1 UNITED STATES OF AMERICA + + + + + DEPARTMENT OF HEALTH AND HUMAN SERVICES + + + + + SECRETARY'S ADVISORY COMMITTEE ON HUMAN RESEARCH PROTECTION + + + + + MEETING + + + + + THURSDAY, MARCH 29, 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 PAGE Welcome and Opening Remarks 5 Report of Issues 11 Swearing-In of New Members 25 Report of Subpart A Subcommittee 26 Report of Subcommittee on Issues Impacting those with Impaired Decision-Making Capacity 198 Panel Discussion on Issues Impacting those with Impaired Decision-Making Capacity 246 Public Comment 354 Wrap-up and Adjourn 355 5 1 P-R-O-C-E-E-D-I-N-G-S 2 (8:35 a.m.) 3 CHAIR TILDEN: Good morning. 4 It's 8:30 or a little after and I've been 5 asked to begin. My name is Sam Tilden and 6 I'll be serving as the Chair of SACHRP for 7 the meeting and for the foreseeable future. 8 The next few meetings, at least, I believe. 9 Of course, this is the first 10 meeting I believe that Dr. Prentice hasn't 11 been the chair. And since I'm new to this, 12 it may not be as well organized as previous 13 meetings, but I'll try to stay to task. 14 I'd like to thank OHRP and the 15 Department for honoring me with this 16 selection as Chair and I appreciate it. And 17 as most of the colleagues on the committee 18 said, they really congratulated me. And as 19 Mike said, he didn't know, following that, 20 he expressed his condolences. So, at any 21 rate, I'll certainly do my best to make sure 22 the committee moves forward. 6 1 I had a couple of slides here. 2 First of all, we have three new members that 3 are joining SACHRP for their first meeting 4 today and I'd like to introduce them. 5 First is Lisa Leiden. Dr. 6 Leiden, I'm going to read their bio, short 7 bio here, has over 25 years of experience in 8 research administration beginning with 9 medical schools and including academic 10 hospital administration and have held a 11 variety of leadership positions at several 12 research institutions. She, most recently, 13 she was recruited by the University of Texas 14 at Austin to develop and establish the 15 office of research support and compliance. 16 In her current position, Dr. Leiden provides 17 leadership and oversight for the 18 University's Research Departments and 19 Colleges. She has experience in the 20 accreditation process for human subjects 21 protections programs and the University of 22 Texas and is also involved with the IRB 7 1 office. 2 Next is Dr. Patricia Marshall, 3 who is Professor of Bioethics and 4 Anthropology in the Department of Bioethics 5 at Case Western Reserve University. Dr. 6 Marshall conducts empirical research aimed 7 at broadening the historical focus of 8 bioethics to include concerns of culturally 9 diverse communities, both nationally and 10 internationally and she has served on 11 numerous boards and counsels, including the 12 advisory board for the Fogarty International 13 Center at the National Institutes of Health, 14 where she has helped establish a program for 15 training health professionals and 16 international research ethics. She has also 17 served as a consultant to the World Health 18 Organization, counsel for international 19 organization medical societies and national 20 bioethics advisory commission and was a 21 member of the counsel and accreditation for 22 the association of accreditation of human 8 1 research protections programs. 2 And the third member is David 3 Strauss. Now David is not new to SACHRP, he 4 served on a Subpart A Subcommittee and is 5 going to co-chair a new subcommittee that 6 we'll hear about today and is in the process 7 of being formed and beginning meeting. And 8 for the last six years, he has served as the 9 chair of the New York State Psychiatric 10 Institute IRB and director of the office of 11 Human Subjects Research in the Department of 12 Psychiatry at Columbia. He's co-director of 13 the ethics corps of a National Institute of 14 Health funded clinical research center for 15 clinical and behavioral research in HIV. 16 He also serves on the executive 17 steering committee of the Columbia 18 University Center of Bioethics and sits on 19 the Medical School Conflict of Interest 20 Committee and Standing Committee on the 21 conduct of research. 22 So, I hope you'll join me in 9 1 welcoming the three new members. 2 Now, before I go over the agenda 3 for the meeting for today and tomorrow, I 4 have been reminded that all the members need 5 to submit their lunch orders to Kelly before 6 lunch is served today. So, be sure to do 7 that as soon as possible. And so I'm just 8 going to pass my lunch order right over to 9 you, Kelly. Okay. 10 And in the tradition, I thought 11 we'd just run over what the agenda will be 12 for the meeting for today and tomorrow. Do 13 you have any slides? No slides. Okay. 14 Well, let me just, we're going to, following 15 this review, we'll have Dr. Schwetz give us 16 a report of the issues. And we also will 17 handle the minutes from the previous 18 meeting. 19 Following that, we, if everything 20 works out in order, we'll have swearing in 21 of the new members by a designated 22 department official. At 9:15 we are 10 1 scheduled to get the report of the Subpart A 2 Subcommittee from Dan Nelson and Felix Gyi. 3 At 10:30 we'll break. And then we'll 4 continue the Subpart A Subcommittee report 5 from 10:45 to 12:15 p.m. 6 There will be a working lunch at 7 12:15 to 1:30 p.m. for SACHRP members. And 8 that working lunch will consist of ethics 9 training. Annual ethics training is 10 mandatory and this is an opportunity for us 11 to get that annual requirement out of the 12 way. 13 At 1:30 we'll have a report of 14 the Subcommittee on Issues Impacting those 15 with Impaired Decision-Making Capacity from 16 David Strauss. And then -- that's the new 17 committee I just previously mentioned. So, 18 we'll break following that. And then we'll 19 have a panel this afternoon which is 20 scheduled at 2:45 p.m. to discuss issues 21 which impact on those with impaired 22 decision-making capacity and research. And 11 1 we have a, I think, quite distinguished 2 panel for discussion. 3 And then we'll open for comments 4 at 4:30, for public comment, and wrap-up 5 following that. 6 On Friday, we'll have further 7 discussions related to conflict of interest 8 or conflicting interests for IRB members and 9 then we'll have a panel and a discussion 10 related to training and certification for 11 investigators. So that will take up most of 12 tomorrow. 13 Except, I forgot one important 14 thing. I believe we're due a visit from the 15 Assistant Secretary of Health, Dr. Agwunobi. 16 That might the most important thing. And 17 he'll be here in the morning to talk to us. 18 Okay, so with that out of the 19 way, I'd like to go ahead and proceed and 20 ask Dr. Schwetz to give us a report of 21 issues. 22 MEMBER SCHWETZ: Thank you, Sam, 12 1 and good morning to all of you. And thanks 2 to all of you in the audience for being 3 here. 4 Let me extend some 5 congratulations, as well. Congratulations 6 to Lisa Leiden and to Patty Marshall for 7 agreeing to serve on SACHRP. We really 8 appreciate it and are anticipating the help 9 that you will be to us in the variety of 10 things that come before SACHRP. 11 David, thanks for agreeing to be 12 on SACHRP and also to be one of our co- 13 chairs on an important new subcommittee. So 14 thank you for the help that you have been 15 and we look forward to your continuing help. 16 Another piece of congratulations 17 that involves another one of our SACHRP 18 members but not because he's a new member, 19 is to congratulate Dr. Powe on something 20 that some of us have learned very recently. 21 And this is a new honor that has been 22 bestowed on Dr. Powe. Let me just read the 13 1 first paragraph and it will summarize what 2 this is and the relevancy to today's and 3 tomorrow's meeting. 4 "Johns Hopkins internist and 5 epidemiologist, Neil Powe, who has trained 6 hundreds of clinical researchers and medical 7 students in the past two decades, has been 8 named the 2007 distinguished educator by the 9 National Association of Clinical Research 10 Training." 11 Neil, that reflects the 12 importance of your presence on this advisory 13 committee because of the importance of this 14 topic and the discussions that we've already 15 had and will continue to have. So, 16 congratulations on the award. 17 (Applause.) 18 MEMBER SCHWETZ: And as this very 19 specific topic comes up tomorrow, we're 20 looking for additional input because of 21 your, the large amount of experience that 22 you have on this. 14 1 CHAIR TILDEN: I'll be, we'll be 2 looking to you, Neil. 3 MEMBER SCHWETZ: Okay, some 4 progress on things that have been going on 5 relative to SACHRP recommendations. And 6 I'll go through some of the various sets of 7 recommendations that SACHRP has made and 8 tell you what the progress is. 9 Regarding Subpart D, Dr. Kevin 10 Prohaska, Kevin is sitting toward the back 11 of the room. Kevin, raise your hand. Kevin 12 is the person within OHRP who is the lead on 13 developing the response to the 14 recommendations that were made on Subpart D, 15 so he has organized all of those 16 recommendations that were made and has 17 started a series of discussions internally 18 to decide how we're going to respond to 19 individual recommendations and how these can 20 be packaged in a manner that would make the 21 most sense to the community that we're 22 trying to help. 15 1 Subpart D -- is Julia here? No, 2 she isn't. Julia Gorey is the OHRP person 3 who is the lead relative to the 4 recommendations that SACHRP made and the 5 recommendations that came out of the report 6 from the Institute of Medicine regarding 7 prisoners in research. 8 We briefed the Assistant 9 Secretary for Health on what our plan is for 10 handling that set of recommendations. And 11 as you recall, some of the recommendations 12 that are in the IOM report go beyond the 13 purview of what OHRP can deal with. They 14 require activities outside of OHRP, and some 15 even out of the Department, to be able to 16 deal with some of those recommendations. 17 So, we were laying out what OHRP, what we 18 can do relative to the recommendations, 19 versus things that were recommended that we 20 kind of transferred to the Assistant 21 Secretary for Health, for his advice on how 22 to follow them elsewhere. 16 1 So, we got approval of our plan. 2 And in the meantime, we have notified all of 3 the other federal agencies and departments 4 under the common rule that we are about to 5 consider these recommendations and what 6 input do you have as all of these other 7 departments represented by the ex officios 8 behind us, what are you recommendations as 9 an agency or a department, at a time when 10 we, as OHRP, are just beginning to develop 11 our responses to all of these 12 recommendations. 13 So, we have gotten almost all or 14 all of the inputs from the other federal 15 agencies. And we're in the process of 16 reviewing them to determine what impact that 17 has on how we proceed with the rest of the 18 recommendations. So, both of those are in 19 progress at OHRP. 20 SACHRP made recommendations on 21 the privacy rule, HIPAA, and as you recall, 22 those recommendations have been forwarded to 17 1 the Office of Civil Rights and they are 2 working on them, but I have not had a 3 specific discussion with OCR to know exactly 4 what they're doing. We have representation 5 on the working group, so we're expecting it 6 sometime, hopefully in the near future, to 7 see something come out of that activity. 8 Subpart A has made 9 recommendations and those recommendations, 10 the first set of recommendations from the 11 Subpart A Subcommittee have now gone to the 12 Department. So we are looking at those, but 13 we're waiting for a response to come back 14 from the Secretary's office to give us clear 15 guidance on how they want us to respond to 16 them. 17 One of the things that SACHRP 18 recommended a couple of years ago, was that 19 FDA and OHRP would develop guidance on 20 adverse event reporting. And you're aware 21 that we put up, OHRP put up its draft 22 guidance on our website last year, well, as 18 1 of January of this year, we now have final 2 guidance from OHRP relative to unanticipated 3 problems and adverse events. And FDA is 4 continuing to work on theirs. They took a 5 different route on how to get there. So 6 they're also working on it and making 7 progress, but we're glad to have ours in a 8 final form up on our website. 9 Some other items, independent of 10 SACHRP recommendations. OHRP's draft 11 Guidance on Engagement of Institutions in 12 Human Subject Research has been posted for 13 public comment. And that window of time for 14 public comment will close on February 6th -- 15 no, it did close on February 6th, and we're 16 currently looking at those comments. We got 17 comments and we will look at those as we 18 revise this and view all those comments. 19 Let me summarize where we are 20 relative to the education conferences that 21 OHRP sponsors. We had one at Baylor 22 University in January. And it was a quite 19 1 successful training conference, a regional 2 training conference at Baylor in Dallas. We 3 will have another one in Pittsburgh, 4 Pennsylvania on June 22nd. 5 We are working with our Denver 6 office, regional office, to develop a 7 workshop for August 22nd and 23rd that will 8 look at research issues of American Indians. 9 And this is not the first time that we have 10 engaged in that discussion with this 11 community. So we're pleased to be planning 12 another meeting where we look at what those 13 issues are that are involved in research 14 involving Native Americans. And at that 15 meeting, we would expect to bring together 16 people from the tribal nations, academic 17 researchers, whether they are American 18 Indians or not. IRBs, local and state, 19 federal government people, all being brought 20 together to discuss these issues. 21 In addition, in the context of 22 educational conferences, Shirley Hicks, the 20 1 Director of our Division of Education, has 2 had four what we call quality assurance 3 workshops. It's different than a 4 conference, where everybody comes who wants 5 to from the IRB community, research 6 community, institutional officials. The 7 quality assurance workshops is an effort to 8 reach out to people who have less experience 9 in the IRB community and they're taught how 10 to write SOPs and they're taught how to look 11 at some of the subtleties of the regulation 12 that may be new to them. So, it's a 13 training course for people who have less 14 experience than those who typically attend a 15 PRIMR meeting, or those who typically attend 16 one of the education conferences. 17 In addition, Shirley is looking 18 at another part of the enterprise that, to 19 be honest, we're uncertain how effectively 20 we reach. And it's those institutions that 21 have federal-wide assurance with us for 22 conducting research, but they do not have an 21 1 IRB. There is a surprisingly large number 2 of FWA-holding institutions that do not have 3 an IRB. And my concern is that we have not 4 effectively reached that community. So this 5 is an effort to target that group of 6 institutions where there is no IRB chair. 7 There is no IRB there helping to instruct 8 the investigators about what the culture 9 requires. 10 Just one other topic that I will 11 mention. It is my continuing effort to 12 reach out to institutional signatory 13 officials. Institutional officials in 14 general bat, in particular, that subset of 15 institutional officials who have signed to 16 commit that their institution will comply 17 with the regulations for human subject 18 protection, HHS regulations. 19 There's been a lot of enthusiasm 20 among institutional officials to gather in 21 meetings to begin to talk to each other. 22 And this is something that hasn't been 22 1 traditional among institutional officials to 2 talk to each other about human subject 3 protection-related issues. So, just in the 4 last few months, I've had meetings at 5 Michigan State University, at East Lansing, 6 a meeting, a day-long meeting, these are 7 typically, the Medical College of Wisconsin 8 in Milwaukee, the regional conference of 9 Western IRB in Newport Beach, California. 10 We had a session at the training conference 11 at Baylor University in Texas. I 12 participated at the AAHRP annual conference 13 in Baltimore just a few weeks ago, where we 14 had an opportunity to meet with a bunch of 15 institutional officials. 16 So, I'm very pleased that there 17 is a momentum that allows me to reach out to 18 institutional officials and get the 19 attention of this part of the enterprise, 20 about their responsibility for training 21 investigators, their responsibility for 22 creating a culture at their institution that 23 1 addresses the protection of human subjects, 2 and the other things that we want in that 3 culture at the research institutions. 4 So, this is a priority for me and 5 I will continue to reach out to 6 institutional officials. It's at the stage 7 now where, instead of me begging for an 8 audience, they're calling us and saying how 9 can we organize something? If you'll come, 10 I'll bring them together, kind of a 11 situation. So, that's what I was hoping 12 for. 13 Sam, with that, I'll quit. Thank 14 you. 15 CHAIR TILDEN: Great. Any 16 questions? Mike? You will take questions, 17 won't you, Bern? 18 MEMBER SCHWETZ: Sure. 19 CHAIR TILDEN: Okay. 20 MEMBER GENEL: Bern, I note that 21 the letter from this committee on the HIPAA 22 goes back two years before I joined this 24 1 committee several months ago. And the sense 2 I got from your report is that this is still 3 somehow churning through the Office of Civil 4 Rights. I regret that the Assistant 5 Secretary isn't here so that I could voice 6 my concern that something that is, I think, 7 vitally important to the medical research 8 process has been stymied within the 9 bureaucracy of our government. 10 Having made that speech, can I 11 ask you, what are the prospects of this 12 getting out? 13 MEMBER SCHWETZ: I don't know, 14 Mike, how to specifically answer that, but I 15 appreciate your raising it. I would 16 recommend that you might raise this again 17 tomorrow, when the ASH is here. He'll be 18 here tomorrow morning and typical, if he 19 follows the same pattern that he has in 20 previous visits, he will make some comments 21 and then ask you what's on your mind. And I 22 would encourage you, Mike, to raise that. 25 1 It's a very legitimate and appropriate 2 point. Thank you. 3 CHAIR TILDEN: Okay, well, thank 4 you, Bern. 5 MEMBER SCHWETZ: Sure. 6 CHAIR TILDEN: The next item on 7 the agenda is the swearing-in of the new 8 members. And we have Ms. Deborah Wise here 9 from the Department of Health and Human 10 Services to do the swearing-in ceremony. 11 MS. SLATINSHEK: Excuse me. And 12 I would ask that all the three new members 13 please come to the front here for the 14 swearing-in ceremony. Thank you. 15 (Whereupon, Patricia Marshall, 16 Lisa Leiden, and David Strauss were sworn in 17 as Members of SACHRP.) 18 CHAIR TILDEN: Okay. The next 19 order of business is the report from the 20 Subpart A Subcommittee, with Felix Gyi and 21 Dan Nelson. 22 MEMBER NELSON: Well, thank you, 26 1 Sam and fellow Members, and guests. 2 I've lost count of how many -- I 3 guess I should say this is the 7th or the 4 27th report we've given and I can't remember 5 how many there have been. We've been 6 reporting a couple years now at every SACHRP 7 meeting and we're pleased to bring you our 8 latest today. A brief recap of what we've 9 been up to with some new recommendations for 10 your consideration and, hopefully, approval 11 today. 12 Just a quick overview of the 13 presentation. A review has been our custom 14 of the charge of our membership, which 15 continues to change out over time. Again, a 16 very brief recap of work today and then some 17 specific recommendations in areas relating 18 to training and education and to minimal 19 risk. And at these points, we'll stop and 20 ask for your further deliberation and vote. 21 And then we'll wrap up with some next topics 22 for our consideration, so you can see where 27 1 we're going next. And I think the timing of 2 this will work that there will be likely a 3 break between the training and education 4 part and the minimal risk where we'll ask 5 David Strauss to join us up front. And I 6 think that should likely coincide with the 7 break. 8 So the charge as explicated in 9 the letter from the Chair in January of '05 10 and elaborated further with discussion by 11 SACHRP, is to review and assess all 12 provisions of Subpart A of 45 CFR 46 and all 13 relevant OHRP Guidance documents. And based 14 on this review and assessment, to develop 15 recommendations for consideration by SACHRP 16 in three categories. Roughly in order of 17 increasing difficulty, if you will, 18 interpretation of specific provisions in 19 Subpart A, development of new or 20 modification of existing OHRP Guidance, and 21 possible revisions to Subpart A. And, 22 although the last may be the most difficult 28 1 to achieve, we haven't shied away from that 2 and some of the recommendations that have 3 been approved and, as Bern noted, submitted 4 to the Secretary actually asked for 5 revisions to the regulatory language itself. 6 The goals of our work are to 7 enhance protection of human subjects, to 8 reduce regulatory burdens that do not 9 contribute meaningfully to the protection of 10 human subjects and to promote scientifically 11 and ethically valid research. And as you 12 heard me say every time, we do not view 13 these as exclusive or incompatible goals. 14 We think they're closely interwoven and 15 mutually supportive of each other. 16 Felix was convinced that I should 17 once again take a stab at spending a little 18 time to attempt to answer these questions, 19 especially with new members come onboard, 20 although I have a sneaking suspicion he just 21 likes to watch me see how far I'll go to 22 mangle a metaphor or push a point in 29 1 answering these deeper questions, beyond 2 just the words of the Regulations and the 3 Guidance. But, what are the problems? What 4 are we trying to fix in real world terms? 5 The next two slides are not in 6 your handouts. Just so I didn't get OHRP in 7 copyright trouble. It is said that Thomas 8 Aquinas posed this as a theological question 9 centuries ago. I'm fairly certain that 10 Aquinas was not talking about bowling pins. 11 And I'm 100 percent certain that Aquinas was 12 not talking about IRBs, but we have found 13 this a useful metaphor in describing what we 14 see as the current state of affairs and what 15 we increasingly see happening in the IRB 16 world. Angels dancing on the heads of pins. 17 Just a single example from my own 18 institution and there are many many more, 19 and that's what keeps our subcommittee busy. 20 My institution, you might imagine, we try to 21 keep pin-dancing to a minimum, given my 22 mission here, but just last month, we passed 30 1 leap year. And there was a flurry of 2 activity. My staff went into scramble mode 3 in our office, because we had computers 4 churning out different dates on approval 5 documents than they had been used to seeing, 6 and investigators were used to seeing, which 7 is next year at this time, minus a day, 8 calculating the approval period with a 9 default of one year. And of course, we can 10 shorten that, but we can't go beyond that. 11 And the dates started to be slightly off 12 because we had passed leap year and this 13 hadn't been programmed into our computer 14 system. So, should we adjust the computer 15 calculations? Do we just let it stand for a 16 year, that the dates are slightly off and it 17 will catch up next year? These sorts of 18 questions. And will PIs or sponsors be 19 confused when the dates seem to be off by 20 what they're used to seeing, what other 21 concerns that we should be addressing? 22 And we worked our way through 31 1 that. But when I think of our office 2 dealing with that and then the thousands of 3 offices across the country doing the same 4 machinations and calculations all for the 5 sake of a leap year, a calculation and 6 approval document, and step back and think, 7 you know, were subjects protected any less 8 because of that? Were they protected any 9 more? Because, truth be told, we're 10 actually shortening the one approval date by 11 three or four days, however that works out 12 for the next year, and that's okay. But, of 13 course, we want our documents to be 14 accurate, we want our systems to be 15 predictable and clear to all. 16 But, in the bigger scheme of 17 things, who have we protected? And I hold 18 that out as just a single example. We have 19 animated arguments across the IRB world, 20 whether approval expires at 1:00 a.m. of the 21 day of approval or whether it's at midnight 22 of that day. And again, during that 24 32 1 hours, was anybody protected, more or less? 2 Now, when we add to that the 3 dozens, perhaps hundreds, of routines and 4 subroutines and processes that have crept 5 into our activities to do this job, that, I 6 think, arguably, had very little to do with 7 actually protecting human subjects, 8 multiplied by the thousands of IRBs, each 9 coming up with their own ways to approach 10 those, each equally convinced we have the 11 one right way that must be done, or we'll 12 get in trouble with somebody. You know, the 13 sheer weight and bulk and clutter added to 14 the system, I think, keeps us from doing the 15 real job, diverts us from the real job at 16 hand. And I think, also, unfortunately, 17 sends a signal to investigators, and I fear 18 sometimes even to ourselves, that this is 19 the kind of activity that it's all about. 20 And of course, we think it's not. 21 Another cartoon, just to mangle 22 one more metaphor, there are inherent 33 1 tensions in much of what we do, of course, 2 in the area of research ethics and research 3 oversight, there are natural tensions 4 between conducting human subjects research 5 and overseeing that research, very healthy 6 tensions. And there is a tension 7 represented by the tug of war, if you will, 8 on this slide. There are dangers on either 9 side. In the water, the sharks and 10 alligators waiting for those who find 11 themselves in regulations that leave too 12 much to the imagination, that are vague 13 enough but flexible enough to allow 14 appropriate variability and adjustment to 15 the local circumstances. But yet, sometimes 16 they are too open-ended and there are 17 dangers in that. There are dangers on the 18 other side with overly restrictive 19 interpretations of how we must apply those 20 sometimes vague regulations. And I think we 21 find investigators and subjects and IRBs 22 caught in the middle, so to speak. And I 34 1 think that we sense that, although the 2 pendulum has swung, over time, we seem to be 3 in a state of relatively over-restrictive, 4 in terms of interpretations, and that's some 5 of what our subcommittee has been looking at 6 to bring us back to the middle, if you will, 7 in this healthy tension, the healthy balance 8 in the middle. 9 These are our members assembled 10 to help us address those questions, both big 11 and small. I'll run the list again. You've 12 heard them before, although we have some new 13 members highlighted in orange or, in once 14 case, a departing member. Ricky Bluthenthal 15 has just recently joined us, a sociologist 16 from the RAND and will bring us added 17 expertise in the area of social and 18 behavioral research. He does studies in 19 this area with sensitive topics in 20 vulnerable populations. 21 Gary Chadwick from the University 22 of Rochester, well known to most of you. 35 1 Bruce Gordon, Chair of the 2 Pediatric Central IRB for NCI and Chair of 3 the University of Nebraska Medical Center 4 IRB. 5 Felix Gyi to my right, my co- 6 chair and compadre in arms. Thank you for 7 being here. 8 Isaac Hopkins, a community 9 representative on an IRB in New Jersey. 10 Nancy Jones from Wake Forest 11 University Medical School, but currently in 12 a fellowship at NIH in policy areas. 13 Moira Keane, from the University 14 of Minnesota. Susan Kornetsky from Boston 15 Children's. 16 Gigi McMillan, the founder of the 17 Weekend Pediatric Brain Tumor Network and a 18 forceful advocate for informed consent and 19 protections in clinical research in 20 particular. 21 Myself, from the University of 22 North Carolina. Ernie Prentice, again, 36 1 every well known to all of you, both old and 2 new to us. Ernie was an ex officio member 3 of sorts with our committee because as he 4 was SACHRP chair, he attended all of our 5 subcommittee meetings and participated. And 6 as he stepped down from the Chair, we were 7 able to twist his arm to stay on as a formal 8 member of our subcommittee and keep him in 9 the loop and keep his expertise in play. 10 And that's been very useful, of course. 11 Ada Sue Selwitz from the 12 University of Kentucky. And David Strauss, 13 who you all known here has now ascended to 14 the SACHRP and regrettably has left our 15 committee, but with our thanks and 16 continuing gratitude for the work that he 17 has done in many areas with us. We've, our 18 practice has been to list the members, as 19 they stepped off the committee here, for one 20 last time, and both formally and informally 21 note their accomplishments and their 22 contributions. So, David, thank you for the 37 1 work in the past and we look forward to more 2 in the future. 3 And of course, the input from, 4 actually, David, I'll note that in the list 5 of committee members that was included in 6 the binder here today, you have been 7 appropriately removed as of the February 8 meeting from the list of subcommittee 9 members, but were included as our retreat 10 moderator, which was yet another important 11 role that we thank you for. And more on 12 that in just a second. 13 These are the meetings that we've 14 held both in person and by teleconference 15 over the last two years. Most recently -- 16 whoop, and I see I have a typo -- 15th and 17 16th in Arlington in this hotel, just across 18 the lobby here. And we actually went into 19 retreat mode for the first few hours on the 20 first day. This was not the sort of retreat 21 that organizations or departments sometimes 22 do when they're at each other's throats or 38 1 collapsing, but rather a much more 2 proactive, collegial forward-looking 3 approach, just to see where we've been, what 4 we're doing, where we should be going. To 5 help set priorities, we, at our meetings, 6 have always had these discussions, but they 7 tended to be dispersed or tended to be at 8 the end of a long grueling two-day meeting 9 when everyone is tired and/or running for 10 the airplane. So this was a chance to 11 really step back and, with Bern Schwetz and 12 David Strauss moderating some of our 13 discussions, we were able to get a lot of 14 issues covered and think a bit more 15 globally, if you will, stepping back from 16 the content-specific discussions that so 17 often drive our activities. 18 So that was very useful, a 19 recommitment of sorts, to the job at hand 20 and a clear game plan for the next year and 21 how we're going to get there. We followed 22 that up with a teleconference earlier this 39 1 month to finalize the recommendations that 2 are brought to you today and, of course, 3 many working group calls and emails in 4 between. 5 So this is, I think, the entirety 6 of my recap of previous work just to note 7 that SACHRP has previously received and 8 reviewed all of our recommendations in two 9 areas, continuing review and expedited 10 review and those recommendations from that 11 set. And it was the majority of 12 recommendations, but not quite all, but the 13 majority were approved by SACHRP, with some 14 revisions at times, and those have been 15 packaged together in a letter to Secretary 16 Leavitt that, I gather from Bern's 17 statement, has actually been sent to the 18 Secretary, now. This was complied over the 19 last month or so with great help from OHRP, 20 Mike Carome, and others, to make sure that 21 we were capturing all the recommendations 22 appropriately. 40 1 There were 20 in number. I think 2 they were split about 14 for continuing 3 review and expedited review had 6, for what 4 it was worth, although some of those were 5 paragraphs long and could have been split 6 into more. The numbers are not important 7 but we think we covered a lot of important 8 topics within those two broad areas, again, 9 addressing things that both will reduce 10 regulatory burden, but simultaneously 11 increase protection for human subjects. 12 So, those have now been 13 submitted, now that we have a SACHRP Chair 14 to sign that letter, have been submitted to 15 the Secretary. And we await a response to 16 that. 17 Moving on now to our specific 18 areas of concern, and again, there are two 19 that we would be bringing to you today. One 20 we haven't really addressed before and the 21 other we have. 22 The first is in the area of 41 1 training and education. And I'll admit that 2 this hasn't necessarily been on our laundry 3 list of potential items as a separate 4 breakout topic or a stand-alone topic, but 5 it kept coming up so often as we deliberated 6 on other issues, that we realized during our 7 last meetings that this really deserves some 8 special attention on its own and that we 9 would bring forward these recommendations to 10 you, as a discrete category, if you will. 11 The need for training and 12 education is implicit in regulatory 13 requirements for IRB membership, if not 14 explicit. The IRB shall be sufficiently 15 qualified through the experience and 16 expertise of its members to promote respect 17 for its advice and counsel that sufficient 18 qualifications would imply training and 19 education in the job at hand. 20 In addition to assessing the 21 professional competence necessary to review 22 specific research activities, the IRBs shall 42 1 be able to ascertain the acceptability of 2 proposed research in terms of institutional 3 commitments and regulations, applicable law 4 and standards of professional conduct and 5 practice. These are excerpts from 45 CFR, 6 the sections dealing with IRB membership. 7 I will note that on the next few 8 slides, which tend to be text-dense, we've 9 erred on the side of keeping the full text 10 there, just so you don't have to go 11 elsewhere to see what might have been in our 12 abstracted version. So the full text of 13 these Guidance documents is up there or on 14 your paper just for reference. And we have 15 time today to be able to work slowly 16 through, so we don't have to shortchange 17 this discussion. 18 In the OHRP Terms of Assurance, 19 item 11, Assurance Training, states that 20 "the OHRP Assurance Training modules 21 describe the major responsibilities of the 22 institutional signatory official and the 43 1 human protection administrator, and the IRB 2 Chairs that must be fulfilled under the FWA. 3 OHRP strongly recommends that these 4 individuals personally complete the relevant 5 OHRP assurance training modules, or 6 comparable training that includes the 7 content of these modules, prior to 8 submitting the FWA." 9 The next item, item 12, states 10 that "OHRP strongly recommends that the 11 institution and the designated IRBs 12 establish educational training and oversight 13 mechanisms appropriate to the nature and 14 volume of its research to ensure that 15 research investigators, IRB members and 16 staff, and other appropriate personnel, 17 maintain continuing knowledge of and comply 18 with the following: relevant ethical 19 principles, relevant federal regulations, 20 written IRB procedures, OHRP Guidance, other 21 applicable guidance, state and local laws, 22 and institutional policies for the 44 1 protection of human subjects." 2 The section goes on to read, 3 furthermore, "OHRP recommends that a) IRB 4 members and staff complete relevant 5 educational training before reviewing human 6 subjects research, and b) research 7 investigators' complete appropriate 8 institutional educational training before 9 conducting human subjects research." 10 Another guidance document more 11 recently put out by OHRP is a set of FAQs. 12 And FAQ 1549 from the OHRP website addresses 13 this question. Must investigators obtain 14 training in the protection of human 15 subjects? The answer is that HHS 16 regulations for the protection of subjects 17 do not require investigators to obtain 18 training in this area; however, an 19 institution holding an OHRP approved 20 federal-wide assurance is responsible for 21 ensuring that its investigators conducting 22 HHS conducted or HHS supported human 45 1 subjects research understand and act in 2 accordance with the requirements of the 3 regulations. 4 The answer to the FAQ continues. 5 "Therefore, as stated in the terms of the 6 FWA, OHRP strongly recommends that 7 institutions and their designated IRBs 8 establish training and oversight mechanisms 9 appropriate to the nature and volume of 10 their research to ensure that investigators 11 maintain continuing knowledge of and comply 12 with the following principles: relevant 13 ethical principles, relevant federal 14 regulations, written IRB procedures, OHRP 15 Guidance, other applicable guidance, state 16 and local laws, and institutional policies." 17 And finally, the FAQ concludes, 18 "Furthermore, OHRP recommends that 19 investigators complete appropriate 20 institutional educational training before 21 conducting human subjects research. In some 22 cases, other federal requirements regarding 46 1 training for investigators must be met, such 2 as the NIH requirement for the training of 3 key personnel in NIH-sponsored or -conducted 4 research. 5 Further evidence of the 6 importance of training can be taken from the 7 fact that OHRP has cited institutions for 8 failure to provide adequate training at 9 times. From the list of common findings, 10 from the OHRP compliance oversight 11 activities list, last updated on the web, at 12 least, in October of '05, and this is a nice 13 compilation of things that the compliance 14 branch of OHRP see in a recurring fashion, 15 enough to bring it to our group attention, 16 item 35 on that list is that the IRB chair 17 and members lack sufficient understanding of 18 HHS Regulations. OHRP is concerned that the 19 IRB chair and members appear to lack a 20 detailed understanding of the specific 21 requirements of the regulations for the 22 protection of human subjects. As a result, 47 1 IRB determinations have sometimes deviated 2 from these requirements. 3 One final bit of background in 4 the most text-dense slide, for which I 5 apologize, but again, it's on paper there, 6 hopefully in big enough print in your tab 7 inserts that you can follow along. And we 8 included this in its entirety because we 9 were not aware this was out there and we're 10 assuming a lot of people don't. And this 11 has been published in the Federal Register, 12 a notice and announced plan to issue an 13 advanced Notice of Proposed Rulemaking has 14 been, to my understanding, published more 15 than once, but most recently, in the 16 December 11, 2006 Federal Register under the 17 Department's Unified Agenda and the volume 18 and page number are cited there, if you want 19 to go look at it yourself. 20 But, it reads that "This Notice 21 of Proposed Rulemaking proposes to add 22 Subpart E." And I'll just note, David, then 48 1 that's off the books for you to use for your 2 decisionally impaired subpart when you write 3 it, because they've claimed that for this 4 now. But many of us have talked about 5 Subpart E for decisionally impaired in the 6 past and it's interesting to see that it's 7 proposed here for a training and education 8 subpart. 9 "To add Subpart E to the 10 Department of Health and Human Services 11 Regulations for Protection of Human 12 Subjects, 45 CFR Part 46, and would require 13 that institutions engaged in human subjects 14 research, covered by an assurance of 15 compliance filed with OHRP, ensure that 16 institutional officials, IRB chairpersons, 17 human protection administrators receive 18 appropriate training and education about the 19 institution's assurance and that IRB 20 chairpersons and members, IRB staff, 21 investigators, and other personnel involved 22 in the conduct or oversight of human 49 1 subjects research receive appropriate 2 training and education about relevant human 3 subjects protection requirements. The 4 proposed training and education requirements 5 will help to ensure that responsible 6 individuals at assured institutions 7 understand and meet their regulatory 8 responsibilities." 9 So the point being that there's 10 quite a bit out there already, sometimes 11 implicit, sometimes quite explicit in terms 12 of training requirements and the importance 13 of this training to the protection of human 14 subjects. But our committee, subcommittee, 15 as we again deliberated in a number of 16 different areas, kept coming back around to 17 the notion of training and not leaving it to 18 chance that this is looked after. And 19 having become aware that OHRP was already 20 headed in this direction with the published 21 notice, with the intent to put out an 22 advanced Notice of Proposed Rulemaking, 50 1 really wanted to take a stand and would like 2 you to take a stand with us in endorsing 3 this action and, if anything, lighting a 4 fire under this process to move this ahead. 5 And so, the next four slides 6 overlap in many ways, and with your 7 forbearance, I would suggest that I work 8 through the next four, because you will see 9 that there was a fair amount of cutting and 10 pasting going on. They're aimed at four 11 different target audiences, with slight 12 differences in the wording, but they come as 13 a set, if you will, and I would like to, and 14 with the Chair's permission, work through 15 these four and then will return and ask for 16 your deliberations on each of them 17 separately. But I think it might help if 18 you see them as an intact set, first. 19 So the first reads, "SACHRP 20 strongly recommends that OHRP require that 21 institutions provide initial and continuing 22 training for IRB members. Such training 51 1 should include relevant ethical principles, 2 such as," and I'll stress there, that's not 3 meant to be a prescriptive list, but "such 4 as the Belmont Report, Nuremberg Code, 5 Declaration of Helsinki, relevant federal 6 regulations, written IRB procedures, OHRP 7 Guidance, other applicable guidance, state 8 and local laws, and institutional policies 9 for the protection of human subjects. 10 Training should be initiated before members 11 review human subjects research and IRB 12 duties should be commensurate with the level 13 of training completed. Ongoing training 14 should occur in a manner appropriate to 15 assure the continued competence of IRB 16 members." 17 Recommendation number two in this 18 set. "SACHRP strongly recommends that OHRP 19 require that institutions provide initial 20 and continuing training for IRB staff. Such 21 training should include relevant ethical 22 principles, relevant federal regulations, 52 1 written IRB procedures, OHRP guidance, other 2 applicable guidance, state and local laws, 3 and institutional policies for the 4 protection of human subjects. IRB duties 5 should be commensurate with the level of 6 training completed. Ongoing training should 7 occur in a manner appropriate to assure the 8 continued competence of IRB staff." 9 The third. "SACHRP strongly 10 recommends that OHRP require that 11 institutions provide initial and continuing 12 training for the institutional signatory 13 official and the human protection 14 administrator as identified in the FWA; for 15 example, the human subjects administrator or 16 the human subjects contact person. Such 17 training should include relevant ethical 18 principles, federal regulations, 19 institutional policies for the protection of 20 human subjects and the terms of the 21 institutions' federal assurance. Ongoing 22 training should occur in a manner 53 1 appropriate to assure the continued 2 competence of these institutional 3 officials." 4 And finally, in an area that 5 we'll hear more about, I think, tomorrow and 6 many of us, of course, are doing already. 7 "SACHRP strongly recommends that OHRP 8 require that institutions provide initial 9 and continuing training for investigators. 10 Such training should include relevant 11 ethical principles, relevant federal 12 regulations, and institutional policies for 13 the protection of human subjects. Initial 14 training should be completed before 15 investigators are allowed to conduct 16 research that involves human subjects. 17 Ongoing training should occur in a manner 18 appropriate to assure the continued 19 competence of investigators." 20 And with that, Mr. Chairman, I 21 would return to the first of the set of four 22 and invite SACHRP questions and feedback. 54 1 CHAIR TILDEN: Okay. Thank you, 2 Dan. I think I'd like to get a sense from 3 the committee. Should we consider all of 4 these as one item or is there, would, I 5 would entertain a motion we separate the 6 individual items, or they're so closely 7 linked that you think we can discuss all 8 four of them in block? 9 So we'll consider all four of 10 them in block. And it looks like you've put 11 the changes among the four recommendations, 12 so they are obvious for us to consider. 13 So we have a motion on the floor 14 to consider these recommendations for 15 approval. Do we have a second? 16 MEMBER ROMERO: Second. 17 CHAIR TILDEN: Seconded. And so, 18 it's open for discussion. Questions? Jeff? 19 MEMBER BOTKIN: I guess two 20 questions in terms of whether we need to be 21 more explicit with some of the terms here. 22 And one would be, do we have a definition 55 1 already of who constitutes investigators, 2 who on the research team would be covered by 3 this recommendation? 4 And then, secondly, a question 5 about whether we may want to be more 6 explicit about the time period in which 7 individuals should be retrained. I think 8 we've settled in our institution as three 9 years as a reasonable time period. Would it 10 be appropriate to make a more explicit 11 recommendation in that vein? 12 MEMBER NELSON: Without 13 attempting to answer, I'll just say that I'm 14 glad to have those questions on the table. 15 And they were things we grappled with, where 16 we were trying to walk a line between 17 sending something more than just a 18 philosophical message, but stopping short of 19 being prescriptive in terms of how we phrase 20 this so that institutions were handcuffed in 21 terms of the kinds training and tailoring 22 the training to the types of research, et 56 1 cetera. 2 In terms of the, I assume your 3 first question, Jeff, really applies to this 4 fourth item and investigators. And that, 5 too, as I think most of you know, the NIH 6 regulations were aimed at key personnel, the 7 NIH policy for training in this area. And 8 many institutions, at least ours, but most 9 that I know of have extended that beyond the 10 more rigid limited definition of key 11 personnel listed in grants to people on the 12 research team who are involved with the 13 research. If you have a study coordinator 14 who may be getting consent from subjects, 15 even if they're not listed on the grant, we 16 expect to see those people trained. And I 17 think that's become almost a conventional 18 wisdom out there. A common practice if you 19 will. And so, I think we'd be very open to 20 SACHRP's input on how broadly to define 21 this. 22 MEMBER LEIDEN: At our 57 1 institution, faculty want to make that 2 decision. I don't know if that means 3 anything but PIs would like to be able to 4 make the decision about how far down the 5 ladder to go in terms of deciding who needs 6 to be trained, in terms of who is touching 7 the data, who is collecting, who is 8 interacting with participants. 9 So what we've done is to make a 10 broad general statement about how we define 11 key personnel and leave that up to the 12 investigator. The three year period, I 13 think is reasonable. And I think it would 14 be useful to campuses and institutions 15 around the country for us to state the three 16 year period. 17 CHAIR TILDEN: Mike, you had a 18 comment? No? Okay. 19 MEMBER MARSHALL: I do. One of 20 my concerns about having investigators, 21 faculty and academic institutions make the 22 decision about how far down to go, who 58 1 should be trained, is that often it may not 2 be the investigators themselves, whether 3 they're doing medical or social or 4 behavioral science research. It may not be 5 the investigators who are doing things like 6 obtaining consent from individuals. And I 7 know that it's, I think that it's important 8 to have research assistants who are going to 9 be actively involved in data collection 10 trained in some way. 11 CHAIR TILDEN: Okay. David? 12 MEMBER STRAUSS: My hope would be 13 that we leave a lot of latitude, a lot of 14 discretion to the institutions. That 15 institutions and their human subjects 16 programs are of enormously varying size and 17 shape. And I think that if we're go 18 proscriptive in terms of both the content or 19 the timing of training or who requires 20 training, then I think we really err on the 21 side of adding a lot of regulatory burden. 22 I think what we want to 59 1 accomplish here, and I think what these 2 proposals do accomplish, is just sending the 3 message that we think that education and 4 training is a critical part of conducting 5 human subjects research activities and human 6 subjects research oversight. 7 You know, I can already imagine 8 the kind of questions that will emerge about 9 how OHRP is going to monitor in compliance 10 with these rules and what kind of 11 documentation is required. And you know, 12 even with the NIH rules, we see a lot of lip 13 service and sometimes only that to 14 compliance with the regulations. And 15 whether a 30 minute online course actually 16 provides adequate training or not is 17 something that, frankly, is an empirical 18 question that hasn't been asked. 19 So, I think that maybe until we 20 have clear evidence on how best to train 21 people, until a local institution can decide 22 what works best, given the nature of the 60 1 research that they do and the research that 2 they oversee, it might be best to simply 3 send a message that research, I'm sorry, 4 education and training is important, but not 5 dictate the terms of that. 6 CHAIR TILDEN: Yes, I would like 7 to see if any ex officios have any comments. 8 Neil do you have a comment? 9 MEMBER POWE: Yes, I would echo 10 what David said. I was thinking the same 11 thing that, do we have any evidence that the 12 system is broken in allowing institutions to 13 be specific as they need be on these items. 14 I don't know that while three years, I 15 think, is a reasonable time frame, I'm not 16 sure that there's any evidence about the 17 decay in skills or that there's enough 18 changes within a three period to warrant 19 that. Some institutions might want to do it 20 yearly. Some institutions might want two, 21 three, five years. But I would like, I 22 really would like to see are 61 1 recommendations, evidence-based, if we're 2 going to go to that degree of specificity. 3 CHAIR TILDEN: Yes, for example, 4 our institution does it annually. There's 5 an annual requirement. So as soon as a 6 three year or a five year recommendation 7 comes out, I know exactly what our 8 continuing education requirements are going 9 to be. So it has some proscriptive effect, 10 once you put a number out there of what's 11 present or not. 12 Mike, you had a comment, Mike? 13 Okay. We have a couple of ex officios, I 14 believe, that had a comment. Jeff Rodamar? 15 MR. RODAMAR: Good morning. I'm 16 Jeff Rodamar, Department of Education. 17 CHAIR TILDEN: Microphone, 18 please. 19 UNIDENTIFIED SPEAKER: It's on. 20 (Speaking from un miked location.) 21 MR. RODAMAR: I'm Jeff Rodamar 22 MEMBER NELSON: Sam, if I could - 62 1 - boy, that's now loud. If I could just 2 respond to the last comments, which are well 3 taken. And we probably do need to allow for 4 the fact that institutions may not always be 5 providing but should be ensuring. And I 6 think we can take that as a friendly 7 amendment and maybe even edit it on the 8 screen here. 9 On the first point, I guess, just 10 to be clear, the city, the collaborative IRB 11 training initiative is not an institution, 12 per se, but a training vehicle that many 13 institutions avail themselves of. So while 14 that may not be the most relevant example, 15 where I thought you were going with this was 16 acknowledging that sometimes investigators 17 aren't at institutions, per se, and yet we 18 would want to see them trained prior to the 19 conduct of human subjects research. So 20 whether they're loosely knit networks across 21 an SMO or whatever setting they might be in, 22 if they don't see themselves in an 63 1 institution, we would still want to supply 2 them. 3 I think the latter point, too, we 4 could certainly consider including a 5 reference to relevant professional standards 6 or association standards. 7 CHAIR TILDEN: Okay. We had 8 Sally Flanzer. 9 MS. FLANZER: Hi, I'm Sally 10 Flanzer. I'm with the Agency for Healthcare 11 Research and Quality. 12 While I'm generally in favor of 13 investigators doing as much as they can on 14 their own, we find it's difficult to leave 15 some decisions to investigators, but require 16 others, require that they go to the human 17 protections administrators for others. And 18 regarding how deep to go in their training 19 team, I really do not want to leave that to 20 them. I want them to check. Send me a 21 roster of their training team and let me 22 work with them to select who needs training. 64 1 They tend to underestimate. We 2 tend to differ on how important we think 3 training might be to people who seem to an 4 investigator doing a rather low level job. 5 Very often, those are the people who have 6 the most contact with the raw data or with 7 the subjects themselves. So I would 8 encourage, I would not encourage leaving 9 that to the investigator. 10 And I would also echo the 11 comments of not being too proscriptive about 12 how many years. Our young investigators 13 turn over quite often. And if we put a 14 three year requirement in, we would miss 15 some people all together. 16 So, it might be that the 17 institution needs to actually look at their 18 turnover rates for their investigators and 19 empirically select what their retraining 20 period is. And the Guidance could suggest 21 something like that. 22 CHAIR TILDEN: Okay. Any other 65 1 discussion? Jeff? 2 MEMBER BOTKIN: Yes, a couple 3 thoughts. I guess I would be attracted then 4 to potentially, including additional 5 language on this investigator 6 recommendation, that perhaps more attracted 7 to the general concept that we need to be 8 flexible here. But the use of an 9 investigator, per se, I think, tends to 10 suggest PI and sort of faculty level 11 investigators when we really want that to 12 mean all the staff who are going to be in 13 key decision-making roles within the 14 research enterprise. 15 And so, I would recommend that we 16 think about expanding that language perhaps 17 to say that, investigators and all 18 individuals who have responsibility for the 19 conduct of the research, or something to 20 that effect, so that that point is made. 21 The second question is whether 22 OHRP is in a position to potentially endorse 66 1 an educational program. There's a number of 2 good ones out there like the Miami CITI. Is 3 there a way to either officially or 4 unofficially say that this is the type of 5 content that's acceptable from OHRP's 6 standpoint in this regard? 7 And then one final point. I 8 think our institution has struggled with the 9 ongoing education piece. We have a retreat. 10 Folks are trained who are new members of the 11 IRB. Older members get updated on an annual 12 basis. We struggle to try to incorporate 13 updates in the course of individual panel 14 meetings. Sometimes that gets crowded out. 15 But particularly with the work of SACHRP, 16 for example, there's always new things 17 coming onboard and so, since this is a 18 mechanism by which we're encouraging 19 institutions to pick up responsibilities 20 without necessarily requiring it, might we 21 want to include language to say that 22 mechanism should exist to keep IRB members 67 1 abreast of continuing changes in the 2 regulations and literature relevant to the 3 protection of human subjects. Something 4 along those lines. 5 CHAIR TILDEN: Okay. Bern, you 6 want to comment? 7 MEMBER SCHWETZ: Yes, this has 8 been a good discussion. But I'll say more 9 than that, Jeff. 10 We're not in a position to 11 endorse any one program, whether it's for a 12 computerized base of managing IRB data, or 13 whether its training or what it is. We are 14 best, and I think the community is best 15 served if we endorse a concept as opposed to 16 an organization. For all we know, our 17 guidance might outlast whatever system we 18 might name if we did. And we don't want to 19 be caught in that position of interfering 20 with private business or competition or 21 anything else. 22 So, we would endorse the concept 68 1 but not a specific training program, or 2 whatever else it might be. 3 Another question that hasn't been 4 asked is what is the floor that 5 accreditation creates, as an expectation, 6 relative to what you might have in mind as 7 recommendations for training? 8 CHAIR TILDEN: Does anyone want 9 to opine on what the accreditation might 10 require? 11 I could, I'd like to just throw 12 in a couple of cents here. Number one is, I 13 see these four recommendations as sort of 14 being sort of fringe benefits. You have a 15 situation where you have obligations in the 16 assurance process to do things in a certain 17 way. And it appears to me that these 18 recommendations are saying, rather than 19 encouraging, there should be some 20 requirement that institutions, if they're 21 going to make this commitment, provide the 22 infrastructure for their investigators, for 69 1 their IRB members, for the IRB staff, and 2 for their IOs, okay, to achieve those goals. 3 And of course, if you may be in a position 4 where you could be knowledgeable and don't 5 need necessarily to take a test or go to a 6 training session every year or every two 7 years, three years, but you might be able to 8 demonstrate your competence in some way. 9 Really, that would be something 10 for the institutions to deal with because 11 it's the outcome, okay, that one wants to 12 achieve, not necessarily to provide, to 13 create training, but not and we may not know 14 what the outcome is. So the expectation is 15 that you're going to achieve these outcomes. 16 How do you get there? And these, our 17 recommendations, seem to say hey, if you're 18 making these obligations, you also have the 19 obligation to get these individuals to these 20 outcomes in some way. And training is 21 having the availability of training at the 22 minimum for all these individuals to avail 70 1 themselves for isn't necessary. 2 That's one take, as I look at 3 this, which is here. And I don't think that 4 anything that's been said, you know, really, 5 its refinement of what the recommendations 6 are, rather than or additional things, but 7 none of them really negate the central piece 8 of these recommendations, is that that 9 institution's responsible for providing such 10 a mechanism for these individuals. So, but 11 anyway, I, that's sort of one take on it. 12 And clearly, in my world, some of 13 the things that I see is the whole key 14 personnel issue and the NIH aspect of 15 things, if somebody from NIH ought to 16 appreciate a comment, you know, that they're 17 backing off. You know, what's key 18 personnel? Well, you know, key personnel is 19 the principle investigator listed on the 20 notice of grant award is the last thing I've 21 seen. And if you're not listed on that 22 notice, you're no longer key personnel. But 71 1 in terms of human subject research, we have 2 many, many individuals what are involved in 3 that research enterprise that are key, you 4 know, with research coordinators, etcetera, 5 that would not maybe meet the definition of 6 key personnel if we adopted a stringent 7 definition. 8 So, any comments on that? If 9 not, I think we need to move to get some 10 motions. 11 MEMBER NELSON: Sam, I've just 12 taken a stab at addressing some of the 13 comments that we've heard thus far. 14 Switching to provide to institutions 15 ensuring and then to address Jeff's 16 broadening, proposal to broaden the 17 definition of investigator, investigators 18 and other members of the research team with 19 responsibility for conducting human subjects 20 research. And that stays away from the 21 notion of key, I think, but gets at the 22 heart of the matter. And then an addition 72 1 of a reference to professional standards. 2 CHAIR TILDEN: Okay, so you would 3 like to amend the proposed recommendations 4 to reflect this? 5 MEMBER NELSON: If you will. 6 CHAIR TILDEN: Okay. 7 MEMBER NELSON: We would be 8 willing to amend this, -- 9 CHAIR TILDEN: You would. Okay. 10 MEMBER NELSON: -- if that's your 11 wishes. 12 CHAIR TILDEN: Okay. Any other 13 discussion or comment? 14 MEMBER MARSHALL: One final 15 comment. I'm thinking about international 16 research, the importance of international 17 research. And I wonder if in the 18 parenthesis where you refer to Belmont, 19 Nuremberg, and Helsinki, if you might also 20 want to put CIOMs there, just to 21 philosophically expand beyond the Western 22 world. 73 1 MEMBER NELSON: Let me provide a, 2 not to argue against that suggestion, but 3 just to give the other side of the debate 4 that we had internally at a subcommittee, 5 there were some of our group that were 6 concerned that we were already listing too 7 many things. Because, for example, the 8 Declaration of Helsinki isn't necessarily 9 adopted by well, the U.S. or by U.S. 10 institutions down to every letter. 11 MEMBER MARSHALL: Right. 12 MEMBER NELSON: Nuremberg Code, 13 we, in some studies, violate every day, if 14 you read it finely enough, beyond the sound 15 principles that still exist six years later. 16 So there was some sentiment to maybe 17 collapsing it down to "such as the Belmont 18 Report" period was all we should be doing in 19 that regard. But SACHRP is who has to 20 approve this, so we'd certainly be open to 21 your suggestions and further debate on 22 either collapsing or expanding that 74 1 parenthetical list. 2 DR. KIRCHNER: Peter Kirchner 3 from DOE. I strongly favor the 4 recommendation made to put the word ensure 5 for what the institution needs to do. And I 6 also agree, Dr. Strauss, that we should not 7 be too proscriptive. 8 And with respect to the timing of 9 retraining, I think it may be more important 10 to emphasize the need that the institution 11 ensures that the training keeps people 12 current with the current guidelines. And 13 I'm wondering if some thought might be given 14 to that, rather than a frequency that's 15 defined in years because sometimes the 16 important changes are made, such as the ones 17 that Subpart A is working on or Subpart E, 18 and the currency is more important, perhaps, 19 than the training every three years or two 20 years, which may be not appropriate. 21 CHAIR TILDEN: Thank you. Lisa, 22 you want to make a comment? 75 1 MEMBER LEIDEN: I just wanted to 2 say that AAHRPP absolutely has adopted, and 3 correct me if I'm wrong, but having gone 4 through accreditation, the attitude and the 5 practice of looking for education towards 6 these different groups in their different 7 elements, in their 77 elements or however 8 many, and it's both initial and continuing, 9 they do leave off the actual material, the 10 year identification of the material. So 11 they allow you to make the proscriptive 12 choices yourself, but they do ask you to 13 detail that in accreditation and they look 14 for that. So, it matches this. 15 CHAIR TILDEN: Mike? 16 MEMBER GENEL: I have been 17 struggling with whether or not there's any 18 value in enumerating the Belmont Report, the 19 Nuremberg Code, and so forth. Why do that 20 at all? Why not just simply say, such 21 training should include relevant ethical 22 principles relating to research in human 76 1 subjects or something of that sort and not 2 specify anything? Because what I'm 3 concerned is that when you compile a list, 4 then you limit the instruction or the 5 training to that specific list and I don't 6 think that's the intent at all. So you're 7 trying to give examples, but I think that 8 has the, I think that could be defined too 9 restrictive. I would remove it because I 10 don't think it helps. 11 CHAIR TILDEN: Would something, 12 some wording like include relevant ethical 13 principles related to the research conducted 14 at the institution? And so that would then, 15 if an institution is conducting something, 16 international research, then they certainly 17 would want to have available resources for 18 people to, for investigators and IRB 19 members, etcetera, to understand the 20 Declaration of Helsinki and the CIOMS 21 principles, etcetera. 22 On the other hand, if it's an IRB 77 1 that's conducting primarily local research 2 review, they may not need that. They may 3 need to, you know, maybe the Belmont 4 principles are the thing they need to know 5 and understand. 6 I'm just saying that in terms of 7 moving this, you know, another step. And 8 then maybe we can get the flavor of the 9 committee in terms of Mike's -- is that, 10 would anyone want to second Mike's 11 suggestion that we just drop the examples? 12 I know that was a lot of discussion in the 13 committee so it wasn't contentious 14 necessarily, but it was certainly 15 deliberated, I'm sure. 16 MEMBER NELSON: No. In fact, I'd 17 say it was a, this was a, where we ended up 18 was a relatively -- 19 CHAIR TILDEN: Compromise? 20 MEMBER NELSON: -- evenly split 21 consensus, if you will, or a compromise. We 22 were very cognizant of the dangers, the 78 1 downside of starting to list. And as I 2 said, there was some sentiment that just 3 listing the Belmont Report. We thought the 4 words "such as" were very operational here 5 and we're hoping to signal that this was not 6 meant to be an exclusive or all inclusive 7 list, but there's a danger in listing 8 anything. 9 MEMBER MARSHALL: My reaction to 10 the list was exactly the same one that you 11 had concerning the way in which individuals 12 respond to a directive, or a guideline, or a 13 recommendation. When they see something 14 "such as" and then a list in parenthesis, I 15 think too often, we're likely to think, oh, 16 this is what we have to do. And so I 17 thought, ah, well, we need something with 18 more guidance such as CIOMS for 19 international research. 20 I'd be very comfortable to take 21 to remove the list entirely. But Sam, I'm 22 not sure that I would use the language that 79 1 you just suggested. This is a paraphrase. 2 You said something like, looking at ethical 3 principles, guidelines that are relevant for 4 research being conducted at your 5 institution. I want to back off from that 6 because I think that there are ethical 7 principles that are foundational for 8 protecting human participants in research, 9 whether it's international, local, however 10 it's defined. 11 CHAIR TILDEN: Okay. 12 MEMBER NELSON: Sam, if I could 13 make a proposal, I guess, with two points in 14 mind? One is that we're hoping, given the 15 umbrella that's over all of these 16 recommendations, we're talking about human 17 subjects research, so I would hope that when 18 we say relevant federal regulations, 19 relevant professional standards, relevant 20 ethical principles, we're talking that those 21 are relevant to human subjects research that 22 hopefully is implicit in everything we're 80 1 proposing. So, there may not be anything 2 needed there. 3 Secondly, I guess, is back to the 4 original point and you're just reiterated 5 it. We're really, we're, there is a clear 6 strong statement already out there in the 7 Federal Register and elsewhere from OHRP 8 that this is important, this is a direction 9 they're heading so there may be a point of 10 diminishing returns for us, crafting our 11 words too finely, because there is, we 12 really want to endorse a process that's 13 already underway. We want to be careful 14 with our words, but one word plus or minus 15 in this probably isn't going to change the 16 train that's already moving. We'd like to 17 just help it down the tracks, if you will. 18 There's another mangled metaphor. 19 CHAIR TILDEN: Now we have Mike 20 and Jeff. 21 MEMBER GENEL: Well, it's a 22 little redundant in this one with the 81 1 changes we've made but I think that we have 2 to say relevant ethical principles relating 3 research in human subjects. I mean, I think 4 that's, I think we have to be at least, at 5 least define it a little bit more because 6 that's what we're dealing with. You could 7 expand ethical principles to cover a whole 8 host of sins, -- 9 MEMBER NELSON: Maybe one way -- 10 MEMBER GENEL: -- omissions and 11 commissions. 12 MEMBER NELSON: Maybe one way to 13 address this would in the opening sentence 14 to elaborate that we're talking about 15 training in human subjects protections and 16 then everything that follows supports that. 17 MEMBER GENEL: You mean in terms 18 of the template for all three or four? 19 MEMBER NELSON: Yes, perhaps. 20 Certainly, for this one. 21 MEMBER GENEL: I'm looking at 22 this as a template that we would then take 82 1 back to the other recommendations. 2 MEMBER NELSON: Yes, I think the 3 questions that Jeff raised about how do we 4 define investigators don't necessarily 5 extend to IRB members or IRB staff. I think 6 that's more self-contained. But here it's 7 needed but I think these other, you know, 8 ensure versus provide, well, we probably 9 need to go back and see if these actually 10 apply to the others. I guess it could be 11 argued that if you have an IRB at an 12 institution, then the institution is the one 13 providing that, whereas, investigators are 14 in a somewhat, are at times in a different 15 relationship with the institution than IRB 16 staff, who are part and parcel of the 17 institution. But we should be looking to 18 see how these changes apply to the other 19 recommendations. 20 MEMBER GENEL: Then maybe we need 21 to go back and look at each one 22 individually. 83 1 CHAIR TILDEN: Right. There's a 2 sentence "such training should include 3 relevant ethical principles, relevant 4 federal regulations, professional standards, 5 and institutional policies for the 6 protection of human subjects." Is that 7 sentence in each recommendation? 8 MEMBER NELSON: Yes, it should 9 be. 10 CHAIR TILDEN: Neil? 11 MEMBER POWE: I just, I had a 12 thought about how to clean up the language. 13 If that sentence said "such training should 14 include ethical principles, federal 15 regulations, professional standards, and 16 institutional policies relevant to the 17 protection of human subjects," it then might 18 -- 19 CHAIR TILDEN: That's exactly 20 what I was thinking, so I second that 21 change. 22 Okay, Jeff, you had something? 84 1 Or if not, Lisa. 2 MEMBER BOTKIN: No, I agree with 3 the general proposal that Mike made to 4 remove the specific list but I think that 5 one thing that is then lost is the sense of 6 history. And I don't think it's possible to 7 understand research ethics without some of 8 the historical context. So I would suggest 9 that we add history in prior to ethical 10 principles or right after ethical principles 11 to -- 12 MEMBER NELSON: Oh, you mean the 13 word history and not a historical benchmark 14 like the Belmont? 15 MEMBER BOTKIN: That's right. 16 MEMBER NELSON: You're talking 17 about the word history. 18 MEMBER BOTKIN: Yes, why was the 19 Nuremberg Code developed. 20 MEMBER NELSON: You're asking for 21 trouble having me do this typing. 22 MEMBER LEIDEN: I would ask that 85 1 you make sure that each of these statements 2 has state law in it. Because some do and 3 some don't. Does that make sense? 4 MEMBER STRAUSS: Sam, I have just 5 a question about process, just to follow up 6 on the point that Dan made earlier. And 7 that is, you know, we learned that there's 8 going to be a Notice of Proposed Rulemaking 9 on this issue. And I wonder how important 10 is it for us to so finely tune a document 11 and whether this committee could or should 12 merely say, we support this principle. That 13 we'd like a statement to come from SACHRP 14 supporting investigator, institutional 15 official, IRB member, training in key legal, 16 ethical, and regulatory aspects of human 17 subjects protections, period. And leave it 18 to you, or whomever else is involved, you 19 know, craft that letter. That we approve a 20 principle, rather than a document, in this 21 instance. 22 I'm just, I'm raising that for 86 1 discussion because I'm new to the process 2 but I worry about having, you know, a room 3 full of people trying to write a document 4 together. 5 CHAIR TILDEN: My thought is that 6 we would like to get this, these 7 recommendations approved and forwarded. And 8 that in the process of deliberation within 9 the committee, if we have to make some 10 changes for the committee to feel 11 comfortable for this to go forward, because 12 it will be published, and I believe we'd 13 want to capture the true sense of what the 14 committee will approve, that changes would 15 be appropriate. The fact that there's a 16 Notice of Proposed Rulemaking, I think that 17 what we say is important because, my 18 understanding and there other people here 19 who know regulatory matters much better than 20 I, but I would think a Notice of Proposed 21 Rulemaking is really a request to get 22 information to generate a rule. So what we 87 1 say now could maybe have more impact in 2 generating a proposed rule than, for 3 instance, once a proposed rule has been 4 published. But maybe, so that, I think, 5 what we say is important and needs to be, 6 and fully reflect the committee's duties. 7 Maybe I'm a little off base on that, but 8 that's my sense of it. 9 So, I think what I'd like to do 10 is have a motion to approve the changes that 11 have been made in the recommendations, okay, 12 the wording of these recommendations and 13 second, and see if we can agree on that. 14 And then take a motion to approve them 15 following that. 16 So would anyone move to -- read 17 it carefully. 18 MEMBER NELSON: Yes, just so I 19 didn't slip anything in when you're back was 20 turned. 21 CHAIR TILDEN: Right. 22 MEMBER NELSON: I've added state 88 1 and local laws as well, which are in, I 2 think, in the other ones. You will see, 3 obviously, or have seen, that there was some 4 cutting pasting going on as we moved from 5 one of these recommendations to the other, 6 but then with some tailoring to the target 7 audience. So, we, some errors or omission, 8 Mike. 9 MEMBER MARSHALL: If the language 10 is as important as you say, I wonder if we 11 could just wordsmith it just a tiny bit. 12 Where you refer to history, thank you very 13 much for that, for recognizing the 14 importance, Jeff, of the historical 15 foundation. So, what I'm thinking is, you 16 might say such training should include the 17 ethical principles and their historical 18 foundation. Or help me out here. It 19 doesn't read right -- 20 MEMBER BOTKIN: That's good. -- 21 MEMBER MARSHALL: --the way it 22 is. Sorry for tweaking it that way, but if 89 1 this is -- 2 CHAIR TILDEN: Yes. 3 MEMBER MARSHALL: Yes, but you 4 have got to get rid of the first history 5 there. Thanks, Dan. 6 CHAIR TILDEN: And I think we'd 7 want to just put some commas in there, 8 instead of semicolons. 9 MEMBER MARSHALL: I know. Sorry 10 for the -- 11 CHAIR TILDEN: If you want to get 12 down to the nitty-gritty, Dan. 13 MEMBER MARSHALL: And also, 14 David, I'm really glad that you asked the 15 question about process. Because I am new 16 here, it's not clear to me how detailed to 17 get in the wordsmithing. 18 CHAIR TILDEN: I think what the 19 Agency does with our recommendations, is 20 what the Agency does. So I think what we 21 need to do is make sure that we feel 22 comfortable that the recommendations reflect 90 1 the sense of the committee. And they're not 2 bound by our recommendations, but it 3 certainly would be helpful if they were 4 articulated to reflect our attitude and 5 conclusions. 6 Okay, Jeff? 7 MEMBER BOTKIN: And I'm assuming 8 we're making all of these changes, except 9 for the investigator language to all of the 10 four separate recommendations? 11 CHAIR TILDEN: Yes. 12 MEMBER BOTKIN: I guess that one 13 thought that we could perhaps combine all 14 these, but I see the text is different 15 enough and appropriately so, that you 16 probably really need four of them, rather 17 than one. 18 MEMBER NELSON: That's where I 19 was going originally, when the subcommittee 20 started drafting these, was just in all a 21 single broad recommendation, but then there 22 was a -- you know, for example, I don't know 91 1 that professional standards necessarily 2 applies to IRB staff in the same way that it 3 applies to investigators who belong to 4 professional associations, or maybe it does, 5 or IRB members, institutional officials. 6 And so there were enough. We haven't, for 7 example, referenced the terms of the 8 assurance in all of these, like we did in 9 the institutional official recommendation. 10 So, there are some slight variants. 11 CHAIR TILDEN: I think, at this 12 point, is it fair that we can consider a 13 motion to vote on these recommendations? 14 MEMBER ROMERO: I make a motion. 15 CHAIR TILDEN: Okay, we have a 16 motion. Second? 17 MEMBER MARSHALL: I second it. 18 CHAIR TILDEN: Okay. So, all in 19 favor? Aye. 20 (Show of hands.) 21 CHAIR TILDEN: Any nays or 22 abstentions? 92 1 (No response.) 2 CHAIR TILDEN: Okay, so the 3 recommendations, all four recommendations 4 are approved. 5 Okay. 6 MEMBER NELSON: So, since I 7 haven't been editing the other three, we're 8 switching "provide" to "ensure" for all 9 three and putting in commas for semicolons. 10 Can we extend that to all? 11 CHAIR TILDEN: In that one 12 sentence, in all four recommendations and 13 commas and semicolons, correct. 14 MEMBER NELSON: Okay. 15 CHAIR TILDEN: Well, that's 16 great. Peter. 17 DR. KIRCHNER: Question. Since 18 these recommendations are for institutional 19 obligations and the institution has to 20 ensure educational processes, I'd like to 21 ask a question which may see a little far 22 afield, but within the DOE, some 93 1 institutions are using IRBs at other 2 institutions or IRBs that are not their own. 3 Is it fair to ask what responsibility the 4 institution itself would have regarding 5 ensuring the educational processes at an 6 other IRB that is used that is not within 7 the institution? Is that relevant to our 8 discussion in any way? 9 CHAIR TILDEN: I think it is a 10 very good question and I have some thoughts 11 on it. But does anybody from the committee 12 want to respond to this? Do you have 13 another, a corollary here? 14 DR. KIRCHNER: Well, I saw a 15 particular example when I visited one of our 16 institutions that was using an IRB from an 17 educational institution that was not 18 accustom to doing human research. And my 19 review of it implied that that was really 20 not an IRB that had the adequate background 21 and training. 22 CHAIR TILDEN: Well, I think that 94 1 these recommendations really are very 2 helpful in that regard because, as you know, 3 if one wants to delegate responsibilities or 4 contract responsibilities with an IRB, 5 etcetera, then I think these are important 6 questions that one would want to ask. Why 7 would you want to have, other than maybe, 8 unless somebody cuts you a good price, or 9 whatever, have an IRB, you know, provide 10 substandard, or I hate to use the word 11 substandard, but in some way, not adequate, 12 inadequate review for research that you're 13 conducting. You're responsible for it and I 14 think these types of recommendations would 15 really support the idea that if you're an 16 institution and you have an IRB of record, 17 or you're using an IRB, you want to get 18 those assurances for yourself that they have 19 mechanisms to assure that their members have 20 adequate knowledge and skills to perform the 21 job for you. So, I don't see these 22 recommendations as being counter to that. 95 1 In fact, I think they're more proactive for, 2 that there is an expectation that 3 institutions would engage this type of 4 process and ensure that. 5 That's just one, that's just my 6 sense. 7 DR. GYI: Sam? 8 CHAIR TILDEN: Yes, sir. 9 DR. GYI: That question actually 10 extends beyond just the common rule of 11 participants. One of the things that we've 12 wrestled with is the lack of harmonization 13 between FDA and the other common rule, if 14 you will, participants. And so when we talk 15 about education, you know, we still have to 16 tread fairly lightly regarding how sponsors 17 in the other sectors address this type of a 18 topic. 19 We are hopeful that through, over 20 time, through things like accreditation, 21 that we'll require as a baseline, certain 22 activities, education will become a part of 96 1 this. And tomorrow you will have a chance 2 to hear about what some of the other 3 initiatives are. 4 But at this particular point, the 5 Subpart A Subcommittee's charge was not to 6 go beyond the particular role of what we 7 were charged with, making a recommendation 8 to the Secretary with respect to how OHRP 9 ought to behave. 10 I would like to make a plea again 11 that we, this committee not lose sight of 12 the fact that we ought to be looking for 13 harmonization at every initiative that you 14 look at, so that we ask FDA to be a 15 participant, an active participant in some 16 of these issues. 17 CHAIR TILDEN: I'm glad you 18 brought that up, Felix, because I, that did 19 cross my mind, is that these recommendations 20 go to OHRP, but FDA regulations are 21 important as well. And maybe if the 22 subcommittee, if you would like to come back 97 1 sometime, I don't want you to tie up, you 2 know, a tremendous amount of time, but maybe 3 there is need for harmonization as well with 4 FDA here. And if they want to add that to 5 the recommendations or whatever, I think we 6 could consider that. 7 Mike? 8 MEMBER GENEL: Reflecting on the 9 previous comment, can you go back to the one 10 on training for IRB members? 11 What I'm wondering about is 12 whether or not substituting the word 13 "require." The term we used was "provide." 14 Is that -- 15 CHAIR TILDEN: "Ensure." 16 MEMBER GENEL: "Ensure?" 17 CHAIR TILDEN: Uh-huh. 18 MEMBER GENEL: I'm wondering if, 19 in this sense, it would be better to change 20 that to the, from the active to the passive 21 sense, so that it would read that 22 "recommends that institutions ensure that 98 1 initial and continuing training is provided 2 for IRB members." I think that might be a 3 little bit more inclusive for the situations 4 in which the IRB may not actually be at the 5 institution, if one would want to make this 6 part of the institutional assurance. In 7 other words, so that, that is, I think, a 8 little broader and would encompass that. 9 MEMBER NELSON: I must admit when 10 Jeff made that proposed wording, those are 11 the missing words that I read into that 12 anyway. So, if that's the committee's 13 wishes, no argument. 14 MEMBER GENEL: Well then, and 15 that would change, and I think that passive 16 sense would be, perhaps, also applicable for 17 the second one in terms of IRB staff. In 18 fact, even more so because the IRB staff may 19 not be at the institution. 20 CHAIR TILDEN: Would you like to 21 make that as a motion? 22 MEMBER GENEL: Yes, I would. 99 1 CHAIR TILDEN: Any seconds? 2 MEMBER BOTKIN: Second. 3 CHAIR TILDEN: It was seconded by 4 Jeff. Any other discussion? 5 UNIDENTIFIED SPEAKER: I thought 6 we had already agreed to it. 7 CHAIR TILDEN: We're voting to 8 amend the approved recommendations. 9 And we'd like to apply this to 10 two recommendations, to the recommendations 11 for IRB members and for IRB staff. 12 MEMBER GENEL: Yes, but not to 13 the institutional officials. 14 CHAIR TILDEN: Or investigators. 15 MEMBER GENEL: That would be the 16 more, that would remain the active. 17 CHAIR TILDEN: Okay. So, we have 18 a motion, seconded, discussed. And so we'll 19 take vote. All in favor? 20 (Show of hands. Seven in favor.) 21 CHAIR TILDEN: Okay. Any nays or 22 abstentions? 100 1 Okay, that's a nay or an 2 abstention? 3 DR. STRAUSS: It's an abstention. 4 CHAIR TILDEN: Okay. Any others? 5 One abstention. Approved with one 6 abstention. 7 Jeff. 8 MEMBER BOTKIN: Can we go back to 9 the investigator one? I want to make sure 10 that we've captured that there, too and the 11 circumstance where the investigators aren't 12 at the same institution as the IRB. 13 Okay, so this places the 14 responsibility on the home institution of 15 the investigator as opposed to the IRB's 16 responsibility to make sure that 17 investigators that they are overseeing have 18 been trained. 19 MEMBER NELSON: One point we did 20 want to stay away from was the implication 21 that the IRB was the body, the entity that 22 necessarily needed to provide this training. 101 1 Sometimes that is, sometimes it isn't. But 2 we didn't want to back ourselves into a 3 corner with wording that implied that. 4 MEMBER BOTKIN: Well, let me 5 continue with that for a second then. What, 6 how about that circumstance in which the IRB 7 is responsible for an institution, but that 8 institution has not provided any training? 9 Does the IRB need to, does the IRB have 10 responsibility to ensure that that training 11 occurs to their satisfaction or can they 12 simply say that's the institution's 13 responsibility to train their own 14 investigators? 15 MEMBER STRAUSS: Can I clarify? 16 If our point is to require institutions to 17 do things or is our point here to see that 18 IRB, institutional officials, and 19 investigators are trained? In other words, 20 in that passive sense? Because we just 21 trained the word of the last one to require 22 institutions to provide something. And 102 1 again, I'm not sure if what we're trying to 2 do here is direct institutions to carry out 3 certain behaviors or if our purpose here is 4 to ensure that the relevant parties are 5 appropriately educated. 6 CHAIR TILDEN: Mike. 7 MEMBER GENEL: Well, I think it's 8 the latter. I think it's to ensure that 9 they are educated. But in the one case 10 where we're talking about institutional 11 officials, there I would say the institution 12 has, clearly has, the responsibility. 13 In the others, in terms of IRB 14 members, in terms of investigators, in terms 15 of IRB staff, I think it is our, I think 16 what we're aiming for is to ensure that the 17 process occurs. So, maybe in that sense, it 18 is, maybe the passive is even better here as 19 well. I hadn't thought of it. 20 DR. GYI: Jeffrey, you know the 21 point that perhaps this group might keep in 22 mind is that OHRP's responsibility and 103 1 jurisdiction is not over individuals, but 2 rather over the institution. And so as we 3 look at how we craft this language, we have 4 to remember that, you know, we don't have 5 the ability to simply say, you, the 6 individual, are responsible for getting 7 training, ensuring that it's done. It has 8 to be through the institutional process. 9 The point that you've gravitated 10 towards is what happens when there is a 11 separation between the traditional 12 institutional umbrella relationship where 13 there are multiple relationships like 14 independent IRBs or collaborative 15 relationships with other groups. I would 16 submit to you that the way we've at least 17 crafted this allows us for that flexibility 18 still to exist where at institution, the 19 word institution still resides as the 20 responsible entity that has to be linked 21 with OHRP. So, if it's an independent IRB 22 that is involved in a relationship with an 104 1 investigator at an institution, the IRB is 2 under the institutional umbrella for IRB 3 related activities to borrow from the 4 accreditation program. Accreditation looks 5 at how those relationships exists and holds 6 those individual entities responsible for 7 assuring that the standards are met or the 8 training has occurred. 9 So I think that we still have 10 that flexibility inherent to what we have 11 crafted here, with the understanding that 12 OHRP's responsibility and jurisdiction is 13 not over individuals. 14 CHAIR TILDEN: Thank you, Felix. 15 I think that is a good point. Indeed, even 16 IRBs, independent IRBs or IRBs separated 17 from the institution, they might even hold 18 their own federal-wide assurance and be 19 considered an institution of sorts anyway. 20 And that means that they have, they would, 21 under these recommendations, they would have 22 a responsibility to make sure their IRB 105 1 members and staff are trained and 2 knowledgeable. So, you'd probably have a 3 double review, one from an institution is 4 sourcing this work to the IRB and also a 5 direct obligation under these 6 recommendations, if they hold a federal-wide 7 assurance, which they would most certainly 8 in federally supported research. 9 So, it may be broad, I think it 10 would be broad enough to cover -- 11 MEMBER NELSON: I've just toggled 12 back to the OHRP FAQ that you saw earlier 13 and this, what Felix has just reviewed in 14 terms of the jurisdiction and the nested 15 authority, if you will, under the FWAs is 16 imbedded throughout OHRP Guidance and also 17 in the terms of assurance, of course. So, 18 it is worth remembering. 19 While we might like to talk 20 generically about all investigators out 21 there, the common rule applies, where the 22 common rule applies to HHS supported 106 1 research and those institutions that have 2 committed to an FWA. 3 DR. GYI: And just to be a broken 4 record again, you know, the gap will occur 5 when we talk about FDA regulated products. 6 Because, in that setting, sponsors are 7 responsible for identifying and using, if 8 you will, trained and appropriately 9 qualified investigators. And the notion of 10 education is implied in that setting, as 11 opposed to defined in the way that we're 12 talking about now. 13 CHAIR TILDEN: I don't have a 14 problem with considering that a statement be 15 made that these recommendations, that if 16 SACHRP wants to consider this at this time, 17 we have just a few minutes left before the 18 break. But whether this should be a 19 statement that these recommendations would 20 fairly apply to FDA regulated research, that 21 the Secretary should, that it be known that 22 this should apply, the concepts or 107 1 recommendations should be harmonized or 2 considered for FDA regulations as well. 3 I don't, I mean, I think that, 4 from my perspective, it's reasonable. But 5 that's not what it was brought, you know, 6 forth in the Subpart A Committee 7 recommendations. It would be something that 8 SACHRP would have to take up de novo. 9 MEMBER NELSON: Just as a bit of 10 historical context, I guess, history, in 11 terms of SACHRP. We certainly are very much 12 interested in harmonization and found 13 ourselves making that point so repeatedly 14 with each of our recommendations that I 15 think, at one point over the last year, the 16 notion of harmonization was backed out into 17 its own separate recommendation. That just 18 about everything we're talking about needed 19 to be viewed in the context of harmonizing 20 with other Agencies so that we didn't find 21 ourselves tacking that on to every 22 individual recommendation. So, there is a 108 1 standing recommendation out there, if you 2 will, that's been approved. I think that 3 that's our stated wishes. 4 CHAIR TILDEN: Any more comments 5 or discussion? 6 MEMBER POWELL: Excuse me, Sam. 7 I've listened to the discussion, I think, 8 and I had a similar thought to what Felix 9 had regarding trials that are conducted 10 under the FDA primarily by sponsors in 11 industry. And I'm having a little 12 difficulty thinking of how this would be 13 adapted to industry sponsored clinical 14 trials, which many of them are done with 15 single investigators, single site 16 investigators, those kinds of things. And 17 they may choose a central IRB to or other 18 IRB that they may use for their trials, but 19 to take all of these and say apply them to 20 FDA. 21 Well, I think we need to 22 harmonize in some way, but I'm not sure that 109 1 as they are, they could really apply to FDA 2 research or research that is overseen by the 3 FDA. 4 CHAIR TILDEN: Well, maybe Felix 5 and Dan, as you go back to your committee, 6 you know, there are a couple of issues that 7 have come up that you might want to consider 8 as corollaries to this. 9 Linda? 10 RADM. TOLLEFSON: I'm Linda 11 Tollefson from FDA and I'd like to point out 12 a couple of things. First of all, you've 13 got in there federal regulations, which is 14 FDA. And the other thing that we have is 15 the investigator signing that 1572 document. 16 So I think they're already covered. So that 17 would be consistent with federal 18 regulations. 19 And then the last comment is that 20 we coordinate with OHRP quite a bit. So 21 we'll have a great deal of comment on their 22 regulations and vice versa. 110 1 CHAIR TILDEN: Excuse me, Linda, 2 could I ask you a question? And that is, do 3 you see anything in these recommendations 4 that have been passed that would eliminate, 5 you know, the FDA regulated research, 6 training and that for institutions? 7