indicated that, "On a case-by-case basis 9 we'll make a decision about whether or not you 10 can stay in the room", without indicating, you 11 know, by what criteria they would make that 12 decision. 13 So -- and the next thing is 14 whether they need to recuse from the voting on 15 the protocol and more IRBs, 83 percent 16 indicated you can't vote if you have a 17 conflict of interest. But again, we found 18 some exceptions. Two IRBs discussed this as 19 a way of addressing but do not actually say 20 it's required. So one of them specifically 21 identified it as an option. And some again, 22 had exceptions based on the type of conflict. 55 1 So what are the findings, 2 implications? To me there are significant 3 gaps and variation among IRBs. And one of the 4 questions for us is, given sort of the lack of 5 guidance from the regulations is, do we need 6 more specific policies or is there a common 7 understanding of what this is? And I would 8 suggest based on our findings, there's not 9 truly that kind of common understanding. We 10 such variation among the IRB policies. 11 And of course, you have a 12 substantial minority who don't have written 13 policies at all. They don't clearly state 14 often what an IRB member must do and they 15 don't actually apply to all those who were 16 involved in the review. So I know IRBs very 17 greatly, probably as much as on their conflict 18 of interest policies but in some, the staff 19 may actually participate as a member. In 20 other cases, they're the ones who are making 21 choices about who gets the assignment and 22 various things and they handle some of the 56 1 review in the office and it may lead to some 2 inconsistency in the application. 3 Most concerning to us were that 4 some policies conflict with regulatory 5 requirements or OHRP guidance. As mentioned, 6 if you permitted conflicted members to serve 7 as a reviewer to vote on a protocol, to 8 participate in the discussion, although this 9 was few, it may actually effect the discussion 10 of a protocol. 11 You know, if I voluntarily decide 12 to sit in, people may be less likely to be 13 critical of my protocol. It may change the 14 discussion and therefore, may change the 15 outcome. And it suggested to us a need for 16 more specific policies. Some limitations, I 17 do want to acknowledge that this study was 18 only possible with a grant from the Greenwell 19 Foundation and just some limitations. We did 20 focus only on written policies. So IRBs may 21 be handling this on a regular basis and that 22 would not be reflected, you know, if they 57 1 don't have a policy, they may have ways of 2 handling this. 3 We only focused on medical 4 schools, so we did not look at independent 5 IRBs or institutions that may not have a 6 medical school. Some of them -- some of the 7 smaller schools, schools that received less 8 NIH funding actually were the -- they had one 9 IRB that handled it and we included that. But 10 there may be differences, so this information 11 may not be generalizable to everything. 12 Thank you. 13 (Applause) 14 CHAIRMAN TILDEN: So we'll hold 15 questions till after each speaker finishes. 16 The next speaker is Dr. Marjorie Speers. Dr. 17 Speers is currently Executive Director of 18 AAHRPP, the Association for Accreditation and 19 Human Research Protections Programs. She is 20 well-known in the human subjects community. 21 She served as -- on the NBAC, National 22 Bioethics Advisory Commission from 1999 to 58 1 2001 and she's been prior to her service with 2 AAHRPP, has been with CDC from 1988 through 3 2000, where she rose to the position of Deputy 4 Associate Director for Science. 5 She has served on numerous 6 committees related to human subjects 7 protection and has a research interest in 8 human research protections and health 9 promotion and she's here today to discuss -- 10 give us her thoughts on conflict of interest 11 in IRB. 12 DR. SPEERS: Thank you and good 13 morning to everyone. I haven't been to SACHRP 14 for awhile and almost all the faces are new 15 now on SACHRP, so I am pleased to be back to 16 talk to you. 17 CHAIRMAN TILDEN: We hope we 18 become familiar to you, Marjorie now and in 19 the future, too. 20 DR. SPEERS: Well, what I am 21 pleased is that there are a number of 22 institutions now on SACHRP that are accredited 59 1 and some that are in the accreditation 2 process. So, that is good news. I 3 specifically want to talk about conflict of 4 interest of IRB members and consultants and I 5 want to talk about it from the accreditation 6 perspective because I think that when Leslie 7 Wolf published her paper about IRB conflict of 8 interest and concerns about it, it really did 9 raise concerns about institutions that might 10 not have policies and procedures and even more 11 importantly, might not be following them but, 12 in fact, IRB members are not disclosing 13 potential conflicts of interest or actual 14 conflicts of interest. 15 And I think that one of the 16 benefits of accreditation is that it can do 17 two things. One is that it certainly narrows 18 that inconsistency that one sees across IRBs 19 or across institutions. The other is, is I 20 hope you will come away from this 21 presentation, is that it can give some 22 assurance to SACHRP, to institutions and to 60 1 the public that, in fact, IRBs are doing a 2 better job, at least the accredited 3 institutions are doing a better job of 4 identifying and managing conflict of interest. 5 In case you're not familiar with 6 AAHRPP, I just want to say that we are an 7 accrediting body for human research protection 8 programs. We were founded in 2001 and 9 launched our accreditation program in 2002. 10 As of this month, we've accredited 52 11 organizations that represent a total of 169 12 entities and we've now accredited 13 organizations in Canada, Korea, Singapore and 14 the United States. 15 We have a specific standard among 16 our accreditation standards that deals with 17 conflict of interest and I have it here in 18 this slide for you which says that the IRB has 19 and follows written policies and procedures so 20 that IRB members and consultants do not 21 participate in the review of protocols in 22 which they have a conflict of interest except 61 1 to provide information requested by the IRB. 2 That standard is based on 3 regulatory and guidance from the Department of 4 Health and Human Services from OHRP and I 5 think it is instructive to actually look at 6 what the regulation says and under the 7 regulation, I've listed the two pieces of 8 guidance from OHRP. The regulation says that 9 no IRB may have a member participate in the 10 initial or continuing review in which the 11 member has a conflicting interest except to 12 provide information requested by the IRB. It 13 is interesting to note that the regulatory 14 requirement is specific to initial and 15 continuing review. It does not speak to 16 review of modifications, review of compliance, 17 non-compliance, or review of unanticipated 18 problems involving risk to subjects or others. 19 There are two pieces of guidance 20 on this topic. One relates to IRB members 21 absenting themselves from the meeting room 22 when the IRB reviews research in which they 62 1 have a conflicting interest and the second is 2 that that absence of the IRB member with a 3 conflicting interest is noted in the IRB 4 minutes. And I want to make the distinction 5 between guidance and regulation because, 6 again, some of problems that we see that I'm 7 going to show you in a subsequent slide, 8 really relate to understanding the guidance, 9 that IRBs do a better job at focusing on the 10 regulation but less on the guidance. 11 The interpretation of our 12 accreditation standard actually does go beyond 13 what is required in regulation and guidance. 14 It extends to any review by IRB members with 15 a conflicting interest. So it would include, 16 for example, review of modifications to 17 approved research. It includes consultants as 18 well as IRB members. Policies must define a 19 conflict of interest to include financial and 20 non-financial interests. When we first began 21 accrediting in 2002, and working with 22 institutions, some focused on financial 63 1 interest, some focused on non-financial 2 interest. 3 The policies that were more 4 comprehensive looking at both types were rare 5 at that time. And the definition of financial 6 interest has to be at least as stringent as 7 the policy for investigators. Early on we 8 would see a difference between what was 9 defined as a financial interest that was -- 10 would represent a conflict for IRB members 11 versus investigators. 12 The procedures also should 13 describe how the IRB identifies interests of 14 IRB members. This was also an area early on 15 that was problematic in that institutions 16 would have perhaps a policy defining an IRB 17 conflict of interest, IRB member conflict of 18 interest but they didn't actually have a 19 procedure in place for the IRB member to 20 disclose it and then for there to be a 21 decision was this is a conflict or not a 22 conflict and then for appropriate actions to 64 1 follow. 2 Procedures should also describe 3 that IRB members with conflicting interests 4 are excluded from discussion and voting. That 5 means absent from the meeting room, except to 6 provide information at the request of the IRB. 7 That if they are excluded, they do not count 8 towards a quorum and it is documented in 9 records, generally, in the minutes. 10 What I have done specifically for 11 this presentation is to look at some of the 12 information we have on academic institutions 13 because I wanted to make it comparable to what 14 Leslie was going to talk about with respect to 15 her survey of the medical schools. And if we 16 look at academic institutions, only 10 percent 17 of those have policies, procedures, and 18 practice that met the accreditation standard. 19 That is to say that when they applied for 20 accreditation, that without -- no changes 21 required, no observations coming back to 22 them, it's only 10 percent that had sort of 65 1 everything in place at the time that they 2 applied. 3 A hundred percent, that is to say 4 everyone who has applied for accreditation, 5 had policies and procedures, although most of 6 them were incomplete in some way. And the 7 common deficiencies that we see and that we 8 continue to see at this point are that 80 9 percent have no procedures to identify 10 conflicting interests of consultants. You 11 know, more and more institutions now are 12 forming policies and procedures to use 13 consultants but they often forget to check to 14 see whether that consultant might have a 15 conflict of interest. 16 About 40 percent of institutions 17 have multiple procedures, not just one 18 procedure, but will have multiple procedures 19 and those procedures will be inconsistent. 20 They can be inconsistent in terms of how they 21 define a conflict of interest in terms of 22 financial interest and non-financial interest. 66 1 It can also be inconsistent in terms of how it 2 is implemented. Thirty percent did not have 3 the conflicted member leave the meeting room 4 and this is a finding similar to what Leslie 5 reported as well. 6 Twenty percent did not document 7 the reason for the absence in the minutes. 8 That is, they will document that the person 9 left the room but they will not say in those 10 minutes the reason for the person leaving the 11 room, that the reason was due to a conflicting 12 interest. 13 Ten percent were missing the 14 inclusion of family members, which is one of 15 the requirements that we have, that a conflict 16 of interest policy for IRB members and 17 consultants applies to their family members, 18 their immediate family members. And 10 19 percent did not have procedures that covered 20 review using the expedited procedure. Most, 21 you know, focused on the review of the 22 convened IRB but hadn't thought about what 67 1 happens with expedited review. 2 Just to summarize, organizations 3 seeking accreditation do have policies and 4 procedures. No organization has applied 5 without a basic written procedure and I think 6 that's important to say that I'm working from 7 a biased sample. This is a select group of 8 institutions. It doesn't necessarily 9 represent the broader community. On site 10 visit, it appears that practice follows the 11 written policies and procedures and I think 12 that that is important. That we're not just 13 talking about having a written document, but 14 in fact, it is implemented and used on a 15 regular basis. 16 We do see fewer deficiencies today 17 than we were seeing five years ago. I think 18 that over time, there has been greater 19 awareness to this particular topic and we are 20 seeing fewer problems with institutions and 21 IRBs are more sensitive to the need to 22 identify and when I say manage conflict of 68 1 interest, the management in this particular 2 area is to recuse ones self. There isn't 3 management as there is with investigator 4 conflict of interest but instead not to be 5 involved if, in fact, it is deemed a conflict 6 of interest. That's it. 7 (Applause) 8 CHAIRMAN TILDEN: Our final 9 presenter today on this topic is Dr. Ernest 10 Prentice. Ernie needs no introduction to this 11 committee since he's a past -- immediate past 12 president and we're still having a little 13 shock of operating without Ernie, so I'll let 14 everybody know that he's participating, maybe 15 not as much but fully as a member of the Sub 16 Parte Subcommittee. 17 He comes here today to discuss 18 conflicts of interest at the University of 19 Nebraska Medical Center in which he is 20 Associate Vice Chancellor for Academic Affairs 21 and Professor of Genetic Cell Biology and 22 Anatomy. He co-chairs the UNMC's IRB and has 69 1 done that for over 25 years. He's one of the 2 most visible individuals in the human research 3 protections arena nationally and 4 internationally. So we're glad to have you 5 here, Ernie, to tell us about conflicts of 6 interest in IRBs. 7 DR. PRENTICE: Thank you very 8 much. Good morning, Mr. Chairman, members of 9 SACHRP, ex officio members, members of the 10 audience. Thank you for inviting me to come 11 here and speak with you today. I promise I 12 won't keep on coming back. I've been asked to 13 talk about conflict of interest, its 14 identification and management for IRB members. 15 So this specifically is what I will address; 16 the genesis of our concern about conflict of 17 interest, what does the regulation say about 18 conflict of interest as well as some guidance 19 from HHS, the definition of an IRB member 20 conflict of interest at our institution, types 21 of conflicts of interests and then how we go 22 ahead and manage such conflicts. 70 1 And some of what I'm going to be 2 talking about today is based upon an article 3 that I and my colleagues wrote that was 4 published in the BNA Medical Law and Research 5 Bulletin, which reflects our initial conflict 6 of interest policy for IRB members. We have 7 undergone and evolution since then. As a 8 matter of fact, as I will speak to in a 9 moment, we had an IRB meeting last week and 10 we're still in the process of revising our 11 policy. 12 So, why are we concerned about 13 conflict of interest? I want to take you back 14 to this tragic event, I'm sure you're all 15 familiar with what happened. Jesse Gelsinger, 16 his father Paul Gelsinger, in September of 17 1999, Jesse who had a metabolic condition 18 called OTC deficiency went to the University 19 of Pennsylvania to participate in a gene 20 transfer experiment. After he was injected 21 with the adenovirus vector, he experienced an 22 immunological meltdown and then he died three 71 1 days later September 17th, 1999. 2 Now, out of that tragic event, 3 ultimately there was a lawsuit and as part of 4 that lawsuit there were allegations of 5 conflict of interest. In fact, the 6 investigator and the University of 7 Pennsylvania had interests in the company. 8 Clearly there was a conflict of interest that 9 Paul Gelsinger felt should have been disclosed 10 to him. Well, that kind of started the ball 11 rolling and less than a year later, August 12 16th, 2000, there was a conference held at the 13 NIH over 700 participants, I had the pleasure 14 of being there, where we talked about conflict 15 of interest. 16 There was a lot of concern 17 expressed, a lot of disagreement as to the 18 significance of the problem and how it should 19 be managed. But I really don't remember prior 20 to Jesse and prior to this conference a lot of 21 talk about conflict of interest. After this, 22 there was a cascade of articles about conflict 72 1 of interest. AAMC, AAU produced guidance on 2 conflict of interest and universities across 3 the United States began to take a look at 4 their policies which in many cases, were not 5 even being enforced, and I think that our 6 university is probably one of those examples. 7 It also struck me in retrospect as 8 I reflect back to those days that nobody 9 really talked about conflict of interest for 10 IRB members. It was always the investigator, 11 the investigator were the bad guys. We got to 12 manage conflict of interest. But what about 13 IRB members? I never even thought about it 14 and I don't recall one single conversation at 15 this conference about IRB member conflict of 16 interest. Well, as Marjorie indicated, AAHRPP 17 was born in 2001 and they issued their 18 standards in 2002 and they had standards that 19 addressed conflict of interest. 20 So when we looked at those 21 standards, we began to think much more 22 seriously about how we should manage not only 73 1 investigator conflict of interest but also IRB 2 member conflict of interest. And we, in 3 accordance, developed a policy. And then more 4 recently, of course, we found that there is 5 more attention being paid to IRB member 6 conflict of interest. Here we have the New 7 England Journal of Medicine article, November 8 30th, 2006 and then Leslie's excellent 9 article, her study that she talked about. So 10 I think we have a new view of how we should 11 identify and manage IRB member conflict of 12 interest. 13 To go back to 2002, to an article 14 written by Ehringhaus and Korn, our charge, 15 "Our charge is to manage research scrupulously 16 so that neither individual nor institutional 17 financial interest result in danger to 18 participants". Now if we take this term 19 "Individual", we normally think of the 20 investigator. Now we need to think in terms 21 of the investigator, IRB members, IRB staff 22 and IRB consultants. So we're really talking 74 1 about the potential for conflict of interest 2 to compromise human subject protection. So 3 perhaps we should begin with what is a 4 conflict of interest? 5 Well, let's talk about what is not 6 a conflict of interest. You're off the hook. 7 In order to have a conflict of interest, 8 you've got to have an interest in the first 9 place. So that's going to be our basic 10 premise and we're going to go from there. 11 Marjorie talked about the regulations which 12 have been in effect since 1981. And this is 13 what it says, which is not a lot. "No IRB may 14 have a member participate in the IRB's initial 15 or continuing review of any project in which 16 the member has a conflict of interest except 17 to provide information requested by the IRB". 18 Now, "initial and continuing 19 review of any project", we can really expand 20 that to include amendments, adverse events, 21 reports of non-compliance, indeed, any action 22 that an IRB takes relative to a protocol. But 75 1 that's not explicit in this definition. How 2 about HHS guidance, what does that say? Well, 3 in 2004 Tommy Thompson, the then Secretary of 4 HHS, had this guidance issued, where 5 institutions were encouraged to establish 6 policies and procedures to address IRB member 7 potential and actual conflicts of interest. 8 And I think that was certainly an important 9 step. So let's get down to how we define a 10 conflict of interest at our institution that 11 an IRB member may have. 12 Well, first a broad definition, 13 any financial incentive or indeed, any other 14 situation non-financial, which could cause an 15 IRB member to lose their objectivity or even 16 create the appearance of losing their 17 objectivity in the review or research which, 18 in turn, may compromise the validity and 19 integrity of IRB review and obviously, we're 20 very concerned about any negative impact on 21 the public's trust and whether or not we place 22 their rights and welfare first. 76 1 Now, I'm reminded when I look at 2 this definition even create the appearance 3 thereof of a conflict of interest, back in the 4 early 1990s, I used to follow my world famous 5 oncologist wife often around the world, 6 carrying her bags and going to five star 7 hotels where the drug companies were paying 8 for the trip. And I remember one time when 9 she was going to go to Japan and she called 10 the company and said, "Well, I want to bring 11 my husband along to carry my bags, could I 12 split my first class ticket into two coaches 13 and then bring him along". And they said, 14 "Hey, don't worry about it, okay, what does he 15 do?" She said, "Well, he's an IRB chair". 16 They said, "Oh, God, let's give him a first 17 class ticket, too". 18 (Laughter) 19 So I went to Japan courtesy of the 20 company and all over Japan as a matter of 21 fact, courtesy of the company with limousine 22 service, et cetera. Now, quite frankly, I 77 1 never thought I had a conflict of interest. 2 I never even thought about whether or not I 3 had a conflict of interest but clearly, there 4 could have been a perception that I had a 5 conflict of interest. And had I known then 6 what I know now, unfortunately, I would have 7 had to forego the trip and she would have had 8 to carry her own bags. 9 (Laughter) 10 So, conflict of interest 11 represents the potential for a biased judgment 12 but it is not an indicator of the likelihood 13 or certainty that such judgment will 14 compromise human subject protection and that's 15 something that's important to convey to 16 investigators and IRB members because when we 17 try to identify potential conflict of interest 18 and manage it, we don't want them to get the 19 impression that we're impugning their 20 integrity or their reputation that they're 21 going to do something wrong. This is just 22 something that we need to do. 78 1 So what is COI at our institution 2 that an IRB member may have? Well, first of 3 all let's talk about the covered person. It's 4 the IRB member, it's an IRB consultant, it's 5 the IRB staff even. It's also the immediate 6 family member of any of the above, which we 7 define immediate family member as the spouse, 8 the dependent child, sibling or the parent. 9 So what are COIs? Well, the covered person 10 serves as an investigator on the protocol. I 11 mean, that's how we review -- we viewed 12 conflict of interest in the old days. If you 13 were listed on the protocol, you had a 14 conflict of interest. You didn't participate 15 in the review and if we knew enough about the 16 regulations, we threw the person out of the 17 room. 18 Well, it's probably important to 19 expand that to situations where the 20 investigator serves as a scientific or medical 21 advisor to the PI. That could represent a 22 conflict of interest, serves as an advisor or 79 1 a director supervisor of a trainee's research, 2 you've got a potential conflict of interest. 3 Receives financial compensation to which the 4 research under review is directly connected, 5 including salary, consulting fees, royalties, 6 licensing payments, so forth and so on, 7 honoraria. And you notice the underlined word 8 "directly". I'm going to get back to that in 9 a moment because this is kind of an ongoing 10 debate at our institution because we have IRB 11 members who serve as consultants to 12 pharmaceutical companies; yet, their area of 13 research may have nothing to do with the 14 research under review. It's a totally 15 different drug. And are we going to say, 16 "You've got two choices; one, give up your 17 consultancy with the company or continue as an 18 IRB member and be able to review". 19 The covered person owns any equity 20 interest in the company sponsoring the 21 research, obviously, excluding mutual funds, 22 or holds a position as a director, officer or 80 1 partner or any other influential position in 2 the company sponsoring the research. Is 3 appointed to the sponsor's scientific advisory 4 board which is directly related to the 5 research under review, now this was a point of 6 contention at our last IRB meeting because we 7 had IRB members who said, "I am a consultant 8 for example for Pfizer," in this case it was 9 a psychiatrist. He said, "But I have nothing 10 to do with the protocol that includes the drug 11 under review, so do I really have a conflict 12 of interest? We're still debating that one. 13 Holds patent rights or royalties from such 14 rights, that's a no brainer. 15 Has a financial interest in a 16 company that has a marketed product or is in 17 the process of developing a new product that 18 is or will be in direct market competition 19 with the product in the protocol under IRB 20 review, so for example, let's take a couple of 21 common drugs. You have an IRB member who has 22 a financial interest in the company that makes 81 1 Lipitor, but there's a protocol under review 2 which is a competitor, maybe Zedia. Well, we 3 would perceive that as a conflict of interest 4 because there is market competition. 5 Involved in research with a drug 6 biological device which is or will be in 7 direct market competition with the sponsor of 8 the research under review. So that means if 9 we have an IRB member who is an investigator 10 working on a research project and that 11 research project involves a test article that 12 ultimately will be a competitor for the drug 13 biologic or device under review, they have a 14 conflict of interest. 15 Has a personal relationship or a 16 conflict with any investigator listed on the 17 protocol that may cause them to be less 18 objective. They don't have a conflict of 19 interest provided their only involvement in 20 the protocol is in the context of providing 21 clinical care to subjects. That means in the 22 team approach to medicine, that if we have an 82 1 IRB member who serves on a treatment team and 2 they provide treatment in the context of a 3 clinical protocol, we don't feel they have a 4 conflict of interest and they don't have a 5 conflict of interest if they're on an NI study 6 section review or a consultant to FDA. 7 Now, how do we manage conflict of 8 interest? Well, every IRB member receives an 9 electronic copy of our policy prior to each 10 convened meeting which is automatically sent 11 out as though they've never seen it before. 12 It's in their packet, their electronic packet. 13 They are required to notify the Office if they 14 have a COI but we don't require them to tell 15 us the exact nature of the COI. Why? Well, 16 we feel particularly relative to a non- 17 financial based conflict of interest, such as 18 a relationship based conflict of interest, 19 that we don't want them to tell us, "By the 20 way, the reason why I can't review this 21 protocol is I'm sleeping with the 22 investigator's technician", okay. We want 83 1 honesty and we want people to say, "I have a 2 COI. I can't review, that's it". We don't 3 need to know what it is. 4 We think that's the best way to 5 handle this. Now, at the beginning of each 6 meeting IRB members must reaffirm that there 7 are no undeclared COIs. If there is a COI 8 that has been declared previously or is 9 declared at the meeting, they're recused. 10 They leave the room. They don't deliberate. 11 They don't vote. They don't count towards 12 quorum. Now, IRB members who have a financial 13 conflict of interest who are also 14 investigators have got to disclose this 15 financial interest in the informed consent 16 process and consent form. 17 Now, that's not unique to just IRB 18 members. That's one of our policies relative 19 to management of investigator conflict of 20 interest. We feel that disclosure in a 21 consent document is an important way to manage 22 COI but it's not the only way. It's just one 84 1 way and it should not be the only way. We 2 don't believe in passing the buck to the 3 prospective research participant. But we feel 4 the way Paul Gelsinger felt, we should tell 5 our patients if we have financial interests. 6 So, to go back to Susan 7 Ehringhaus' and David Korn's quote at the 8 beginning, "Fulfillment of our charge, the 9 integrity, the validity, the objectivity, of 10 IRB review really has to be beyond reproach", 11 and we feel that this is not a question of 12 just minimizing conflict of interest, but 13 rather it's total elimination from IRB review. 14 Thank you very much. 15 (Applause.) 16 CHAIRMAN TILDEN: Thank you, 17 Ernie. If the other presenters would go up to 18 the table and we'll open up the floor for 19 questions. Something tells me we're going to 20 have questions. Okay, we're writing down 21 everyone to indicate if they have questions. 22 The first person I saw was Neil. 85 1 DR. POWE: I thought that was a 2 wonderful group of presentations that brings 3 out a lot of the issues here. I have actually 4 a question that anybody can address, but I was 5 particularly intrigued by the survey that was 6 presented. And my question has to do with, 7 were characteristics of the institutions 8 looked at and their relationship to how they 9 handled conflicts of interest? And this is 10 what's going through my mind. If you're a 11 larger institution that's very research 12 intensive, you may have the capacity to have 13 many IRB members or many IRB committees that 14 could handle such issues -- let me give you an 15 issue. In the NIH, if you're on a review 16 committee, then your proposal wouldn't go to 17 that review committee because you're already 18 believed to be contaminated having been on the 19 committee and sat around the table with 20 others. 21 In other words, there's a conflict 22 of interest by all the other individuals that 86 1 are looking at it, because you're a member of 2 their team. And so I'd like to know whether 3 that goes on at different institutions. If 4 you're in the same organizational unit, 5 division, department, are you always recused 6 from the review, even though you may not know 7 anything about it, but, in fact, that's part 8 of your organizational unit and the success of 9 your organizational unit maybe very important 10 to you in your academic help center. 11 And my final thing is, this is a 12 little unrelated is, what happens when 13 conflicts of interest actually appear in the 14 middle of a review, someone discovers that, in 15 fact, "Oh, gosh, I didn't notice but now I see 16 someone is involved with this proposal, I 17 might have a conflict of interest". So those 18 are my questions. 19 MS. WOLF: In response, in terms 20 of my study, we did look to see if there were 21 differences based on characteristics. Like 22 you, we thought, well, maybe the bigger 87 1 institutions that are doing a lot more of this 2 might be paying more attention, so we looked 3 at it in terms of quartile of NIH funding, I 4 mean, and that was some of how we generated 5 our list. We looked at the 121 institutions 6 that receive NIH funding. 7 We found two differences. One, 8 there were more likely -- the larger 9 institutions were more likely to define 10 conflicts of interest and also to say it's 11 okay for the conflicting member to provide 12 information to the IRB before they leave the 13 room. But those were the only two differences 14 we saw and we looked also were there regional 15 differences. We didn't see any differences 16 there. So we thought there might be a greater 17 difference. We didn't see it in our study. 18 In terms of similar to the NIH 19 study section component, there were some IRBs 20 that did specify that being from the same 21 organizational unit might be a conflict, just 22 like it is for an NIH study section, but it 88 1 wasn't the most common definition. And you 2 could see that that could cut both ways. You 3 know, I'm at a very large institution. I work 4 in a very small group, the Program of Medical 5 Ethics and I'm not a clinician, so I don't see 6 a lot of the people that I might otherwise, so 7 for me, you know, they might be in my 8 department or even in the Division of General 9 Internal Medicine in which I sit and it's not 10 going to make a difference. Certainly, in a 11 smaller institution it may be a bigger issue, 12 because you may work much more closely or 13 again, a clinician within my division that 14 might be different, but we didn't see -- that 15 wasn't an overwhelming trend in the data that 16 we looked at. 17 And in terms of what happens in 18 the middle, we didn't look at that in my 19 study. I can tell you that happens in the 20 reality. I don't know if that's happened for 21 either Ernie or Marjorie, you know. And then 22 in my institutions, we typically handle it 89 1 right then and somebody either leaves, or 2 sometimes we can't review. You know, we may be 3 close to quorum and we lost quorum and that 4 protocol gets pushed over to the next meeting 5 or to another committee, we have four 6 different panels, in order to cope with that. 7 But that's one of the concerns I 8 have and why I'm cognizant, I'm a lawyer and 9 arguing for more policy sometimes just, "Oh, 10 you're a lawyer, you like a lot of paper", but 11 I think providing information to people so 12 they really understand and know that it's 13 important, I think. What Nebraska is doing, 14 you know, the reminder every time, you know, 15 "We think this is really, really important in 16 our institution", so people focus on the 17 concerns and hopefully you minimize that sort 18 of opportunity where, "Oh, my gosh, I didn't 19 realize that I'm actually the mentor of this 20 person", or some other problem that only gets 21 realized at the meeting. 22 DR. SPEERS: We have seen some of 90 1 the same things which Leslie reported, which 2 is I really can't make a statement about 3 larger and smaller institutions. One would 4 think that some of the larger institutions 5 might be more aware and better able to handle 6 conflict of interest, but I wouldn't say that 7 necessarily from what we have seen, where 8 sometimes it's the larger institutions that 9 have had -- that will have multiple policies 10 and procedures and so they really have 11 problems knowing exactly what their procedures 12 are, and for IRB members to be able to 13 articulate that, you know, for them to be 14 clear on what is considered a conflict and 15 what isn't. 16 Most institutions, whether they're 17 small or large, deal with the obvious conflict 18 of interests so you know, if they have -- if 19 a protocol comes in for review and that 20 protocol is from -- you know, is of a member 21 of the IRB, that's obvious. It's like the NIH 22 study section. And so the IRB staff will 91 1 find, you know, you don't necessarily have to 2 declare that. That's picked up by the staff 3 and then if there's multiple IRBs they can 4 route that protocol appropriately. If not -- 5 and then they know when they're putting 6 together the agenda for the one IRB that they 7 might have, that that IRB member cannot be 8 involved in review of his or her own protocol. 9 So I think the obvious conflicts probably for 10 the most part are handled well. It's the less 11 obvious ones and that's where a policy helps 12 but it's the education that has to take place, 13 it's the constant awareness reminder to IRB 14 members that they need to be thinking about 15 potential interests that they might have and 16 the research, you know, that they need to 17 declare and that very often can come up, even 18 during an IRB meeting, because part of the 19 problem with, you know, you declare your 20 conflicts all the time, but you become so 21 routine at doing it, that you don't always 22 think about them until you're actually in the 92 1 middle of reviewing a protocol. 2 And so at that point, you know, 3 what a good IRB will do is to stop and have 4 that person recuse him- or herself from the 5 discussion and if that's not possible, if it's 6 not possible to continue with the review, then 7 you have to table it till you can handle 8 review in a situation where there is no 9 conflict. 10 This issue of conflict of 11 interest, isn't -- it's a difficult one or it 12 can be a difficult one for smaller 13 institutions to deal with. You know, if we 14 think beyond most universities, you know, so 15 if we start to think about smaller community 16 hospitals, for example, where the research at 17 that hospital, you know, is all cardiovascular 18 disease, it's all the cardiovascular disease 19 unit, you know, that's doing the research. 20 And so then when you're putting the IRB 21 together and you want to have the appropriate 22 expertise on the IRB but you basically have 93 1 the same unit, that is sending the protocols 2 to the IRB for review, then that's a difficult 3 issue for the IRB to work through. There are 4 ways around it in terms of external members 5 and bringing, you know, perhaps consultants 6 into it. 7 But I think wherever SACHRP 8 decides to go on this issue, you have to think 9 about the smaller research institutions as 10 well as the larger academic institutions. 11 DR. PRENTICE: Thanks, Neil, for 12 asking those questions. I'm glad I had a pen 13 and paper so I could write down all four 14 because I can't remember that much information 15 at one time. I'll address the last three. 16 NIH study section membership, 17 you're on it just in time. It's quite 18 possible that you could be on an NIH study 19 section and you could review a grant along 20 with your colleagues and then you could end up 21 reviewing the same one on an IRB. I've 22 thought about that and I don't think that that 94 1 is really a conflict of interest because what 2 the study section is doing is they're looking 3 at the funding priority, the importance, the 4 scientific merit, and yes, they do look at 5 human subject protection issues at the same 6 time but I don't view that as a conflict. But 7 certainly if any IRB member felt that it was, 8 then they should recuse themselves. 9 As far as serving in the same 10 department, that issue has come up on our IRB 11 quite a few times. We have protocols 12 submitted by chairs of departments or a study 13 section or section chiefs and, you know, the 14 individuals serving under them are IRB 15 members. And what we do is we tell them, 16 "Listen, if you feel as though you cannot be 17 objective in the review of a protocol, then 18 you need to recuse yourself". Now, that's not 19 been explicitly indicated in our policy but 20 that's certainly understood by all of our IRB 21 members. 22 We've had situations where people 95 1 have said, "I will review, but I don't want to 2 vote". We say, "That's fine, you can do that 3 if that's the way you feel". The middle of 4 the review, that's happened before. Sometimes 5 you'll have an IRB member who all of a sudden 6 notes that, "Oh, gee, Pfizer is the sponsor", 7 they never noted that before for whatever 8 reason so they raise an issue and sometimes 9 it's very clear they have a conflict of 10 interest in which case they're recused. In 11 other cases, they don't have a COI that is in 12 accordance with our policy but they think they 13 may have a COI. And an example would be our 14 community representative noticed that, I think 15 it was Pfizer actually -- Pfizer was the 16 sponsor of a protocol and he said, "My 17 daughter is a drug rep for Pfizer, do I have 18 a COI", and my response was, "Not in 19 accordance with our policy", however he felt 20 he still had a COI, so it was his prerogative 21 to abstain. 22 Now, we didn't throw him out of 96 1 the room because we don't think he had to be 2 recused, but he abstained from the vote 3 because he felt uncomfortable in voting. So 4 all of these are issues that, you know, 5 pertain to conflict of interest. It's 6 identification. It's management and I think 7 that we're just beginning to address all of 8 these issues in a very, very important way 9 now. 10 DR. POWE: Ernie, just, I may have 11 not been clear. What I was saying not was 12 whether it was -- a grant -- that you were 13 reviewed at the NIH for a grant. I was saying 14 if an individual is a member of the IRB, 15 should their research proposal go to that IRB, 16 be reviewed in that IRB? And what I was 17 saying was that the parallel at the NIH was 18 that if you are on a study section, your grant 19 does not go to that study section. 20 DR. PRENTICE: Yes, you would be 21 able to do that at Hopkins probably, but you 22 can't do that at the majority of institutions 97 1 where they've only got one or two IRBs. I 2 mean, in theory it's probably not a bad idea, 3 okay, if you have the ability to do that. 4 DR. POWE: That was my point, in 5 the larger institutions with resources, at 6 more staffed IRBs you might be able to do 7 that. 8 CHAIRMAN TILDEN: Okay, Mike, you 9 had a question? 10 DR. GENEL: Well, some of them 11 have been asked already so I've got a shorter 12 list. But, Ernie, I wondered, that last slide 13 was taken from something in your wallet? 14 (Laughter) 15 DR. PRENTICE: That reflects the 16 amount of money that the government owes me 17 for the last four years of being Chair of 18 SACHRP. 19 (Laughter) 20 CHAIRMAN TILDEN: That sounds bad 21 for me. 22 DR. GENEL: The area that I find 98 1 most troubling is this whole notion of 2 personal relationships, personal beliefs is, 3 I think, very hard to define this, and I'm 4 impressed by the policy or at least the 5 philosophy that you've put in place in 6 Nebraska in which basically, simply, people 7 are reminded of what might be potential 8 conflicts of interest and then can make their 9 decision as to whether this is something they 10 need to be -- they feel they need to be 11 recused on. The problem I have is that there 12 needs to be some sort of boundary set for this 13 because I think the potential for variability 14 and difference in interpretations, I think, 15 can be very, very great. And I'm struggling 16 with how one defines what degree of a personal 17 relationship represents a potential conflict 18 of interest. 19 The reality is, even at large 20 institutions such as mine, the community that 21 is engaged in research from which many of the 22 members of the IRB are drawn is a very small 99 1 community. So it's almost impossible not to 2 have some relationship with somebody and to 3 what extent -- when does that relationship 4 become a potential conflict. And you know, I 5 recognize that if my Chairman were to submit 6 a protocol that perhaps that might be 7 perceived as a conflict one way or another, 8 either positive or negative, but how -- where 9 does one draw the boundaries? 10 And then when you start to get 11 into things such as the survey that you did in 12 terms of personal beliefs, oh my, that's a 13 real one. And then you get into issues such 14 as protocols on egg donation or protocols on 15 the embryonic stem cell research and so forth. 16 So I think there's a -- I think if one were to 17 get too explicit, then I think in terms of any 18 sort of guidance or regulations we're going to 19 end up creating more problems than we solve. 20 I raise this not because I have 21 the answers, but because I think this is the 22 area that I find to be most difficult and most 100 1 troubling. The financial ones, I think, can 2 dealt with, because one can define some sort 3 of numbers. In that respect, Ernie, I didn't 4 see a threshold for your financial conflict of 5 interest on your slide. 6 DR. PRENTICE: The threshold is 7 zero. It was higher in a previous policy. 8 It's been reduced down to zero. As a matter 9 of fact, our investigator financial interest 10 threshold has been also reduced down to 2,000. 11 So the IRB chose to go below the investigator 12 threshold of 2,000. Two thousand is what we 13 define as a significant financial interest 14 which automatically goes to an institutional 15 COI committee. I'm speaking in terms of 16 investigator management of conflict of 17 interest. Anything under 2,000 for 18 investigators is examined. 19 It's disclosed, has to be 20 disclosed, but it's examined by our conflict 21 of interest officer who then makes a decision 22 as to whether or not any management is 101 1 necessary. Even if an investigator has one 2 dollar of financial interest there will be an 3 appropriate disclosure in the consent document 4 of some kind that would alert the prospective 5 subject that the investigator does have some 6 financial relationship with the sponsor. 7 So IRB, zero; investigators, 8 2,000. 9 CHAIRMAN TILDEN: Dan? 10 MR. NELSON: My question is 11 directed at Ernie, I guess, or at least 12 prompted by one of his slides and although I'd 13 be happy for a response from anybody. I'm a 14 firm believer in oversight and policies in 15 this area, but also a believer that we should 16 be careful when we craft our policies that we 17 don't set up situations where we're in 18 violation of them as soon as they get crafted 19 and I'm particularly thinking in terms of the 20 covered persons list and how broadly we cast 21 the net when we define who's covered for 22 conflict of interest. 102 1 And I'm remembering now when we 2 started drafting and refining our own campus 3 policies and the first draft that was 4 presented to me had cast the net to define, 5 you know, the standard group, spouse, 6 dependent children and see if I can remember 7 the exact language, those with whom we enjoy 8 amorous relationships without the benefit of 9 marriage. 10 (Laughter) 11 MR. NELSON: And I came back that 12 we shouldn't have words that caused laughter 13 like that every time somebody read the policy, 14 and then there were other issues as well. And 15 so we modified that. So I was interested, 16 Ernie, in seeing siblings and maybe even 17 parents included in the list of immediate 18 family members. And I'm thinking of my own 19 situation with two older brothers, one in the 20 hills of Iowa and one even further out in the 21 hills of Montana and I have no idea of their 22 personal holdings. They have no idea of what 103 1 would come before our IRB and it would be 2 something of a sham, I think, for me to say I 3 do or don't have a conflict with relation to 4 my siblings, my extended family and I would 5 think that would be true for a lot of people 6 who are quizzed whether they're investigators, 7 IRB members, and the like. 8 So I'm just curious how realistic 9 the net we're casting -- 10 DR. PRENTICE: That's an excellent 11 question. We have a Board of Regents policy 12 that applies to investigators which includes 13 all of those covered persons, so it's not 14 something that we had decided on our own. 15 However, I certainly agree with you. We make 16 a presumption when an investigator fills out 17 a financial disclosure form that they have 18 ascertained that all covered persons, okay, do 19 not have a significant financial interest. 20 The reality is, as you very well know that 21 investigators are not calling mom and dad, 22 okay, Joe and Mary and saying, "You know, gee, 104 1 do you have any Pfizer stock, you know, do you 2 have an Merck stock?" That's not happening. 3 So it's something that we have to 4 put in our policy but it's not something that 5 we pursue in terms of trying to find out the 6 accuracy of the report. We simply make the 7 presumption, "Here's our policy, we expect you 8 to follow it", and that's kind of the end of 9 the story. I don't think we can go beyond 10 thatm, nor should we go beyond that. But all 11 of those covered persons are in our Board of 12 Regents requirements. 13 MR. NELSON: Maybe I can just 14 follow up with a question to Leslie or 15 Marjorie what you have seen in policies. Is 16 there kind of a norm that's distilled down to 17 a list of covered persons? 18 MS. WOLF: I would say it 19 typically is like it is for the PHS policy in 20 terms of investigators, which is your 21 immediate family members with the concept of 22 people who share household income so it's less 105 1 your mom and dad if you have been an adult 2 living alone raising your own family and more 3 so that you can't say, "You know, I can't 4 accept that $20,000 fee but if you split it 5 between my two children that would be okay", 6 sort of that realization. 7 And then I know some institutions 8 include registered domestic partners or some 9 variation rather than the amorous relationship 10 of the proposal there, with the idea again, 11 you should get the spouse equivalents if that 12 person doesn't have a spouse. But that's sort 13 of the concept and that's the fairly typical 14 range of who's the covered person and not 15 casting your siblings who live separately but