1 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES + + + + + SECRETARY'S ADVISORY COMMITTEE ON HUMAN RESEARCH PROTECTION + + + + + MEETING + + + + + MONDAY MARCH 13, 2006 + + + + + The Advisory Committee met in the Jefferson Ballroom in the Radisson Hotel Old Town Alexandria, 901 North Fairfax Street, Alexandria, Virginia, at 8:30 a.m., Ernest Prentice, Ph.D., Chairman, presiding. PRESENT ERNEST D. PRENTICE, Ph.D., Chair BERNARD A SCHWETZ, D.V.M, Ph.D., Executive Secretary CATHERINE SLATINSHEK, M.A., Executive Director CELIA B. FISHER, Ph.D., Member NANCY L. JONES, Ph.D., Member FELIX A. KHIN-MUANG-GYI, Pharm. D., Member SUSAN KORNETSKY, M.P.H, Member NEIL R. POWE, M.D., M.P.H., M.B.A., Member JAMES H. POWELL, M.D., Member ADA SUE SELWITZ, M.A., Member 2 EX OFFICIO MEMBERS PEG BARRATT, Ph.D., National Science Foundation KATHRYN LYNN CATES, M.D., U.S. Department of Veterans Affairs PATTY DECOT, U.S. Department of Defense SALLY FLANZER, Ph.D., Agency for Healthcare Research and Quality DAVID A. LEPAY, M.D., Food and Drug Administration AMY PATTERSON, National Institutes of Health LAWRENCE UHTEG, NIST ALSO PRESENT FROM THE OFFICE OF HUMAN RESEARCH PROTECTIONS KELLEY BOOHER KRISTINA BOOROR MICHAEL CAROME JULIA GOREY SHIRLEY HICKS IVOR PRITCHARD IRENE STITH-COLEMAN 3 C-O-N-T-E-N-T-S AGENDA ITEM PAGE Opening Statement . . . . . . . . . . . . . . . . .4 Report On Issues. . . . . . . . . . . . . . . . . .5 Overview of Charges to the Subcommittee . . . . . 14 Approval of Minutes from November Meeting . . . . 15 Overview of Meeting Agenda. . . . . . . . . . . . 15 Report of Subcommittee on Research Involving. . . 19 Children Recognition of Departing Members/Swearing . . . .189 In of New Member Further Issues of Subcommittee. . . . . . . . . .228 IO Initiative . . . . . . . . . . . . . . . . . .293 Public Comment. . . . . . . . . . . . . . . . . .302 Adjourn 4 1 P-R-O-C-E-E-D-I-N-G-S 2 8:37 a.m. 3 CHAIR PRENTICE: Good morning, everybody. 4 I think we'll get started. Thank you for coming. 5 What I would like to do is what I normally do, provide 6 a brief overview of SACHRP in terms of its charter and 7 charges to the subcommittees, review the agenda for 8 today. As you know, we are charged with advising the 9 Secretary on the protection of subjects who are 10 vulnerable, and that's reflected by our subcommittee 11 work. 12 It gives me great pleasure to introduce 13 our new member, our newest member, Dr. Neil Powe. 14 Would you please stand up and be recognized? Thank 15 you. And we are going to have a swearing in of Dr. 16 Powe this afternoon by the Secretary, so at that 17 particular time, I will go through his biography. 18 This is the list of the members of SACHRP. I want to 19 once again thank Cathy Slatinshek, who is the 20 Executive Director of SACHRP, and Kelly Booher, for 21 all of their work that they've done to make life easy 22 for all of us. It's a pleasure to be able to just fly 5 1 into Washington, show up at this meeting about 15 2 minutes ahead of time, and not have to worry about a 3 thing. The only thing I have to worry about is 4 whether or not I can get here on United Airlines, 5 which was not easy yesterday, by the way. 6 I'd also like to, once again, recognize 7 the work of the ex officio members of SACHRP who are 8 listed on this slide. They interact very closely with 9 Bern Schwetz and OHRP staff. And as you know, we have 10 a special relationship as an advisory committee with 11 OHRP. We work very, very closely with Dr. Schwetz and 12 all of his staff. And I think that's what makes this 13 whole committee work as well as it does, so Bern, 14 thank you very much for all of your leadership and 15 everything that you do. 16 And that leads us to the next item on the 17 agenda, where Dr. Schwetz will give us a report on the 18 issues. 19 SECRETARY SCHWETZ: Thank you, Ernie, and 20 good morning to all of you. I decided to do this 21 short presentation a little bit differently than I had 22 other times. I usually do it from the table, but I 6 1 wanted to take the opportunity this time to summarize 2 for all of you where we are relative to the 3 recommendations that have been made to the 4 Secretaries, and where we are on other activities with 5 SACHRP, so instead of telling you exactly what 6 happened since the last SACHRP meeting, I'm going to 7 review the status of where we are with some of the 8 things that you have been doing. 9 So three sets of recommendations have gone 10 into Secretary Thompson and now Secretary Levitt, and 11 I just want to update you on where these are because 12 I have to check from time to time myself, and I 13 thought if I'm wondering where some of these things 14 are, maybe it would be of interest to you. So the 15 first set of recommendations went to Secretary 16 Thompson in July of 2004, and by the time we heard 17 back, we had already followed up on your 18 recommendation to put into place the new 407 process, 19 and since then, the guidelines have come out and we 20 have now what we consider to be a pretty good working 21 system between FDA and us, and for OHRP independent 22 when it's not a joint process. So that has been 7 1 followed up on, and that particular activity is in 2 place. 3 With the accreditation, one of the 4 recommendations that SACHRP made when it was finished 5 with the accreditation review was that we should, 6 perhaps, have a conference and look at how the 7 entities that would be under accreditation, which is 8 not just the IRB but the whole program, how do these 9 entities self-regulate, and you are well aware that 10 we've never had that conference. And accreditation 11 has been building and adapting, going from two to one 12 accreditation organizations. So this has been a 13 dynamic process. And I'm not blaming you, Ernie, but 14 in consultation with Ernie, we have kind of agreed 15 that the time wasn't right yet for us to have a 16 conference on accreditation if we were going to have 17 one, so the possibility that we would have that is 18 still there. It's not thrown out, but at this point, 19 it's on hold. 20 We had the Subpart C subcommittee that 21 reviewed the issues that needed fixing right then, to 22 allow us to continue to work on research involving 8 1 prisoners, but you remember one of the things that we 2 decided was that Subpart C was, perhaps the word is 3 "broken," to the extent that it shouldn't just be band 4 aided and fixed that way. So OHRP funded a committee 5 through the Institute of Medicine to review the ethics 6 of conducting research in prisoners. And that 7 committee was formed. It's been meeting now for many 8 months, and we are expecting a report from that IOM 9 committee late this spring, this summer kind of a time 10 frame, at which time, presumably, we would be reading 11 it but they -- we would expect that SACHRP would be 12 looking at that report, and we'll decide what to do 13 about it, reconstituting a subcommittee or what the 14 action might be. 15 So that was the first set. The second 16 set, the primary component had to do with HIPAA, and 17 the discussions that were going on that were a 18 directive to us that we need to harmonize the common 19 rule with HIPAA as it relates to research. And in 20 fact, that recommendation was sent to the Office of 21 Civil Rights and they're still working on it. And I 22 don't know exactly what the time is when we're going 9 1 to see a product of that, but I know they're working 2 on it. 3 As of last Friday, the third set that was 4 put together in July of `05 was still in the Office of 5 the Secretary, but by the end of the day last Friday, 6 it was signed off on and is now delivered back to us 7 within OHRP and there were a number of issues there; 8 the wider range of jurisdiction within Subpart C being 9 one of the questions, and the role of the standard of 10 care, medical care in the review of protocols 11 involving prisoners were two of the issues. 12 Regarding research involving children, 13 this was the letter that had all kinds of important 14 recommendations in it that we need now to figure out 15 how are we going to deal with those recommendations 16 that that subcommittee worked on so hard. And there 17 was a recommendation in there to form a Subpart A 18 Subcommittee which has been in place now for some 19 time. So we're making -- we're going to hear more of 20 the progress on that today. 21 There were other topics. You recommended 22 that we would have an IRB workshop, which we did last 10 1 November, and that will be a topic of discussion later 2 today. In addition, the FDA has been working on draft 3 guidance relative to central IRBs, on the use of 4 central IRBs relative to FDA regulator products. 5 They're at the stage now where they are about to -- 6 they have finalized their document and it's about to 7 be printed in the Federal Register. 8 On international issues, we've had two 9 sessions. We're doing one more session tomorrow, and 10 I think that reflects the complexity of international 11 research as an issue, but also the fact that it's real 12 easy to have a lot of discussion about it and walk 13 away feeling, what did we get our hands around. It's 14 just that kind of a topic, so in the session tomorrow, 15 we're going to get our hands around a piece of this 16 whole issue that has to do with international 17 research. 18 Adverse events, you recommended that FDA 19 and OHRP would come out with guidance. We have our 20 draft guidance out. We've got quite a few comments on 21 the guidance, and we will be working hard to get that 22 into a final form. FDA is working on theirs. They 11 1 held a Part 15 hearing to get advice from the 2 community on adverse event reporting, and they are 3 working internally yet to develop what they need to be 4 able to manage adverse event reporting from the 5 standpoint of the FDA. In addition, Amy Patterson and 6 others have been meeting under the heading of a 7 Federal Adverse Events Task Force to try to coordinate 8 between agencies the handling of adverse event reports 9 and the surrounding information and activities around 10 that. 11 They are in the process of final 12 discussions on a document that they're putting 13 together that would then be beta tested in the 14 community. So if you have more specific questions of 15 that, we can ask them of Amy, but this activity 16 continues to move forward. 17 We did have one session in August of last 18 year that had to do with patient advocacy to keep us 19 connected to that part of the community that we need 20 to listen to, and we did hear some good things in that 21 particular session. We talked about the impact of the 22 fear of litigation on IRBs, on investigators, on 12 1 institutions, and there was no action that came out of 2 that discussion. It doesn't mean it's not important. 3 It's just that there wasn't a defined action that came 4 out of it. 5 Okay, status of nominees; five new members 6 are going to be invited to replace people who are 7 leaving SACHRP now, and they will be invited after 8 this meeting and we expect them to be in the mid-year 9 meeting of SACHRP in August. We will need four 10 additional new members in 2007, so that's a lot of 11 turnover of this committee that has been working so 12 well together, and we will have a Federal Register 13 going out yet this month inviting either people to be 14 nominated to self-nominate, or to nominate other 15 people to serve on SACHRP. We would always welcome 16 recommendations from all SACHRP members, and all of 17 you in the audience, if you want to make 18 recommendations for who should be on SACHRP, the 19 Federal Register notice will be out shortly, but we 20 will take recommendations even independent of the 21 Federal Register process. 22 The status of the charter; the charter for 13 1 SACHRP expires on October 2nd of this coming fall, and 2 we already have been working on that, so we're waiting 3 for the Department to receive our recommendation for 4 revisions to the charter and to get that moving to 5 make sure that there is a seamless operation here. I 6 have no -- I can make no absolute certain statement 7 about SACHRP after this expires on October 2nd, 2006, 8 but I would assure you that I have heard absolutely 9 nothing that would suggest that this will be anything 10 but rechartered. So that's about as confident as I 11 can be, but I've certainly heard no indications in any 12 other way. So that's my update, Ernie. I'll take 13 questions, if there are any, either now or any time 14 during the meeting. 15 CHAIR PRENTICE: Okay, thank you, Bern, 16 and thank you to all the members of SACHRP. You've 17 done an incredible amount of work. I think it's very 18 clear by that update of how far we've come since our 19 first meeting in July 2003. Now, the schedule that 20 you have in your notebooks has been altered because of 21 the schedule of the ASH, so we are going to recognize 22 the party members this afternoon. So therefore, I'm 14 1 not going to go through that now, but we unfortunately 2 will actually lose four of our members who will be 3 replaced. 4 Now, as customary, I go through the 5 charges of the SACHRP subcommittees. We've got two 6 subcommittees in operation. The first one is the 7 Children's Research Subcommittee. And as you know, 8 they're look at all aspects of the Subpart D, 9 Additional Protections for Children Involved in 10 Research, and they're going to present their latest 11 report to us on their work. This has been a very, 12 very active subcommittee under the co-chairs of Sylvia 13 Fisher and Susan Kornetsky. 14 The second subcommittee that we have is 15 the Subpart A subcommittee. They are charged with 16 reviewing all aspects of Subpart A, the Common Rule, 17 and they are going to be presenting their 18 recommendations to SACHRP, as well. I think that this 19 is going to be a subcommittee that has a very long, 20 long tenure. I don't see them going away any time 21 soon. Therefore, Felix, don't think you're going to 22 be able to get away from SACHRP just because your term 15 1 is ending today or tomorrow. 2 The next task we have is approval of the 3 minutes. I will entertain a motion. 4 MEMBER SELWITZ: I so move. 5 CHAIR PRENTICE: Thank you, Aida Sue. And 6 do I have a second? 7 MEMBER KORNETSKY: Second. 8 CHAIR PRENTICE: Thank you. Any 9 discussion, any corrections, any amendments? Hearing 10 none, all those in favor? 11 (Chorus of Ayes) 12 CHAIR PRENTICE: Wake up everybody, wake 13 up, wake up. Any opposed? Any abstentions? Motion 14 carries. Did anybody read the minutes? 15 All right, overview of the meeting agenda; 16 I will go over today's agenda, not tomorrow's. We've 17 already gone through the welcome, opening remarks, the 18 introduction of the new member. Again, we're going to 19 go through that in a little bit more formal sense this 20 afternoon because he needs to be sworn in, but we 21 certainly welcome him, and I'm delighted that he's 22 here. 16 1 Bern has given you the report of the 2 issues. We will move into the next part of our agenda 3 momentarily, which will be the Subpart A Subcommittee 4 report delivered by Felix and Dan. At 10:30 we'll 5 take a break. And then we're going to continue on at 6 10:45 with the Subpart A Subcommittee's report. We'll 7 have lunch between 12:00 and 1:00. We'll continue on 8 after 1:00 with the report of the Subpart A 9 Subcommittee, and then at 2:00 we're going to have the 10 recognition of the departing members of SACHRP, as 11 well as a swearing in of our new member by the 12 Assistant Secretary, Dr. Agwunobi, and he will be here 13 at 2:00, unless there is a sudden interruption in his 14 schedule by the Secretary. 15 At 3:00, we'll take a brief break. Then 16 between 3:15 and 4:15, we're going to have a 17 discussion of the IRB workshop that was sponsored by 18 ASCO AAMC, and Bern will present the results of that 19 workshop, and then we'll engage in a discussion of 20 that. 4:15 to 4:30, we have a public comment period. 21 If there's anybody that wishes to be placed on a list 22 of individuals who will comment publicly, you're 17 1 welcome to sign up or simply wait until the appointed 2 time. And then at 4:30 to 5:00, we will have a wrap- 3 up, and we will then adjourn. 4 Okay, Dan, Felix, would you assemble up 5 here, please? 6 MR. NELSON: Felix just asked me what that 7 beeping sound was behind me and some of you know that 8 I don't jump on new technology. I got my first laptop 9 this year, I don't wear a watch, I don't carry a cell 10 phone, I don't have a PBA. I do have a cell phone now 11 at the insistence of my family, and they were just 12 trying to reach me. So see how that works. 13 Well, thank you, Ernie and Bern. It's a 14 pleasure to be back. I've lost count at what number 15 presentation this is to SACHRP, but most of you know 16 that my day job is at the University of North 17 Carolina, and Bern Schwetz just reminded me that my 18 presentation last year about this time often included 19 references, or sometimes moving pictures showing our 20 University's march to the national championship in 21 basketball, and if you've been following us this year, 22 we don't have quite that much glory going on, so you 18 1 can -- you won't have to suffer through that, but it 2 is a pleasure to be here and to continue our 3 discussions, and to present the next installment of 4 our formal recommendations for your consideration, and 5 hopefully for your acceptance. 6 Just to give an overview of today's 7 presentation, a few -- just a quick recap, as Ernie 8 already laid out on our subcommittee's charge and 9 membership, and then we will be giving our 10 recommendations on continuing review, which was 11 started at the November meeting. We'll then begin our 12 recommendations on the next major topic area of 13 expedited review, and finish up in the afternoon 14 session with some updates on other issues that we've 15 been considering. 16 The charge to the subcommittee then, 17 although Ernie also just flashed this up, are to 18 review and assess all provisions of Subpart A, of 45 19 CFR 46, or the Common Rule, and to review and assess 20 relevant OHRP guidance documents, and based on this 21 review and assessment, to develop recommendations for 22 your consideration in three general categories; 19 1 interpretation of specific provisions, development of 2 new or modification of existing guidance, and possible 3 revisions to the subpart itself. And there will be 4 one or two of those that we put out for your 5 deliberation today. 6 The goals of our subcommittee are to 7 enhance protection of human subjects, to reduce 8 regulatory burdens that do not contribute meaningfully 9 to this protection, and to promote scientifically and 10 ethically valid research. 11 Our subcommittee membership, you've seen 12 before. Gary Chadwick from the University of 13 Rochester, Bruce Gordon from Nebraska, Felix at my 14 right hand, and that's both literally and 15 figuratively, as we work hard on this together. Isaac 16 Hopkins is a community representative from New Jersey, 17 Nancy Jones is at our table here as a SACHRP member, 18 Myra Keane from the University of Minnesota, Susan 19 Kornetsky, also at your table here from Children's 20 Hospital in Boston, Geegee McMillan is Director of the 21 We Can Pediatric Brain Tumor Network in California, 22 myself. Lorna Rhodes is an anthropologist and social 20 1 scientist from the University of Washington, Aida Sue, 2 again at your table from the University of Kentucky, 3 and David Strauss is an IRB Chair from New York City. 4 Our subcommittee meetings are listed here, 5 and I should draw your attention, if you haven't 6 already found them in the additional binder that was 7 handed out by Kelly, hopefully all the members at 8 least have the -- all the printed slides in front of 9 you so you can be following along, and we will reach 10 points where the written recommendations are there for 11 editing and closer reading. 12 These are the subcommittee meetings 13 reaching back to January of last year, alternating 14 teleconferences with onsite meetings. The most recent 15 meeting was held in Rockville, Maryland in the FDA 16 Conference Center at the end of this January, and much 17 of what you'll see today was refined and finalized 18 during that meeting. We also split into working 19 groups basically dividing our subcommittee in half 20 that went to work on these two major topic areas 21 you'll hear about today. 22 Just a little orientation to the format 21 1 and process for our recommendations that are soon to 2 follow; we're trying to learn from our previous 3 experience the -- given our task of reviewing and 4 assessing the entire Common Rule, we've taken various 5 tacts to bring in this work forward to you. We're 6 going to spend a fair amount of time today on some 7 general background and context not only for new 8 members, but I think even for existing members, and 9 for people who are quite steeped in the intricacies of 10 IRB work. We're finding this is necessary in order to 11 get an orientation that then supports discussion of 12 the specific issues to follow. 13 We'll lay out some of our subcommittee's 14 working assumptions in these areas, then identify one 15 specific issue of concern, the subcommittee's 16 rationale why is this a problem, why should it be 17 addressed, why does it get in the way of effective 18 human subject protections. Our proposed 19 recommendation will be on paper in front of you, and 20 then we would stop at that point and ask for 21 deliberation and vote rather than throwing an entire 22 package at you and hoping that you remember what we 22 1 discussed several hours earlier in this complex flow 2 of information. 3 And then we would be repeating the above 4 as needed -- well, and it will be needed because we'll 5 have a number of recommendations throughout the day, 6 so we'd like to, with Ernie's guidance and support, 7 complete that cycle and then move onto the next item. 8 Our written report, some of you may remember from the 9 November meeting, we did produce a written report that 10 has proved to be a draft as we continue to work with 11 your feedback and with our own thoughts, and rather 12 than throwing a series of written reports out to you 13 that end up being works in progress, we're going to 14 wait till the end and hopefully tie all this together 15 as needed and then that would be presented, but really 16 what you see in front of you then is the essence of it 17 today on these slides. 18 Before moving onto the actual 19 recommendations, I would like to wax philosophic just 20 for a bit and ask what's wrong with this picture, what 21 are we trying to fix. This is -- you've heard how 22 many angels can dance on the head of a pin, and this 23 1 is an angel. She's dancing, or at least trying to 2 balance. Granted, it may be a bowling pin. I don't 3 know if that's where the metaphor came from, but I 4 would like to suggest that this is an apt metaphor for 5 IRBs in today's environment. I would suggest that 6 IRBs are spending increasing amounts of time dancing, 7 or at least trying to balance on the head of a pin, 8 and proportionately less time protecting human 9 subjects, because of where we're at in the current 10 state of affairs, our current understanding, our 11 current interpretations. 12 We've had the opportunity, and I've had 13 the opportunity to review some of progress, our 14 subcommittee work with different groups over the last 15 few months, and I get varying responses. When I talk 16 to groups of IRB people, their eyes immediately light 17 up. They recognize the issues. They congratulate us. 18 They thank us, they add more issues to the mix, and 19 there's an instant acceptance and recognition that 20 what we're doing is important, and that it's 21 problematic. 22 When I talk to groups that may include 24 1 investigators, public members, ethicists who aren't 2 necessarily involved in the day-to-day routines of the 3 IRBs, their eyes don't necessarily light up. They may 4 tend to glaze over because some of what we're talking 5 about seems so esoteric and so slicing it fine, so 6 advancing on the head of a pin, if you will. And I'm 7 increasingly forced to step back from the daily work. 8 I think Felix and I and many of you on this committee, 9 and certainly many on our subcommittees would consider 10 ourselves reg heads. We can quote the regs. We apply 11 them daily. We can stand shoulder to shoulder with 12 people as we debate issues like, well, does the 13 approval period end on midnight of day 364 of that 14 year, or did it start at noon on day 365 and when does 15 the letter get sent out. 16 And these rules are important, standards 17 are important, process and structure is important, but 18 I think we're increasingly in danger of losing the big 19 picture by focusing on increments that really 20 represent the small picture, the dancing on the head 21 of a pin. So I think as we go through today, what 22 we're really trying to do is get IRBs out of this 25 1 scenario, and even as there is structure and process 2 and rules to be followed and applied closely to allow 3 IRBs to step back to what I think you and all of them 4 would consider as the real job, which is protecting 5 human subjects, and how to best go about that. 6 So onto continuing review. Again, we 7 approach this process by splitting into a working 8 group that was chaired by Gary Chadwick, whom you've 9 heard from at previous meetings and David Strauss and 10 three other subcommittee members, their work of the 11 working group was then brought back to the 12 subcommittee as a whole, further refined and is now 13 being presented to you. 14 Just as a reminder, we did present our 15 first report and recommendations on this topic on 16 November 1st. At that point, there were 16 formal 17 recommendations that were put forth. Nine were 18 ultimately approved. I've listed them by number here 19 but I would urge you to not get hung up on the 20 numbering scheme. That was our attempt as we brought 21 forward this large set of recommendations just to keep 22 things straight on paper but I think as we move 26 1 through on slides, the important thing will be the 2 content and we'll make numerical references just 3 because there was this report already out there 4 previously but I list them here just for your really 5 recollection that we did work through and with your 6 help and input, approved nine out of those 16 in 7 November. Seven were tabled for a variety of reasons. 8 Some just lack of time to really understand the issue, 9 some a failing on our part to provide adequate 10 background, some sending back to the drawing board to 11 rethink our stance on a particular issue. These 12 remaining issues then, are what will be laid out in 13 the next hour or so. 14 Only items then not approved or tabled 15 last time are being presented today for your further 16 consideration. Just a bit of historical context, the 17 requirement for continued review is one of many 18 legacies from the U.S. Public Health Service Syphilis 19 Study. I think many would recognize remembering this 20 historical landmark that even if you could have 21 reached an ethical construct that allowed this study 22 to be conducted back in the early `30s and addressed 27 1 issues like informed consent and other things, the 2 study failed on many levels that even if that study 3 could have been approved in some state, the lack of 4 continuing review that allowed the study to go for a 5 period of decades long after the advent, the 6 introduction of penicillin as an effective treatment 7 for Syphilis is one of the reasons we have continual 8 review requirements today. It's at least got people 9 thinking about the need for this as they set up the 10 regulatory structure. So continuing review of 11 research was intended to prevent continuing research 12 activities in the face of unacceptable harm, futility 13 or scientific or ethical obsolescence. 14 The Belmont Report does not mention 15 continuing review as an application of its fundamental 16 ethical principles; however, we view it as important 17 and indeed, it was embodied in the regulations as are 18 documented on this slide at a number of levels. So 19 Section 46.103 instructs that IRBs must have written 20 procedures to conduct both initial and continuing 21 review to determine which projects require more than 22 annual review, to verify that no changes have occurred 28 1 from sources other than investigators. Again, IRBs 2 are given considerable discretion as to how they 3 establish these written procedures. 4 46.108 talks about IRB functions and 5 operations and although not naming continuing review 6 directly, it certainly applies there because the 7 deliberations, the actions of the IRB must occur at 8 convened meetings unless they qualify for expedited 9 review and we'll spend a lot of time talking about 10 expedited review in the next segment. 11 46.109 is highlighted because that's the 12 only section that really gets into any depth at all 13 and I'll share that with you on the next slide, on 14 continuing review, and it talks or instructs us that 15 continuing review must be conducted at intervals 16 appropriate to risk but not less than once per year. 17 Section 110 deals with expedited review which to the 18 extent it's used to conduct continuing review, 19 applies. 46.111 are the criteria for IRB approval and 20 I'll review those with you later but they apply to 21 both initial and continuing review and one thing I 22 think the subcommittee would throw out for your 29 1 consideration is to what extent must they apply. Do 2 they have to apply with the same rigor with the same 3 intensity in all circumstances? 4 46.116 are the regulations that guide 5 informed consent and obviously all of that applies to 6 continuing review but there is a specific element that 7 requires that significant new findings be provided to 8 subjects that might effect their willingness to 9 continue to participate and that's obviously relevant 10 to continuing review. 11 So this is the primary regulatory 12 citation, Section 109 and this is really the only 13 section that addresses continuing review process with 14 any amount of detail and in its entirety states, "An 15 IRB shall conduct continuing review of research 16 covered by this policy at internals appropriate to the 17 degree of risk but not less than once per year and 18 shall have authority to observe or have a third party 19 observe the consent process and the research. 20 Well, given the relative sparsity of those 21 references, it's predictable and understandable that 22 there's considerable uncertainty and variability in 30 1 how IRBs have historically interpreted and applied 2 those regulations. So we've asked for guidance and 3 have received it from OHRP and others. HHS guidance 4 has become increasingly detailed and I think we would 5 say increasingly restrictive over the years and some 6 of the specific elements that we will be addressing 7 shortly are those areas where we feel that the 8 guidance has become, perhaps, too restrictive in ways 9 that impedes the appropriate implementation, the 10 appropriate conduct of continuing review. 11 The current, most latest guidance is dated 12 July 11th, 2002 and that document notes that it 13 replaced former guidance on continuing review from 14 1995, guidance on IRB approval periods from January of 15 2000 and discussion of continuing review of DSMB- 16 monitored clinical trials from May of 2000, so those 17 are subsumed into the most recent document. 18 By comparison, the FDA guidance has 19 remained comparatively permissive to the HHS guidance 20 and that's one of the things, of course, that IRBs 21 grapple with are the differences at times in 22 interpretation and detail between the FDA and HHS 31 1 regulations and their interpretation. But the FDA 2 guidance from the FDA information sheet says that 3 continuing review. After study approval the 4 regulations for that outline minimum requirements but 5 do not provide specific instructions to IRBs on how to 6 set up their own rules for continuing review within 7 the framework of the regulations. Therefore, the 8 regulations allow institutions or IRBs to impose 9 greater and more detailed standards of protection for 10 human subjects than those specified by the regulations 11 and permit each IRB to develop procedures appropriate 12 to its needs. 13 And, of course, the HHS regs and 14 associated guidance follow the same concept that they 15 provide a floor, of course, and many IRBs can and do 16 go above that floor. So our working assumptions as e 17 entered this task are that continuing review plays a 18 central and often under-valued role in the IRB 19 process. It's critical. We don't want it to go away 20 but it must be applied appropriately and we feel that 21 practices that do not demonstrably enhance the safe 22 and ethical conduct of research actually diminish 32 1 overall human subject protections because at some 2 level it's a matter of resource allocation. The more 3 time we spend dancing on the head of that pin, if you 4 will, the less time we can focus on some of the more 5 critical tasks. 6 So I'd like to, with that general 7 background and overview of continuing review, identify 8 specific issues of concern. Our subcommittee, if you 9 will remember, was given a list of some 12 to 14 10 questions and as they worked through them, then they 11 came up with the following recommendations. And here 12 again I've maintained the numbering schema that we put 13 in place last time around just so it can be inter- 14 digitated with the work already approved but don't get 15 overly focused on the number. I think the content of 16 the question is what will be intact throughout this 17 little segment here. When can continuing review stop? 18 Must review continue as long as identifying data 19 exists or is there a point at which the IRB and the 20 investigator can close the study file? 21 Why is this an issue? HHS regs did not 22 address when research ends for oversight purposes. 33 1 The full application of 46.111 and those are the eight 2 criteria for IRB approval to minimal risk research or 3 I think we would say to any research past a certain 4 point in it's life cycle and that's an important point 5 that we'll return to, does not add meaningfully to 6 protections and is, therefore, not a reasonable 7 requirements. 8 Another complicating factor is that HHS 9 and the FDA have different operational definitions for 10 what constitutes human subjects research and 11 obviously, that complicates not only continuing review 12 but the oversight of research in general. How do we 13 even know what research requires IRB review versus 14 what doesn't. When do we apply expedited review, et 15 cetera, et cetera. FDA frames human subject research 16 within the context of using a test article with 17 patients or controls for example, a clinical trial. 18 HHS on the other hand, rolls in the concept of private 19 identifiable information in addition to a more active 20 intervention and we're not saying that's inappropriate 21 but nevertheless there are differences that must be 22 accommodated especially by IRBs that need to and 34 1 intend to adhere to both sets of regulations. 2 There are additional scientific factors 3 that factored into our analysis. One is that data 4 analysis may go on for years, of course, and there may 5 be differences in single site studies where all the 6 data is in the hands of one investigator within one 7 institution versus multi-center studies, clinical 8 trials, for example, where different locale, different 9 sites conducting the study may be starting and 10 stopping at different points. When does the overall 11 study stop as opposed to the study activities at t 12 single site. 13 An additional factor, sponsor requirements 14 and simply good clinical practice good research 15 practice may dictate keeping identifiable data for 16 years or forever. Many of us have files full of or 17 boxes back in the archives full of identifiable 18 private information that exists from studies long 19 since closed out, nowhere close to being conducted, 20 nowhere close to having any meaningful role for IRB 21 oversight, yet investigators remain in possession of 22 that identifiable data if that's one of our defining 35 1 factors in continuing review starting or stopping. 2 So these are a few examples where 3 interminable and here, I guess interminable can be 4 taken in a number of ways. We really mean it without 5 end or without a concrete end, but some investigators 6 and IRBs may use it in a more pejorative sense. When 7 is it really not value added? I think many in this 8 room could come up with a much longer list of 9 examples, but a few for your consideration; social 10 science surveys or minimal risk surveys of any kind, 11 individual sites in a mut-center trial after activity 12 ceased at that site but continues at other sites 13 conducting the same study, cooperative group studies, 14 cooperative group oncology studies, AIDS clinical 15 trial group studies, that remain open solely to 16 collect survival data. Many institutions have managed 17 this by rolling all of their studies when they reach 18 that point in their own life cycle in the study's life 19 cycle to roll things into an umbrella study that 20 allows collection of survival data but long after the 21 really active phase of the study is done. 22 Is this a meaningful process even at that 36 1 point? And I would suggest that every study at some 2 point we have to be asking this about, at some point 3 every study reaches a point beyond which the repeat 4 application of all the elements of 111, all the 5 elements of the regulations are no longer meaningful 6 and are no longer value added, and so we ask ourselves 7 who are we protecting and from what? 8 So a number of possible staffing points; 9 when does or when should the IRB's oversight 10 responsibility end? Does it end after the last 11 subject is enrolled, after all the interventions are 12 complete, after data collection is complete, after 13 data analysis is finished or all the papers are 14 published or do we go to infinity and beyond which 15 worked for Buzz Lightyear but doesn't necessarily work 16 well for IRBs or for investigators. 17 So as a result of this uncertainty and the 18 lack of a concrete commonly accepted stopping point 19 for continuing review, IRBs have come up with a number 20 of ways to handle this. Some err on the side of 21 keeping things open forever, which again, we would 22 argue is not meaning full and it's not value added or 37 1 we establish local compromise solutions. At our 2 institution just as a single example, we advise 3 investigators when they come and say, "How long do I 4 have to keep this darn thing open, how long do I have 5 to keep coming back to you", we advise them to keep it 6 open at least through the active phase of data 7 analysis and publishing the results because journal 8 editors may send them back to the data for further 9 analysis. They may even send them back to the 10 subjects themselves to collect more data and at that 11 point, certainly none of us are arguing that we 12 shouldn't have -- that the IRBs shouldn't have an 13 active oversight role. 14 That's sort of a local finesse, if you 15 will, and that's not necessarily commonly practiced Or 16 I'm not saying that's a gold standard that should be 17 practiced around the horn. What is that gold 18 standard, what is -- what should the conventional 19 wisdom be, because that's what we really like people 20 to be following and not making it up on our own 21 somewhere. 22 So as we grappled with this at our last 38 1 subcommittee hearing, I stepped up to the white board 2 and tried to sketch out the -- sort of frame the 3 direction with this diagram and some members of our 4 subcommittee found it helpful so I've tried to 5 translate that into a slide. One of the problems with 6 the communication that the SACHRP received in 7 November, I think, was that it was filled with 8 references to, "When does the study end", and I think 9 we really need to separate in our thinking and 10 conceptualize that we have an entity called the study 11 by which we mean all study related activities and 12 that's quite different and should be different and 13 should be thought of separately and analyzed 14 separately than the parts of the study that require 15 IRB oversight. 16 IRB oversight doesn't necessarily end with 17 the study, which both starts before and ends after, we 18 would argue, IRB oversight as required. So I think if 19 we needed to, although that isn't the point of today's 20 discussions, we could identify a discrete starting 21 point for the study as whole, study related 22 activities. We could also identify and have, although 39 1 that's not at issue today, when is IRB oversight 2 required. I think we would all agree before human 3 subject are enrolled, before human subjects are put at 4 risk in a study the IRB needs to be involved. 5 But there is a gap there. There's a time 6 lag. And activities that may include and do include 7 developing the protocol, going after funding, all of 8 these things occur before we say IRBs really need to 9 have an active role before the study needs to be 10 approved in the eyes or in the files of an IRB. 11 At the back end of things, although this 12 also isn't up for debate today and doesn't need to be, 13 I think we could identify a point at which "the 14 study", all study related activities are done but 15 here's where we're having problems and here's the 16 point of today's discussion; when does IRB oversight 17 end, and that's a much more blurry squiggly line and 18 we're having trouble defining that and that's what 19 we're going to take a shot at on the next slide and 20 ask for either your acceptance or modification. 21 So and actually, I think for ease of 22 reading, this goes onto two slides and after I lay 40 1 these out then, Ernie, we would ask for you guys to 2 step in and ask questions and discuss and give us some 3 feedback on this. So our recommendation is that OHRP 4 should clarify its guidance on the required duration 5 of continual review. Continual review may end when 6 all research interventions and interactions with 7 subjects are over and when data collection for 8 research purposes is complete as described in the 9 approved study plan protocol at the research site for 10 which the IRB has oversight. 11 And it continues, the IRB must have 12 reviewed and approved the investigator's plan for data 13 analysis and the safeguards in place for 14 confidentiality protections. The investigator still 15 retains the responsibility to notify former subjects 16 and the IRB of subsequent analysis and/or new 17 information, raises concerns about rights, safety and 18 welfare of human subjects. 19 So those two slides encompass our 20 recommendation as a whole. The second page is really 21 added as we debated internally how this should be 22 handled. That first -- the first page is very similar 41 1 to what you saw before, that we consider the data 2 collection phase to be the part that really needs 3 oversight, if you will, the part where subjects need 4 most protection. We recognize certainly and there was 5 a fair amount of internal debate and discussion over 6 what happens after that active data collection phase 7 is complete. We recognize that there are still risks 8 when people are retaining data, when data are in hand 9 and that things may come to light months, years later. 10 We don't want the IRB to be completely removed from 11 that process but neither do we feel that ongoing 12 active approval, that requires an IRB file to be kept 13 open by the IRB and the investigator is value added. 14 So the subcommittee members were 15 comfortable with noting that the investigator's plans 16 for data analysis and safeguards, for confidentiality 17 protections which is really the primary risk that 18 we're talking about once active interventions, once 19 active data collection is over. Now we're into the 20 area of confidentiality risk as the primary concern. 21 If those are being adequately addressed and they 22 should have been as part of the up front approval, and 42 1 through the life of a study, if those are in place, 2 and if we remind investigators that they still have a 3 responsibility to come back and, of course we would 4 hope that's in place right now, long after we close a 5 study, if something comes to light, we'd still like to 6 know about it, we'd like subjects to know about it. 7 If those caveats and qualifiers are added 8 to this, this was out subcommittee's feeling as an 9 appropriate recommendation. And with that, I'll turn 10 it over to you, Ernie. 11 CHAIR PRENTICE: Thank you, Dan. What we'd 12 like to do is consider each recommendation as they are 13 presented and, if possible, actually vote on 14 recommendations as appropriate. So let's enter the 15 discussion phase. We'll follow our standard 16 procedure. You raise your hands if you want to ask a 17 question or discuss something in particular and I'll 18 recognize you and we'll try to proceed in an orderly 19 fashion. So does anybody have any questions? 20 Okay, hearing none, let me ask a question 21 with regard to the CR Recommendation 1.1 (continued), 22 I understand the rationale for requiring the 43 1 investigator to still assume the responsibility for 2 notifying former subjects of any new risk information 3 or any other information that may have clinical 4 utility for them or impact them in any way. But you 5 also have a statement to notify the IRB. 6 When studies close, IRBs have various 7 mechanisms to either maintain records for the three 8 years or they actually eliminate records of studies. 9 So I'm trying to understand the rationale for keeping 10 the IRB in the loop, particularly if we're talking 11 about a study that's been closed for let's say a 12 decade. Could you comment on that? 13 MEMBER GYI: Subcommittee did not consider 14 the logistics issues regarding the IRB's decision to 15 destroy the records beyond following the regulatory 16 requirement of three years. I suppose just to hazard 17 a guess, if it were to come before an IRB and the 18 records had either been archived or destroyed, the IRB 19 would then have to sort of rethink what that process 20 is. Just by way of example, let me share with you the 21 story of the Salk Vaccine. 22 I had shared this experience with a couple 44 1 of investigators awhile back and we had talked about 2 the fact that the Salk Vaccine came to the marketplace 3 very quickly following research and without the 4 appropriate oversight and protections in place today 5 back in 1954/1955. And I was reminded that the 6 original vaccines were harvested from the monkey 7 kidney cells and subsequent exposures to subjects 8 resulted in kidney damage. And the person who was 9 talking to me reminded me that perhaps, this is the 10 role where the IRB might have had an impact. If they 11 had known about it, even after the fact, the IRB could 12 have made some determination as to what the research 13 related implications were. 14 And I think that that has value here as 15 well. Even if the research records had been 16 destroyed, I think it would be incumbent upon the IRB 17 to make some determinations of how they wanted to 18 address that particular issue. Our initial impulse, 19 though, was stimulated by the discussions around this 20 committee of oncology related studies that Susan 21 Weiner had reminded us about and I think we had a 22 great deal of discussion surrounding that, and you 45 1 know, the IRB, I think there was a strong feeling that 2 the IRB ought to know, even if the study had been 3 closed and archived the record is destroyed. 4 So that was the reason behind the 5 subcommittee's continued discussion about making sure 6 that the IRB was informed of that, especially relating 7 the handling for the rights and welfare of the study 8 participants. 9 CHAIR PRENTICE: Okay, thank you. Other 10 questions? Celia? 11 MEMBER FISHER: I was trying to figure out 12 the relationship among 102(d)-(e) and (f)(2) in terms 13 of the continuing review because I think one of the 14 points that Dan was making was that HHS includes 15 identifiable information which then would mean, as 16 long as you're analyzing data and you have the records 17 of the -- the researcher has the records of the 18 identities of the individual, it would continue to be 19 under IRB review but I was just wondering if they 20 could help out why -- how they reached that assumption 21 because -- and whether the regulations actually say 22 that. Do you understand what I'm asking you? 46 1 MEMBER NELSON: Not entirely. 2 MEMBER FISHER: Okay, I'm sorry. You 3 point out that there's a difference -- you point out 4 there's a difference between the FDA and HHS, right, 5 on page 11, I don't know what slide it is, and you say 6 that HHS includes the concept of private information 7 in addition to intervention. 8 So I'm assuming -- what is the 9 relationship between when continuing review can stop, 10 the definition of research, the definition of human 11 subjects and why you would assume that as long as a 12 researcher can identify the subjects well after data 13 collection is over, the HHS regulations in and of 14 themselves, are creating an obstacle. I guess that's 15 my question. 16 MEMBER GYI: Just as a point of 17 clarification, I wonder if there's an FDA 18 representative. I don't see Dr. LePay here, so -- 19 because this is an issue that sort of touches on both 20 sides. There is one, thank you. 21 MEMBER NELSON: Okay, a fair question, but 22 if I can paraphrase slightly but not to lose the gist 47 1 of your question, Celia, if you go back to the 2 beginning of a study, what requires IRB review in the 3 first place, IRB review and approval, well, it doesn't 4 have to be an active intervention at all. You create 5 a human subject. You make someone into a human 6 subject by obtaining data about them even if they 7 don't even know you exist. Going to do a medical 8 records chart review study, retrospectively, creates 9 human subjects. So I guess taking that to its logical 10 extension through the life of a study, as long as you 11 have those data that person remains a human subject. 12 I think what we're saying is that at some point, we're 13 accepting that even though those data remain under the 14 control of an investigator, if appropriate 15 confidentiality measures are in place, it's not value 16 added to continue, I guess to continue to regard that 17 person as a human subject in need of IRB protections 18 for the rest of -- well, for the rest of their life or 19 for the life of those data, accepting that the data 20 may be out there forever. 21 And that's the dilemma here. I don't 22 think we have any problem up front saying, you know, 48 1 back to that right here, the beginning of IRB 2 oversight, we're all in agreement, I think that an 3 investigator obtaining data, whether or not it's 4 reactive intervention, creates a human subject, 5 creates the need for IRB -- triggers the need for IRB 6 oversight and protection, and it's on the back end 7 where extending that rationale, that solid logic 8 creates problem. 9 And I think what the subcommittee is 10 trying to say is that at some point we have to be 11 comfortable that those data are out there. They may 12 have gone off to sponsors. They may be sitting in 13 locked files. They may be in computers forever, but 14 the act of oversight by an IRB is no longer value 15 added. 16 I might, if Mike Carome or others are 17 willing, invite OHRP's response to that same question 18 because some of this gets back to -- well, a lot of it 19 gets back to obviously, OHRP's definition of the -- 20 not the end of a study but the end of need for IRB 21 oversight. 22 CHAIR PRENTICE: We can certainly do that, 49 1 Dan, but I do want to offer what I think might be a 2 clarification for Celia, which is not self-evident 3 necessarily in the slide you're referring to. The HHS 4 definition of human subject, of course, includes the 5 attainment of identifiable private information but 6 that's in the context of conducting research. So if 7 the research is complete and you can debate when that 8 is, but if you look at the recommendation of the 9 subcommittee, basically what they're saying is when 10 the analysis of the data as described in the protocol 11 is complete then the research is complete. 12 So even though you would still retain 13 identifiable private information, it does not 14 constitute research any longer, and therefore, not 15 subject to IRB review assuming that we accept this 16 particular recommendation. Does that help? 17 MEMBER FISHER: Well, I absolutely agree 18 and I guess I agree with the recommendation. The 19 question is, how it should be phrased and I think in 20 the earlier slide, it suggested that OHRP or whoever 21 would make the -- with this guidance that in some 22 sense one is saying something different from what is 50 1 in the regulations and so that's what I was trying to 2 articulate. I think the recommendation is excellent. 3 Whether or not it's a shift from how the regulations 4 could have been interpreted for a very long time, I 5 think is the essence of how it will be framed when 6 it's a recommendation. So that's why I was asking is 7 this now a new direction or have IRBs been overly 8 conservative in tying (f) to (d), when, in fact, 9 they're two different letters, which is, I think, what 10 you were saying. So it's really how it would be 11 phrased. 12 CHAIR PRENTICE: Okay, I think it's new 13 direction but I would certainly invite OHRP to comment 14 on their view as to whether or not this is a new 15 direction. Dr. Carome, would you care to comment? 16 DR. CAROME: What OHRP has long-stated is 17 that the use and analysis of identifiable private 18 information from living human individuals represents 19 human subject research. And so with respect to when 20 does continuing review need to continue at least 21 annually, we have not said that as long as 22 investigators hold identifiable private information, 51 1 they must continue to subject the research in which 2 that data was collected to continuing review. 3 We have said that the analysis and use of 4 the collected identifiable private information as 5 described in the protocol as proposed usually in the 6 statistical or analysis section of the protocol, that 7 represents ongoing human subject research. And so 8 this recommendation would, if adopted by the 9 Department and our office would reflect a change in 10 our current position. 11 CHAIR PRENTICE: I don't understand what 12 you just said because you said that as long as an 13 investigator is using or analyzing data for the 14 purposes of research, it would necessitate continuing 15 review and you also mentioned the -- when the analysis 16 as described in the protocol is complete, then there 17 would no long be a requirement for continuing review 18 which seems to reflect this recommendation. How is 19 that different then than OHRP's position? 20 DR. CAROME: I think the recommendation 21 would allow for the investigators to continue to 22 conduct the analysis as proposed in the research of 52 1 the identifiable private information collected but no 2 longer required for continuing review. Dan, that's 3 how I read it, so I think Ernie is reading the 4 recommendation differently that we are reading it. 5 CHAIR PRENTICE: Yeah, I'm reading it 6 differently. Dan? 7 MEMBER NELSON: Well, let's read it 8 together. So "Continuing review may end when all 9 research interventions", and I should have probably 10 had a follow-up slide with some of the operative words 11 here highlighted, but I think speaking for the 12 subcommittee, research and interventions, the subjects 13 are over, that's nearly a no-brainer, I think. We 14 all want that to be done before we would close out a 15 file. And data collection for research purposes and 16 that was added at the last subcommittee hearing, 17 perhaps, Ernie, at your suggestion but certainly 18 agreed to by the subcommittee, that there may be other 19 data collection that goes on, for example, for 20 clinical purposes, if it's a patient in a clinical 21 trial, but data collection for research purposes is 22 complete as described in the approved study plan and 53 1 then the -- after the comma, at the research site for 2 which the IRB has oversight recognizing that if you're 3 part of a multi-center study, other sites may continue 4 with these activities. 5 So I guess the point of discussion right 6 now is data collection for research purposes is 7 complete. We are recognizing that data analysis may 8 go on. Again, if you go back to those scientific 9 factors as I term them in that slide, that impact on 10 our discussion, data analysis may go on for years and 11 we're saying that IRB oversight during those years is 12 not value added. That you know, if something came up 13 today that would send an investigator back to a study 14 that had been closed out two years ago, and they 15 realized that by going back and pulling up the file 16 already in their possession, that the sponsor has told 17 them should -- in good practice, has told them should 18 stay in their possession for what seven years if it's 19 NIH funded, forever if you were brought up the way I 20 was, which is to not throw anything away, if those 21 remain in your possession going back to them, 22 analyzing unless you're going to need to go back 54 1 through medical records, back to recontact subjects 2 directly and re-engage them in the process, that 3 they're okay without our IRB protection at that point. 4 CHAIR PRENTICE: Okay, Mike, I agree with 5 you. It is different. I was not looking at the term 6 -- I was looking at collection and probably we need to 7 refer to analysis as well. It doesn't -- so this is 8 a difference between your current position and the 9 recommendation. Celia? 10 MEMBER FISHER: I was jut wondering and I 11 don't know enough about how IRBs operate. I do 12 understand that we want to reduce burden and at the 13 same time protect human subjects. So I'm just 14 wondering as some kind of a midway point between 15 OHRP's concern about the continued protection of 16 subjects when there is identifiable data, and the 17 concern about not having full IRB review, for years 18 when data is being analyzed, whether or not there's a 19 way to do something akin to an expedited. 20 Once data is -- data collection is 21 completed, confidentiality protections have been 22 approved, then there's some kind of yearly update to 55 1 insure the IRB as the data is being analyzed or kept, 2 that the confidentiality continues to -- protection is 3 continued to be maintained. Is that possible within - 4 - is there a way to streamline the continued review of 5 confidential information storage? 6 MEMBER NELSON: Go ahead, Ada Sue. I bet 7 you have the same answer I do. Go ahead. 8 MEMBER SELWITZ: In fact, that's what we 9 do. So that mechanism is in effect. It is 10 streamlined. It is expedited but that doesn't negate 11 the fact that it does require a substantive review, 12 even if it's expedited. I mean, just because it's one 13 person versus an entire committee and from an 14 administrative standpoint and the burden on managing 15 the entire system, it's -- it is a problematic. 16 I mean, from a staffing standpoint, you 17 spend as much effort on expedited as you do full 18 except that it isn't in the minutes. So that, in 19 fact, is currently being done. I think the reason it 20 is so important in this particular recommendation that 21 we include that PI's have an obligation to report any 22 problems that should occur with the data analysis, I 56 1 think that's an important part of this recommendation 2 because that -- otherwise, I would be uncomfortable 3 with saying, "We never hear from you", but on the 4 other hand, I think if you tell PI's that if there is 5 a problem and they have an obligation to report. And 6 I'm not worried about the logistics on that, Ernie, 7 now that so many of us are moving to not even 8 electronic submission. 9 I mean, most of us have an electronic 10 record that we do not destroy over a long period of 11 time. So I think the logistics of receiving a report 12 we could manage it quite effectively and would want to 13 receive it. But I think ethically, that does a great 14 deal to strengthen the merit of this particular 15 proposal. 16 MEMBER FISHER: Can I just say this? I 17 don't see the oversight on a sloppy investigator here. 18 I only see in the recommendation that if the 19 investigator decides that the data analysis itself 20 raised a safety issue, that then they should be 21 encouraged to report it to the IRB but I guess the 22 question I have is, where is the oversight which is 57 1 the purpose of the IRBs? 2 I guess the other question I was asking is 3 I understand that regular expedited review is the same 4 as a review. You have to look at lists of benefits, 5 et cetera, et cetera. I was asking whether or not 6 there's even something more streamlined for 7 termination of data collection, data analysis and then 8 the only thing that needs to be reviewed is something 9 that says confidentiality, procedures are continued to 10 be in existence. That -- I was wondering if that's a 11 possibility. 12 MEMBER SELWITZ: You know, it's not a 13 possibility in terms of the current existing guidance. 14 It's not. 15 MEMBER GYI: I think that perhaps we ought 16 to put on the table as well, the differentiation that 17 Celia is making and that is something along the lines 18 of an investigator initiated study where perhaps an 19 oversight may be a little bit different than a multi- 20 center FDA regulated sponsored research where the 21 investigator may not have any access to the analysis 22 information but may have access to data as we're 58 1 talking about right now. 2 And so part of the dilemma that the 3 subcommittee had was in trying to balance those 4 differences between what constitutes an investigator 5 initiated study, perhaps even spanning into behavioral 6 science where data analysis as Dan was talking about, 7 and data access may go on for years and the very large 8 volume of sponsored research where once it leaves the 9 investigator's shop, that study essentially ends at 10 the investigator's site and the analysis and access to 11 further data resides primarily in the sponsor's shop. 12 MEMBER NELSON: Let me just add to that, 13 that the members of our subcommittee who are most 14 experienced and spend their time in the social 15 sciences felt quite strongly stemming from the point 16 Felix just made, this is not all about clinical trials 17 where you have concrete bundles of -- maybe concrete 18 is the wrong word, they're heavy but there's discrete 19 bundles of data that are analyzed numerically and 20 statistically. That's quite a bit different than a 21 qualitative data analysis. 22 We lump it all together under the rubric 59 1 of data analysis but the qualitative assessment that 2 an ethnographer may do that also goes on for years is 3 quite a bit different, done in different ways, 4 certainly than the clinical trial data analysis. And 5 they felt quite strongly that subjecting that "data 6 analysis" in quotes to this continuing review is 7 really one of the things that make IRB oversight of 8 social and behavioral research such a mismatch in 9 their eyes. 10 A second point, I guess I'd make is that 11 I returned to this slide just a couple slides earlier, 12 this list here of possible stopping points, what was 13 drafted at midnight on Saturday was put in a -- I 14 think a logical sequence in terms of chronology. So, 15 nobody is proposing that we stop it as soon as the 16 last subject enrolled, after interventions are 17 complete, too soon we feel. After data collection is 18 complete, this is where we're comfortable drawing the 19 line recognizing that below that line so data 20 analysis, publication, again, across the scope of 21 research that we're talking about, everything, is a 22 reasonable place. 60 1 And there was a lot of discussion amongst 2 the subcommittee, and we have three of the members 3 sitting at your table today and they can add to this 4 discussion, there was a lot of question about where to 5 draw that line. It was felt that after data 6 collection is over, but not necessarily after data 7 analysis is over was our comfort zone, if you will, 8 and that's why it was brought forward in the present 9 manner. 10 CHAIR PRENTICE: Dr. Powe? 11 MEMBER POWE: Yeah, one situation that 12 commonly comes up in my experience has been the issue 13 where data finished being collected and an 14 investigator has a colleague, another investigator, a 15 trainee that would like to use that data and actually 16 might like to use identifiable data, in fact, let's 17 say, you know, medical record reviews or whatever, 18 that is related to the parent study that falls under 19 the aims of the parent study, but pursues a slightly 20 different hypothesis. The universities are 21 responsible for assuring that any individual who 22 engages in human subjects research is certifiable and 61 1 has undergone training. 2 And so when that new investigator comes 3 in, that's usually reported to the IRB to make sure 4 that, in fact, they have had training. 5 So my question here or if there is a 6 dilemma here, if continuing review ends and there are 7 new investigators who join and then want to explore 8 new issues, would they have to submit a whole IRB 9 proposal -- 10 CHAIR PRENTICE: Yes. 11 MEMBER POWE: -- to undertake that 12 investigation -- 13 CHAIR PRENTICE: It would be a new 14 proposal. 15 MEMBER POWE: -- as opposed to falling 16 under the original one and this could be for studies 17 that go on for, you know, years and years. 18 MEMBER NELSON: Excellent question and I 19 think many of us recognize that scenario. I think the 20 operative phrases in your words as you've described 21 that were new issues, new hypothesis and one of the 22 reasons we tried to incorporate that and maybe we 62 1 haven't gone quite far enough but so as described in 2 the approved study plan or protocol, the idea was that 3 the investigators -- what we're closing the books on, 4 if you will, staffing IRB oversight is as described, 5 as -- they've done what they said they were going to 6 do. Now, if somebody new comes along, a trainee and 7 they're exploring new avenues, that would -- yes, that 8 would require -- we wouldn't want that to occur 9 without IRB oversight. 10 MEMBER POWE: Right. 11 MEMBER NELSON: And I suppose it could be 12 up to the local IRBs whether they had -- now we're 13 back to logistical issues. It would not be out of the 14 question that an IRB could find itself comfortable or 15 doable to reopen the former study adding on a new sub- 16 investigator, assuring training, et cetera, and 17 allowing an amendment, but I could hear other people 18 arguing that by the time you do that, maybe that 19 person should have just brought forth a concrete study 20 on its own merits recognizing that the data came from 21 a pre-existing study. 22 MEMBER POWE: Yeah, and I think a study 63 1 that was very active and a number of investigators 2 wanted to use that data, my concern was would it then 3 trigger, you know, 20 new full IRB reviews so the 4 balance of what the intention of this would be to 5 reduce burden would actually increase burden. 6 MEMBER NELSON: I think -- do you want to 7 respond? That's a good point. That could happen. 8 MEMBER POWE: I don't know -- it's a 9 dilemma. 10 CHAIR PRENTICE: Right, it is. I think 11 Susan is next and then Ada Sue. 12 MEMBER KORNETSKY: And serving on the 13 subcommittee for this and struggling between the way 14 that OHRP has interpreted it and understanding, the 15 way that I personally, you know, feel comfortable with 16 this is that when we review our research protocol and 17 talk about data analysis, part of that data analysis 18 usually includes that identifiers are removed, they're 19 kept separately and the data analysis, you know, 20 continues. So I don't -- my own feeling is that as 21 long as the IRB in the initial protocol reviews and 22 approves that, that as long as that continues to 64 1 happen that we can stop it after the data collection. 2 Now, if an investigator were to then say - 3 - we would have to educate them and then they'd say, 4 okay, now they forgot a data point and they need to go 5 back, then that would need to come back to the IRB. 6 So I'm almost looking at this as sort of a -- that 7 we're looking in the future and approving a plan for 8 data analysis which should include that identifiers 9 shouldn't be on the primary data, and that as long as 10 that is followed, there's no reason that the IRB -- 11 there's nothing additional that the IRB is going to 12 add. 13 However, if anything changes, even to the 14 point of having to go say, "Whoops, you know, we have 15 to go back to 10 subjects because we didn't know that 16 this data" -- you know, we want this data analysis 17 point, this data point", then that would be a need to 18 come back to the IRB. So that's the way I've tried to 19 sort of pull together the concerns of OHRP, what the 20 regulations say plus sort of what's really protected 21 for the research subject. 22 MEMBER FISHER: Building upon what Susan 65 1 said, I think that's what's missing from the language 2 of the recommendation. That is that -- I don't know 3 how to put it in, but that once the removal of 4 identifiers from the data occurs, because that's true, 5 in much research you don't need the identifiers any 6 more when the data collection is truly over, even if 7 you're doing longitudinal research. And then it could 8 be that what -- so if the limit was once the 9 identifiers have been removed, then the -- for the 10 first part, then the obligation on the investigator 11 is, is that they must inform the IRB if for some 12 reason there is a need to go back to the identifiers. 13 But I also think one would then have to 14 address what happens, are you going to be keeping a 15 subject code book in terms of subject numbers and 16 identifiers and how that would be considered within 17 the mix. 18 MEMBER NELSON: That's an interesting or 19 I think a good point conceptually at least but I 20 think, again, viewing the scope of all research that 21 we're talking about, if we made it a requirement that 22 data were coded or stripped of identifiers and that 66 1 link broken, now we've moved truly to not human 2 subjects research based on OHRP's August, 2004 3 clarification. So if that was the case, if you have 4 in your possession data that are de-identified or 5 coded in such a manner that the current investigator 6 does not have access, the -- Dr. Powe's downstream 7 trainee who is going to do a secondary data analysis 8 if you will, that no longer in the eyes of OHRP 9 guidance and in the processing the procedures of many 10 IRBs is no longer human subjects research requiring 11 IRB review. 12 MEMBER KORNETSKY: I'm not suggesting that 13 the link be broken. It's that the link not be used. 14 I mean, that's the way I'm looking at it. The link 15 maintains -- the code book maintains, it's there but 16 for purposes, you know, the way I'm interpreting -- 17 this is the way I would think about it and maybe I'm 18 interpreting it wrong, is that once you have -- you've 19 collected your data and you're ready to analyze it, 20 there's really no need that someone need -- although 21 the link is there, there's really no need that anyone 22 as to go and look at it. If for some reason they have 67 1 to go and look at it, then that is where I'm thinking 2 it needs to come back to the IRB but as long as 3 there's a plan that the analysis is ongoing. 4 MEMBER NELSON: And, indeed, I think that 5 already happens in a lot of settings. Maybe the 6 question is could we impose that on all research which 7 is really what we're aiming at with a recommendation 8 of this nature. 9 CHAIR PRENTICE: You know, I like this 10 recommendation, but I want to raise a couple of issues 11 for discussion. One is the definition of research 12 which is a systematic investigation, et cetera, et 13 cetera, which obviously includes data analysis. 14 That's what a systematic investigation is. And in 15 some protocols, it is the investigator that performs 16 the data analysis and in other protocols like co-op 17 studies, or pharmaceutical sponsored studies, the data 18 is submitted to the sponsor and the investigator does 19 not perform any analysis. 20 So I'm wondering what kind of impediment 21 it would be to change this to say when data collection 22 and analysis for research purposes is complete as and 68 1 I emphasize the word "as" described in the approved 2 study plan protocol. And I know that, Dan, I think 3 you made comments about, you know, sometimes the data 4 analysis takes years. 5 Well, I would contend that in the vast 6 majority of research projects it doesn't take years to 7 analyze the data according to the plan described in 8 the protocol because investigators are not going to 9 spend five years working on a publication that results 10 from the data that they gathered in an IRB approved 11 research project. 12 So what do you think the downside would be 13 to insert the word "and analysis as described in the 14 approved protocol", because sometimes there is going 15 to be no data analysis described at all. It's not 16 there because the investigator is not doing it. And 17 sometimes they are doing it and if you -- that would 18 be consistent with OHRP's interpretation of what a 19 systematic investigation means. I mean, I think 20 that's where Mike was going when he said, it's got to 21 be not only collection of the data but also the 22 analysis of the data assuming that the investigator is 69 1 the one who's doing that. 2 So I'm just throwing that out for 3 discussion. 4 MEMBER GYI: Ernie, I think that that gets 5 us in the right direction but the concern that I have 6 and a question to you was we're now looking to help 7 bridge the OHRP 45 CFR 46 language and part of the 8 difference interpretation-wise in 45 and 21, if we say 9 completion of data analysis, then that hamstrings the 10 IRBs that are overseeing FDA regulated products 11 because then you'd have to provide that oversight 12 until the sponsors have finished with their analysis. 13 CHAIR PRENTICE: No, no, it's -- the key 14 phrase in your recommendation is "as described in the 15 protocol". You're not going to have data analysis 16 described in the sponsor's protocol, because you know, 17 the investigator's not doing it. 18 MEMBER GYI: No, but you do though. I 19 mean, many times you do have data analysis that's 20 described in sponsored -- commercially sponsored 21 research protocol and there are people like Dr. Powe 22 here who may want to address that but it may take 70 1 years for the data base to be cleaned up and locked 2 and then the data analyzed. 3 MEMBER SELWITZ: I'm getting confused. 4 Can I ask for a clarification, Ernie, because I 5 thought I agreed with Ernie but I want to make sure I 6 understand. I thought you weren't -- I thought you 7 were proposing that we do stop after the data 8 collection, just as proposed here. You were just 9 proposing that the analysis has to be the analysis 10 that was originally approved in the protocol, which I 11 would agree with that. I mean, I think that is a 12 condition, but you weren't changing the line where we 13 would -- you were leaving the line, right, Ernie, 14 after -- before data analysis. You're just saying 15 that the data analysis that's going to be done, has to 16 be that which we approved and rather than going in a 17 new direction. 18 CHAIR PRENTICE: Well, I don't know. I 19 know what you're saying. I guess I'm trying to get a 20 handle on -- trying to make a bridge between this 21 recommendation and what I understand OHRP's position 22 to be. And I think that they feel like systematic 71 1 investigation includes data analysis. The PI is 2 responsible for the data analysis and therefore it's 3 got to be subject to IRB review and this 4 recommendation may be contrary to OHRP, interpretation 5 of the regulation which I can understand, you know, 6 the rationale for that interpretation. 7 I don't have too much of a problem unless 8 someone wants to enlighten me, when the PI -- the PI, 9 let's take an investigator initiated study. They're 10 responsible for the analysis of the data, okay. I can 11 understand perhaps a rationale for saying, "Okay, 12 continuing review under those circumstances is 13 warranted. On the other hand, once you've collected 14 the data it's out of your hands, like in a co-op study 15 or a typical pharmaceutical sponsor stud, it's out of 16 your hands. Then you're no longer performing a 17 systematic investigation. 18 The systematic investigation is basically 19 ended with the data collection. So obviously, there's 20 no reason for an IRB to conduct continuing review 21 under those circumstances. So what I'm trying to get 22 a handle on, is there a down side in terms of 72 1 additional undue burden on IRBs to say, all right if 2 the PI is responsible for the data analysis, then it's 3 still subject to continuing review. That's what I 4 want to get on the table, because I heard your comment 5 about years and years and years, but I'm trying to 6 understand under what circumstances a particular 7 research project, as described, as described, the 8 initially approved IRB protocol would take years and 9 years and years. I can understand Neil's comment 10 about utilizing existing data and having different 11 hypotheses. You're going down different tracks, okay, 12 that's an amendment of a protocol or it's a new 13 protocol. 14 But you're talking about years and years 15 and years and I don't know any investigators who spend 16 years and years and years analyzing the originally 17 collected data for the same purpose described in the 18 project. 19 MEMBER SELWITZ: All the time, I mean, I 20 just have to say, I wish I could say that 21 investigators don't and I think -- I unfortunately was 22 not at the subcommittee meeting but I read the minutes 73 1 and I read this recommendation and I'm extremely 2 supportive of it from the perspective that I think 3 it's ethically viable, I mean, appropriate plus I 4 understand what's happening in the field. If we don't 5 find a way to take off our plate those issues that 6 really aren't, as Dan says, value added, we're going 7 to continue to drown to the point that we're 8 ineffective on those things that aren't terribly 9 important. So let me just be clear. 10 I support this. I also fully understand 11 and was hoping see, you wouldn't bring that question 12 up, the regulatory problems that this recommendation 13 will invariably, if it goes forward, be left with 14 OHRP to sort out, but I don't see -- for me this 15 recommendation, the value is for my single 16 investigators in the social science area, in the 17 education area, that simply do not get around to 18 analyzing their data and keep it for years and years 19 and years. 20 I also think your point about the new 21 protocol and the change, I think that's very 22 important, that it be very clear that new comes in, 74 1 but see, that's my current policy. So in a way, what 2 you're proposing, this is not -- would not be at least 3 in my system an increased burden because we bring it 4 in as new. Do you understand? When they switch to 5 something new and they're talking about a different 6 kind of analysis, and they've got identifiers, we 7 bring it in as a new protocol. So then at least I my 8 system, the issue you raise, sir, this wouldn't be an 9 additional burden. 10 All right, but if you cut that -- you 11 know, I mean, if you cut that line before or after 12 data analysis for those single investigators, then 13 this will not be value added. 14 CHAIR PRENTICE: All right, I have a 15 question. I want to go back to the regulatory 16 considerations that this recommendation may 17 precipitate and I guess I'll have to ask OHRP to 18 comment on that. The definition of research is the 19 definition of research. It should apply equally 20 across all situations, so to go back to the two 21 examples that I gave earlier; one, you have a co-op 22 study which involves a systematic investigation 75 1 designed to contribute or develop generalizable 2 knowledge that obviously must necessitate analysis of 3 the data which is not carried out by the PI. It's 4 not, okay? 5 Under the current OHRP guidance, as I 6 understand it, you say, well, all right if the IRB, if 7 the PI is not involved in the analysis of the data, 8 therefore, you don't -- the IRB does not have to do 9 continuing review. That's what you said and I think 10 you said that at a subcommittee meeting, Mike, right? 11 Okay. 12 On the other hand, if the PI is 13 responsible for analysis of the data, then it's the 14 position of OHRP that research is continuing; 15 therefore, you need to have IRB review. Now, in terms 16 of consistency of human subject protection, across 17 institutions and across types of studies, how does 18 OHRP justify having what is more or less two different 19 standards where the IRB is involved in one 20 circumstance but the IRB is out of the loop on the 21 other circumstance because of a technicality in that 22 they don't have the data for analysis. 76 1 To me, I understand the definition of 2 research but this doesn't make a lot of sense when we 3 apply it that way. So would you care to respond? 4 DR. CAROME: I don't think there's an 5 inconsistency. It depends upon which sites or 6 institutions continue to be or remain engaged in the 7 human subject research activity. So if you have a 8 multi-center study in which 10 sites have enrolled 9 people interacted with them, collected identifiable 10 private information and now they're sending all that 11 information to say a coordinating site at another 12 university or to a sponsor or to an oncology group 13 site. Only that site or institution that continues to 14 do the analysis of the identifiable information would 15 continue to be engaged in the research and it's that 16 site, if the research is subject to our regulations, 17 that we would say needs to continue to have continuing 18 review done at least annually. 19 The other sites that are down there, were 20 they sent the information and the data and they have 21 no other involvement in the research. Well, they're 22 no longer engaged and they don't need to have their 77 1 IRB continue to have continuing review because they're 2 not engaged in the research any more. So we don't see 3 an inconsistency there. It's just a matter of who 4 remains engaged in the human subject research and it's 5 that site or institution that continues to need 6 continuing review. 7 And just because I'm highlighting the 8 differences between the proposed recommendation and 9 what our current view is, you should not interpret 10 that as we're rejecting the recommendation a priori at 11 this point. I'm just -- you asked me to clarify what 12 our position is and how it's contrasted. It doesn't 13 mean because there's a contrast we are a priori 14 rejecting the recommendation. 15 CHAIR PRENTICE: Do you have the power to 16 reject our recommendations? 17 (Laughter) 18 MALE PARTICIPANT: He does have a uniform 19 on. 20 MEMBER SELWITZ: Ultimately, Ernie, 21 ultimately, they do. 22 (Laughter) 78 1 MEMBER GYI: Ernie, there's just, if we 2 stay with that notion of being engaged defines 3 systematic investigation, if we use that as an 4 assumption, then this definition should work, right, 5 because then if the investigator is no longer engaged 6 in systematic investigation because the data has been 7 submitted elsewhere, then this definition should work. 8 MEMBER SELWITZ: It does for biomedical 9 multi-center trials. It does not work for those of us 10 that are involved with social science, single 11 investigator trials. 12 MEMBER NELSON: That's right. 13 CHAIR PRENTICE: Dr. Powell, do you have 14 something? 15 MEMBER POWELL: Yeah, I was going to 16 comment on a couple of things. And that is with 17 industry sponsored types of clinical trials, perhaps 18 two cases where in the protocol we may state that 19 we're going to continue to conduct follow-up on people 20 that were participating in trials. For instance, we 21 often have a situation where we include women of 22 child-bearing potential that requires us to continue 79 1 to follow up on if someone, for instance, becomes 2 pregnant during the course of a study, which it says 3 in the protocol you're going to continue to follow up 4 and that may be for quite a long period of time. 5 The other place in -- that's becoming more 6 frequent in the types of trials we do for industry are 7 biomarker analysis, meaning we are including 8 statements in our protocols that say we are collecting 9 samples, some type of samples for biomarker analysis 10 that we, in fact, may not totally describe in the 11 protocol except that we're going to do it from time to 12 time and that may be genetic analysis, other kinds of 13 things that may take years and years and years to 14 really do, and I wonder if this -- how that fits upon 15 -- under your plan for discontinuing -- stop the 16 continuing resolution at the completion of analysis 17 when that analysis may, in fact, be triggered by other 18 things that are within the protocol that you can't 19 anticipate. 20 CHAIR PRENTICE: I assume that based upon 21 what you said, there would be a description in the 22 protocol about, you know, looking at biomarkers at 80 1 some point in time, so I would say that that's further 2 collection of research data, so it would be subject to 3 continuing review because it's in the protocol. Your 4 data is not completed yet. It's not collected yet. 5 And it might have to go on for years and years and 6 years. That's the way I would interpret this 7 definition applied to your scenario. 8 On the other hand, routine clinical 9 follow-up data not obtained for research purposes 10 would not factor in. There would be a difference. So 11 you could follow, for example, a cohort of patients 12 for life as long as you're not collecting data for 13 research purposes. It's considered routine clinical 14 follow-up. To be doing anything for research 15 purposes, it would be research subject to continuing 16 review. Okay, questions, discussions and see if we 17 can move on. 18 MEMBER FISHER: I was just trying to 19 figure out how to reword it to try to add what you 20 were talking about as well as the issue of 21 confidentiality. I know that the one thing we can't 22 solve is the fact that if the data analysis as planned 81 1 continues for a long time, that seems, you know, is 2 going to be a remaining issue, but if it said 3 something like OHRP should clarify its guidance on the 4 required duration of continued review, continued 5 review may end when all research interventions and 6 interactions with subjects are over, and data 7 collection and analyses for research purposes is 8 complete as described in the approved study plan 9 protocol that the research cycle which the IRB has 10 oversight and confidentiality protections remain in 11 place. 12 Now, the only thing that doesn't answer 13 is, is that if they continue to analyze the data as 14 planned, it has to continue to be reviewed. 15 MEMBER SELWITZ: And if you do that, then 16 for all practical purposes, this is no different -- 17 we're not making a recommendation. I mean, for all 18 practical purposes that's what we have now. 19 CHAIR PRENTICE: That's correct. It's no 20 different. All right, look, we've spent a lot of time 21 at the last meeting discussing this. We spent more 22 time on this one recommendation last time and it looks 82 1 like we're repeating what we did before. I think we 2 need to, you know, get off the mark and decide what we 3 want to do. I would certainly entertain a motion with 4 regard to this recommendation. I don't' see it being 5 modified. I mean, you either go one way or the other. 6 Well? Ada Sue? 7 MEMBER SELWITZ: I move that we accept it. 8 CHAIR PRENTICE: All right, you all know 9 parliamentary procedure. How long does it take to 10 get a second on something here? 11 MEMBER KORNETSKY: I'm going to second it. 12 CHAIR PRENTICE: All right, very good. 13 Moved and seconded. Further discussion? Hearing 14 none, I want a show of hands. All those in favor of 15 the motion raise your hands. We're going to need to 16 get a count here. We've got one, two, three, four, 17 five. And we have -- yeah, we do have a quorum and 18 it's a majority of the quorum, yeah. Okay, so yes, 19 the motion passes. 20 All right, let's see. We have some more 21 time, would you like to try to get through your next 22 recommendation? 83 1 MEMBER NELSON: Yes, that would be great. 2 Thank you for that. Despite the time, and Ernie's 3 right, we spent time last time and we spent time again 4 today, but in our minds this is a big ticket item. 5 There's a reason, I think this was number one and we 6 appreciate the good discussion that just occurred. 7 This is just what we need to have happen. 8 So question number 2, are there 9 circumstances when continuing review can appropriately 10 begin to be conducted less often than once per year? 11 I'll spend comparatively less time painting the 12 backdrop for this but one part of this historical 13 context is to share with you the preamble to the 14 original regulations at that time Department of 15 Health, Education and Welfare, that came out in 1981 16 which stated that, "The precise procedure adopted by 17 the IRB for continuing review without unnecessarily 18 hindering research," that was part of their thinking 19 at that time, "should be left to the discretion of the 20 IRB". 21 The next sentence of the same preamble 22 stated that, "Reporting requirements may vary from a 84 1 simple annual notification in the case of research 2 involving little to no risk to more frequent reporting 3 or for clinical trials the IRB may require a special 4 mechanism to carry out data and safety monitoring 5 functions", and in a previous presentation to you, I 6 think Gary Chadwick, our task force chair, asked 7 somewhat rhetorically if we had moved quite a ways 8 beyond the notions that were embedded in that 9 preamble, the simple annual notification, are we 10 making adequate use of the special mechanisms to carry 11 out data safety monitoring functions which were 12 anticipated way back then but as we know, IRBs are now 13 trying to remove themselves from roles that might 14 better be covered by DSMBs and other bodies that are 15 in place to do these analyses. 16 Just to repeat the reference that I shared 17 before, the discrete reference in the regs to 18 continual review. "An IRB shall conduct continual 19 review of research covered by this policy at intervals 20 appropriate to the degree of risk but not less than 21 once per year". There is no regulatory basis for the 22 current content of the continual review process 85 1 itself. Both Health and Human Services and FDA have 2 pointed IRBs to Section 111, the criteria for IRB 3 approval that must be satisfied whether full board 4 review or expedited review, whether initial review or 5 continuing review. 6 The subcommittee feels that the 7 requirement for at a minimum annual review limits the 8 flexibility of IRBs to employ appropriate procedures 9 and criteria for ongoing review. For minimal risk 10 research, the requirement for annual review is neither 11 related to nor, in quotes, "appropriate to the degree 12 of risk". So this is, I think of all the changes 13 we'll put forth, the first one and the only one today 14 that would actually require a regulatory change as 15 opposed to a change in interpretation and guidance. 16 But the recommendation is that OHRP should 17 issue an advanced notice of proposed rule making to 18 seek comments regarding changing Section 46.109(e) to 19 allow IRBs latitude in setting review dates beyond one 20 year and the subcommittee would propose on further 21 discussions beyond what you saw last time, that there 22 be a cap of two years put in place, recognizing that 86 1 open-ended terms are not desirable, for minimal risk 2 studies but potentially for other studies as well". 3 This recommendation received a lot of 4 further discussion and debate and I think I would 5 stress the point that we're not rewriting the 6 regulation with this recommendation. We are 7 suggesting that a call be put out for comments from 8 the research community, from IRBs, from investigators, 9 from the public as to the desirability of the current 10 limit for one year. 11 This recommendation actually comes in 12 three parts and perhaps let me go through the next two 13 slides and then we'll return to these and you can take 14 them in order if you wish or as a set. In this 15 advanced notice of proposed rule-making, OHRP should 16 also seek comments on the regulatory application of 17 46.111 to continual review and/or adding a new section 18 that would define simplified criteria and the 19 expectations for the content of continuing review 20 being based upon current risk level and this somewhat 21 addresses Celia's earlier point whether a streamline 22 process could be put in place at continual review 87 1 beyond what's currently practiced or replacing what's 2 currently practiced. 3 In the interim, OHRP should revise its 4 interpretation and develop new guidance to permit IRBs 5 to develop within their written procedures, policies 6 and procedures for the selective application of 7 Section 46.111 to continual review and we'll return to 8 this theme. We would like, to the extent possible, 9 that FDA guidance be harmonized with this so in this 10 case, that should, likewise be updated. 11 Those are our recommendations on question 12 number 2. 13 CHAIR PRENTICE: Okay, thank you. You 14 indicated, Dan, that you're not proposing changing the 15 regulations. You're proposing that OHRP seek comments 16 with regard to changing Section 46.109(e). And you're 17 also recommending that OHRP seek comments, presumably 18 at the same time, in order to define, simplify 19 criteria and the expectations for the content of 20 continuing review being based upon current risk level. 21 Then you go onto recommendation 2.3, which 22 basically states that in the interim and I don't know 88 1 how long that would be, before not only a proposed -- 2 advanced notice of proposed rule making would be 3 published in the Federal Register and comments 4 analyzed, it's obviously not going to be within a 5 matter of months. It will be longer than that. 6 But you're saying that OHRP should revise 7 its interpretation and develop new guidance to permit 8 IRBs to develop within their written procedures 9 policies for selective application of Section 46.111 10 to continuing review, so here's the thrust of my 11 question. On the one hand, it would appear in 12 recommendations 2.2 you want the public to comment on 13 this issue but for the period of the next couple of 14 years, you're suggesting that IRBs be permitted to 15 develop their own procedures. Is this in any way a 16 bit of a contradiction and could that create problems 17 ultimately or not? 18 MEMBER NELSON: A fair question. It's 19 clear to us and clear to all of you that the change in 20 timing of review extending beyond a minimum of one 21 year would be -- or a maximum of one year, sorry, 22 would require regulatory change. It's our sense that 89 1 the application of 111 in its full-blown glory, if you 2 will, to continual review, would not require the same 3 regulatory change but is based more on current 4 understanding and interpretation. 5 Now, whether we're trying to have our cake 6 and eat it too by asking for comment at the same time 7 we're starting to implement which is really your 8 question, Ernie, it could be interpreted that way. 9 Again, I think the sense is that the current 10 application of 46.111 in all its elements to continual 11 review is unnecessarily burdensome, it's not value 12 added and should be addressed sooner rather than 13 later. 14 Felix, go ahead. 15 MEMBER GYI: Part of the subcommittee's 16 discussion revolved around the preamble and 17 understanding of what the initial intention of 18 continuing review was meant to be. OHRP has, in its 19 guidance, said that the continuing review should carry 20 the full force, if you will, of initial review and I 21 think part of the discussion for the subcommittee 22 revolved around is there something we can do in the 90 1 interim while we're waiting to see if we can extend 2 the period from one to two years to see if we might be 3 able to get some flexibility regarding what the IRB 4 has to do at the continuing review period. I don't 5 know if that helps, Ernie. 6 CHAIR PRENTICE: Okay, let me adopt a 7 slightly different tact. I fully understand the need 8 for an advance notice of proposed rule making for 9 recommendations 2.1. With regard to recommendations 10 2.2, I certainly endorse the recommendation but I'm 11 also reminded that it took OPRR/OHRP a very long time 12 to issue an guidance on continuing review, despite the 13 fact that regulations never changed and we all know 14 that. It's been an evolving process. 15 Therefore, given that fact, is there even 16 a need for OHRP to go through the advanced notice of 17 proposed rule making rather than come up with a 18 response to simplified criteria based upon current 19 risk level which is certainly something we considered 20 anyways? That's inherent in the application of the 21 regulations and thereby, try to avoid the -- you know, 22 the couple years this is going to take to have any 91 1 changes actually made. So I guess that's what I would 2 like to throw out on the floor for discussion. 3 MEMBER NELSON: So to paraphrase, Ernie, 4 you're basically suggesting striking 2.2 and indeed, 5 these are, although they're related elements, they 6 could have been presented to you as truly two separate 7 recommendations, because one deals with the timing of 8 review, the other deals with the content or structure 9 or intensity, if you will, of that review. 10 CHAIR PRENTICE: Yeah, I guess what I'm 11 suggesting is that you go with 2.1 which is obviously, 12 distinct, separate, but in terms of 2.2 and 2.3, you 13 eliminate the need for the proposed -- advanced notice 14 of proposed rule making and you simply indicate to 15 OHRP, you know, you need to issue guidance that is 16 relevant to the nature and risk level of the project 17 as opposed to what is considered current guidance 18 which is very, very comprehensive which I think is 19 what we're saying is needlessly detailed and 20 comprehensive; is that not correct? 21 I'm just throwing that out for 22 consideration. Susan first. 92 1 MEMBER KORNETSKY: Yeah, I mean in 2 thinking about this trying to think about it with the 3 subcommittee, it makes sense, and then you think about 4 it months later and it's different. I tend to agree. 5 My concern would be if IRBs are given the latitude to 6 start doing this and then after that we get comments 7 and then it gets potentially tightened up on it, then 8 it's going to be looking like we're being very 9 restrictive and over-regulating. 10 CHAIR PRENTICE: That's where I'm going. 11 MEMBER KORNETSKY: So I mean, I think I do 12 have a concern with that. I do think OHRP probably 13 has it within their power to issue guidance about what 14 elements should be applied and I totally -- I think 15 thinking about this a second time, agree with trying 16 to separate the issues out, handling what we need to 17 by regulatory change and not making the -- you know, 18 not adding additional regulation where we don't need 19 it. And I think that's maybe what we would end up 20 doing here in thinking about this a second time. 21 CHAIR PRENTICE: Ada Sue? 22 MEMBER SELWITZ: I like this idea, Ernie. 93 1 I think it's a good idea. I think it's a good idea to 2 separate this out into two totally different 3 recommendations; one deals with the period of time, 4 the other deals with whether you apply 46.111 when you 5 do a continuing review and make them separate. And if 6 I understand you correctly, Ernie, what you're really 7 saying is the issue of 46.111 could be handled with 8 guidance. And I think it could be handled with 9 guidance and I'm a big proponent of continuing review 10 for particularly certain types of protocols and don't 11 think that 46.111 really serves as the best model when 12 you do continuing review. 13 You know, that there are some issues that 14 don't -- aren't, in fact, necessary and there are 15 other issues that you need to add that aren't in 16 46.111. So I love this idea, Ernie, of separating 17 them out, two separate recommendations and one of 18 which could be done by guidance, we hope. 19 CHAIR PRENTICE: Okay, we are five minutes 20 past the break. Do you want to try to bring 21 resolution to some of this? Let's take recommendation 22 2.1 first. I'll entertain a motion. Well, we can go 94 1 on a break. 2 MEMBER KORNETSKY: Let's get this done. 3 I motion that we accept recommendation 2.1. 4 MEMBER JONES: Second. 5 CHAIR PRENTICE: That's a good motion, and 6 seconded. Any further discussion of 2.1? All those 7 in favor, raise your hands. Any opposed? Any 8 abstentions? Motion carries. 9 I'll entertain a recommendation of a 10 combination of 2.2 and -- no, not even 2.3. It's 2.2 11 with the elimination of the necessity for an advance 12 notice of proposed rule making. You can tinker with 13 the language a little bit but we all know what the 14 intent is. The intent is to apply the IRB approval of 15 continuing review criteria in consideration of the 16 nature of the research and the risk level, et cetera, 17 right? And that's what we're asking, correct? 18 All right. I'll entertain a motion. 19 MEMBER POWELL: I move. 20 CHAIR PRENTICE: Okay. 21 MEMBER SELWITZ: Second. 22 CHAIR PRENTICE: Okay, all right, it's 95 1 been motioned and seconded. Any further discussion? 2 All those in favor raise your hands. Any opposed? 3 Any abstentions? Motion carries. We're going to take 4 a break until, let's see, five of, five of 11:00. 5 (Whereupon, a short recess was taken.) 6 CHAIR PRENTICE: All right, Felix, Dan, 7 would you proceed? 8 MEMBER NELSON: So the next item formerly 9 labeled question 6 and so we've kept that number 10 intact for this first report on continuing review was, 11 "Can existing guidance on continuing review be 12 consolidated and integrated? Let me start out by 13 stating for the record my personal sense that actually 14 OHRP has already come a long way toward this goal. My 15 sense is, as I go out both for the subcommittee 16 efforts and for my own use at my own institution, it's 17 easier and easier to find guidance all the time and 18 pull it together and integrate it into practice. 19 We may still have some issues with the 20 content of the guidance and we've identified some of 21 those issues and we're talking about some of that now, 22 but I think that's coming along and nevertheless, the 96 1 subcommittee has identified the guidance issue, the 2 format and the complexity and the accessability of it 3 as an issue that overarches all of our deliberations 4 and therefore, I'm bringing that forward on their 5 behalf. 6 So the observation has been made that 7 absence of consolidated guidance makes regulatory 8 compliance more difficult than is necessary. IRBs 9 have been forced to explore extensive case law in the 10 form of FDA and OHRP determination letters, old OPRR 11 reports, Dear Colleague letters, et cetera, et cetera 12 and pull that all together and make sense of it, and 13 there was a strong sense that the field needs 14 simplified, unified and practical guidance for 15 continuing review. 16 This is something of a follow-on to the 17 November meeting because there were actually two 18 components to this recommendation that we brought 19 forward at that time and really just the vagaries of 20 process left us approving 6.2 but leaving 6.1 on the 21 table. And in that context, because they were to 22 tightly related, let me repeat what SACHRP approved in 97 1 November, which read, "OHRP should prepare simplified, 2 unified and practical guidance for continuing review 3 that focuses on the substance of review", and that was 4 approved. Left as a loose end of sorts, and that's 5 why I won't spend a lot of time on this, I think is 6 that OHRP should revise its continual review guidance 7 and clearly delineate those continual review actions 8 required by the regulations from those that are 9 derived from the regulations by interpretation. 10 I've noted there that this sub- 11 recommendation, 6.1 was tabled on November 1st and 12 previously, in the earlier iteration included a 13 reference to delineating from those that are common 14 practice or best practice and we struck that not 15 wanting to embed those, even by reference, to best 16 practices and so the qualifier of that element of this 17 recommendation was stricken. So the recommendation in 18 front of you is, "OHRP should revise continual review 19 guidance delineating those that are regulatory and 20 those that are derived by interpretation". Ernie? 21 CHAIR PRENTICE: Thanks, Dan. I want to 22 understand, when you say "consolidated guidance", I 98 1 assume what you're saying is that the current OHRP 2 guidance which is posted on the website, really needs 3 to incorporate guidance that has been issued in the 4 form of OHRP determination letters and an example, of 5 course, would be the literature review which we'll get 6 into a little bit later. That's where you're going on 7 this. 8 It's confusing because of this lack of 9 integrated guidance, right? 10 MEMBER NELSON: Yes. 11 CHAIR PRENTICE: Okay, my next question 12 refers to the recommendation that's on the screen 13 right now, 6.1. It would appear that 6.1 is pretty 14 closely tied to 2.2, which has just been passed. Do 15 you see those as two distinct recommendations or do 16 you see it as one recommendation being integrated? 17 MEMBER NELSON: I think the focus of 18 question 6 was just really the integration, the 19 consolidation, the accessibility of guidance so I see 20 it as separate, I guess, even though they may be 21 related conceptually. Felix, would you disagree or 22 agree? 99 1 MEMBER GYI: Now that we've changed 2 to 2 be a little bit more correct, I supposed we could 3 blend 2 and 6 because it does have some common ground. 4 Just by way of background, Ernie, one of the things 5 that stayed with the subcommittee was the fact that 6 there was -- there were determination letters and 7 there were some other actions relating to continual 8 reviews that people were sort of extracting from in 9 terms of calibrating their own behavior regarding 10 continual review. 11 And so the thinking behind 6, correct me, 12 Dan, was that there were lots of bits of information 13 that were out there and so the subcommittee felt that 14 OHRP probably ought to take a look at what's out there 15 and try and streamline what IRBs do in extracting from 16 other citations, whether they're determination letters 17 or guidances And so that was part of what led to us 18 separating out 6.2 from 2. 19 If we can blend both those concepts and 20 have one recommendation, it might make sense but at 21 this point, it still may make some sense for us to 22 have 6 separate from 2. 100 1 CHAIR PRENTICE: Okay, one more point; 2 there's a reference to consolidated guidance, 3 including FDA and we know that we've got FDA 4 information sheets which I have no idea about the 5 status of revision of those information sheets. And, 6 of course, we have ongoing issuance by OHRP of 7 guidance in one form or another on their website. I 8 understand the need for harmonized guidance. So I 9 guess I'm just asking for a comment about the 10 difficulties of trying to accomplish that goal. 11 MEMBER NELSON: And I will, indeed, end 12 the day if we get to slide 99 with a plea for really 13 formalized and aggressive attention to harmonizing 14 across the agencies that IRBs must follow. With this 15 particular recommendation in mind, I would note that 16 although on the framing the question slide previously, 17 we did note the FDA guidance along with OHRP, OPRR and 18 other sources. The recommendation itself does not ask 19 for what may be an impossible task in this setting or 20 perhaps, an inappropriate task to broaden the scope, 21 to FDA. The recommendation itself is focused on OHRP 22 guidance. 101 1 CHAIR PRENTICE: Okay, questions, 2 comments? Celia? 3 MEMBER FISHER: Yes. So it seems to me 4 we've already voted on, yes, we want some streamlining 5 of continued review. And then if we look at 6.1, I'm 6 not sure I heard what the advantages are, what the 7 goal is of OHRP distinguishing between what's in the 8 regs and how the interpret the regs. How does that -- 9 do IRBs not follow how the OHRP interprets the regs? 10 I just didn't understand what the goal is of OHRP 11 making that distinction, although I certainly 12 understand that advantages of hoping to consolidate 13 all the different guidelines that are there and have 14 the most up to date one, the first that one sees. And 15 I think that the fact sheets and things like that, 16 that are being produced are really helping in that 17 regard but I wasn't clear on why this distinction is 18 that important and even if it can always be made. 19 CHAIR PRENTICE: Felix, Dan, would you 20 like to respond? 21 MEMBER NELSON: Well, I'm not sure on the 22 last part of that and that would be up to OHRP to 102 1 address, but on the first part of your question, the 2 second being whether that distinction can be made 3 always but the first part of your question I think 4 you've put your finger on an issue that a lot of IRBs 5 would identify as problematic, namely the elevation of 6 single cases or single institution cases or guidance 7 to defacto regulation without necessarily the process 8 in consensus making that would normally underlie that 9 process and I think that's why there was a sense from 10 the subcommittee that it may be a helpful distinction 11 to clearly indicate what is regulatory requirement 12 from what is -- what are examples on how to apply this 13 that don't necessarily illustrate the only one true 14 way but one acceptable way of satisfying regulator 15 requirements which is how many of us would view 16 guidance as distinct from this is required no 17 questions asked under the regulations. 18 And that's a difficulty that I think many 19 IRBs grapple with and I think like it or not, when the 20 Feds say, "This is our recommendation", it has the 21 impact in the field of having passed into regulatory 22 requirement even if it was intended, perhaps, as an 103 1 example, a helpful instruction or guidance. Felix, 2 anything to add to that? 3 MEMBER KORNETSKY: I mean, I exactly 4 understand, Dan, what you're saying. I guess my 5 question in thinking about it again, not going against 6 the recommendations but why wouldn't that concern or 7 comment apply to all regulatory -- all the guidance 8 sheets then? 9 MEMBER NELSON: I doesn't -- I think when 10 we distributed work to the task force, we made this 11 question a generic question that we expected all task 12 force to answer in the context of their individual 13 area, whether expedited review, continuing review, but 14 really pulling it out, you're right, it applies to 15 everything we're doing. 16 CHAIR PRENTICE: And I think that's 17 potentially a problem. We understand that when OHRP 18 issues guidance, it's interpreted by the IRB community 19 as regulations, when, in fact, it's not always totally 20 supported by the regulations and I'm unaware of OHRP 21 ever issuing guidance that provided the clarification 22 as to what is a regulatory requirement versus what is 104 1 an interpretation and you can follow it as it is 2 appropriate to do so and not follow it under other 3 circumstances. So I guess I'm having a little bit of 4 trouble with that because as Susan indicated, it 5 really -- this clarification applies to all -- almost 6 all, maybe not all, but almost all guidance issued by 7 OHRP. Over the last, you know, 20 something years, 8 guidance has evolved which represents OHRP's 9 interpretation of the regulations. 10 So I'm trying to understand what the 11 specific advantage would be in terms of continuing 12 review to say okay, this is what's required, this is 13 what is an interpretation. It may or may not be 14 appropriate. And I go back to recommendation 2.2, 15 which is going to require OHRP to do exactly that, to 16 come up with what is a reasonable interpretation of 17 the regulations as applied to certain kinds of study 18 based upon risk. 19 MEMBER SELWITZ: Question, Ernie, so 20 basically what you're proposing is that at this point 21 we don't send this particular recommendation 4, 22 because in a way it's like mom and apple pie. You 105 1 know, it's something that we want throughout. And I'm 2 sitting here trying to think back and I sort of look 3 to the other people that were on the -- in the 4 subcommittee meeting. Is there something we're 5 missing here if we don't send this forward? Is there 6 something that we're missing looking at our co-chairs? 7 MEMBER NELSON: Well, I've thus far tried 8 to view my role as co-chair in bringing forth the 9 subcommittee consensus and the recommendation that 10 they did vote on and approve without necessarily 11 clouding it with my own personal sense, but on this 12 one, I'll say this is not a hill that I wish to die 13 on. So, I -- 14 (Laughter) 15 MEMBER NELSON: So you won't be hurting my 16 feelings and in fact, Felix and I were just whispering 17 to each other that, you know, maybe an appropriate 18 counterproposal here is to take this off the table 19 because indeed, we're getting at the content issues in 20 2.2 and other recommendations that you are addressing 21 and approving. 22 MEMBER GYI: Second. 106 1 (Laughter) 2 CHAIR PRENTICE: I don't think we vote to 3 take recommendations off the table. 4 MEMBER NELSON: I think Felix and I are 5 voting on that one. 6 CHAIR PRENTICE: All right, any objections 7 to removing 6.1? Hearing none, it's been deleted. 8 MEMBER NELSON: Moving onto something that 9 is a bit more complex and let me spend just a little 10 more time than the previous ones walking you through 11 some of the issues. So the questions to the task 12 force and to the subcommittee and, again, this was the 13 10th question in the previous report, "Does current HHS 14 guidance on setting the date of continual review, the 15 so-called 30-day rule, need to be changed to allow 16 more flexibility in the timing of review? How should 17 temporary lapses in approval be handled"? 18 So the genesis of this question lies in 19 the fact that many IRBs and their investigators find 20 it helpful to retain the anniversary date of a study 21 that goes over a period of many years. Bookkeeping, 22 getting in the habit, ease of record keeping, for 107 1 whatever reasons this is viewed as some IRBs, not all, 2 as advantageous. OHRP guidance in its current 3 consolidated format as it exists, is dated July 2002 4 and one section reads that, "OHRP recognizes the 5 logistical advantages of keeping the IRB approval 6 period constant from year to year throughout the life 7 of each project when continual review occurs annually 8 and the IRB performs continual review. Within 30 days 9 before the IRB approval period expires, the IRB may 10 retain the anniversary date as the date by which the 11 continuing review must occur. 12 A couple problems with this scenario; the 13 need for IRB review to be substantive and meaningful 14 at the time of continual review requires time for the 15 IRB to ask questions, for investigators to respond, 16 and for the IRB to seek further clarification. In 17 other words, it's an iterative process that simply 18 requires time and effort. There's an opposing, an 19 opposing influence from the 30-day rule which imposes 20 an artificially shortened time window, a compressed 21 time window, for -- within which that approval must be 22 granted. 108 1 In other words, you can't start before 2 that 30 days, you can't finish after. So these two 3 requirements tend to work each -- against each other 4 and therefore, in our minds, work against human 5 subject protections. The 30-day rule is functionally 6 an logistically problematic for IRBs and investigators 7 to apply and to work within. It can have the 8 unintended effect of generated automatic lapses if the 9 IRB requests clarification of the progress report 10 during review, which, of course, you would like an IRB 11 to be free to do, to explore questions, to clarify 12 issues, but if that IRB, like many, doesn't meet again 13 for another month, you've already expired the study, 14 it's a done deal and now you're into a different 15 scenario with a lapsed approval. 16 It may also have the unintended 17 consequence of resulting in IRB review of stale 18 information, if you have an investigator who responds 19 promptly to the IRB reminder or request for a progress 20 report. So many IRBs are in the habit and their 21 systems support a reminder notice or sometimes two or 22 three notices that are sent out before an approval 109 1 period expires of 60 days, 90 days, 120 days, 2 depending on the local system. 3 So if you have an investigator, and we'd 4 also like to encourage this, that investigators are 5 responsible and respond promptly. If one happens to 6 respond to let's say a 90-day reminder notice, that 7 information may then sit on the shelf of the IRB 8 waiting for 60 days to get within this 30-day time 9 window and what has happened during those two months? 10 A reminder of our underlying working 11 assumption; it's like paraphrasing interpretations 12 that restrict IRBs in establishing procedures that are 13 reasonable and appropriate to their local setting add 14 burden without any meaningful benefit and we think 15 this is one of them. 16 We would propose that if a defined time 17 window is still deemed necessary, that a 60-day rule 18 would be preferable to the current 30-day rule. This 19 would be more likely to avoid those automatic lapses 20 that I just described. It would be more responsive to 21 prompt submissions, better turnaround for responsible 22 PI's who we would like to encourage rather than punish 110 1 in effect, by this process. It would result in the 2 IRB reviewing fresher data and we would argue that the 3 additional four weeks that would come from extending 4 the so-called 30-day rule to a 60-day rule would 5 lessen administrative impact without any appreciable 6 loss to human research protections. 7 Because not everybody is steeped in these 8 intricacies of timing, I've tried to take another stab 9 at graphically laying this out if the foregoing text 10 didn't make this scenario clear enough. So picture, 11 if you will, a time line where a study received 12 approval on June 1st of 2005 and across this horizontal 13 time line then are the anniversary dates, which our 14 hypothetical IRB would like to maintain into the 15 future of the study. 16 The current 30-day rule would mean that 17 May 1st would be the earliest review occur under the 18 30-day rule and what we're asking for is that this be 19 extended by one more month effectively so that April 20 1st and I'm sure somebody is going to be counting how 21 many 30 days has September, April, June and November 22 and figuring out if I'm really 30 or 60 and I think I 111 1 counted this right, but you get the conceptual point, 2 I hope from this diagram. 3 And, of course, we'd be asking for the 4 same thing then on the next cycle around. So there 5 would still be annual review in effect but the time 6 window would not be quite so artificially compressed 7 and we think this additional 30 days would avoid or 8 minimize at least some of the problems that some IRBs 9 again, not all -- Felix and I don't happen to have 10 dogs in this hunt. We don't practice this at our 11 organizations, our IRBs. The approval date is the 12 approval date and if it changes, then so be it, and 13 our electronic systems manage that. 14 But for some IRBs and for some 15 investigators, this is an important tool, and if it's 16 going to be used, this would be what the subcommittee 17 would recommend. So our recommendation on this point 18 is that OHRP should revise its 30-day rule to remove 19 unnecessary restrictions on IRBs in scheduling 20 continuing review. If a defined time window is deemed 21 necessary, 60 days would be more appropriate. Ernie? 22 CHAIR PRENTICE: Okay, thank you, Dan. I 112 1 have to confess that the 30-day rule has always 2 confused me. I understand the term no less often than 3 annually because annually means 365 days a year. Then 4 you start throwing in the 30-day rule where you've got 5 an IRB that reviews a project 30 days in advance and 6 they can still maintain the same continuing review 7 date, so theoretically you could end up the next year, 8 and correct me if I've got my math wrong, but you 9 could end up the next year with a -- theoretically, a 10 13-month review, which seems to me to be inconsistent 11 with the regulatory language, so I never have 12 understood how OHRP was able to justify the 30-day 13 rule from a regulatory standpoint. Okay, so that's 14 one comment I want to make. 15 And so if you extend it to 60 days, then 16 theoretically, the next year might have a 14-month 17 approval period, if I'm correct in my calculations. 18 The second point I want to make is that I don't know 19 how many IRBs practice this 30-day rule. We, as you, 20 do not. The approval date is tied to the date of the 21 IRB meeting regardless of when we review the project. 22 We send out like 60-day notices and if an investigator 113 1 is responsive, then they get it in and then we usually 2 review it the next month, so basically, we're on an 3 11-month review cycle, but every now and then they 4 don't, right? They simply ignore us and then we have 5 to end up suspending projects. So one of the things 6 that I would like to see which I'm not so sure is 7 accommodated by your recommendation is that if a 8 continuing review process is already in place, in 9 other words, an investigator has submitted his or her 10 application for continuing review, the IRB is in the 11 process of reviewing it and maybe they're doing it at 12 the 12th month, okay, but at least they're doing it and 13 they're reviewing it, then if they ask for 14 clarifications or modifications or whatever they ask 15 for, okay, it should not require an automatic 16 suspension because you've gone beyond the 365-day 17 maximum window. 18 That kind of flexibility would certainly, 19 you know, help a lot of IRBs that are faced with 20 suspensions because, you know, you're two days out of 21 sync or you're a week out of sync and you have to 22 suspend the project. So I'm throwing that out for 114 1 discussion by the group in addition to the 60-day 2 window, okay? 3 MEMBER NELSON: Well, now things get a 4 little more complicated and let me note the following 5 slide here which was intended as an editorial note but 6 maybe it will become more functional. So previously, 7 again, just by the way these -- the motions and the 8 individual sub-recommendations were dealt with last 9 November, this group has previously approved items 10 10.1 and 10.4. 10.1 was a fairly major item that, 11 "OHRP should revise guidance to reflect that the final 12 approval of a study starts the clock for continuing 13 review". So this was the question and we spent a 14 great deal of time on this in November. 15 But without repeating that, when does the 16 clock start ticking? Did it start with the convened 17 IRB meeting or with the final approval, given that 18 there may be a substantive lag between those times? 19 10.4 was that wording in the guidance that refers to 20 individual requests should be revised to clarify that 21 the approval of a general request for all enrolled 22 subjects to continue in the research during the review 115 1 process is acceptable. So this refers to the scenario 2 where in patient-oriented research, treatment oriented 3 research, where it's often the practice to not 4 disenroll subjects when there's been a temporary lapse 5 in approval and things are being worked on for their 6 medical benefit or for their best care, that was 7 approved. 8 So we have modified what you're looking at 9 today with regard to the 30-day rule. We had an 10 element, 10.3, which read as follows, and Ernie, this 11 is to your point now, "OHRP should modify guidance so 12 that when continual review is underway," in other 13 words, both the IRB and PI are acting in good faith, 14 if you will, and the process is underway, "automatic 15 study suspension is not required when the expiration 16 date passes before review and approval are complete. 17 Guidance should specify strategies to prevent routine 18 delays and unlimited or open-ended review, i.e, 19 extensive time in the lab state, and specify 20 conditions and activities that will be permitted in 21 such circumstances". 22 Now, our subcommittee at its January 116 1 meeting, considered this set of recommendations and 2 realizing that you already approved 10.1 and 10.4 and 3 that you would hopefully be approving 10.2 in some 4 state today, the one that's on the table for the 30- 5 day rule, we agreed that 10.3 was effectively obsolete 6 and that was withdrawn. So you're not even going to 7 see a slide on that but effectively, you've brought it 8 back on the table and I -- that's not inappropriate 9 and we'd be happy to, I think, reconsider if you see 10 that solving an issue or addressing an issue that 11 isn't captured by one of the other three parts of this 12 recommendation. And I hope that outline was clear. 13 CHAIR PRENTICE: Okay, thanks for the 14 clarification. I just wanted to bring that out in the 15 open for discussion because I think it impacts looking 16 at this particular recommendation. The second thing 17 I'd like to get a clarification from OHRP so that I 18 understand how the 30-day rule fits in with the 19 regulatory requirements in the scenarios that I 20 outlined where an investigator goes ahead and at one 21 point in time submits early but the next time they 22 don't. So perhaps OHRP could clarify how that is 117 1 consistent with the regulations, that would help me 2 understand the regulatory consideration relative to 3 the 60-day rule that we're talking about. Michael? 4 It's the uniform, that's why we call on you. 5 DR. CAROME: The 30-day rule goes back at 6 least 10 years, I believe, although it's part of the 7 2002 guidance. Guidance on that topic goes back, I 8 think, to `95. So it's been there a long time and it 9 predates me. So I wasn't there when it was first put 10 into place. It's my understanding that the staff who 11 developed that at the time felt that within the 12 constrains of the 30-day rule over the life of a 13 multi-year project, on average the protocol would be 14 to do it at least annually. 15 But I understand the concern you're 16 raising and when the 2002 guidance was written, we 17 talked about does this meet the absolute requirements 18 of review at least annually. And depending upon how 19 you want to read a project, you know, continuing 20 review averaging out to be at least annually over a 21 lengthy multi-year project, we thought that that was 22 still an acceptable rationale but I see where if you 118 1 read -- strictly one could see that conflicts with 2 that language. 3 CHAIR PRENTICE: Okay so let me ask you 4 this; so you've made perhaps a case for the 30-day 5 rule by averaging the periods over the life of a 6 project, okay, and I can maybe see that with a little 7 stretch. Would it be harder to justify a 60-day rule 8 under those circumstances, using the same kind of 9 rationale? 10 DR. CAROME: I think you'd have the same 11 averaging out within those constraints. Over the life 12 of the project you'd still have a review that averaged 13 out to at least annually. So -- 14 CHAIR PRENTICE: Okay, all right. Ada 15 Sue? 16 MEMBER SELWITZ: And I'm not sure I should 17 jump in on this. I don't use the 30-day rule either. 18 I think most high volume IRBs do not use or even 19 moderate volume IRBs don't use the 30-day rule and I'm 20 sorry that the co-chair for this subcommittee, Gary 21 Chadwick, is not here because, in fact, he does use it 22 and he might be able to shed some light, but what I 119 1 will share, unfortunately, I was here in `95, okay, 2 and I do know that part of the reason -- or course, I 3 look at lot younger than Michael Carome, I want that 4 on the record. 5 (Laughter) 6 MEMBER SELWITZ: I wish. Okay, but 7 essentially, where -- who does typically use this are 8 small IRBs and it's a very important rule for them 9 because -- I mean, by small, I mean, low volume. Like 10 I work with an IRB that has 10 protocols a year. They 11 don't -- they aren't going to meet every month. They 12 simply aren't going to meet every month. They depend 13 on the 30-day rule. They need to have one approval 14 period. And that was what -- I mean, this was 15 actually -- we're here to talk about flexible 16 interpretations. This was done in an effort, what was 17 then OPRR, to give a flexible interpretation that 18 could help the low volume IRBs. 19 Now, I'm just throwing that out. I don't 20 use it myself so I had trouble throughout this process 21 quite understanding what were the implications of 30 22 to 60. I have no doubt the people that were on our 120 1 subcommittee that aren't represented today would be 2 very upset if we went forward with anything that said 3 we didn't support the 30-day rule. And I do know it 4 has significant impact for low volume. 5 I don't know if that helps, but that's 6 just a little institutional -- 7 CHAIR PRENTICE: Other questions, 8 comments? Yes, Celia? 9 MEMBER FISHER: I'm still not clear from 10 the discussion whether this is advantageous or more 11 confusing for IRBs, based on, you know, I just want 12 Ada's opinion or Susan's, those people who do a lot of 13 the IRB work. I'm just not sure given what Ernie said 14 and whether or not, is this going to make it more 15 confusing. Is it going to be 14 months or 10 months 16 or does this facilitate the review? 17 CHAIR PRENTICE: Susan? 18 MEMBER KORNETSKY: We don't use this 19 either because we're more moderate volume, but I would 20 say just from my experience in what it take sometimes 21 when you do a substantial review and you do raise 22 concerns and you want thoughtful answers and 121 1 discussion, 30 days is not a long period of time. And 2 so for those IRBs that use this, you know, it takes 3 time after meeting to generate letters, investigators 4 to respond, to bring it back to the committee to have 5 that back and forth. So I think that, again, just in 6 sort of the amount of time it would take, if something 7 came up, it probably is a little more reasonable. 8 CHAIR PRENTICE: Other comments? Dan, 9 remind me again what you said. I got kind of confused 10 over all the numbers, the 10.3 recommendation or 11 whatever it was. Is that the one that says that -- 12 MEMBER NELSON: 10.3 which we had planned 13 to take off the table, I guess because we had 14 convinced ourselves that the problems were addressed 15 adequately in the other parts of this -- of number 10, 16 but the current reading as was brought forward last 17 time was that OHRP should modify guidance so that when 18 continual review is underway automatic study 19 suspension is not required when the expiration date 20 passes before review and approval are complete. 21 In other words, it was to avoid this -- 22 well, it was to address the first question you asked. 122 1 CHAIR PRENTICE: Okay, then I don't see 2 the 60-day rule helping with that situation. All I 3 see the 60-day rule doing is that you can submit the 4 project 60 days ahead of time. Okay, if you're still 5 up against that review date set by the IRB, you know, 6 you're stuck. 7 MEMBER NELSON: Well, I think the sense 8 was that 60 days would lessen the chance that it will 9 -- that we'll have automatic passive, if you will, 10 lapses of approval as often as we do now under the 30- 11 day rule and I think that's where the recommendation 12 came from that we withdraw this one, but other 13 subcommittee members can correct my memory or extend 14 it. 15 CHAIR PRENTICE: Okay, then I would 16 suggest that for institutions that don't follow this, 17 you know, 30-day rule, this recommendation, whether 18 it's 30 days or 60 days, have no impact, okay. 19 Whereas, the 10.3 which was withdrawn and was -- was 20 I at that meeting? I was. 21 MEMBER NELSON: With bells on, Ernie. 22 CHAIR PRENTICE: Okay. That, you know, it 123 1 seems to me that that's an important, you know, 2 interpretation of the requirements for continuing 3 review as long as its underway, all right, that would 4 allow IRBs the flexibility of not having to -- you 5 know, to actually expire IRB approval unless they 6 chose to do so which they could. 7 I mean if the -- if during the course of 8 continuing review, you're up against that set IRB 9 review date, you have identified significant 10 clarifications or modifications, you know, you can 11 always suspend but if you haven't then you have to 12 give the investigator an opportunity to respond. So 13 I like recommendation 10.3 and I don't understand why 14 I didn't say something when it was withdrawn because 15 I don't even remember it being withdrawn. 16 MEMBER NELSON: Let me ask, perhaps as 17 devil's advocate, but from a regulatory perspective, 18 if we don't -- if we don't expire the study on -- at 19 the end of that 365-day period, have we not 20 effectively extended beyond the -- we're back to the 21 earlier question 2, can we review less often than once 22 per year? By not expiring it, haven't we effectively 124 1 granted ourselves a longer than one year approval 2 period? 3 CHAIR PRENTICE: I think if you look at 4 the guidance that's contained in the preamble, and if 5 you look at the exact regulatory language, it doesn't 6 say that the study has to be, I don't think, 7 reapproved. It says it has to be reviewed. Isn't 8 that an interpretation of OHRP that says you've got to 9 not only review the study but you have to reapprove 10 it. I don't think that that's necessarily supported 11 by the regulatory language. 12 So as long as the review is underway, 13 okay, at the time of the set review date, then it 14 seems to me that there is no regulatory requirement to 15 actually terminate, you know, or expire IRB approval. 16 I would invite OHRP to correct me if I'm wrong about 17 that. Would OHRP like to do that? Dr. Carome is 18 consulting his regulations. 19 MEMBER GYI: While he's doing that, Ernie, 20 just as a reminder, when the subcommittee met, we also 21 spoke about the fact that the larger volume IRBs that 22 get information ahead of time simply recalibrate the 125 1 approval date to the date of the meeting. 2 CHAIR PRENTICE: Right. 3 MEMBER GYI: And it was with that thinking 4 in mind that I seem to recall the subcommittee saying 5 if we had this 30-day rule extended to the 60-day 6 rule, then it allows for flexibility of those smaller 7 volume IRBs to be accommodated for their less frequent 8 meetings and low volume and for the larger IRBs to 9 simply continue to do what they're doing. And if it 10 exceeds that 365 days, I seem to recall somewhere that 11 we had to have some level of rule-making that had to 12 change to allow for IRBs to be able to provide 13 oversight for a greater than one year period. 14 And so if I recall correctly, the 15 discussions went along the lines that you know, if the 16 investigators violated that particular time frame, 17 that we do suspend the research but we don't have to 18 report it to OHRP because the guidance says that for 19 those simple lapses, we don't have to automatically 20 report information of those suspensions, if you will, 21 to OHRP but we could handle it on a local basis and 22 reinstitute the investigator back into compliance. 126 1 CHAIR PRENTICE: I understand what you're 2 saying, Felix, but if you look at the exact language 3 in the regulations, "An IRB shall conduct continuing 4 review of research covered by this policy at intervals 5 appropriate to the degree of risk but not less than 6 once per year". "Shall conduct continuing review", 7 now it doesn't say it shall conduct continuing review 8 and reapprove the research project, okay, no less 9 often than annually. It doesn't say that in the 10 regulations. That's an interpretation of OHRP. So it 11 seems to me that the regulations as they stand now, 12 could be interpreted to mean as long as continuing 13 review is underway no less often than annually. That 14 would be supported by the regulations. 15 Now, I understand the problem which is the 16 reverse of the 30, 60-day rule. That means that 17 continuing review has started, correct, and an 18 investigator is non-responsive. And you know, you 19 send out a letter asking for certain clarifications, 20 modifications to the consent document, what have you, 21 you know, and 30 days go by, they have not responded. 22 Sixty days go by, they've not responded. That's a 127 1 problem, yes, but that could be corrected by guidance 2 as well. Susan? 3 MEMBER KORNETSKY: Okay, I think you're 4 getting at -- if I remember correctly, I was in and 5 out of the discussions of the subcommittee but that -- 6 we had a lot of discussion about what you're talking 7 about but it also -- it was what constitutes "in 8 progress". Does this mean that investigators will 9 fill out a form sloppily to get it in progress? And 10 I think when we started looking at what the other 11 recommendations were, we felt that the issue was 12 covered, that IRBs did not necessarily have to suspend 13 that and I think we sort of, if I remember correctly, 14 stopped the discussion of what you're talking about 15 because we felt it was accommodated for both large 16 volume and small volumes in other ways. 17 I mean, whether we should have dropped it 18 or not, but if I remember correctly, we got into lots 19 of discussion about what does "in progress" mean. Is 20 that simply -- can that be simplified in guidance. I 21 mean, there were lots of discussions. 22 CHAIR PRENTICE: Ada Sue? 128 1 MEMBER SELWITZ: Again, and I may not be 2 correct on this and that's the minutes that was passed 3 down about this discussion and I may be incorrect but 4 I know we're heading up to lunch and again, I'm not -- 5 it seems to me we almost have two different issues 6 we're discussing and I'm not absolutely convinced 7 they're totally intertwined. I mean, the 30-day 8 versus the 60-day rule has one set of implication. 9 The implications of whether you can continue after a 10 lapse of approval provided is was in the system to me 11 is a different issue. 12 And I started this discussion just 13 thinking that it should have not been on -- that we 14 did the right thing in the subcommittee but your issue 15 on review I think is important, but I'm talking about 16 the second issue. And I wonder again, I will 17 obviously, leave it up to your discretion but maybe, 18 I guess what I want to do is I want us to complete 19 wherever we're going to go today. I don't want the -- 20 the Subpart A group has a lot to do and I'd hate to 21 see us hold up one issue to send it back to 22 subcommittee if we can avoid it. 129 1 So it seems like to me we could vote on 2 the 30 versus 60-day rule and then go to lunch, come 3 back, if we want to bring this issue back up. I'm 4 pretty -- your issue of review versus approved, Ernie, 5 I know that was talked about at one of the 6 subcommittee meetings but I think that's a very 7 important issue and so I would actually support now 8 what you're, you know, bringing the recommendation 9 back in that we be allowed to let them continue, all 10 right, if they're in the system because of the 11 distinction between review and approve. 12 And I think what is critically important 13 in all of this is that we don't lose sight of 14 protection issues, that we don't get so caught up and 15 every one of these recommendations, I think are still 16 consistent with insuring their human subjects 17 protections. And I don't want us to lose sight on 18 that, because that's the problem with some of this. 19 We get so caught up on 30 days versus two days, versus 20 three days. And I really do believe in talking about 21 the second recommendation, bringing it back into the 22 fold, that you have to have a stopping point, but if 130 1 something is in the system, that it does make good 2 sense that it's not always in the best interests of 3 anyone to just shut everything down, all right, even 4 though I know that we can extend it for those that are 5 in the system. 6 But I propose that maybe we separate 7 these, move on, come back after lunch with more of a 8 concrete -- maybe go back to what was originally Dan, 9 if you have it, the recommendation that came in and 10 let us look at it. 11 CHAIR PRENTICE: Okay, that's a good idea. 12 All right let's look at recommendation 10.2. I think 13 we've already discussed it. Any further discussion? 14 Hearing none, I'll entertain a motion. Well, we can 15 go to lunch. 16 MEMBER KORNETSKY: I make a motion that we 17 accept recommendation 10.2. 18 CHAIR PRENTICE: And -- 19 MEMBER JONES: Second. 20 CHAIR PRENTICE: Thank you very much, 21 moved and seconded. Any further discussion? Those in 22 favor hands. Any opposed? Any abstentions? One 131 1 abstention. Okay, motion carries so it's approved. 2 Shall we move on? 3 MEMBER NELSON: We are now done with 4 continual review with the exception of 10.3 which 5 we'll resurrect from the November slides with Kelly's 6 help and pull up after lunch but I think with your 7 forbearance in the 10 minutes or so, I could lay the 8 background materials for expedited review recognizing 9 again, that we have people coming from lots of 10 different perspectives in the audience and this first 11 section will be introduction and won't require any 12 deliberations or voting. So I think I could move 13 through that and then we could break and come back for 14 specific issues with your permission, Ernie? 15 CHAIR PRENTICE: Yes, thank you. 16 MEMBER NELSON: All right, so the 17 regulatory basis for expedited review, HHS and FDA 18 regulations, and they're cited at the bottom, there 19 are analogous regulations for both HHS and FDA in this 20 area, provide for an expedited review procedure under 21 which the IRB chair or one or more experienced members 22 designated by the chair may approve activities that 132 1 occur in two different areas. 2 One is research in categories appearing on 3 a list that is published in the Federal Register and 4 found by the reviewer to involve no more than minimal 5 risk and so there's two parts to that. It's on the 6 list and it's determined to be no more than minimal 7 risk. Secondly, minor changes in previously approved 8 research, potentially even greater than minimal risk 9 research but if the change is minor and most IRBs have 10 operationalized that to mean does not substantively 11 impact on the risk of the study or at least doesn't 12 increase it, minor changes in that research during the 13 period of one year or less for which approval is 14 authorized. 15 Those are the types of, the categories of 16 research activities that may be approved through an 17 expedited means. I've used this slide before just to 18 conceptualize the idea that in general, the triaging 19 of -- by an IRB to level of review tends to track 20 along with the level of risk as we move from so-called 21 exemptions to expedited review to full committee 22 review with the minimal risk setting a threshold for 133 1 those things that must be handled by the full 2 committee at a convened meeting. 3 We'd like to remind and make that point 4 that expedited review should not be confused with 5 review light. The rigor is the same as full review. 6 The number of reviewers is different and in reviewing 7 the research, the reviewers may exercise all of the 8 authorities of the IRB except that they may not 9 disapprove the research. Research activity may be 10 disapproved only after review in accordance with the 11 non-expedited procedure, that means the full convened 12 IRB meeting. 13 Continuing on that point, expedited review 14 is to be used with minimal risk research as noted and 15 as therefore, calibrated for that setting. So 16 although the issues are the same to be identified, 17 there is a sense and a reality, I think that it is 18 calibrated for minimal risk types of activities or 19 again minor changes to previously approved research an 20 can be applied appropriately and usefully. As with 21 review by the convened IRB, expedited review must 22 fulfill all of the requirements for approval that are 134 1 found under 46.111 and subparts B, C and D, if 2 applicable. 3 We've made references before to 46.111 and 4 these are those criteria familiar to all of you, I 5 think, both on the IRB end and the receiving end of 6 research review, that risk be minimized, that there be 7 an acceptable risk benefit ratio, in other words, that 8 the risk should not outweigh the proposed -- the 9 anticipated benefits of the study. That there be 10 equitable selection of subjects, that the informed 11 consent process be attended to if there is to be a 12 process and it may be waived under these regulations. 13 That there be documented informed consent 14 unless that aspect is waived, that there be a 15 monitoring plan for safety. That's not to say that 16 the IRB has to do that monitoring but that there be a 17 mechanism in place and that that be reviewed before 18 approval. That privacy and confidentiality are 19 protected and that, when applicable, there be 20 additional safeguards for vulnerable populations. So 21 these apply, whether expedited or convened review and 22 that is something we discussed before, whether they 135 1 all need to be applied with the same rigor, in fact, 2 at the time for continuing review for certain minimum 3 risk activities. 4 IRBs are reminded that the requirements 5 for informed consent or for altering or waiving that 6 requirement apply regardless of whether research is 7 reviewed by a convened IRB or under an expedited 8 procedure. In terms of mechanisms, the IRB shall 9 adopt a method for keeping all members advised of 10 research proposals that have been approved under the 11 expedited review procedure. Effectively the Chair or 12 designated member is acting on behalf of the IRB 13 membership and IRB's established mechanisms; 14 therefore, for bringing back and notifying them after 15 the fact of actions that have been taken on their 16 behalf. 17 These are the categories of research that 18 are eligible for expedited review. At the setting or 19 at the time of initial review, clinical studies 20 wherein investigational new drug application or an 21 investigation by exemption are not required. Blood 22 samples that are obtained by routine methods and under 136 1 certain volume, non-invasive prospective collection 2 of biological specimens, non-invasive collection of 3 clinical data, materials whether it be data, 4 documents, specimens that have been collected or will 5 be collected for non-research purposes, voice video 6 digital recordings for research, individual or group 7 behavior surveys, interviews or oral histories, so 6 8 and 7 tend to be where a lot of social and behavioral 9 research gets accommodated under expedited review 10 procedures. 11 There are two categories, 8 and 9 that 12 address using expedited review mechanisms in the 13 setting of continual review. Continual review of 14 research that's been previously approved with no 15 further direct subject participation and I can see 16 that in our haste to -- we may have left out some of 17 the side elements of this, but that's the gist of it, 18 so this is Celia, addressing your scenario whereby a 19 study, even though it's received, convened full board 20 review the first time around or the second or the 21 third time around when it reaches a certain stage in 22 its life cycle, i.e., data analysis only follow-up 137 1 that could be downgraded, if you will, from full board 2 review to expedited review. 3 And 9, continuing review of research where 4 the IRB has determined and documented a convened 5 meeting that the risk involves no greater than minimal 6 risk and no additional risks have been identified, and 7 again, we haven't restated the entire 1998 list. This 8 was published in the Federal Register in November of 9 1998 and has provided useful examples of categories to 10 guide IRB processing. 11 So our working assumptions in the area of 12 expedited review is that expedited review is a 13 valuable mechanism that allows IRBs to triage studies 14 to an appropriate level of review and oversight. That 15 expedited review affords effective oversight of 16 minimal risk research while permitting the majority of 17 IRB members to focus their efforts on protecting 18 subject's rights and welfare in research with 19 potentially serious risks. 20 To the extent that expedited review can be 21 used for minimal risk research, the time and resources 22 of IRBs can be concentrated on protecting subjects 138 1 facing the greatest levels of risk. 2 So again, I will say that regulatory 3 reburden should not be confuse with work avoidance on 4 the part of IRBs but in a world where time and 5 resources are not unlimited, where we spend our time 6 is increasingly becoming an issue. That brings us up 7 to our specific issues of concern and we'll follow the 8 same pattern as before, so Ernie, this may be an 9 appropriate time to break for lunch unless you would 10 like us to plow ahead and knock off one and pick up 11 where we left off. 12 MEMBER GYI: Let's break for lunch. 13 MEMBER NELSON: Let's break for lunch says 14 Felix and that sounds good. 15 CHAIR PRENTICE: Okay, the lunch break is 16 between 12:00 noon and 1:00 p.m. Please reconvene so 17 that we can start on time at 1:00. We still have an 18 ambitious agenda to go through. Thank you very much. 19 (Whereupon, at 11:59 a.m. a luncheon 20 recess was taken until 1:05 p.m.) 21 CHAIR PRENTICE: Shall we get started 22 again? Dan and Felix, would you take over, please? 139 1 MEMBER NELSON: Thank you. So hopefully, 2 not to break the momentum into expedited review, but 3 this seems to be the point to return then to the item 4 tabled from this morning, which was finalizing the 5 recommendations under question 10 of continual review 6 and this was -- with Kelly's help, we've pulled up 7 what was presented in November and this was the 8 wording that I was reading to you. 9 "OHRP should modify guidance so that when 10 continual review is underway, automatic study 11 suspension is not required when the expiration date 12 passes before review and approval are complete. 13 Guidance should specify strategies to prevent routine 14 delays and open-ended review and specified conditions 15 and activities will be permitted in such 16 circumstances". And just to frame your discussion, 17 the preceding slide had 10.1, OHRP should revise 18 guidance to reflect the starting of the clock with the 19 actual IRB approval rather than the day of the 20 convened meeting. Again, that was approved in 21 November. 10.2 was on your table today for 22 discussion, "OHRP should withdraw" at that point we 140 1 said, and today we've said revise and offered 60 days 2 as a compromise. And here's 10.3 and then here's 10- 3 4, working of current guidance that refers to 4 individual requests. Revises the scenario where 5 generally under treatment patient oriented research 6 subjects can remain on study if it would to their 7 medical disadvantage to take them off study or to halt 8 study related procedures and treatments. 9 So 10.3 because we seem to return to that, 10 is still a missing gap, is back up for consideration 11 and Ernie, I think there's also the remaining question 12 of what to do with the 30-day rule and our 13 recommendation that addresses that. 14 CHAIR PRENTICE: Okay, in looking at the 15 issue of the 30-day rule, the 60-day rule and the 10.3 16 recommendation, there is a concept that perhaps should 17 be put on the table called the pre-30-day review rule 18 and the post-30-day review rule. Got that, Ada Sue? 19 MEMBER SELWITZ: Not yet but I'm hanging 20 on every word. Don't stop now. 21 CHAIR PRENTICE: The 30-day rule would be 22 exactly the same as it is now. Okay. The post-30-day 141 1 IRB review rule would be allowing an extension of IRB 2 approval before mandatory expiration providing that 3 the IRB is already engaged in an substantive process 4 of continuing review. They would always have the 5 option of not exercising that post-30-day review rule. 6 If the application was so deficient, they could say, 7 "No, we're not going to do that", but assuming that 8 it's a legitimate application but the IRB has got some 9 questions, maybe the consent form needs to be improved 10 a bit, so you give the investigator another 30 days to 11 get everything reapproved. So, in effect, that's a 12 60-day rule divided up into two 30-day sections. 13 So I'm throwing that out for your 14 consideration, not to complicate this whole matter any 15 further. Yeah. 16 MEMBER NELSON: Ernie, I don't know if it 17 helps to put back up, I guess you have this on paper 18 and I can return to 10.3 from the November 19 presentation but this again, would maybe help orient 20 people to that scenario. So you're basically 21 proposing a modified version of this where there would 22 be a 30-day, plus or minus straddling the current 142 1 expiration date that would allow them 30 days before 2 and 30 days after, so the 60 days would just be slid 3 to straddle the expiration date. 4 CHAIR PRENTICE: Exactly, and that would 5 seem to be able to accommodate the problem of the 6 small, low volume IRBs as well as the problem of the 7 large volume IRBs where investigators kind of wait 8 till the last minute and you just can't get everything 9 done by the 365-day set limit. Susan. 10 MEMBER KORNETSKY: Yeah, I think 11 conceptually, I'm in favor of that and that was 12 interesting because they passed -- as I was talking 13 last time, they passed the minutes down to see what 14 happened to the other thing and I guess it was because 15 of me that it may have been sort of taken off. But 16 I'm -- conceptually, I'm okay, but I think, again, the 17 issue for me is some -- you know, what does 18 substantially engaged in review mean and I think 19 that's where we sort of started getting caught up and 20 then we sort the last time figured, well, it seems to 21 be covered. 22 I don't have a problem with that. You 143 1 know, does that mean that the IRB has looked at it and 2 taken some action, provided comment, does that mean 3 that the investigator got it into the office, but it 4 couldn't make it on the agenda for the next meeting? 5 I mean, I think that's where I would feel more 6 comfortable, because I think there are a whole host of 7 reasons that you know, things that could go on during 8 that period of time, and I just wouldn't want to see 9 there would be a lot of slippage there. 10 CHAIR PRENTICE: I would be personally 11 comfortable if the review process had begun, not just 12 submitting the application into the office, you know, 13 waiting for the next IRB meeting which who knows when 14 that's going to be. If -- you know, there are two 15 ways to do continuing review. One is expedited 16 review. If you already started the process and it's 17 under review by an expedited reviewer, or it's gone to 18 full committee review and, you know, you've reviewed 19 the application, but you've got some questions, I 20 would say that should be the cutoff as far as I'm 21 concerned, that would prevent this slippery slope that 22 you're referring to. Susan? 144 1 MEMBER KORNETSKY: I agree with those 2 types of things. 3 MEMBER FISHER: What I think is important 4 that we articulate as a committee is why are we doing 5 this and I think we have multiple responsibilities. 6 One is to the burden of IRBs and whether or not 7 they're unjust and actually getting in the way of 8 human subjects protection. The other is what is there 9 with respect to investigators. But what's not here is 10 the human subject protection part in terms of what is 11 the benefit to the human subject. So, you know, I see 12 this as very open-ended and I agree with Susan, 13 certainly, in terms of having to more say what 14 substantial is, but what I don't -- you know, I 15 understand this with respect to if it's an 16 intervention study and withdrawal or suspension will 17 create undue harm to participants. That makes 18 complete sense to me but there's a whole other side of 19 that continuum that because an investigator didn't 20 respond on time, I'm not sure that I'm comfortable 21 with that in terms of the protection of human 22 subjects. 145 1 So I would just like to see a little more 2 of that either in our discussion or in what we're 3 really talking about, the whys of this guidance 4 modification. 5 CHAIR PRENTICE: Okay, well, let me 6 respond to that. When an IRB reviews an application 7 for continuing review, even if it's in advance of the 8 365-day set limit or sooner, if an IRB finds that 9 there are significant problems with the protocol, you 10 know, you have an obligation, literally, to suspend 11 IRB approval until the problems are corrected. 12 And example might be maybe you have a 13 consent document that for some reason or other got 14 through the IRB upon initial review and it is 15 deficient, it's not in compliance, you've got to fix 16 it, okay? Now, you can't very well say, "Well, you 17 know, the investigator's still got another 30 days to 18 go ahead and you know, respond because they're not up 19 to their 365-day limit. Therefore, let's not worry 20 about it". You have to worry about it right then and 21 there. So that's a latitude that the IRBs already 22 have. 146 1 So certainly, if you have an extension of 2 the -- you know, the post-IRB 30-day period, an IRB 3 can say, "Look, we can't do it, because the 4 modifications, clarifications, what have you, are so 5 substantive that we feel uncomfortable doing that". 6 So you have that latitude. That's one point. 7 A second point in terms of issues 8 pertaining to protection of human subjects is the 9 current position of OHRP is when IRB approval expires, 10 all activities cease, all activities. Now, if you 11 have subjects on study, and it's in their best 12 interest to continue participating, i.e., clinical 13 interest, then you can, you know, grant that approval. 14 IRB chair can do that, but what about all of the 15 social science, behavioral science studies where 16 there's no clinical, you know, objective at all. It's 17 not necessarily in their best interest. However, 18 you've got people who would have, perhaps, 19 participated in the study incurred some degree of 20 risk, all right, where you can't use the data because 21 you have to cease all research activities. That's 22 compromising as far as I'm concerned. 147 1 Maybe the risk benefit relationship, as 2 originally approved by the IRB for that particular 3 study. If you have a 30-day extension, you don't get 4 into this arbitrary requirement that you've got to 5 stop all research activities if it's at least 6 justifiable from a risk management perspective to 7 allow them to continue. So I would argue that that's 8 a reason to go with this. Ada Sue? 9 MEMBER SELWITZ: And I think your point is 10 well-taken but I will add to what Ernie has said 11 because, you know, we tend to talk as though we're 12 assuming that research has no direct benefit and often 13 some research does have direct benefit for the 14 subjects. And even if it doesn't for the subject, 15 there's a lot of the research that's being done that 16 is low risk, but in fact, has potential to advance 17 science, particularly in the social science areas, all 18 right. 19 And so I think, I believe if that protocol 20 as been to an IRB and I think that was a critical 21 addition, if that protocol has actually received a 22 review, not just paperwork that's come in but actually 148 1 received a review, then the protection of human 2 subjects issues are going to be addressed. And this 3 is a system that depends upon the judgment of an IRB. 4 So I don't think that having this proposal 5 that says, "Well, once it's in the system you have a 6 little leeway", will lead IRBs to say, "Well, we think 7 this is horrible what's happening to subjects since 8 we've got an extra month here". I mean, my experience 9 has been IRBs are going to still be doing what's in 10 the best interest of the subject. 11 What it should do, though, is allow in 12 those cases where either there's a direct benefit for 13 the subjects or an -- and I might add, often in these 14 cases, the delays aren't occurring because of 15 significant substantive issues. They're sometimes 16 occurring quite frankly, because it is peer review and 17 certain members want to change these three words, 18 these three ways. 19 Now, I can say that never happens and 20 maybe it doesn't happen in anybody else's IRB but it 21 certainly has been my experience that can happen. And 22 what this would do I think it would open that door to 149 1 not put an unnecessary barrier. But admittedly, it 2 depends on the judgment, the professional judgment of 3 the IRBs and yet, I don't -- I think this whole system 4 is based on that assumption that we have to, at some 5 point, say the judgment is made. 6 And I really -- so I would support with 7 the conditions, Ernie -- I mean, I do believe there 8 has to be these conditions, that have to be in there, 9 including those already been and I don't think it can 10 go on for an extended period of time. And there's a 11 point at which you've got to say this is it, even if 12 it is low risk or else you could have a two-year 13 continuing review period. 14 CHAIR PRENTICE: That's the 30-day 15 extension. Nancy, and I want to try to bring this t 16 closure and move on to expedited review or refer this 17 back to the subcommittee. So bear that in mind as we 18 progress because we've got to get going. Nancy. 19 MEMBER JONES: I guess I have two 20 questions or two points. One just in response to 21 Celia in restating some of the points; one of the 22 reasons in the subcommittee that why some flexibility 150 1 is needed is so that you don't get wedded to the dates 2 and the process but you can actually spend the time 3 that you need to get your questions answered and 4 that's where they said that the tight restrictions 5 sometimes procures people from saying, `Well, I really 6 want just a little more information". 7 But if you do it, then a study gets shut 8 down, you know, if it doesn't fall in all of those 9 windows. So that was one of the things to say that 10 you could actually have the time to do more 11 substantive reflection on what's going on or if you 12 really did have a question, and you wouldn't feel so 13 restricted that if I don't get my decision made by a 14 certain point then it really does have a lot of 15 ramifications. So I think that was the justification 16 that the committee, you know, came from these 17 different things, that it was also in the interest of 18 the subjects that people actually reflected rather 19 than got wedded into process to hit the dates. 20 MEMBER FISHER: Let me just say, as I 21 understand the 30-day and what Susan said and what 22 Nancy is saying in terms of its proposal, that it had 151 1 to have been reviewed and that within the 30-day 2 period allows a response from the investigator. 3 CHAIR PRENTICE: Correct. 4 MEMBER FISHER: And that's -- and you 5 know, I think that makes a lot of sense. What -- one 6 of the problems I was hearing was when, oh, they get 7 in their materials too late. I don't think that 8 should be rewarded. So I just think we want to make 9 very clear what we're talking about in terms of what 10 is acceptable for the 30-day because it does improve. 11 It does improve human subject protections by allowing 12 a more informed dialogue between the investigator and 13 the IRB because there's already been the meeting and 14 recommendations have been made. And I think if that - 15 - I don't like the -- I guess just the phrasing of 16 10.3 is just so open-ended that it makes me 17 uncomfortable, but in principle, I understand 18 everything that you're saying. 19 CHAIR PRENTICE: Okay, any further 20 discussion? I would like to have a motion if anybody 21 cares to make one. 22 MEMBER SELWITZ: I'm willing to move it. 152 1 I just -- you know, we do have to be clear. I mean, 2 I'm not sure that I can articulate it with all the 3 conditions. I mean, our conditions are that one, the 4 protocol will have been reviewed by the IRB, all 5 right, and that two, it would be a 30-day extension -- 6 is that the right -- that isn't the right word. 7 CHAIR PRENTICE: Well, no, it's a -- we 8 could come up with the exact terminology but basically 9 if you were to decide to adopt this particular 10 recommendation that we're talking about, you would 11 eliminate that previous one that had the 60-day rule 12 because you would have -- 13 MEMBER SELWITZ: You mean the one we voted 14 for -- 15 CHAIR PRENTICE: Yeah, because you don't 16 need that. Now, you've got 60 days, which would apply 17 to the small IRBs as well. It wouldn't matter, would 18 it or do I have that calculation wrong? 19 MEMBER KORNETSKY: Ernie, what I -- I 20 mean, I think that we're sort of -- I feel like I'm 21 thinking on the fly here in this and I think there's 22 some important concepts that we don't want to take 153 1 this off the table. I'm wondering whether it makes 2 sense to convey our desire to have something like this 3 back to the subcommittee. I mean, are you asking for 4 a motion to -- 5 CHAIR PRENTICE: Only if you feel 6 comfortable. If you don't feel comfortable, then we 7 don't do it. 8 MEMBER KORNETSKY: I haven't given enough 9 thought sort of the 30, the 60, what's impacted. It 10 just seems like a house of cards here. So my 11 suggestion would be to send it back to the 12 subcommittee with the strong emphasis that we want 13 something for this -- you know, this period after and 14 to maybe have that and think it through and to bring 15 it back to us. 16 CHAIR PRENTICE: Okay, we can certainly do 17 that and even though you've approved the 60-day, 18 nothing is final until it actually goes into a letter 19 to the Secretary and unless you're prepared to do that 20 at this time, I don't know whether you are or not. 21 You're shaking your head. That means you're not quite 22 ready. 154 1 MEMBER NELSON: Prepared to go to the 2 Secretary? 3 CHAIR PRENTICE: Yeah, I mean, you know, 4 the subcommittee work is in increments. Okay, when 5 you reach a certain point where you feel you have 6 enough recommendations to send in, that's what you do. 7 MEMBER NELSON: I hear what Susan is 8 saying and I think we could probably with a little 9 time, come back with something more concrete for you 10 to respond to. I think we all grasp the concepts and 11 endorse most of the concepts being discussed, but it's 12 hard for all of us -- 13 CHAIR PRENTICE: Okay, let's refer it back 14 to the subcommittee. 15 MEMBER FISHER: Can I just have a point of 16 clarification? I'm of the understanding that a letter 17 sent to the Secretary comes following approval of -- 18 CHAIR PRENTICE: No. 19 MEMBER FISHER: -- SACHRP? 20 CHAIR PRENTICE: No. 21 MEMBER FISHER: That we send -- that a 22 subcommittee can independently have a letter sent? 155 1 CHAIR PRENTICE: No, no, no, no, no, no. 2 When SACHRP has accepted, okay, a whole series of 3 coherent linked recommendations, as a package, you 4 know, as a consequence of the subcommittee's work, 5 then a letter goes to the Secretary but it does not go 6 every time you accept a recommendation of a 7 subcommittee because you may not be done with your 8 task. And you can always revisit recommendations 9 you've approved in the past by saying, "You know, now 10 that we're looking at this and we've looked at some 11 additional material, we got to go back and revisit, 12 rethink this". 13 MEMBER FISHER: That's really now what I 14 was asking Ernie, but it's okay. I was just when you 15 turned to Dan to say, do they think it should go 16 forward to the Secretary, I don't' think that's the 17 subcommittee's role. 18 CHAIR PRENTICE: No, but they can -- when 19 they think they've done enough work and they presented 20 it to SACHRP and if SACHRP agrees, then SACHRP 21 makes the decision that it goes to the subcommittee or 22 it goes to the Secretary, okay? Okay, let's -- we 156 1 know what we're doing with continuing review. We're 2 going to go back and revisit some of these. Right? 3 Let's try and see if we can get through some of the 4 expedited review. 5 CHAIR PRENTICE: All right, so this is 6 where we ended before lunch with the background and 7 regulatory basis for expedited review and now I'd like 8 to walk through really two or three specific issues in 9 this area. 10 So the questions in the first set of 11 recommendations, "Must clerical and administrative 12 changes to approve research be subjected to at least 13 expedited review, is it necessary for an IRB member to 14 review and approve changes to research that are 15 totally clerical or administrative in nature and is 16 there a need to define administrative changes as some 17 IRBs practice but on their own, in effect, to research 18 that does not warrant even expedited review and 19 approval"? 20 So the context for this question is that 21 IRBs often receive changes to approve research that 22 are entirely clerical or administrative in nature and 157 1 have no effect on either the conduct of the research, 2 the underlying signs or methodology, the associated 3 risks and benefits or the potential willingness of 4 subjects to continue participation and these were for 5 factors or criteria that the subcommittee identified 6 as key and as effects that would warrant higher level 7 review and more formalized review under the IRB 8 regulations. 9 Examples of such changes include 10 correction of typographical errors in either the 11 submitted application protocol or consent forms, 12 updating of contact information for investigators or 13 perhaps, even the IRB in cases, for example, where the 14 IRB has approved consent forms and there's a contact - 15 - there is contact information and therefore, subjects 16 who have somebody other than the investigator to 17 approach if they had concerns about their rights or as 18 a subject, many of us, of course, insert the IRB in 19 that spot and give IRB contact information, but we 20 have scenarios right now where let's say the IRB 21 office gets a new phone number. Does that really 22 warrant an official, a formalized amendment because 158 1 the IRB has contacted all their investigators and 2 said, "You have to update your consent forms", and we 3 now have under the current structure and current 4 understanding, IRBs approving their own phone numbers 5 that are updated in consent forms. 6 Reformatting or renumbering of pages in 7 documents, changes in biostatisticians or other 8 personnel at sponsor headquarters and again, this list 9 could go on for pages and days and, indeed it does in 10 the daily routine of the IRB which, in many cases, 11 elevates these two formal amendments that are formally 12 reviewed and approved by expedited -- one would hope 13 expedited review at most, but we're saying that's 14 probably overkill. 15 So current requirements that only the IRB 16 chair or designated members can approve any aspect of 17 research means that low impact changes in previously 18 approved research are handled by expedited review or, 19 heaven forbid, full convened review. We would argue 20 that this does not contribute meaningfully to the 21 protection of subjects and may actually reduce such 22 protections by diverting IRB time and effort for more 159 1 substantive considerations. 2 So our recommendation here, I think goes 3 over to the next three slides inter-related text, 4 implementation of changes to approve research that are 5 solely clerical or administrative should not require 6 convened or expedited IRB review. OHRP and FDA should 7 issue guidance permitting IRBs to define in their 8 written policies and procedures changes to approve 9 research that can be processed by qualified IRB staff. 10 Such changes should be limited to those 11 that are entirely clerical or administrative in nature 12 and have no effect on, and now you'll recognize these 13 four criteria from before, conduct of the research, 14 the underlying signs for methodology, associated risks 15 and benefits or the potential willingness of subjects 16 to continue participation and I apologize for the 17 amount of detail packed onto this slide but this was 18 the recommendation in the halls. It was approved by 19 the subcommittee and I thought rather than spreading 20 it out over too many slides, I'm pack in onto this 21 one. So please bear with me. 22 In parenthesis some examples, correction 160 1 of clerical or typographical errors, changes to 2 telephone numbers, addresses, other contact 3 information, renumbering of pages or sections without 4 changes in content, other changes as defined in 5 written IRB policies and procedures that clearly have 6 no effect on, and then we repeat those same four 7 criteria. 8 The last related recommendation is that 9 IRBs should be encouraged to give appropriately 10 qualified staff authority for clerical and 11 administrative functions conceptually linked to that 12 above processing. Those are our recommendations in 13 this area. 14 CHAIR PRENTICE: Okay, Dan, Felix, are 15 those like recommendations 1, A, B and C or is it like 16 1, 2, and 3? 17 MEMBER NELSON: Yeah, given the -- let's 18 number them right now. I think these first two slides 19 go together and as I mentioned before, we got down to 20 the tenth and hundredth decimal point and numbering 21 our changes and that broke down, since we didn't get 22 them all approved and in order and bringing them back 161 1 became confusing for both subcommittee and for SACHRP. 2 So we opted not to number these but for 3 today let's call this number 1,which goes over two 4 slides and number 2 is this more general point of 5 encouragement. 6 CHAIR PRENTICE: Okay. 7 MEMBER NELSON: And our note-taker is on 8 board with this because we discussed this point over 9 lunch. 10 CHAIR PRENTICE: All right, great, 11 questions, discussion? Motion? Yes. 12 MEMBER KORNETSKY: Unless there's 13 controversy over this, I motion that -- and people 14 want to talk about it, I mean, this is a huge issue. 15 It's a lot of time. It's a lot of effort. I think 16 IRBs and chairs know what this administrative changes 17 are. Their policies should outline how they will 18 address this and I would move to accept it unless 19 people want to discuss it. 20 CHAIR PRENTICE: So you're moving to 21 accept recommendations 1 and 2 as written. Is there 22 a second? 162 1 MEMBER SELWITZ: Second. 2 CHAIR PRENTICE: Okay, two seconds, that's 3 good. We're making improvements this afternoon. 4 Okay. 5 MEMBER FISHER: Is recommend -- I don't 6 know which one is 3 but IRBs should be encouraged, is 7 that in this? 8 CHAIR PRENTICE: No, that's number 2. 9 MEMBER FISHER: Okay, so are we -- is that 10 part of the proposal? 11 CHAIR PRENTICE: Yes, recommendations 1 12 and the recommendation continued is part of 1, and 13 then the second one you're referring to is number 2, 14 which is linked to number 1. 15 MEMBER FISHER: Yes, I guess the only 16 slight discomfort I have is the word "encouraged", 17 because I think IRBs should be able to make a decision 18 about whether or not they want their own members to do 19 that, so it's just the encourage. 20 CHAIR PRENTICE: Would you like to suggest 21 an amendment? 22 MEMBER FISHER: I would like to suggest, 163 1 yes -- I don't even understand what it said. 2 MEMBER KORNETSKY: Just IRBs should give 3 appropriate qualified staff authority for clerical and 4 administrative -- 5 MEMBER FISHER: No, I think -- may, yes, 6 may. May. 7 CHAIR PRENTICE: Okay, IRBs may give 8 appropriately qualified staff authority. Does the 9 movers accept this friendly amendment? 10 MEMBER KORNETSKY: Yes. 11 CHAIR PRENTICE: The two seconds, you 12 accept the friendly amendment? 13 MEMBER SELWITZ: Yes. 14 CHAIR PRENTICE: Okay, any further 15 discussion? All those in favor? Any opposed? Okay, 16 any abstentions? Very good. Let's try to move on. 17 MEMBER NELSON: Thank you. Question; 18 "Should the term expedited review be revised to better 19 reflect the intent and process?" The term expedited 20 review is widely misunderstood or perhaps hoped by 21 investigators to imply increased speed and decreased 22 thoroughness of review. Nevertheless, both the spirit 164 1 and letter of the regulations requires the expedited 2 review be a substantive and meaningful as can be 3 meeting review. Criteria for approval and the 4 requirements for informed consent are identical as 5 reviewed earlier and the major difference is that one 6 or more experienced IRB members are delegated, and 7 you'll understand in a second why I've highlighted 8 that term, to perform the review on behalf of the 9 entire membership. 10 Analogous oversight bodies for animal 11 research, known as Institutional Animal Care and Use 12 Committees or IACUCs for those of you who don't 13 operate in that area, do not use expedited review but 14 their regulations provide for IACUCs to establish 15 mechanisms for so-called designated review that 16 function much like our expedited review does in the 17 IRB world. A term other than expedited review would 18 remove misconceptions or at least minimize those 19 misconceptions about expedience while emphasizing that 20 this mode of review is based on the delegation of 21 authority by the full IRB to the chairperson or other 22 member. 165 1 So, the recommendation that had been 2 drafted actually relied on designated review or 3 proposed that but after considerable discussion and 4 somebody pulling out a dictionary, we decided that 5 delegated review is what would best reflect what the 6 intent and purpose of this process which we all value 7 and rely on. So our recommendation is that OHRP and 8 FDA should initiate the process of modifying their 9 respective regulations to replace the term "expedited 10 review" with the term "delegated review" which more 11 accurately describes the process and regulatory 12 intent. 13 SACHRP is requested to encourage all 14 agencies under the Common Rule to harmonize this and 15 other changes. That is our recommendation in this 16 area and I think we've kept that on one page, 17 thankfully. 18 CHAIR PRENTICE: Okay, Dan, in the second 19 part of your recommendation you indicate SACHRP is 20 requested to encourage all agencies under the Common 21 Rule to harmonize this and other changes. What other 22 changes are you referring to in this recommendation? 166 1 MEMBER NELSON: Everything we ever do or 2 plan to do. 3 (Laughter) 4 MEMBER NELSON: He said with tongue 5 partially in cheek although clearly harmonization of 6 these changes, I -- and seriously, I will return to 7 this notion. It's increasingly apparent and the FDA 8 and OHRP have learned through the current discussion 9 on adverse events reporting and review, that 10 harmonization is viewed as key by the research 11 community. If we don't get FDA in particular but 12 other common rule agencies on board with this, we may 13 only create more confusion for example, by modifying 14 the HHS regs but leaving everybody else operating 15 under, in this case, expedited review. 16 So in for a penny, in for a pound and we 17 would like to encourage harmonization. 18 CHAIR PRENTICE: I certainly endorse that. 19 Can I suggest that that should be a separate 20 recommendation and not just tied to this one because 21 the other changes have nothing to do with expedited 22 review? 167 1 MEMBER NELSON: That would be fine. I -- 2 that may have been a little editorializing on our co- 3 chair's part, perhaps to -- I think it originally said 4 to harmonize this change, but indeed we would see it 5 as extending to just about everything we are doing. 6 So that would be fine. 7 CHAIR PRENTICE: Okay, Nancy. 8 MEMBER JONES: I thought, though, there 9 was some discussion though, that some people felt that 10 if it wasn't harmonized, it would be worse to have one 11 term in FDA language and another term so that they 12 would either want it all or not. 13 CHAIR PRENTICE: No, no, it's -- no, the 14 recommendation -- the first recommendation says that 15 both OHRP and FDA should initiate the process to 16 modify the regs. 17 MEMBER JONES: Right. 18 CHAIR PRENTICE: Okay, and then the second 19 and that's HHS and FDA, that's not the subscribers of 20 the Common Rule. Then SACHRP is requested to 21 encourage all agencies under the Common Rule to 22 harmonize this change, which basically means, you 168 1 know, NSF, you know, DOD, DOE, all of those, that's 2 separate. Okay? All right, further discussion about 3 this, what I consider to be kind of like a no-brainer 4 here, guys. This is not something that really 5 requires a lot of discussion. Yeah. 6 MEMBER FISHER: No-brainer that we reject 7 it? 8 CHAIR PRENTICE: No, no, no, no-brainer 9 that you don't need to consider it any further. 10 MEMBER FISHER: Well, I don't think that - 11 - I think we can range from the trivial to the very 12 important and to make a recommendation in isolation 13 that expedite -- that the term "expedited review" be 14 changed because some people don't understand it, seems 15 to me that we could very nicely say on a wish list of 16 things that may build up to be important for the 17 change in regs, this is one of them but I would not 18 recommend Congress, OHRP or HHS to take the effort 19 here. 20 CHAIR PRENTICE: It doesn't have to go to 21 Congress, Celia. 22 MEMBER FISHER: Well, whoever, whoever 169 1 approves this. I just think it's very trivial and is 2 not a way of increasing human subject's protections. 3 CHAIR PRENTICE: Well, let me play devil's 4 advocate, okay? There are a lot of investigators 5 who look at the term "expedited review" and they think 6 two things. They think one it's a very quick review 7 when, in fact, it's not. Sometimes it's even longer 8 than full committee review. By the time you send it 9 out to an expedited reviewer and get a response back, 10 and the second thing they think is expedited review, 11 simple review, abbreviated review, less detailed 12 review. 13 It gives investigators the wrong 14 impression about, you know, human subject protection 15 and their obligations. That's probably why in the 16 IACUC, you know, regulations the USDA and the PHS that 17 came out in `85 and `89 they chose not to use the term 18 "expedited review" and they went with this designated 19 member review. We don't have that problem now with 20 researchers who use animals. They don't have this 21 misconception. So it seems to me it's just a name 22 change, it's not -- in terms of a regulatory process, 170 1 it's not that significant. It's sort of like changing 2 OPRR to OHRP. Yeah. 3 MEMBER KORNETSKY: I don't feel -- I mean, 4 this is fine. I think the way it's sort of hitting me 5 as well, even though I sat on the subcommittee I was 6 sort of quiet on this is, you know, in the scope of 7 issues that we need to be concerned about, this seems 8 minimal and sort of the tax dollars that may be 9 required to change every document and I do think that 10 if it doesn't get changed throughout everyone that 11 it's going to be -- that it's going to add a lot of 12 confusion. So I think that's the sentiment that I'm 13 feeling I certainly endorse. I have no problem with 14 it. 15 CHAIR PRENTICE: I don't disagree with 16 you. Okay, yeah, a lot of documents would have to be 17 changed, sure, but we always said that we're going to 18 make recommendations we think make sense, right? 19 We're not going to consider the regulatory impediments 20 so if you think this makes sense, then you should act 21 on it. If you don't think it makes sense, then 22 disapprove it or send it back to the subcommittee for 171 1 discussion. So what is your pleasure? 2 MEMBER GYI: As a point of clarification, 3 you know, it's not as if we're going to make a 4 recommendation where OHRP has to simply act on this 5 particular recommendation in isolation. There will be 6 a bundle set of ideas and concepts that would have to 7 be addressed. So in the overall scheme of things, you 8 know, it's not as if we are taking out pieces of the 9 puzzle and then acting on them individually. OHRP now 10 has the responsibility to react to the recommendations 11 that SACHRP has made and find the most efficient and 12 best uses of resources that it has. 13 CHAIR PRENTICE: That's a very good point, 14 Felix, because there's a reference to the Common Rule 15 but that reference could almost equally apply to 16 everything the subcommittee has done which impacts the 17 Common Rule and the 18 agencies that have signed onto 18 the Common Rule. So it's not an isolated 19 recommendation. It would be packaged. So I would be 20 happy to entertain a motion or not. There's the 30- 21 second rule here. 22 MEMBER POWELL: I move that we accept the 172 1 new terminology of "delegated review" as described. 2 CHAIR PRENTICE: And what has to happen 3 next? 4 MEMBER SELWITZ: I will second it. 5 CHAIR PRENTICE: Okay, any further 6 discussion? All those in favor raise your hands. Is 7 your hand up or not? You're abstaining. Okay, we 8 have to get a count. Kelly, get a count, will you, 9 please? One, two, three, Felix is four. All right, 10 four. Any voting not to approve raise your hands. 11 Any abstentions? Three abstentions. That's four, 12 three, we have seven people here, so it's a simple 13 majority so the motion carries. Well, unless we -- 14 unless -- you know, we have a philosophy here that, 15 you know, when we don't come close to unanimous votes, 16 we like to send it back to subcommittee. You're 17 certainly free to choose to do that and say, "You 18 know, we're close but we're not close enough". 19 MEMBER GYI: May I ask what we would be 20 sending back to the subcommittee? 21 CHAIR PRENTICE: Oh, I'd just ask them to 22 talk about it for awhile. 173 1 MEMBER KORNETSKY: No, no, no, I mean, I'm 2 abstaining just for sort of conflicted reasons. I 3 don't have any real problem with this going forward. 4 I don't think there's anything more for the 5 subcommittee to discuss or I feel really silly telling 6 them to rediscuss this. That's my own opinion. 7 MEMBER GYI: I would second that. I mean, 8 the subcommittee already has other important issues to 9 address. If this is going to have to go back to the 10 subcommittee, let's just -- let's tell them what we 11 want them to do. 12 CHAIR PRENTICE: Okay, so we've approved 13 that recommendation. Move on. 14 MEMBER NELSON: Thank you. Those were 15 admittedly, the first two items. There are quite 16 substantive and complex issues still under 17 deliberation under the umbrella of expedited review 18 that will be coming at future meetings. Those two 19 were, indeed, what we thought were either things that 20 would be accepted rapidly or shot down in flames but 21 wouldn't need a lot of back and forth. So this one, 22 however, is more complex and, indeed, I've packaged it 174 1 separately because it's not exactly expedited review. 2 It was considered by the expedited review task force, 3 grew out of the discussion of expedited review. I 4 think many of us consider it a big ticket item in 5 terms of regulatory burden and IRB processing. But 6 it isn't quite expedited review and hopefully the next 7 slides will explain what I mean by that. 8 So the questions here are as follows; do 9 minor stipulations identified as contingencies for 10 approval by the convened IRB but not explicated for 11 quote, unquote, "simple concurrence" really need to 12 return to a convened meeting? Can the IRB chair or 13 other primary reviewer be given the authority to make 14 discretionary judgments on behalf of the IRB? Should 15 such mechanisms be considered a form of expedited 16 review and if so, how should the expedited review 17 procedures be applied in this context? 18 So the background for this, for those of 19 you who don't sit on IRBs or see this happen every day 20 and, indeed, it does happen every day that a common 21 outcome of convened IRB review has a list of minor 22 stipulations or contingencies that must be resolved 175 1 before the IRB grants final approval. This contingent 2 approval mechanism permits timely verification by the 3 IRB chair or designated member of clarifications or 4 modifications required or approval of the closed 5 research. 6 Current OHRP guidance and whether it's 7 exactly guidance or not we'll get to in a second, on 8 contingent approval is open to overly restrictive 9 application. And this is the guidance that I'm 10 referring to on the previous slide. This is from the 11 list of Common Findings and Guidance under OHRP 12 compliance activities, the 2005 version from the OHRP 13 website and the sixth item out of a growing list of 14 issues that OHRP has found as they visited or audited 15 sites in the field relates to this scenario, 16 contingent approval of research with substantive 17 changes and no additional review by the convened IRB. 18 So the beginning of this guidance states 19 that OHRP finds that the IRB frequently approves 20 research contingent upon substantive modifications or 21 clarifications that are directly relevant to the 22 determinations required by the IRB under 46.111 and 176 1 you've seen those eight criteria in the background 2 that I provided, without requiring additional review 3 by the convened IRB. 4 This is not from that consolidated 5 guidance, but from an individual oversight 6 determination letter to a suspended institution. The 7 institution in question is not relevant to this 8 discussion and you can find very similar wording in 9 determination letters to a number of institutions if 10 you know where to look on the OHRP website. 11 So in this particular case, in this 12 particular institution, the letter read that, "OHRP 13 recommends the following guidelines in such cases. 14 When the convened IRB requires substantive 15 clarifications or modifications regarding the protocol 16 or informed consent documents that are directly 17 relevant to the determinations required, under 46.111 18 IRB approval of the proposed research should be 19 deferred pending subsequent review by the convened IRB 20 of responsive materials." And again, for those of you 21 who aren't steeped in this a deferral then means 22 coming back to the convened IRB as opposed to 177 1 subsequent review and approval of minor stipulations 2 by the Chair outside of the setting of a convened 3 meeting. 4 Section B of the same letter goes on to 5 state, "Only when the convened IRB stipulates specific 6 revisions requiring simple concurrence by the 7 investigator may the IRB chair and other member 8 designated by the chair, subsequently approve the 9 revised research protocol on behalf of the IRB under 10 an expedited review procedure". 11 Several problems with this guidance. 12 Number one, it's a prime example of the kind of case 13 law that we referred to before. You really have to 14 know where to go to look to find this. It's not in 15 the -- to my knowledge, any consolidated guidance from 16 OHRP. It's passed into conventional wisdom in the IRB 17 community that if you've heard of simple concurrence, 18 that this is required for this scenario. These have 19 to be items that an IRB explicates so that all the 20 investigator has to do is agree to them, "Make this 21 change and we will approve it", in order for this to 22 happen, this so-called contingent approval of minor 178 1 stipulations. 2 Knowing -- and I guess I'll hold myself 3 out as a case example, as we were preparing these 4 slides, I knew of the simple concurrence but I 5 couldn't remember where I found it and only by going 6 to the OHRP website and doing search did I find it not 7 even in the compiled list of compliance findings but 8 in a single determination letter to a single 9 institution. And I think we would hold this out as an 10 example of what we can't expect for the word-a-day 11 world, the IRBs out there to know, first of all, that 12 they've heard of this; second of all, that this be put 13 into practice and know where to go and finding in a 14 single letter that they may or may not come across. 15 And although some of us have staff who like to go and 16 read those determination letters because you learn 17 valuable things, I don't think any of us can afford to 18 make that part of a person's daily job to go and see 19 the latest sanction letter, nor is that probably how 20 we want to influence or guide practice in the field. 21 The third problem with this is the simple 22 concurrence which we think is overly restrictive and 179 1 unnecessary for reasons I'll explain on the next 2 slide. So what are the problems with the current 3 understanding and application of OHRP guidance? And 4 the $64,000.00 questions in this topic are what 5 constitutes a substantive clarification or 6 modification as opposed to what level of detail 7 supports simple concurrence. 8 And I've taken a stab with Felix's help 9 here at putting out some representative communications 10 between IRB and PI and I think many in the room could 11 add to this list because again this is probably for 12 many of us the most frequent outcome of a convened 13 meeting review is this list of what we would consider 14 relatively minor issues to be addressed but some of 15 them go beyond what can be stated in a form that would 16 only require simple concurrence. 17 So please rewrite the sentences describing 18 the purpose of the study to be understandable to a lay 19 person, that may require some subjective judgment on 20 the part of the recipient, the IRB chair or designated 21 member, whether they accomplish that but it stops 22 short of rewriting those few sentences for them and 180 1 saying, "Here's how we -- here's the words for you, 2 just stick them in your consent form". 3 Please confirm who will be obtaining 4 consent. I think once that may be for record keeping 5 purposes. It may be substantive. It may well warrant 6 a come-back from the IRB if they don't like the answer 7 but on the other hand, if the IRB hears, "Well, I'm 8 going to obtain consent or my study coordinator, who 9 is trained in this process," et cetera, again it may 10 not be something that can be explicated for simple 11 concurrence but nevertheless is something that I think 12 we would like to see IRBs have the discretion to 13 accept an answer to. 14 Please provide data collection forms for 15 our files. Please clarify whether specimens will be 16 stored beyond the end of this study. That may or may 17 not turn into a much bigger exchange. Please explain 18 what is meant by the statement on page 6 that says, 19 dah, dah, dah. So these are the kinds of statements 20 that I think IRBs often make in part of their review 21 back to the investigators and I think many in the 22 field are afraid in the current environment and with 181 1 the current understanding of this simple concurrence 2 requirement, if they heard of it, that these are too 3 open-ended and require too much subjective judgment on 4 the part of the IRB chairs. 5 So review of stipulations for simple 6 concurrence has as part of that guidance I just shared 7 with you been identified or termed expedited review in 8 at least some OHRP communications. This creates 9 potential confusion by either shifting the final 10 approval of a full board study to expedite a review, 11 which it's not, or limiting approval to minor changes 12 in previously approved research which is not, because 13 it hasn't been approved yet, so there's a breakdown in 14 the logic, if you will, by terming this expedited 15 review. 16 So we would ask that expedited like 17 handling of full board contingencies not be confused 18 with true expedited review as defined in the 19 regulations. Another breakdown in the logic we've 20 tried to outline on this slide, IRB chairs or 21 designated members are routinely given broad latitude 22 and make substantive judgments on behalf of the IRB in 182 1 other context and three of them are here; determining 2 whether an unanticipated problem warrants immediate 3 suspension of research to insure subject safety, 4 approving changes to previously approved research 5 under expedite or review or the one that really, I 6 guess rings loudest for me is we give IRB chairs the 7 wherewithal, the discretion to approve entire studies 8 under expedited review mechanisms and all that comes 9 with that, the entire consent form, the entire 10 application. If that's okay, why are we forcing a 11 full board to return items that are must less 12 substantive in part or in whole than the entire study 13 that may be reviewed under expedited review? 14 So there is a double standard, in effect, 15 to limit your authority so severely for less 16 substantive issues that happen to be identified in the 17 setting of a convened meeting. Overly restrictive 18 application of OHRP guidance is unnecessary and 19 wasteful while IRB members' times could be devoted to 20 more meaningful human protection activities. So our 21 recommendation in this area and Ernie, you will have 22 to flag me if it's time to stop with out guest coming 183 1 in the door, 2 CHAIR PRENTICE: Let me indicate that when 3 Dr. Agwunobi comes into the door, he will come here 4 and sit down, and when he comes here and sits down, 5 that's your clue to, you know, wrap it up. 6 MEMBER NELSON: All right. So the 7 recommendation over the next couple slides. OHRP and 8 FDA should issue expanded guidance in several parts, 9 clarifying that final approval of stipulations from 10 convened meeting review so-called contingent approval, 11 is not a form of expedited review and the same 12 guidance should permit IRBs to describe in their 13 written policies and procedures stipulation mechanisms 14 or whatever you want to call them for verifying 15 changes required for approval of proposed research 16 under which -- and these mechanisms under which the 17 IRB chairperson or designated member reviewer may 18 exercise reasonable judgment in verifying that the 19 stipulations of the convened IRB have been satisfied 20 and under which a qualified IRB administrator may 21 verify that the investigator has implemented specific 22 language, for example, in the protocol informed 184 1 consent documents or advertisements dictated by the 2 convened IRB and requiring no subjective judgment on 3 the part of the administrator. So in effect, small 4 Roman numeral two returns to that previous -- the 5 first recommendation that you've already approved, 6 that we should free ourselves up to rely on qualified 7 staff under appropriate circumstances. And that's our 8 recommendation in this area and I would just 9 editorialize a bit by saying I think this is a pretty 10 big ticket item for a lot of IRBs in this room and out 11 in the field, the return -- the over return, if you 12 will, of minor stipulations to convene meeting review. 13 CHAIR PRENTICE: Questions, comments? 14 Yes, Ada Sue? 15 MEMBER SELWITZ: Can I move acceptance of 16 this recommendation? 17 CHAIR PRENTICE: No. Yes. 18 MEMBER SELWITZ: Then I'm not going to 19 second it. 20 (Laughter) 21 CHAIR PRENTICE: Yes, you can move 22 acceptance of this recommendation. Do I have a 185 1 second? 2 MEMBER POWE: Second. 3 CHAIR PRENTICE: There is a second. Is 4 there any further discussion? This is a record. All 5 right, hearing none, all those in favor of the 6 recommendation raise your hands. Any opposed? Any 7 abstentions? The recommendation carries. 8 MEMBER NELSON: Our work here is done, 9 Ernie. 10 CHAIR PRENTICE: Why don't you give us a 11 little bit of an update on investigator -- 12 MEMBER NELSON: Let me just mention 13 because this is truly the last comment, somewhat 14 tongue in cheek, but I think IRBs around the country 15 and around the world will thank you for this if it 16 goes ahead in the way we intended. There are no more 17 specific recommendations today on expedited review. 18 There are some pretty big thorny issues that we could 19 not reach consensus and I don't think you would have 20 given us the time today to lay out anyway but that 21 we'll be bringing at future meetings. So we are 22 refining additional recommendations in the area of 186 1 expedited review which will be presented at your 2 future meetings and these will include very likely, 3 suggested clarifications and expansions of the 1998 4 list of categories of research that may be approved 5 through expedited review. 6 We do have some additional issues that are 7 under consideration and I think with the exception of 8 the last, these are not being presented today for your 9 deliberation or approval or voting, but we wanted to 10 make you aware of what we're working on and they 11 include discussion of investigator responsibilities, 12 ongoing discussion of minimal risk, endorsement of 13 draft guidance from another subcommittee and 14 harmonization of guidance. 15 So the first topic our subcommittee 16 considerations on investigator responsibilities; the 17 concept of shared responsibility in the protection of 18 human subjects is broadly understood to include 19 investigators as key players and indeed, in our 20 training sessions, many of us in IRBs around the 21 country drive home this point and I know OHRP and 22 others share this understanding that the investigators 187 1 along with IRBs, with sponsors, with institutions, 2 share a key role, share a key responsibility on 3 protecting their subjects. 4 The regulations we follow implicitly 5 involve investigators in many aspects. They 6 explicitly name investigators in the process of 7 informed consent. However, the focus of regulations 8 may send a message that the prime responsibility for 9 protection a subject lies with institutions and 10 investigators to the exclusion of -- or IRBs to the 11 exclusion of investigators and with that, I will stop 12 and turn the floor over. 13 CHAIR PRENTICE: Okay, thank you, Dan. 14 SECRETARY SCHWETZ: The room got awfully 15 quiet. It is certainly an honor for me to be able to 16 introduce Admiral John Agwunobi, the Assistant 17 Secretary for Health of the Department of Health and 18 Human Services. You have his bio, so I'm not going to 19 go through that line by line, but I do want to say a 20 couple of things. Dr. Agwunobi was confirmed by the 21 Senate in December, just a few months ago and has been 22 heavily involved in a lot of our issues, including 188 1 those of human subjects protections, even before he 2 was confirmed and since then, before on an informal 3 basis and since then on a day-to-day basis. Let me 4 remind you that he is a pediatrician and comes to us 5 from that background of training and practice. He was 6 Florida's Secretary of Health and the State Health 7 Officer before coming to us as the ASH, but this 8 wasn't his first job in the Washington area. 9 He also served as the Medical Director and 10 Vice President of Medical Affairs and Patient Services 11 at the Hospital for Sick Children in Washington DC for 12 a number of years. One other thing that I would point 13 out is that he clearly was involved in human subject 14 protection issues before becoming the ASH and, in 15 fact, OHRP paid him a visit while he was the State 16 Health Officer in Florida, not -- it was a not for 17 cause visit but it wasn't -- 18 (Laughter) 19 -- and it wasn't because of something that 20 he did or didn't do. This was relative to an issue 21 that existed before Dr. Agwunobi was brought in as the 22 State Health Officer, and, in fact, was in the process 189 1 of fixing the problems which he had. So it was a good 2 visit for us but I had confirmed, since then in my 3 interactions with him, that protection of human 4 subjects of research as well as patients and everybody 5 else, is a very high priority for him. So thank you. 6 CHAIR PRENTICE: Thank you very much, 7 Bern. We're delighted that you've been able to come 8 and stay with us a little while and listen to our 9 discussion and present some recognition awards to some 10 of our departing SACHRP members. We'd like to invite 11 you to make a few comments, if you would, at this 12 time. 13 ASSISTANT SECRETARY AGWUNOBI: Thank you. 14 I'm not sure if I'm on. Does this make things better? 15 SECRETARY SCHWETZ: That works, yes, there 16 we go. 17 ASSISTANT SECRETARY AGWUNOBI: Thank you. 18 Thank you so much for inviting me. I am a 19 pediatrician at heart but I've had the opportunity to 20 work over the years in a number of different settings 21 both clinical and public health. And before I start, 22 I'm just going to embarrass one of my colleagues, 190 1 Captain, we're very proud of that uniform that you 2 have on. It's good to look out into the crowd and to 3 see folks who are dedicated to public health and all 4 things related. It fills me with great pride whenever 5 I look out into the crowd and see the uniform, 6 commissioned, I'm assuming, yes, of the U.S. Public 7 Health Service Commission Corps. 8 As a pediatrician, I served in a small 9 hospital. I focused on children who had special 10 health care needs. These were children who spent an 11 inordinate amount of time growing up in health care 12 facilities, many of them with orphan diseases or 13 particularly complex clinical situations. Through the 14 course of their lives, they very often were exposed to 15 the benefits of research, both clinical trials and 16 other situations. And I, very often, as a young 17 pediatrician, would be called upon to advocate in 18 their behalf as their clinician. 19 As I progressed through my career, I began 20 to notice certain patterns, certain common situations 21 that required my advocacy and felt it necessary to 22 learn more and, as such, I started serving on the 191 1 hospital's ethics. As many of you know, service on an 2 ethics committee or with a group of folks dedicated to 3 reviewing ethical issues requires first and foremost, 4 an ongoing commitment to education. There are no -- 5 oh, I see another uniform back there, an Admiral. How 6 are you, sir? Good to see you. 7 I recognized and -- Sam's a friend of 8 mine. I'm just messing with him. He knows that. I 9 noticed patterns and I realized that one of the 10 commitments of being on the ethics committee was an 11 ongoing need to learn, that no two situations were 12 ever going to be the same and that the whole field of 13 ethics was a moving concept. It rolls over time 14 across changes in community's values and principles, 15 across changes in science. 16 When I left, by the time I left the 17 Hospital for Sick Children where I practiced, I had 18 been privileged to serve as the chair of the ethics 19 committee for a short while. I left to join public 20 health in all its glory in Florida where I served 21 initially as a Deputy Secretary over a portion of the 22 department that focused on children with special 192 1 health care needs. That was the connection, and in 2 that role was asked to join the State's IRB. We 3 called it something else but that was what it did. It 4 reviewed research protocols that were being applied to 5 children for the most part but adults as well who were 6 under the protection, under the care of state 7 government, enrolled in our programs. I found that 8 there was more that needed to be learned and I've been 9 learning ever since. 10 At one point I did serve as the chair of 11 that committee when I was called in help clean up and 12 to help progress and to help as we euphemistically 13 said take advantage of opportunities for improvement. 14 I was struck during the course of that work improving 15 our IRB, I was struck by the fact that when OHRP would 16 come to visit, how professional they were, how 17 dedicated to the calling the staff were. They brought 18 with them, I think, I believe others from other 19 institutions who joined them as a part of their 20 review. I was struck by the fact that there was an 21 entire community that I really had not been aware of 22 out there that was dedicated to this -- to protecting 193 1 humans enrolled in research. 2 Since I've come now to the Office of 3 Public Health and Science in this capacity, I began to 4 realize that there is so much more to learn. I stand 5 here a perpetual student of this process and I've had 6 multiple meetings and mostly processes where they 7 teach me different pieces of what's going on and why, 8 with staff and with leadership of OHRP. 9 One of the reasons I ceased upon the 10 opportunity to join you here today was because I want 11 to learn how this process works, how things are 12 deliberated, what the issues really are, what the 13 priorities are, where we're headed in the future. I 14 recognize that there's no manual for how to assure 15 safe and fair and ethical research and or at least the 16 protections of human subjects of research as we move 17 forward. There are guidelines, there are guideposts 18 but a lot of the detail is worked out through thought 19 and discussion and debate. I recognize that the 20 Secretary has gathered in this advisory committee some 21 of the finest experts in the world on this subject and 22 I would imagine that those that are left in the 194 1 audience -- I understand this is a very dedicated 2 community of advocates and experts. I would urge you 3 to advise the Secretary, educate him, educate me so 4 that I can stand with you and bolster the messages 5 that you're passing on. 6 I happen to know that this is a very 7 important subject for him and I hope I leave you with 8 the impression that this is a very important subject 9 for me. I had the good fortune of practicing here and 10 abroad and I recognize that we must not just focus our 11 attention on research here. We need to also look 12 around the globe in this ever-increasing 13 globalization, especially of research. We need to 14 look around the world and fight for research subjects 15 wherever they might be, where we can be of assistance, 16 where we can be -- where we can make a difference. 17 You know, the Department itself is moving 18 along a number of transforming initiatives in parallel 19 where the Secretary's initiatives such as the American 20 Health Information -- not committee, Community, 21 forgive me, AHIC, is an initiative where he hopes to 22 transform the health system through a dramatic 195 1 increase in the use of health information technology, 2 a notion that would make a lot more of the data and of 3 the science and of the process and procedures of 4 health care would make it more visible to the world, 5 would make it more transparent. I have no doubt that 6 with the ubiquitous use of technology and the 7 availability of data that we will be moving research 8 into areas that perhaps research hasn't gone before 9 and I think it's critical that we, we, this group, you 10 advise us on how we can do so without harming research 11 participants. 12 There are other initiatives, pandemic 13 influenza preparedness, we're -- there's this notion 14 that we'll be preparing countermeasures whether they 15 be new anti-virals or new uses of old anti-virals, new 16 vaccines, I think we're guaranteed at some point in 17 the not too distant future in response to a pandemic 18 an entirely new vaccine and the expedient distribution 19 of that vaccine into our community. Now, I recognize 20 that it may or may not involve research, but I do 21 think that we need to be there. We need to be a part 22 of it. We need to, where we can, build in the 196 1 protections ahead of time, try to, as Wayne Gretsky 2 said, skate to where the puck is going to be in terms 3 of taking on not just issues that we face today but 4 issues that we are entirely likely going to have to 5 face in the future. 6 I have no doubt that the expertise that 7 you represent will be called upon. I think when all 8 is said and done, whether it be in genomics or in 9 other areas of scientific excellence and progress, I 10 think it's fair to say that things are changing and 11 changing rapidly and it is groups just like you that 12 are absolutely essential to making sure that we do it 13 right the first time. I hope today, not only do a few 14 housekeeping things in terms of swearing in and 15 congratulating -- swearing in new members and 16 congratulating outgoing members, but I also hope to 17 spend a little time answering questions and listening 18 and having a conversation with folk on the panel, 19 perhaps, even in the audience if it's appropriate. 20 I'll let the Chair decide, but I am hoping that over 21 the succeeding months and years that I am able to 22 learn, recognizing that no one person has all of the 197 1 information, I hope to be an asset to OHRP, a leader 2 that helps OHRP do its work but I also hope to be a 3 student of the system and hopefully I'll leave a 4 little more educated than when I arrived. 5 I think I'll stop there. I have prepared 6 notes here but the five pages of this speech probably 7 would bore you, so I'm going to -- having touched on 8 the main things I wanted to say, Mr. Chairman, I'm 9 going to turn this back to you. 10 CHAIR PRENTICE: Well, thank you very much 11 for your comments and on behalf of SACHRP I want to 12 thank you for your support and I would like to thank 13 the Secretary for his support. It's reassuring that 14 our work is recognized by HHS and I also want to 15 assure you that you refer to us as experts. We are 16 all perpetual students in the subject of protection. 17 You know, the regulations became effective in July of 18 `81 and they remain largely unchanged since then. 19 What's happened is the interpretation of those 20 regulations, so we find ourselves revisiting basic 21 terminology that again, has been in existence since 22 `81. We have been utilizing it. We have been 198 1 applying it but, you know, we don't often really 2 understand what it means. So that's the exciting and 3 challenging thing about what we're doing here for the 4 last three years. 5 And we would certainly invite you to come 6 to any SACHRP meeting at any time that you have an 7 inclination to do so and you schedule permits you -- 8 ASSISTANT SECRETARY AGWUNOBI: I'll be 9 sitting in the back row every once in awhile listening 10 to the deliberations. 11 CHAIR PRENTICE: And I think I've told 12 SACHRP members before, you know, we do get paid a 13 nominal amount to serve on this advisory committee but 14 quite frankly, it's so interesting that we ought to 15 have to pay to do this work. 16 ASSISTANT SECRETARY AGWUNOBI: Thank you. 17 Everyone is nodding their heads. 18 CHAIR PRENTICE: Okay, well, we have some 19 housekeeping chores to do and we would like to invite 20 you and Bern Schwetz up to the front so that we can 21 get on with the swearing in ceremony and some 22 recognition of some very involved departing members. 199 1 Okay, let's see. Okay. Okay, first of 2 all, it's my pleasure to recognize our newest member 3 of SACHRP, Neil Powe who will be sworn in today and I 4 would like to read extracts of his bio which is quite 5 extensive and very, very impressive. So if you'll 6 forgive me, I won't read the whole bio. 7 "Dr. Powe is an MD, M.P.H., M.B.A. and 8 he's director of the Welch Center for Prevention 9 Epidemiology and Clinical Research which is a multi- 10 disciplinary research and training center at Hopkins. 11 He's also the director of the new NIH Roadmap K12 12 Multi-Disciplinary Clinical Research Career 13 Development Program and the new NIH Roadmap T32 Pre- 14 Doctoral Clinical Research Training Program also at 15 Hopkins. 16 At Hopkins, he directs a multi- 17 disciplinary team for one of the largest multi-center 18 prospective cohort studies on incidental dialysis 19 patients ever conducted in the US. He is author or 20 more than 230 articles. Dr. Powe completed his MD at 21 Harvard Medical School, M.P.H. at the Harvard School 22 of Public Health, M.B.A. from Wharton School of the 200 1 University of Pennsylvania, very, very impressive 2 universities that you graduated from. Dr. Powe has 3 received numerous awards and distinctions for his 4 research including election to membership in the 5 American Society for Clinical Investigation, the 6 Association of American Physicians, the Institute of 7 Medicine of the National Academy of Sciences and the 8 American Epidemiological Society." 9 So, again, Dr. Powe, we are absolutely 10 delighted to have you on SACHRP and we look forward to 11 interacting with you over the coming years. So now, 12 I think it's time for the formal swearing in ceremony. 13 Would you please come up? 14 ASSISTANT SECRETARY AGWUNOBI: Dr. Powe, 15 congratulations. This is what I'd like you to do, if 16 you would. Put your left hand on this Bible and 17 repeat after me. 18 (Dr. Powe sworn in.) 19 ASSISTANT SECRETARY AGWUNOBI: 20 Congratulations and welcome to SACHRP. 21 (Applause) 22 CHAIR PRENTICE: Okay, it's my actually 201 1 sad task to recognize departing members from SACHRP, 2 three of which have been on SACHRP from the very 3 beginning, one of which joined when another member was 4 relocated to the Caribbean on a better assignment, a 5 sunnier assignment, and I will call you up in order, 6 but before you come up, I would like to say a few 7 words about you, and when I say order, I'm talking 8 about alphabetical order. 9 The first departing member would be Dr. 10 Felix Gyi, and you know the word scholar and a 11 gentleman comes to mind when I think of you, Felix. 12 You've always been very concerned not only about the 13 welfare and comfort of all your colleagues and the 14 SACHRP members, but you just go well beyond the call 15 of duty. Not only that, you're a very analytical, 16 thoughtful individual who has helped us achieve 17 resolution of a number of difficult issues over time. 18 You are the co-chair of the Accreditation 19 Subcommittee, and you performed wonderfully in that 20 capacity along with Tom Adams. Now you're the co- 21 chair of Subpart A Subcommittee, and even though you 22 are departing as a member of SACHRP, you're not really 202 1 departing at all, are you, because you're going to 2 continue as a member of the Subpart A Subcommittee, 3 actually as one of its co-chairs, probably 4 indefinitely. 5 So on behalf of SACHRP, I thank you for 6 all that you have done. Will you please come up and 7 be recognized? 8 (Applause) 9 ASSISTANT SECRETARY AGWUNOBI: Thank you 10 for your work. I wonder if I might present you, Dr. 11 Gyi, with this plaque. It's just a piece of wood with 12 a piece of paper stuck to it, but it does mean an 13 awful lot to us. I recognize that -- my colleagues 14 and I -- that if it weren't for people just like you, 15 we could never protect the many millions of citizens 16 that are protected in any given year. In appreciation 17 for the service you provided as a member of the 18 Secretary's Advisory Committee on Human Resource 19 Protections from January 2003 to January 2006, it's my 20 great pleasure and honor to present you with this 21 token of our appreciation. Thank you. 22 (Applause) 203 1 CHAIR PRENTICE: Okay, the next departing 2 member, Susan Kornetsky. I've known Susan for, I 3 probably shouldn't say how long, actually, but many 4 years, and Susan is really a credit to the IRB 5 community ever since she got involved with IRB issues. 6 As you know, she's at Children's Hospital of Boston, 7 where she is a well-recognized IRB administrator, an 8 expert on IRB review of pediatric research. She is 9 one of the co-chairs of our subcommittee that's 10 examining the additional protections for children in 11 research Subpart D. And she's done an absolutely 12 admirable job in that particular capacity. 13 Also, not having enough to do with her 14 involvement on the Subpart D Subcommittee, she also 15 volunteered for our Subpart A Subcommittee, of which 16 Felix is a co-chair. So, Susan, we thank you for all 17 of your contributions, and as I said, with Felix, 18 we've not lost you yet because you're going to be 19 continuing on the Children's Subcommittee along with 20 your co-chair, Celia Fisher, so please come up and 21 accept our thanks. 22 (Applause) 204 1 ASSISTANT SECRETARY AGWUNOBI: Thank you. 2 Thank you for working with us. All right, let me read 3 this one, just to embarrass you a little more here. 4 "In appreciation for the service you provided as a 5 member of the Secretary's Advisory Committee on Human 6 Research Protections from January 2003 to January 7 2006," it's my great pleasure to give you this piece 8 of wood with a piece of paper stuck to it with the 9 understanding that you understand that it means so 10 much more than it would appear. We are deeply 11 grateful for your service. Thank you so much. 12 (Applause) 13 ASSISTANT SECRETARY AGWUNOBI: Don't go, 14 stand in the line. 15 CHAIR PRENTICE: Okay, our next dearly 16 departed member, Ada Sue Selwitz. What can I say about 17 Ada Sue Selwitz from Kentucky that hasn't already been 18 said? You know, we've got many stars in the IRB 19 world, and certainly Ada Sue is one of those stars. 20 I remember my first PRIM&R conference way back when, 21 a long time ago, Ada Sue, and I didn't know -- 22 MEMBER SELWITZ: That's enough, Ernie. 205 1 (Laughter) 2 CHAIR PRENTICE: And I didn't know 3 anybody. And that was back in the days when we didn't 4 have 3,000 or 4,000 people attending these 5 conferences. We had maybe 200, and Ada Sue took it 6 upon herself to make everybody feel welcome, everybody 7 feel involved. She sought me out, and she's become a 8 good friend ever since. And I've been involved with 9 Ada Sue on a number of different occasions on 10 committees, et cetera, and I'm always struck by how 11 intuitive she is, how committed she is. She is just 12 one of our stars. And I really am saddened that you 13 came on in sort of like midterm and you have to leave, 14 but hopefully, you'll be back again some day. 15 But again, like your two colleagues we 16 just talked about earlier, you're not leaving us, 17 because you're one of our integral members on the 18 Subpart A Subcommittee, so we look forward to 19 interacting with you for many, many months if not 20 years in the future. So thank you for everything 21 you've done, Ada Sue. 22 (Applause) 206 1 ASSISTANT SECRETARY AGWUNOBI: Okay, Ada 2 Sue, let me add to the embarrassment that he has 3 heaped upon you with a little of my own. "In 4 appreciation for the service you've provided as a 5 member of the Secretary's Advisory Committee on Human 6 Research Protections, from October 2004 to January 7 2006," this humble plaque expresses our deepest, 8 deepest appreciation and gratitude. Thank you so 9 much. 10 (Applause) 11 MEMBER SELWITZ: You make me look like 12 Jennifer Lopez. 13 ASSISTANT SECRETARY AGWUNOBI: You look 14 like Jennifer Lopez. 15 CHAIR PRENTICE: All right, we have one 16 other individual that we want to recognize publicly 17 who is unfortunately not here, and that is Dr. Mary 18 Lake Polan. Dr. Mary Lake Polan was the former Chair 19 of the Ob/Gyn Department at Stanford University. 20 She's one of the original members of SACHRP, and she 21 contributed significantly to all of our discussions 22 and we are -- we miss her, and we're sorry that she 207 1 could not be here to accept the recognition she so 2 deserves in public, but our thoughts are with her and 3 our thanks our for her efforts. 4 (Applause) 5 ASSISTANT SECRETARY AGWUNOBI: Mr. 6 Chairman, I've been sitting here doing a little math. 7 One in and three out, aren't we down two? 8 CHAIR PRENTICE: We're down two. We're 9 down two, but we've got some replacements coming on 10 board, coming on base, so to speak. 11 ASSISTANT SECRETARY AGWUNOBI: All right, 12 so there's a lot of work to go and a lot of stuff to 13 do. Thank you. 14 CHAIR PRENTICE: Okay, now I would -- 15 (Off the record for picture taking.) 16 CHAIR PRENTICE: Why don't we take a 17 couple of minutes and invite members of SACHRP to ask 18 Admiral Agunobi any questions that they would like, or 19 if there are any comments you would like to make, I'm 20 sure he would be delighted to hear them. Ada Sue? 21 MEMBER SELWITZ: First of all, I want to 22 thank you for your comments. I was very impressed and 208 1 reassured, because what we want at the highest levels 2 within HHS is commitment to human research protection. 3 And I thought your comments were excellent. Thank you 4 very much, and I can't tell you, we are thrilled 5 you're here. And even though I may be going off, we 6 hope you come back. 7 ASSISTANT SECRETARY AGWUNOBI: I will, I 8 promise. 9 MEMBER SELWITZ: We want you back. One 10 thing that we've struggled with, and that the Subpart 11 A Committee continues to struggle with, is balancing 12 the need for human subjects protection against 13 creating unnecessary regulatory burden, and it truly, 14 I think, in the area of human research protection, is 15 reaching a crisis point in how you balance the two. 16 And I just wondered if you had any thoughts in this 17 area. 18 ASSISTANT SECRETARY AGWUNOBI: I do. I 19 served for a short while as the chair of a group in 20 Florida that was designed to try and improve access to 21 research for minorities. There was a sense that there 22 was a disparity in the access to cancer clinical 209 1 trials specifically, but I get the impression that 2 there was as sense this extended well beyond that 3 fairly focused forum. 4 And there was a notion that a part of the 5 reason, not the only reason, by any means, but a part 6 of the reason why there appeared to be a barrier to 7 research was the fact that it was a highly regulatory 8 environment with a lot of paperwork, a lot of forms, 9 a lot of requirements to be compliant with statute and 10 with rules both at the state level and at the federal 11 level and within institutions, and that it was a 12 highly intimidating endeavor for a young teenage 13 mother to engage or for an old Hispanic gentleman to 14 engage in that setting. 15 And so we started to do a review of what 16 was the interface like between human research 17 participants and the system, the research system. It 18 struck us that that interface was simply a reflection 19 of the entire process, whether it was the PI sitting 20 across a table from a research subject, or the PI 21 sitting in front of an IRB, or indeed the IRB sitting 22 across a table from OHRP or some of the other 210 1 regulatory oversight that might have applied to FDA 2 and others. It just struck us that the entire process 3 was very complicated, and it seemed to have multiple 4 layers and a certain complexity to it. 5 I also recognize that I'd rather be that 6 way than be a system that is lax, inconsistent, filled 7 with opportunities for error in terms of oversight, or 8 a lack of clarity in terms of what expectations are. 9 So you're right, I guess the issue is balance, and 10 although I don't have the answer, you guys have 11 struggled -- people smarter than me have struggled 12 with this question, finding the right balance over 13 time. I've experienced it. I've seen it first-hand, 14 and I recognize that we always have to work towards 15 reducing that complexity where we can. 16 Bern and I have had multiple conversations 17 about things like this where, how much is too much. 18 I think it's important that we have some feedback, 19 that the best way to seek balance is to never be an 20 isolated part of the continuum pumping out edicts, 21 pumping out interpretations, that the only way to seek 22 balance is to make sure that there's a feedback loop 211 1 from each of the different downstream competence of 2 your actions, in other words, the IRBs, the PIs and 3 the research, those who are research subjects are 4 protected. We need to make sure that there's feedback 5 coming back into law, those that would make law into 6 OHRP, those that would interpret and implement 7 regulation and all -- so I think my answer to you is 8 that I hope we find ways to encourage active input 9 from all of the participants on the continuum. And if 10 we're in appropriate dialogue, it's our best chance of 11 finding the right balance. 12 CHAIR PRENTICE: Thank you for that 13 question, Ada Sue. I think one of the premises by 14 which we operate is to try to find that right balance 15 and in trying to do so, I would like to comment upon 16 the relationship that SACHRP has with OHRP. It's a 17 very active working relationship in that Bern Schwetz 18 and all of his key staff are active participants at 19 all of our subcommittees that meet sometimes as often 20 as three times a year in Washington, and then outside 21 of that time, sometimes by teleconference. And by 22 having the opportunity to carry out interactive 212 1 discussion with OHRP, you ultimately implement 2 recommendations, assuming that they're accepted by the 3 Secretary, we think this makes our work product a lot 4 more adoptable and efficient in the long run. 5 And you know, I'm just absolutely -- I 6 often comment, as a matter of fact, I comment every 7 time we have a SACHRP meeting about this relationship 8 that we have, because I think without that 9 relationship we would not have a very functional 10 advisory committee because we wouldn't be able to 11 implement our recommendations. So Bern, once again, 12 publicly, I want to thank you for everything that you 13 have done and all your staff have done. 14 ASSISTANT SECRETARY AGWUNOBI: I had the 15 honor of serving on at least one SACHRP committee. I 16 served as the chair of the CDC's Advisory Committee to 17 that Director, Julie Gerbinding (phonetic) and I 18 recognize that this is work for which you probably get 19 very little gratitude and appreciation expressed. 20 It's -- I imagine it's tough and it's hard and there's 21 lots of stuff to wade through before each meeting and 22 lots of deliberation during each meeting and I may not 213 1 have this opportunity again, so I'm going to jump on 2 it right away. I know that Bern would join me in 3 agreeing that we thank you. I can't say it any 4 better, any more articulately. We thank you for your 5 work and I hope that you will find that your work 6 helps change the system. 7 Hopefully, there will be some reward in 8 the fact that you get to look back and over time see 9 a strengthening of the system because of your input 10 and your energy and your time. We know it's not for 11 the money. We are deeply grateful and I know the 12 Secretary is as well and I'm going to be meeting with 13 him later today and I'll be sure to pass on your 14 regards to him and to urge him to recognize how much 15 work you do and will be doing in the future on his 16 behalf. 17 CHAIR PRENTICE: Thank you. Yes, Susan? 18 MEMBER KORNETSKY: One other comment, as 19 an outgoing member; thank you very, very much for 20 being here and it's really a highlight to have you 21 here as I've gone off and worked for the last three 22 years. One of the things that we also struggle with 214 1 and I think, you know, it would be helpful at the 2 higher levels is harmonization of the different sets 3 of regulations between OHRP, HHS and FDA and really, 4 you know, to put in institutions need to work under 5 many of us and we're trying, and I know Dr. Schwetz 6 works very closely with FDA as with all of the 7 agencies, but I think in the end will continue to be 8 important and a challenge because their sets of 9 regulations are different, and really just anything 10 that, you know, you could do to help, I think will in 11 the end help IRB and also help our citizens. 12 ASSISTANT SECRETARY AGWUNOBI: I'm 13 committed to working in that direction. 14 CHAIR PRENTICE: Okay, any other 15 questions? All right, Admiral Agwunobi indicated an 16 interest in listening to some of our discussions. 17 Considering the fact that it sometimes takes you 45 18 minutes to adopt a recommendation that has two 19 sentences, I'm not so sure he has enough time to -- 20 ASSISTANT SECRETARY AGWUNOBI: I'll come 21 back. 22 CHAIR PRENTICE: However, I thought to 215 1 provide him with kind of a flavor of what some of the 2 issues are that you have already addressed today, we 3 might prevail upon Dan to kind of in the next -- we 4 have about 17 minutes before you have to leave, to 5 kind of present an overview of what were the issues 6 that -- the key issues, probably not all of them but 7 whatever you consider to be the key issues that we 8 sort of addressed and feel free if you want to talk 9 about some of the recommendations we think are 10 important. Would that be all right with you, Dan? 11 MEMBER NELSON: I can fake it. 12 CHAIR PRENTICE: Thank you. 13 MEMBER NELSON: Thank you, Ernie, and 14 before I do, let me add a personal note of thanks and 15 congratulations to Susan and Ada Sue and Felix for 16 their work. I've had the privilege to work with each 17 of them in many settings inside and outside of this 18 group and I think we've all developed friendships that 19 go beyond the professional activities. 20 Just last night over dinner, some of us 21 were remarking that we've joined each other eating out 22 more often than we have our own spouses over the last 216 1 month and that may or may not be a good thing, but I 2 think we appreciate each other's company and 3 professional contributions. So it's hard for me to 4 think of three people I hold in any higher regard and 5 I'm delighted that each of you are continuing on with 6 our subcommittee. 7 If we can get the -- there it comes, thank 8 you. So with a little advanced warning that Ernie 9 would like an overview of what we've been doing, we 10 went back to actually last August slides which give a 11 more general overview of our activities on this 12 subcommittee than what we've been dealing with today 13 and let me just briefly recap out charge which is to 14 review and assess all provisions of Subpart A of the 15 so-called Common Rule, which extends beyond HHS, of 16 course to several other agencies, 18 agencies which 17 have adopted this and applied it to research involving 18 human subjects and to review and assess all relevant 19 OHRP guidance documents which, of course, help IRBs to 20 implement these regulations. 21 Based on this review and assessment we 22 have been bringing forth for consideration by the 217 1 SACHRP parent committee recommendations in three 2 categories; interpreting specific provisions of 3 Subpart A, developing new or modifying existing 4 guidance and possible revisions to the regulations 5 themselves and we have reached that envelop today. 6 The goals of this subcommittee and of our work is to 7 enhance protection of human subjects above all, to 8 simultaneously reduce regulatory burdens that do not 9 contribute to the protection of human subjects 10 recognizing that the more time we spend on some of the 11 more esoteric aspects of this reduces the time that we 12 can actually contribute to the global protection of 13 subjects and that's increasingly an issue in today's 14 environment and to simultaneously promote 15 scientifically and ethically value research and we 16 hold these goals to be compatible and that's mutually 17 exclusive, one feeds into the other. 18 Our subcommittee membership comes from 19 around the United States in a variety of settings; 20 private, public, community, and I won't go through all 21 of these but a very hard working group of people. 22 Meeting that started in January of last year and this 218 1 was a group of general topics that will give you some 2 feel for the kinds of issues that we've been 3 deliberating on. Continuing review and expedited 4 review are specific mechanisms within the regulations 5 that impact on the daily flow of protocol review 6 through IRBs and we have divided into two task forces 7 that brought forth recommendations and today we 8 finished the last of the recommendations on continuing 9 review, with some -- I think some fairly major issues. 10 Again, they may sound esoteric to the 11 outside world looking in on this but realizing the 12 impact on the daily activity of IRBs and the 13 investigators that we oversee and the protocols we 14 review, I think we'll have very meaningful impact as 15 these recommendations go from now SACHRP to the 16 Secretary. These included such issues as the timing 17 of continual review, at what point in the process must 18 this occur, can this occur, at what level of detail 19 must this occur, how should it be applied to various 20 levels of research based perceived risk with minimal 21 risk being a definition that impacts on the 22 application of these complex regulations. 219 1 Expedited review is another topic area 2 that provides a mechanism for certain areas of 3 research that would not require review by the convened 4 full committee but, as you know from your previous 5 lives, the committee work can be handled by the chair 6 designated member. This is an important mechanism and 7 I would say probably the majority of research that 8 we're talking about may well go through an expedited 9 review mechanism leaving the more risky activities, 10 like clinical trials with investigational drugs for 11 full committee review and the combined efforts of the 12 assembled committee. 13 Inherent to that discussion are topics of 14 what defines minimal risk and that's invariably 15 understood and therefore, invariably applied by IRB 16 and I think one of the more important tasks of our 17 subcommittee and SACHRP is to help better define that 18 working operational definition. 19 Minor changes to previously approved 20 research, how is that handled? How are contingencies 21 from convened IRB review handled. This is an issue 22 that drives -- brings back a lot of minor stipulations 220 1 to the convened meeting rather than allowing that work 2 to go ahead and surprisingly for us, although a one or 3 two sentence redefinition or wording change may well 4 take half an hour to 45 minutes for this group, this 5 major topic issue took all of five minutes because 6 they automatically ceased on the importance of this 7 issue, the impact of the proposed change and perhaps 8 to or surprise endorsed and accepted it and it will 9 now hopefully go on to the Secretary for final 10 implementation and approval. 11 Assurances, how are these handled? This 12 is, of course, one of the major mechanisms under the 13 existing regulations to hold institutions and 14 organizations responsible. It's effectively a promise 15 by an engaged site to the federal level, but they know 16 what the rules are and they agree to play by them and 17 in return it's the license that many of our 18 institutions have that receive hundreds of millions of 19 dollars of external research funding and an important 20 mechanism in this process. How are these understood, 21 applied? What engages an institution in research? 22 How to handle offsite research in non-traditional 221 1 settings and I would extend this to international 2 settings as well, and this committee will hear quite 3 a bit of deliberation on international research 4 tomorrow. 5 Multi-site research, research these days 6 is conducted in a much different way than it was 25, 7 30 years ago as these regulations were formulated. 8 Back then a clinical trial, if there as such a thing, 9 might have occurred at a single institution with a 10 single investigator and a small handful of subjects 11 and now we may well have 1,000 or 2,000 subjects at 12 100 sites around the country, around the world. Whose 13 regulations do we follow? Do we really need 100 IRBs 14 at 100 sites each individually reviewing those studies 15 or are there ways to cooperate in that review and 16 share that review? And indeed, there are ways and I 17 think one of our charges is to make sure those ways 18 are being taken full advantage of. 19 Record keeping and reporting; investigator 20 responsibilities is something that we've just recently 21 been discussing, recognizing it's important, 22 recognizing that investigators are key players in this 222 1 process but are not explicitly identified as such in 2 many aspects of the regulations and there may be -- at 3 least a perceived diminution of their responsibility 4 with IRBs and institutions carrying the ball, if you 5 will, in protecting subjects in our committee has been 6 deliberating on how to best send home the message that 7 many of us preach in our training sessions, that 8 investigators truly share and may hold a shoulder-to- 9 shoulder responsibility for the joint protection of 10 subjects in this process. 11 Informed consent, obviously, a key element 12 in this with what our federal friends have called the 13 twin pillars of protection, independent review by -- 14 of proposed research by somebody other than the 15 investigator themselves and informed consent being the 16 two pillars that support the rights and the welfare of 17 human subjects. How is this applied, when can it be 18 waived, when should it be waived to let research go 19 ahead. Exemptions, exemption from the policies that 20 govern this, how is that applied to certain low risk 21 research activities and are there different funding 22 agency interpretations that impact on the use of this 223 1 mechanism. 2 IRB review of exceptions and deviations, 3 variably understood, variably practiced. Vulnerable 4 populations, what constitutes vulnerability, what are 5 the additional safeguards that should be put into 6 place? There is some specific language in the 7 regulations but a lot left up to IRBs to determine who 8 is vulnerable in what way, how to best protect them. 9 The notion of an additional regulatory section that 10 would address the needs and the vulnerabilities of 11 decisionally impaired subjects is something that's 12 been debated for years and remains unresolved. 13 How to handle legally authorized 14 representatives, the enrollment of subjects by 15 somebody other than themselves into research and 16 studies. And finally, the definitions that are 17 embedded within and indeed, drive the application of 18 these regulations which are vague in some parts, 19 poorly understood in other parts, may need 20 redefinition in other parts, who should these be 21 approached? 22 I think with that, Ernie, that's a broad 224 1 overview of the things that we've been grappling with 2 and unless you want me to return to the specific 3 details, that's where we left off, which I'd be happy 4 to do, I would stop there. 5 CHAIR PRENTICE: Thank you, Dan. That's an 6 overview of the work of just one SACHRP subcommittee. 7 You can multiply that by three or four to reflect the 8 work of the other subcommittees. Initially, we had 9 three subcommittees that began in July of 2003. And 10 one subcommittee was on the process of accreditation 11 of HRPPs, Human Research Protection Programs, and that 12 subcommittee completed its work. The second 13 subcommittee was dealing with additional protections 14 for prisoners who were research subjects, that's 15 Subpart C and that committee recommended two sets of 16 improvements. One would be what we call a short-term 17 fix of some of the problems of Subpart C which would 18 not require an amendment of the regulations which 19 takes time, and the second was the long-term fix which 20 would require an actual amendment of Subpart C and in 21 order to do that, we felt we needed more information, 22 so OHRP contracted with the OIM to do a study of the 225 1 current, you know, penal environment and what kind of 2 ethical considerations should underlie additional 3 protections for prisoners and we're expecting that 4 report to be given to us late spring, possibly early 5 summer and then we'll go back and revisit the whole 6 issue of what should be additional protections for 7 prisoners who are involved in research. 8 The subcommittee dealing with Subpart D, the 9 additional protections for children involved in 10 research continues its work. They will be presenting 11 a report tomorrow. Their work is not done. They will 12 continue to present reports and thus far, we've had 13 two recommendations sent to the Secretary, sets of 14 recommendations, both of which have been accepted, one 15 of which has already been implemented. It was our 16 first set of recommendations. 17 In addition to subcommittee work, we've had 18 a whole series of panels dealing with various issues. 19 One that we'll have tomorrow will deal with 20 international research issues. That's going to occupy 21 pretty much the entire afternoon, but we've had panels 22 on litigation, adverse events, the involvement of the 226 1 institutional official in the Human Protection Program 2 and other areas, litigation, so forth and so on. And 3 the way we work panels is we bring in experts from the 4 community, scientists and IRB experts. They address 5 SACHRP and then we look at the area of the issues and 6 we decide, you know, is there an action that SACHRP 7 should take relative to what's been presented, and the 8 action might be a subcommittee or it might be 9 something else. And to give you an example of another 10 action by SACHRP, would be a panel dealing with 11 various models of IRB review. 12 When the regulations were first promulgated, 13 they were based upon local autonomy in an environment 14 where we didn't have multi-center clinical trials for 15 the most part. So the idea was that, you know, IRBs 16 would be located at institutions where the research 17 was conducted; hence, the term, institutional review 18 board, but since then we've got independent IRBs, 19 central IRBs, community based IRBs, you know, all 20 sorts of IRB models and we felt that we needed to 21 understand what the issues were so we can make the 22 entire system more efficient. 227 1 So OHRP arranged with ASCO and the AAMC to 2 conduct a workshop looking at alternative review 3 models. And we have the results of that workshop 4 today to discuss which will probably culminate in a 5 conference being organized nationally to pursue this 6 issue further. So when I look at the list of 7 accomplishments of SACHRP, you know, I'm actually 8 very, very amazed and I want to make sure that 9 everybody understands where the credit goes. 10 It doesn't go to me, I just make sure people 11 vote on various recommendations. The credit goes to 12 the co-chairs of each subcommittee and the 13 subcommittee members. They're the ones that do all 14 the work and the credit goes to OHRP, as I indicated 15 earlier who are involved at every step of the way as 16 well as to our administration, Cathy Slatinshek and 17 Kelly Booher, who keep us on time and make sure we 18 have briefing books and we get to where we have to go 19 next, so it's just been a delight to be involved in 20 this particular advisory committee. 21 And I know that you have to leave, so I'll 22 leave the last words to you and thank you for coming. 228 1 ASSISTANT SECRETARY AGWUNOBI: I'm going to 2 keep them very short. Audience, join me in thanking 3 this SACHRP for their work, the chair especially. 4 (Applause) 5 CHAIR PRENTICE: Well, we have 30 seconds 6 before break time. Do you want to try to accomplish 7 anything more before break? Okay, let's take a 15- 8 minute break, okay? 9 (A brief recess was taken.) 10 CHAIR PRENTICE: Okay, folks, we are 11 scheduled to talk about the IRB workshop between 3:15 12 and 4:15. We're going to cut into that time because 13 we don't feel as though we need an entire hour for 14 that particular discussion. So we want to give more 15 time to Dan and Felix to talk about some of the 16 additional issues considered by their subcommittee. 17 And these are issues that are on the table, that are 18 going to require further consideration. So, Dan and 19 Felix. 20 MEMBER NELSON: We thank you. We're 21 pleased to have the opportunity to wrap up today. 22 With your help and active participation, I think we've 229 1 moved through -- well, we have moved through all of 2 the formal recommendations that we had ready for 3 consideration and I think that's a job in itself, but 4 we are pleased to share with you some of the work in 5 progress and we actually do have one final 6 recommendation bringing up the rear that's -- that we 7 would bring for a formal endorsement hopefully. 8 But let me -- I had already started on t his 9 before and let me just to reorient you walk through 10 these same, I guess just a single slide. That we had 11 started before, so that this segment is intact. The 12 concept again, of shared responsibility in the 13 protection of human subjects is broadly understood to 14 include investigators as key players and again, we -- 15 many of us preach this and teach this as we give 16 training sessions and I think investigators themselves 17 clearly believe this and feel this. The regulations 18 implicitly invoke, involve investigators in many, 19 perhaps all aspects of this but explicitly only 20 identify investigators in a subset of the regulations 21 that deal with informed consent. The FDA regulations 22 are a bit different in this regard, having more 230 1 regulations specifically aimed at investigator 2 conduct, investigator responsibility. 3 So there is some sentiment that the focus of 4 the HHS regulations may send a message, an 5 inappropriate message, that primary responsibility for 6 protecting subject lies with institutions and IRBs and 7 by not naming, if you will, investigators more 8 explicitly, somehow may send a signal that that's a 9 subordinate or a secondary role. The SACHRP, the 10 Subpart A subcommittee has considered in some depth 11 the proposal that would insert new regulations aimed 12 specifically at investigators into the current version 13 of 45 CFR 46. There happened to be a couple of unused 14 numbers in the flow of the numbering scheme and there 15 was a proposal to fill those with regulations 16 specifically aimed at investigators. Areas of 17 responsibility that would be addressed in this 18 included but not limited to qualifications and 19 resources available to investigators, medical care of 20 subjects in clinically oriented research, 21 communication with the IRB, compliance, use of 22 research product and research procedures, informed 231 1 consent and reporting. Again, hard to argue with any 2 of these as areas that investigators should not be 3 concerned about. However, there was considerable 4 argument about the need for or the format that these 5 regulations should take and so that take-home message 6 here and why there is not a recommendation for you to 7 consider is that after considerable discussion and 8 debate, our subcommittee reached no consensus on the 9 need for or that advisability of additional 10 regulations. There were strongly held opinions on all 11 sides about this approach. 12 There was general endorsement of the 13 underlying principle that investigators do have 14 primary responsibility for protecting the rights and 15 welfare of their subjects. No one argues against 16 that, but how to go about enforcing that if you will, 17 or stressing that was up for grabs and we did not come 18 to any consensus or agreement. One of the 19 alternatives to new regulations that was discussed 20 focused on investigator training and obviously, that's 21 something that goes on now but perhaps an increased 22 focus on that would have some of the same impact 232 1 without -- we're worried, frankly, about introducing 2 a whole new set of idiosyncracies and interpretations 3 and compliance issues similar to what we've just been 4 discussing and trying to fix by introducing yet 5 another complex set of regulations and all that would 6 entail and we weren't quite on board with the need for 7 that at this time, but important in concept how to 8 proceed then in detail is subject for future 9 discussion. 10 CHAIR PRENTICE: Dan, if I could interrupt 11 you, do you want to ask for comments after you go 12 through each section? 13 CHAIR PRENTICE: That would be fine, at your 14 pleasure, Ernie. 15 CHAIR PRENTICE: All right, would anybody 16 like to offer comment about investigator 17 responsibilities? Yes. 18 MEMBER JONES: Well, this is one of those 19 areas that I do feel very strongly about and I guess 20 the one take-away where you said there might be an 21 alternative to training while that was one of the 22 things on the table, I think another consensus or I 233 1 thought somewhat of a consensus was that also when 2 we're looking at investigator responsibilities, that 3 the people that need to be at the table in terms of 4 how it would impact them, what are processes or ways 5 to increase investigator stake and the culture of the 6 investigator's role in protecting human subjects, is 7 to engage investigators in that discussion as well as 8 having the viewpoint from IRB regulators and oversight 9 mechanisms to also really increase ways that we can 10 get at what are mechanisms that would do this in the 11 culture from the perspective of the investigators 12 themselves. 13 So I think you know, I wouldn't default 14 necessarily to training because I think some of the 15 comments at the committee, too, were that some of the 16 trainings that we have currently may not hit at the 17 heart of really increasing a culture where the 18 investigators see themselves and take the primary 19 responsibility in protecting human subjects. 20 CHAIR PRENTICE: Any other comments? I 21 assume it's your intention to continue to debate this 22 issue; is that correct? 234 1 MEMBER NELSON: Yes. 2 CHAIR PRENTICE: Okay, Gary Chadwick has 3 developed an abbreviated set of investigator 4 responsibilities to be incorporated into -- supposedly 5 into Subpart A. I don't know if you've seen that but 6 it's much more abbreviated than the big long version. 7 It's longer than the regulations. 8 MEMBER GYI: Just as a point of 9 clarification, when we get to that stage of discussing 10 regulations, it is the subcommittee's plan to make 11 sure that we engage conversations with all the 12 different stakeholders in an appropriate way. It is 13 really premature for us to even talk about how that 14 looks like because the early discussions led us to 15 simply put the topic on the table and then bat it 16 around a little bit and then come to the conclusion 17 that we just didn't have enough time or the resources 18 to address this at this particular point in time. 19 MEMBER JONES: One thing I have in response 20 to that is that I still think that if we got to the 21 point where the question was what should the right 22 regulations look like, rather than asking what is the 235 1 way that we can do the intent which is to increase the 2 investigator's social responsibility of protecting 3 human subjects. If you already start with it's going 4 to be regulation and it's externally imposed because 5 it is a committee that's basically it's not 6 investigators -- I mean, we have investigators as part 7 of our committee but really we have had a strong view 8 from the regulatory world rather than necessarily from 9 the research driven investigator world. And so it 10 would still be perceived as externally imposed. 11 So I guess I would suggest as we move 12 forward that we take one step back and that is to 13 recast the question, instead of saying do we need 14 regulations and what are they going to look like, to 15 say what are ways that are out there, what can be 16 learned from other things, like the responsible 17 conduct of research movement, the scientific integrity 18 movement, that we can learn about what is the best way 19 to increase the social responsibility or the culture 20 that investigators see it as part of their identity 21 top protect human subjects, and then you know, have 22 regulation be one of the ideas that we consider but 236 1 not go from it, now we have a new set of abbreviated 2 regulations that we're going to see if they work, 3 because you've already set the question at a different 4 stage that just in past experience from the research 5 community's response to the responsible conduct of 6 research movement, if you will, has been negative 7 because they felt it was externally imposed on them. 8 MEMBER GYI: And Dr. Prentice, you know, 9 that's exactly the type of discussion that we engaged 10 in that had led us to really explore lots of different 11 avenues and in the interest of time, at this meeting, 12 I wonder if we might let that be the last word on this 13 particular topic. 14 CHAIR PRENTICE: My sentiments exactly, Dr. 15 Gyi. This will continue to be debated. You're on the 16 Subpart A subcommittee, you'll have opportunities, of 17 course, to express your opinions. So let's let this 18 one die for now and move onto the next topic. 19 MEMBER NELSON: Thank you. So we also 20 spent a fair amount of time at our meeting at the end 21 of January as well as several preceding meetings on 22 minimal risk, a very complex topic, one that has been 237 1 discussed far and wide and I'm afraid will be 2 discussed further. We're not bringing anything 3 forward formally for you today but I'll move through 4 this very rapidly because, again, that will be a 5 future topic. 6 But as you know, there's built into our 7 current approach the notion of risk escalation as an 8 underlying principle or motivating guiding factor in 9 protections. So as the risk of research rises above 10 the threshold of minimal risks there are restrictions 11 and additional protections that come into play 12 particularly for vulnerable subjects. I shared this 13 slide with you before. It's just an example of a 14 single item within the regulations within IRB 15 processing where that definition comes into play, the 16 decision on whether something can be handled by 17 expedited or full committee review. 18 This is a more complete listing of the areas 19 under 45 CFR that reference and hinge on minimal risk 20 in one way or another. Everything from waiving or 21 altering consent, waiving or altering signed informed 22 consent, the stratification of approvable categories 238 1 of research involving children and so on and so forth, 2 and you're familiar with these. 3 This is the current definition, if anybody 4 doesn't have the emblazoned on their minds already, 5 "Minimal risk means that the probability and magnitude 6 of harm or discomfort anticipated in the research are 7 not greater in and of themselves than those ordinarily 8 encountered in daily life or during the performance of 9 routine physical or psychological examinations or 10 tests". A great deal of time and a great deal of 11 uncertainty and variability on how that single 12 paragraph, single sentence, is applied by IRBs across 13 the country. 14 So we have spent considerable time on these 15 questions that come out of that single sentence. 16 Whose daily life are we talking about in that 17 definition; the daily life of a healthy person or the 18 daily life of a subject of research some of whom may 19 not be healthy? Does a relative standard the subjects 20 of research at a slippery slope that allows things we 21 don't wish to permit, is the notion of a healthy or a 22 general population or an average population, also 239 1 itself relative? Does it matter if we're talking 2 about a healthy general population in Chapel Hill, 3 where I live, versus downtown Detroit versus downtown 4 Baghdad or insert your own city and how does this get 5 applied? Does it matter if the normal person is a 6 skydiver or a couch potato or a SACHRP member? And 7 you can see how this plays out in the processing of 8 protocols. 9 Do clarifications in the 1981 preamble set 10 precedent? And we had some good feedback from the 11 legal perspective on this question at our meeting. 12 Does your own recommendation from last year on Subpart 13 D for the definition of minimal risk and its 14 application to research involving children set 15 precedent? In other words, are we required to have 16 the same or might we have a different interpretation 17 in research involving adults versus children? 18 Does the current definition imply 19 equivalence, in other words, does daily life in that 20 definition, is that meant to be the same as routine 21 exams or tests which may be more invasive or less 22 invasive than daily life depending on what kind of a 240 1 life and what kind of an exam we're talking about? 2 Is it possible to downgrade greater than 3 minimal risk to minimal risk via minimization 4 procedures? I've heard this concept and this practice 5 especially discussed by social and behavioral IRBs 6 that review social and behavioral research or does the 7 intrinsic risk remain a constant no matter -- despite 8 our efforts to minimize. Do we need to harmonize 9 differences across the regulations? Is there an over- 10 estimation in social and behavioral research? And 11 this is a common complaint as IRBs apply regulations 12 that many feel were set out to really govern by a 13 medical research and then social and behavioral 14 research was shoe-horned into that. 15 Would a list of examples be helpful such as 16 NHRPAC, the SACHRP predecessor and other groups have 17 laid out to distinguish between minimal risk versus a 18 minor increase over minimal risk versus greater than 19 minimal risk and all risk to be taken into 20 consideration versus those that are reasonably 21 foreseeable? 22 So after numerous meetings and hours and 241 1 hours on debate and discussion on this, this is the 2 working plan that came out of our last onsite meeting. 3 That we will prepare a short, by which we mean, I 4 think, a one to two-page guidance document that we 5 will prepare and put forth for SACHRP consideration 6 and this is to address what we see is the most 7 problematic elements, the most difficult elements for 8 IRBs and investigators to handle. The guidance would 9 include interpretation and clarification of these most 10 problematic elements in the definition and those would 11 include whose daily life are we talking about, a 12 uniform versus relative standard or maybe some 13 combination thereof. 14 And it would address the idea of risk 15 equivalence, the daily live versus routine exams or 16 tests. It would include examples of the application 17 of these definitional clarifications to common 18 research scenarios and we would intend to do this. We 19 would propose to do this without revising the current 20 definition. Perhaps much like wading into PI 21 responsibilities on a regulatory level, I don't think 22 we have the stomach or perceive the need to rewrite 242 1 the definition, but clearly we see a need to add more 2 clarity to the implementation, the application of the 3 current definition. And Ernie, that would be the end 4 of that little subsection, if you want to invite any 5 discussion. And if you don't that would be fine, too. 6 CHAIR PRENTICE: I think we won't invite 7 discussion on this particular issue. 8 MEMBER NELSON: Thank you. 9 CHAIR PRENTICE: So let's just go ahead and 10 move on. 11 MEMBER NELSON: All right, two slides left 12 and they will be quick. The subcommittee would like 13 to endorse -- we spent considerable time reviewing a 14 document that has been prepared by another 15 subcommittee. The Human Subjects Research 16 Subcommittee is an inter-agency committee, I believe 17 chaired by Dr. Schwetz and this involves 18 representatives from several agencies and this group 19 form a social and behavioral working group that has 20 produced a draft that you see entitled there, 21 "Expedited Review of Social and Behavioral Research 22 Activities". And to the extent that this fed directly 243 1 into some of our ongoing deliberations, we've spent 2 considerable time with the help of Bern and Ivor 3 Pritchard and others working through this draft and 4 thinking and learning from it frankly, and although 5 they don't need this from us, we are impressed enough 6 with this work and thankful enough for it and think it 7 would be helpful for the field that we would like to 8 endorse this and our understanding is that this was 9 approved by the Human Subjects Research Subcommittee 10 in December 2005 and will be made the -- it's my 11 understanding that the HSRS is considering various 12 options for taking this forward now and that their 13 goal is to make it available to IRBs and investigators 14 and to the extent that this will provide helpful 15 guidance, especially for those in the social sciences 16 and behavioral sciences. 17 Our subcommittee, although we don't have any 18 role to play in terms of editing it or taking it 19 forward in any formal way, would like to endorse it as 20 it goes ahead. 21 CHAIR PRENTICE: Let me interrupt your 22 briefly. The subcommittee is endorsing the document. 244 1 I assume that you might want SACHRP to consider 2 endorsing the document. Would that not be correct? 3 MEMBER NELSON: That would be even better. 4 CHAIR PRENTICE: Okay, we can't do that 5 until everybody has read it. So for the next SACHRP 6 meeting, we will insure that that document is placed 7 in everybody's packet. Would that be acceptable? 8 Okay. Yes. 9 SECRETARY SCHWETZ: Dan, if I could just 10 clarify one thing. I am a co-chair and Peg Barratt is 11 the other co-chair from NSF, so the two of us are the 12 co-chairs of this Human Subjects Research 13 Subcommittee. 14 DR. BARRATT: Just to add a little bit, 15 that report will need to go from our HSRS which is a 16 subcommittee to the Committee on Science before it 17 becomes a publicly available document. 18 CHAIR PRENTICE: Okay. 19 MEMBER NELSON: All right, our last item is 20 an observation and a plea. Harmonization of 21 regulations and their interpretation and the guidance 22 that comes out of that across agencies is critical to 245 1 the success of SACHRP efforts and to the efforts of 2 our subcommittee. We have found participation by the 3 Common Rule agencies in addition to the active 4 participation that we have from OHRP and for which 5 we're very grateful, to be extremely helpful to our 6 subcommittee deliberations. 7 We have been somewhat lacking in active 8 participation by all the agencies and we appreciate it 9 when we get it and we would like to, at this time, 10 based on our previous work and our anticipated work in 11 the future, bring forth as formal a recommendation as 12 we can make it, I guess, that we would request that 13 representatives of ex officio agencies including but 14 not limited to the Food and Drug Administration being 15 encouraged to attend subcommittee meetings and 16 participate in our deliberations. 17 CHAIR PRENTICE: Okay, so noted relative to 18 the last recommendation, Bern, through his interaction 19 with the ex officios, will initiate that kind of 20 encouragement, okay? All right, any questions from 21 any SACHRP members before we move on? 22 Okay, listen, thanks, Felix. 246 1 MEMBER GYI: Sorry to take us back a little 2 bit but just as a point of bookkeeping clarification, 3 on page 35 of your handout, there were two 4 recommendations that were made. I'll give you a 5 minute to get there. I wondered if you might help us 6 to just remember if we acted or voted on the second 7 recommendation which is to dovetail on Peg's, her last 8 comment about the inter-agency collaboration, and 9 "SACHRP is requested to encourage all agencies under 10 the Common Rule to harmonize this and other changes". 11 And I think just for our minutes, if you could help us 12 understand how we left that. Did we vote on this the 13 last time? 14 CHAIR PRENTICE: Yes, yes, we voted -- it's 15 my understanding we voted on an amendment of the 16 second one, "SACHRP is requested to encourage all 17 agencies under the Common Rule to harmonize this 18 change", you know, whatever the exact language is. In 19 other words, we removed the reference to all other 20 changes in the world, okay, feeling like that is 21 something that applies to a lot of the work and 22 recommendations of the subcommittee and I would 247 1 suggest for your consideration that at some point in 2 time, obviously, when a letter goes forth to the 3 Secretary, that would be an extremely important point 4 to make in terms of a recommendation. 5 But as a single recommendation tied to a 6 specific, you know, aspect of the regulations like 7 expedited review, I think it's kind of -- a little bit 8 out of sync. 9 MEMBER GYI: So we did as the SACHRP 10 committee voted on this as a separate recommendation. 11 CHAIR PRENTICE: That's my understanding, 12 yes. 13 MEMBER GYI: Thank you. 14 CHAIR PRENTICE: Does anybody have a 15 different recollection? Okay. All right, I want to 16 thank the both of you and all of your subcommittee 17 members for all of the work you've done. It's very 18 clear that this required a great deal of effort and we 19 look forward to your next report at our July meeting. 20 Okay, now we're going to move on to the next 21 item on our agenda and that is the discussion of the 22 IRB Workshop sponsored by AAMC and ASCO back in, I 248 1 think, December of this year. What's that? Oh, and 2 NIH as well, sorry about that. And Bern Schwetz is 3 going to provide us with an overview of the results of 4 that workshop. 5 SECRETARY SCHWETZ: Let me just give you a 6 15-second follow-up on Dr. Agwunobi's visit. As I 7 accompanied him out to his ride, he said several times 8 in different ways how impressed he was to be here and 9 he asked a favor of me. He said, "See to it that 10 attending one or two SACHRP meetings a year gets on 11 my calendar". So that's good. 12 Okay, I want to talk about the IRB workshop 13 that we had and, in fact, I want to thank the people 14 who are here who were on the planning committee, who, 15 I want to thank them but I also want to identify a 16 handful of other people to whom you might address your 17 questions when we get to the discussion phase. This 18 is for the Planning Committee for the workshop that we 19 held in November. And Amy Patterson and Alan Ship 20 from NIH, Alan and Amy; and Lynn Cates and Genevieve 21 Nowolinski, Genevieve is back there, Lynn is here; and 22 Susan Ehringhaus, Susan, where did you go? Oh, right 249 1 here, oh, great. Good, Susan Ehringhaus from AMC and 2 the one party that did most of our planning who isn't 3 here today is Lowell Schnipper from ASCO, who as you 4 recall, wrote the letter to SACHRP a year and a half 5 ago asking that this be considered. So that was the 6 team. 7 You have the report, the summary in your -- 8 in the materials that you have so one more time, I'm 9 not going to go over that in detail but I want to set 10 the stage for discussion. So let me proceed very 11 quickly with some of this information. And it came as 12 the basis of a recommendation from SACHRP in October 13 of 2004 and as we developed the program and figured 14 out just exactly how we would do this and who we could 15 invite, then, the workshop ended up being in November 16 17th and 18th of 2005. So my reason for bringing it 17 back today is to stimulate some discussion with SACHRP 18 on whatever you want to recommend as a follow-up now 19 having had that workshop. 20 We had about 50 people attend and one of the 21 important things in selecting individuals was that 22 they represented all parts of the enterprise. So I 250 1 haven't even listed them all there but we had people 2 from the academic setting, business, government, 3 independent IRBs, subject advocates, attorneys, 4 scientists, IRB types. It was a major effort to get 5 representation from all of these various groups from - 6 - I don't have industry on here but we had people from 7 industry as well. 8 And it was a combination of people who were 9 invited and public. It was primary discussion time, 10 but there were plenary sessions but the major activity 11 took place in the breakout groups and the charge to 12 the whole activity was to discuss the pros and cons of 13 alternatives to local IRBs, as the models were 14 achieving the responsibilities of IRBs. As you recall 15 the letter from ASCO that started this activity, the 16 emphasis was on central IRBs and in the oncologic 17 community why aren't central IRBs being used to a 18 greater extent than they are, because of the perceived 19 benefits that everybody has talked about, but for some 20 reason that hasn't translated into widespread use of 21 central IRBs. 22 So we expanded this a little bit that it 251 1 wasn't just an either/or situation of the local IRB or 2 a central IRB but, in fact, as we talked about this, 3 the group identified 10 different models of IRBs that 4 could be considered that were operating today that 5 could be considered as alternatives to local IRBs. So 6 we wanted to discuss the pros and cons and how could 7 we encourage not just central IRBs or not just 8 regional or independent or any alternative -- any one 9 to the alternative local IRB but how could we 10 encourage using the best model that is suited for the 11 protocols and the research program that's under 12 discussion? 13 So that was the thrust of this meeting. The 14 factors that influenced the choice in the model 15 occupied a lot of the discussion and these are things 16 that are included to you who have been involved in 17 these kinds of discussions about the pros and cons of 18 various kinds of IRB models. 19 I've highlighted out the key challenges that 20 are summarized in your report as well to set the stage 21 for the next thoughts but things that were really 22 talked about that were of concern here for whatever 252 1 model might be used, one of them was the quality of 2 the review. And again, this isn't unique to any one 3 model. The question of quality of the review applies 4 to every model. 5 Local context, obviously, this is a 6 situation where the local IRB is perceived to be the 7 only one that can understand the local context but 8 that's not true. Other models are successful in 9 understanding the local context. It isn't just the 10 local that has a handle on that. 11 Liability was a major topic of discussion, 12 as you would believe, liability of individuals, 13 liability of institutions and to what extent is this 14 different from one model to another. Then control and 15 accountability, turf is very important in IRB 16 activities and people who are perceived as having to 17 take care of things at home, don't want to necessarily 18 share parts of this with IRBs who aren't on site. So 19 that's clearly part of the discussion. And then 20 accountability, who is actually responsible for 21 anything that might happen or the implementation of 22 the protocol if, in fact, we use a combination of 253 1 different models at one institution? 2 So there were a lot of issues that were 3 raised. Going beyond what is in the minutes of the -- 4 or in the summary now, I want to share with you some 5 of my observations as we met there for two days and 6 heard the discussion. I think people clearly wanted 7 to be heard. This is a contentious issue and has 8 already been primed -- the well was primed because 9 people had argued about this, talked about it in 10 numerous meetings before but what was a little bit 11 different in this meeting and some of the other ones 12 that I've been involved in is, I think people actually 13 listened to each other in this one because we forced 14 them to sit and talk about it for two days in a row. 15 So they had to listen a little bit as opposed to in 16 other meetings of an hour or couple hours, after the 17 warm-up antics are done, people just talk past each 18 other and stop listening to each other with the hopes 19 that if they talk loud enough, they'll prevail. 20 Well, that didn't work here. We held them 21 too long. So fortunately, I do think people listened 22 to each other. But clearly there was no evidence of 254 1 a mass conversion from a different view. People who 2 came in convinced that the local IRB was the only way 3 this could be done, probably left convinced of the 4 same thing but they did engage in the discussion. 5 There were probably people who were in between being 6 totally open-minded or being not open-minded who might 7 have been converted and I'm hoping that they left with 8 more information anyhow but certainly it wasn't our 9 objective in these two days to convert everybody from 10 whatever position they were at to a different one. 11 One of the things that I want to talk about 12 in the next slide is as we've talked about central 13 IRBs or alternatives to local IRBs, we have gotten a 14 long list of reasons why it won't work, why in my 15 institution I would never give that serious 16 consideration to use anything other than the local IRB 17 and I think some of this is based on real concerns but 18 some of it is just an excuse of convenience. And if 19 we can't find any other reason why we're not going to 20 take some alternative to the local IRB, I can off 21 liability and turf and a number of these other things, 22 and that kind of stops the discussion. 255 1 So I think if we're going to make progress 2 here, we have to sort out those things that are just 3 smoke from those that are real concerns and fix those 4 that are the real concerns. There was a lot of 5 interest in the group to move this forward, to move 6 the process of looking for alternatives to local IRBs 7 for certain kinds of protocols in research programs. 8 There was also a lot of interest in a national 9 conference as evidenced by the fact that after the 10 official meeting was done, quite a few people stayed 11 on for a couple more hours to talk about what a 12 national conference might look like. 13 Okay, this issue of what are the real 14 concerns and what are those that are used as excuses 15 that somehow we have to bring that closer to reality 16 and not let just excuses be the reason for why my 17 institution isn't considering any other alternative. 18 Liability fears was one of the loudest discussions but 19 in reality as we went through this discussion, there 20 isn't one model that is without liability. There 21 isn't a different model that has all the liability. 22 Every one has some liability associated with it. So 256 1 to assume that if I use that model, I won't have much 2 liability, if any, is not something that really works. 3 They all have some liability. The idea that my 4 institution, if I have a review done by someone else, 5 my institution can be absolved of responsibility for 6 something that happens in this study when it was 7 reviewed by somebody else's IRB. 8 That's not -- that doesn't really make sense 9 that I can be totally free of, for example, any harm 10 to subjects that might occur in a study done in my 11 institution just because a different IRB reviewed the 12 protocol. It really doesn't work that way. The 13 institutions are responsible for what happens at their 14 institutions. So you just can't give that away. 15 Local context is probably a real concern. 16 There are some IRBs, some IRB mechanisms, that clearly 17 have worked hard at being able to handled the local 18 context issue and I believe they can. There are 19 others who probably have not gotten there yet and 20 would struggle with local context. So I don't think 21 every model is equal or every IRB approach is equal in 22 being able to understand local context. So that's one 257 1 that I think has a strong element of reality behind 2 it. 3 Another one, and I guess I forgot to mention 4 this on an earlier slide, one of the things that was 5 kind of new to me was the loudness of the voice that 6 if my IRB, my local IRB allows another IRB to do some 7 of this work, I'm not going to free up time of my IRB 8 members to do a better job on what remains. I'm going 9 to lose people, lose resources, and as a result, it 10 isn't a given, then, that the local IRB will have a 11 better opportunity to do a more thorough job of what 12 remains and, in fact, it could have a negative effect 13 on the local IRBs. 14 Quality of alternatives, again you can 15 address the question of quality within any category of 16 IRBs. Not all local IRBs are of the same quality. 17 Not anybody else in other categories are equally of 18 the same quality as everybody else in that category so 19 again, this is not something that by virtue of going 20 to a different model you automatically lessen the 21 quality or that you necessarily upgrade the quality. 22 This is something that you have to assume 258 1 responsibility for when you look for a different 2 model. 3 Cost and time required for review, there is 4 some information on this, a bit of published 5 information, but not enough to make it real clear that 6 you can use some kind of a calculus to say that if you 7 use this type of IRB it costs this much more and it 8 takes this less time, whatever the case might be, that 9 if you use this model or that model. So we need more 10 information to be able to deal with that kind of a 11 question. 12 Some points for further discussion; and I'm 13 not meaning to limit what you will talk about here in 14 your SACHRP meeting on this whole workshop but I did 15 want to focus on a couple of things. One of the 16 recommendations in there is that OHRP and FDA should 17 provide additional guidance particularly guidance that 18 would address the issue of shared responsibilities, 19 what I really have to take care of as a local IRB and 20 what are the responsibilities of the other IRB who 21 might be helping us in our portfolio of reviewing 22 protocols and all the rest of the responsibilities for 259 1 IRBs. Now, obviously, we can write guidance but my 2 question is, would it make a difference if FDA and 3 OHRP took a lot of time to write further guidance on 4 this. It might be worth it, but the point to you is, 5 it comes at the cost of working on some other 6 guidance. And if this is the highest priority thing 7 we should be working on, well, then maybe we should, 8 but if it isn't, I just remind you that whatever you 9 would recommend in terms of guidance creates 10 competition with other things that are already on the 11 list that you and other have recommended. 12 There was a clear feeling that targeted 13 workshops might be better than one national 14 conference. We have been thinking of having the 15 national conference as a sequel to the workshop but 16 there was a clear message that made sense also that we 17 should have a targeted series of workshops with 18 institutional officials being one group, investigators 19 being another, IRB types another. So there could be 20 a series of these or they could be distributed across 21 the country that you'd meet with institutional 22 officials here and there in the US to try to deal with 260 1 this. So I would welcome some discussion from you. 2 This all boils down to what we want to accomplish and 3 who do we want to talk to, to accomplish it. Would a 4 national workshop do that or is it a pre-requisite to 5 going to the regional or to the specific workshops 6 with targeted groups? 7 Then the last category since we lack 8 information on a number of these, including the cost 9 of alternatives, including the locals, I don't have a 10 good handle on how much it costs. It is applies and 11 oranges as we look at different institutions 12 describing how much their IRB responsibilities cost. 13 That's pretty hard to nail down, so what are the 14 costs? How are we going to measure performance so 15 that if we're going to recommend a model, we know that 16 this is the one that performs -- this is the model 17 that performs best for this kind of a protocol and may 18 not be the best for another kind of a protocol. How 19 do we get that performance information? 20 And then the questions of quality and 21 effectiveness, efficiency, if we're really going to be 22 able to convince people, we have to have some of this 261 1 kind of information. Who sponsors it? Who collects 2 it? Who analyzes it? Who publishes it? How do we 3 use it as a basis for making decisions? So I will 4 stop there and I will welcome input from some of the 5 rest of you who were participants, Ernie as there as 6 well, and partners on the planning of this. If there 7 are some specific things that we can help SACHRP with 8 as you discuss this, we're all here to help in this 9 discussion. 10 Ernie, I'll turn it back to you. 11 CHAIR PRENTICE: Okay, thank you, Bern. As 12 you know the sponsors of the workshop were the AAMC 13 and ASCO and the NIH and VA, so perhaps it would be 14 appropriate to ask representatives from those sponsors 15 if they would like to make any comments beginning with 16 you, Susan. 17 MS. ELLENBERG: Only that it was great 18 privilege for AAMC to participate in this effort and 19 for my part, until SACHRP begins to get into the 20 specifics of the items that Bern brought up, I think 21 I'd like to reserve comment. I think you've 22 summarized it very well, Bern, and so I'd like to hear 262 1 from SACHRP. 2 CHAIR PRENTICE: Okay, Amy? 3 DR. PATTERSON: I think Bern summed it up 4 nicely. I will say that from the NIH perspective, we 5 came out of the workshop a little but surprised, 6 perhaps because we went into it naively thinking that 7 much of the discussion would center around the pros 8 and cons of different types of IRB review models for 9 different research context and instead found that the 10 discussion very interestingly, that it is quite a 11 different focus of the discussion really centered on 12 very practical matters, how reviews are done, the 13 allocation of resources, concerns about 14 responsibility, accountability, and when there was 15 attention to the issue of what model of IRB would be 16 the best fit and optimize human research protections 17 for a given protocol, the conclusion seemed to be that 18 well, you can almost make any model fit with the right 19 expertise, the right people on it. 20 So I think we came away a little bit 21 surprised by the workshop and I'll just stop there. 22 It was a general observation on our part but I 263 1 certainly agree with the comments that Bern has made 2 and look forward to hearing what the committee would 3 like to do in terms of next steps. 4 CHAIR PRENTICE: Lynn? 5 DR. CATES: We at the VA were also very 6 pleased by this workshop and we found it very useful 7 and educational. I think Vern did an excellent job of 8 summarizing it and I'd like to hear what the committee 9 has to say about next steps. Thanks. 10 CHAIR PRENTICE: Okay. Committee, Susan? 11 MEMBER KORNETSKY: Can I ask a question 12 about the document that we got, which was a summary? 13 CHAIR PRENTICE: Yes. 14 MEMBER KORNETSKY: Is that okay? 15 CHAIR PRENTICE: Yes. 16 MEMBER KORNETSKY: I went through and I 17 found your -- the summary, I think, very useful. I 18 was not there and I just want to question. On the 19 page that talks about suggestion for dividing 20 responsibilities, one of the issues that often comes 21 up that maybe folks addressed but I wasn't here, is 22 for handling non-compliance and issues of 264 1 unanticipated problems because every time we start 2 getting into discussions with others, this seems to 3 be, you know, one of the more major issues in trying 4 to figure out who is responsible and I'm just 5 wondering whether that came up at all during the 6 discussions or perhaps it didn't. 7 SECRETARY SCHWETZ: Yes, Susan, it did come 8 up and that was, personally the question of, you know, 9 who is responsible. If I have a protocol that's 10 approved by another IRB, and then the study is carried 11 out at my institution, if something goes wrong, surely 12 that responsibility lies with the other IRB and our 13 institution is free of responsibility. So that was 14 discussed loudly by a small number of people. 15 DR. CATES: Susan, also we heard from quite 16 a few people how they found that very -- they used the 17 word "crisp agreements" carefully delineating the 18 roles and responsibilities of the alternative model 19 versus the local institution where that made all the 20 difference in handling those situations for people who 21 are already using alternative models. 22 CHAIR PRENTICE: Felix? 265 1 MEMBER GYI: Just as a point of information 2 for this committee, in our working group, I was one of 3 the public attendees and as Dr. Schwetz said, there 4 were breakout sessions where there were working groups 5 discussed various items and then there was a 6 collective discussion again, so I think that while 7 there was some shared experiences we primarily got the 8 benefit of the individual working groups and then 9 translated into a larger model. 10 At least in our group, one of the discussion 11 points that kept coming up over and over again under 12 the rubric of liability was there are two different 13 types of liabilities that institutions are concerned 14 about. One is the financial litigation type of 15 liability and the other one is regulatory/public 16 relations liability. And so the question of how is 17 liable for doing something wrong really needs to be, 18 I think, addressed a little bit more specifically. 19 So if you stay with your question of adverse 20 events, that's a great example of a liability concern 21 that transcends both aspects. Because if there is 22 harm that's done, where an institution might be found 266 1 to be legally liable, who are the players and who is 2 going to be found culpable, I think came up in a 3 number of different discussion points. And then the 4 question of has the institution abducted their 5 responsibility by choosing a different model also came 6 up in a number of different ways because who will the 7 regulatory agencies sanction? Will it sanction that 8 other IRB or will it sanction the institution? And if 9 we were to take a look at the FDA regulated world, you 10 know, the FDA has a mechanism to tease out the various 11 components whereas an OHRP and an HHS side of things 12 the institution is held accountable so irrespective of 13 who is providing that oversight, that institution 14 ultimately feels as if they're going to be sanctioned 15 and then that has a public relations translation to it 16 as well. 17 And so, you know, those are some of the 18 issues that were raised, at least in my group. 19 MS. ELLENBERG: Just one more comment, 20 Susan, I think your question is excellent and what it 21 prompts in me is my reflection on the workshop and 22 that is the extent -- I was surprised in some ways Amy 267 1 was surprised. I was surprised at the extent of 2 misinformation about liability and about 3 responsibility and what I would really believe or 4 really miss about things that might happen, which are 5 just that in my view. So I think that we illuminated 6 in the workshop a number of areas, all of which could 7 be lumped into the liability/accountability label, 8 that cry for more information, more education and 9 more, perhaps guidance but especially information and 10 education that could come in through the device of 11 national workshop or in the focus groups. 12 CHAIR PRENTICE: Celia? 13 MEMBER FISHER: Well, I think this is a 14 wonderful start and looking at the summary, some of 15 the models, I agree with you, they seem very exciting. 16 It would seem -- so certainly, I believe our committee 17 should certainly support continuing to go forward, 18 because I think that at other meetings, we constantly 19 come up with the issue of centralized or what do you 20 do with multi-site studies. So it's not an issue 21 that's going to go away. So I think we should 22 certainly support continued dialogue on it. 268 1 I also agree with Susan, that in some sense 2 in terms of process, it sounds like until there are 3 legal models of liability, that many people will not 4 be able to hear alternative models in a way that is 5 distinguished. So one approach may be to begin to 6 have models of liability, shared liability, getting 7 legal advice if that exists, but one of the things it 8 sounds like is that the fear is so great that it's 9 creating in some sense a practical resistence to 10 wanting to move ahead with some of those others. 11 So, you know, in a working group or in some 12 kind of way to -- I'm thinking of how the OIM 13 sometimes has a -- they contract somebody to write 14 what the potential legal models might be or liability 15 models. That might be helpful to begin to move this 16 ahead in a more conceptual fashion. And I was also 17 wondering whether there's a distinction between multi- 18 site projects that want to move to have some kind of 19 centralized review versus looking at cost sharing for 20 a centralized IRB that there's not this shared project 21 that's going on and whether or not it's of any benefit 22 to begin to separate out those issues and it may be 269 1 easier to begin with the multi-site studies 2 themselves, because that's where we hear -- you know, 3 over the years we hear most of the concern especially 4 in terms of time lags an then disagreements and I 5 think what Bern mentioned about the cost and the 6 quality effectiveness and the performance of various 7 models, I don't know if you had provided data on that 8 at the meeting itself but I think the more facts 9 people have to in some sense alleviate the primary 10 risks, the more they're going to be able to begin to 11 talk about the real issues. 12 CHAIR PRENTICE: Ada Sue? 13 MEMBER SELWITZ: First, I want to 14 congratulate all of the sponsors of this particular 15 workshop and thank you for taking this on and I also 16 read the summary and thought it was very useful. I'm 17 also out in the field and I'm at an institution that 18 is not exactly rushing to embrace centralized review. 19 And I think if you want to go forward, I mean, and the 20 underlying assumption as I understand it, the 21 underlying goal here is to try to eliminate barriers 22 to using centralized review where it's appropriate. 270 1 Now, I don't know where appropriate means, 2 but that that's the overall goal. And it seems to me 3 that it might be a little bit premature to be moving 4 on to guidance at this point, that there's still -- 5 you know, when I read the summary, I thought, this is 6 great but I need more solutions. Certainly, like 7 Susan and like many others, are interested in who's 8 going to be responsible for what and what then does 9 that mean from ethical and regulatory issue. 10 And then I think once I understand that, 11 I'll know whether I think these are concerns, real 12 concerns or convenient excuses in some of these. And 13 Susan, I thought your comment and Lynn's, yours as 14 well, well, people were misinformed, I think it's 15 important to try to maybe have some focus, more 16 focused discussion groups that try to get at who's 17 responsible for what and what are the implications. 18 And then Susan, I couldn't agree with you 19 more, I think there needs to be education. Now, does 20 education need to be in the form of OHRP guidance? I 21 don't know that answer. I have no doubt that in my 22 mind, if you look at the current options we have, it's 271 1 clear that centralized view is acceptable from a 2 regulatory standpoint. I couldn't have said that a 3 few years ago, but I feel like I can say that now. 4 But I'm not sure that has filtered down, the reality 5 of that has filtered down. I don't know how you get 6 at the liability issues that Felix mentioned that were 7 public relations issues. 8 I mean, I'm at a state institution in a 9 fairly small conservative state in which we have one - 10 - well, we have two research universities but one 11 flagship. And so there is this constant public 12 relations concern and I think it gets back to how you 13 sort out who's responsible for what and what it means, 14 and not strictly from a legal standpoint but also from 15 a regulatory standpoint. I mean, and I think that's - 16 - those are two -- in my mind, they're intertwined 17 when you go to court, but they are, in fact, can be 18 two separate issues. What does FDA, OHRP -- I mean, 19 who are you going to hold accountable in what way in 20 these circumstances and I understand your point about 21 absolving an institutional responsibility and why they 22 can't be done. And I would agree with that, but I 272 1 think an institution likewise before it decides that 2 it wants to endorse this approach, has got to 3 understand what the implications are. And I think 4 that's where there needs to be not just more education 5 but maybe more thinking. And then after the thinking 6 more education which might, perhaps, be done better in 7 guidance. 8 CHAIR PRENTICE: Other comments? 9 MEMBER JONES: One -- it sounds like two 10 things also are a broader concern and the one that 11 came out was the -- first, that it would jeopardize 12 the resources for IRBs and I think that seems to be a 13 broader concern that you know, people say that there 14 aren't motivation to put the resources that are needed 15 into human research protection and maybe there's 16 something here that can be gleaned in a broader 17 context because, of course, my understanding that's a 18 common theme, that unless you have a teachable moment, 19 we heard from one of the former testifiers that your 20 institution is forced to relook at are they putting 21 enough adequate resources. 22 And then the other question I have is that 273 1 you highlighted that could we get information on 2 performance of various models and just, I guess my 3 understanding is that NIH, I don't know if this is 4 true to other agencies, that you have to set aside a 5 certain amount of funds for evaluation. Is there a 6 source that, you know, the valuation studies could be 7 proposed to get at some of the data that OHRP has 8 accessible to it through like HHS or something? 9 SECRETARY SCHWETZ: There is money that's 10 set aside within -- it's set aside money to evaluate 11 program performance. And we compete for this money 12 every year to the extent that we want to submit a 13 proposal for how to get it. The thing that's probably 14 even more difficult than getting money to do this kind 15 of work is what are the criteria that you're going to 16 use to measure performance of the IRB system? And as 17 I've had discussions with a lot of people on that in 18 the last two years, the guidance that I get back 19 ranges from we've been there, we've tried to figure 20 that out and we failed, so don't waste your time on 21 it, on one extreme, to on the other side saying, there 22 isn't much that we could do that would be more 274 1 important than this and why can't we get some people 2 together to help reach agreement on what are the 3 criteria that we could use to evaluate the performance 4 of the IRB system? 5 And the opinions that you hear as well as I 6 range from the IRB system is working fine, why are we 7 feeling we need to go through this exercise of 8 measuring how it's performing to people on the other 9 side who say it's totally broken and we need to fix 10 it. So I don't think we can just sit back and say 11 it's working fine. I think we need to be 12 introspective in the system that we manage and figure 13 out how can it be done. 14 MEMBER JONES: Actually, I'm involved in a 15 little bit of learning more about evaluation tools but 16 I'm not an expert, but I think there are even types of 17 evaluations you can do to see things that need 18 assessment or even if it's feasible, to do an outcome 19 measure which ultimately you want to do performance so 20 that you know, while the long-term goal of developing 21 a performance, an evaluation tool that measures 22 performance may not be able to be reached at the first 275 1 step, you can even do types of evaluation to see if 2 there's any hope to reach it. 3 So I don't know. I mean, this seems -- it 4 also came up at SACHRP the last time that sometimes 5 we're stymied by the lack of reliable data, and, you 6 know, of course we like data because it helps us make 7 more of an informed decision. But if there was a way 8 to leverage some of the resources that were available 9 through HHS to increase the performance of OHRP, and 10 this might be one of the areas that it would be really 11 useful to get some of that data. 12 MEMBER SELWITZ: Ernie, may I clarify one 13 thing about the set-aside money? The money that's 14 used by federal agencies is to analyze how well they 15 are doing in whatever program is the substance of the 16 evaluation. We could not get HHS money as OHRP to 17 evaluate how is the IRB system working because we 18 don't have control over the whole IRB system but we 19 could address the question of how well does OHRP, the 20 role that we have in the performance of the IRB 21 system, how well are we doing but that may just be a 22 very narrow sliver of how the whole IRB system is 276 1 working and we do not -- we would not get the 2 resources to do that. 3 At any rate, whoever does that it's going to 4 be a major task of identifying the criteria before you 5 start it out. 6 CHAIR PRENTICE: Any other comments? Okay. 7 The genesis, as you know, of the workshop was the 8 letter written to SACHRP by ASCO, basically pleading 9 with SACHRP to try to, you know, to intervene and fix 10 what they consider to be a broken system in terms of 11 acceptance of central IRB review. And then of course, 12 the workshop expanded upon that particular issue and 13 incorporated other IRB models. And the report is now 14 before you and it's up to us to try to decide what the 15 next step, steps should be. 16 We have to try to make a recommendation 17 concerning whether or not it's more appropriate to 18 have a national conference versus having targeted 19 workshops in advance of a national conference or 20 perhaps in lieu of a national conference, you know, 21 what comes first. In looking at the issues, I think 22 the issues are very well presented in the summary and 277 1 I see three major issues that could be addressed in my 2 opinion because I think that there is available 3 information or available data and I'm not presenting 4 these in any order of priority. 5 One is cost of alternatives. You can find 6 out, you know, what local IRB review costs at a given 7 sample of institutions if they're prepared to share 8 that information with us. You can also find out what 9 a typical cost of a -- you know, of a central IRB is 10 to run as well, as an independent IRB, so I think that 11 information could be made available with regard to 12 cost issues. The second one which is not on points 13 for further discussion but we certainly talked about 14 it, is liability and as has been mentioned, there are 15 two aspects of liability; one's legal, one's 16 regulatory. 17 From a regulatory sense, it's sanctioned by 18 OHRP or citationed by FDA and then we can interject 19 public relation damage. That's something that could 20 be, I think, addressed. I think there's a lot of 21 misinformation with regard to liability, on the part 22 of university attorneys who over-react, perhaps, to 278 1 what they have as a fear of liability and I don't 2 think that they have the information to support, you 3 know, that fear. 4 So certainly that's an area that could be 5 explored at either a national conference or a targeted 6 workshop. Probably in my opinion the most important 7 area which intersects with all of these other issues 8 would be divided responsibilities. What is the 9 relationship between a local IRB and a central IRB or 10 an independent IRB? There's a lack of education on 11 the part of local IRBs as to how such an interaction 12 would work, what kind of a model would be best and 13 it's because of that lack of information, I think, 14 that a lot of local IRBs and institutions are 15 reluctant to move in the direction of a central IRB. 16 So certainly that's something that could be explored 17 further. 18 As far as performance of various models, 19 there's no data. Okay, we just don't know for sure. 20 I mean, we know that independent IRBs can turn around 21 protocols very quickly. They are very efficient. Is 22 that an index of quality? It might be and then it 279 1 might not be. We just don't have a handle on that, 2 there's no data and I don't know how you get that 3 data, not in the foreseeable future. 4 And as well, and that also feeds into 5 quality and effectiveness and efficiency. I mean, how 6 do you measure that and I think you can measure 7 efficiency but efficiency is not necessarily tied to 8 effectiveness. So that's a problem. So given 9 available information as well as a lack of 10 information, I certainly think there are enough issues 11 that were explored in this workshop that warrant 12 further exploration to move this to the next step. 13 And I've been thinking as we've been talking 14 about should it be a national conference, should it be 15 targeted workshops, I guess my bias, not hearing any 16 you know, opinions yet from the group is that a 17 national conference, first to give another airing of 18 the issues and then going to targeted workshops. I 19 mean, I can see one on just liability alone for a 20 bunch of university attorneys. You know, get them 21 all together and get a facilitator in there and hash 22 it out if that's possible with a bunch of academic 280 1 attorneys. 2 So I don't see going with a targeted 3 workshop -- targeted workshops first as opposed to a 4 national conference, but I want to throw that out for 5 discussion because we want to provide some advice to 6 OHRP and the sponsors of this as to which direction we 7 think we ought to go. Ada Sue? 8 MEMBER SELWITZ: Let me ask a question and 9 this is very helpful, Ernie, because I was thinking 10 just the opposite but I think it comes down to -- I 11 was thinking that the conference would be designed to 12 educate, you know, to do what Susan was talking about 13 and that the targeted workshops would be to try to get 14 a little bit meat and a little bit closure on what 15 needs to go in the education, so to speak. But on the 16 other hand, I really think one of the primary barriers 17 is that people just don't know. So you could start -- 18 so having said that, I like your suggestion to start 19 with a national conference. The question is, will 20 people come. I mean, how do you target it and 21 people's travel budgets are tied, and is it invite 22 only or is it open to the general community. 281 1 But you have a national conference and then 2 maybe based on that conference, you do identify some 3 target groups and then you come out with -- again, I 4 think education, I really liked what Susan said about 5 education. I do think there's a lot of confusion. I 6 consider myself fairly sophisticated but I struggle in 7 this area, what does it mean? What will it mean to 8 Kentucky? And I support centralized options, provided 9 I'm informed enough to know what the implications are 10 and that's what I struggle with. 11 So I like your idea of a national conference 12 and then targeted and then education but we don't need 13 to draw this out for two years or three years. And I 14 think right now, Bern, I think education on the 15 regulatory -- how this is permissible in the current 16 regulatory environment, I understand it, a lot of 17 people do, but a lot of people don't and I think that 18 word could start being encouraged and get out there 19 now without all of the other fancy workshops. 20 CHAIR PRENTICE: Susan, I think, and then 21 Felix. 22 MEMBER KORNETSKY: I flip flop which way is 282 1 first but I think in thinking about it, I mean, you 2 had 50 people come to your conference and probably a 3 lot of the people even if they came from the public 4 that were people interested in seeing this going 5 forward. You know, I think whatever we should do, we 6 should try and get the people who are, you know, not 7 in favor of this or more hesitant and I think if you 8 sort of so targeted groups first, and then sort of 9 come out and say, "Well, here are some 10 recommendations, use it", it may not go over as well 11 as if you had an open forum where people who don't 12 necessarily, you know, go in this direction have an 13 opportunity to participate and from that, the 14 recommendations come. 15 CHAIR PRENTICE: Felix. 16 MEMBER GYI: I simply wanted to endorse that 17 sentiment and the impetus as you said, came from ASCO 18 with a focus on one central IRB and I think we have to 19 remember that that now has mushroomed into a larger 20 topic of discussion which makes a lot of sense, but 21 you have to remember that it came out of one barrier 22 to using that particular centralized efficiency that 283 1 we had identified before. 2 And I would also encourage us to think along 3 the lines of not having it as an invitee only because 4 I think that that creates more of a dimension of cloak 5 and dagger and somewhat of a surreptitious nature that 6 I don't think helps the cause or the discussion or the 7 education. So I would vote for a level of open 8 sunshine national forum where we can discuss things 9 out in the open and get the information out there for 10 everybody to hear. 11 CHAIR PRENTICE: Okay. Yes. 12 MEMBER JONES: I guess, too, I would -- 13 maybe you could help articulate what you would -- some 14 of the processes you would suggest for a large 15 national. Do you still want the forum of open 16 dialogue, the kind of expectations you have from that. 17 Like is it still gathering information or, you know, 18 beginning to educate because the other added thing 19 when you go to a larger group is then you lose the 20 ability to hear, just like Bern was saying. So you 21 might have some thoughts on, you know, what the next 22 step of information or buy-in or, you know, input is 284 1 needed to move it forward rather than just saying now 2 it's time to go to the national because then that 3 would dictate how they would do the forum for the 4 meeting, you know, whether or not you would still have 5 a lot of breakout groups or special interest topics 6 that were discussed. 7 CHAIR PRENTICE: That's a good question. I 8 haven't thought about this very much until maybe the 9 last five minutes actually but if I were going to 10 organize this national conference assuming we're going 11 in that direction, given what I've heard and my 12 current feelings about how it should be organized, I 13 would have -- I would have, you know, didactic 14 presentations on various issues and I would have 15 breakout sessions like workshops where people could 16 come and they could express their viewpoints. 17 And probably the one that I'm more familiar 18 with than anything else is the liability issue. And 19 I can certainly see how I would structure that. You 20 know, I'd get a panel up there and I'd get a bunch of 21 lawyers and I'd get some litigators who are not 22 academic lawyers, you know, people like Millstein who 285 1 want to sue everybody, and I would get some academic, 2 you know, like general counsel, and you know, and we 3 would talk about the issues of liability and then 4 there would be a breakout session that you would have 5 an opportunity as a participate in the conference -- 6 you know, attendee, where, you know, just like a 7 PRIM&R breakout for a couple hours. You can get in 8 there and you can provide feedback and you would end 9 up doing a couple of things. 10 You would end up, one, educating people 11 about the liability issues, and secondly you're going 12 to gather information about the issue that perhaps you 13 didn't know before, which would form the basis maybe 14 to branch out later on and start having targeted 15 workshops because you're not going to reach that many 16 institutions. 17 I mean, any time you organize a national 18 conference you can't expect 3,000 IRBs are going to 19 show up. It isn't going to happen. But this would be 20 a step in the right direction. So the short answer to 21 your question is, I see all of those goals being 22 embarked upon. 286 1 MEMBER SELWITZ: And again, I'm just -- 2 there were some -- you know, on your action proposed 3 next steps that were in the summary, I mean, when I 4 read it, there were a lot of things that made sense 5 and I'm trying to -- you know, I mean because I do 6 think the stakeholders and how do you get to the 7 stakeholders and adding legal counsel, and that's a 8 good point, to the stakeholders that aren't listed 9 here but how do you get to the institution officials 10 and the legal counsel and I know how to get to the IRB 11 administrators and to the IRB chairs and you know, I 12 know that network but how do you -- 13 CHAIR PRENTICE: Well -- 14 MEMBER SELWITZ: I'm sorry. 15 CHAIR PRENTICE: I'm sorry, yeah, we're 16 going to have a -- this is a topic for discussion in 17 a moment. We're going to be talking about targeting 18 OI's and how we can do that. And as far as, you know 19 academic counsels there's an organization of those 20 attorneys where, you know, I'm sure that we can get 21 access to, you know, to mailing lists or something 22 like that. Okay, and we'd probably be able to target 287 1 them and you know, I can tell you right now, you have 2 a conference on this and you talk about legal 3 liability, our chief compliance officer, who's a 4 lawyer, is going to be the first one to sign up. 5 I don't think you're going to have any 6 problems attracting people. Hopefully, you're going 7 to get the IO's through a mechanism we're going to 8 talk about in a moment. You can get the academic 9 counsels through another, you know, list and 10 organization and certainly the IRB community, okay, 11 can be solicited. And the independent IRBs, I 12 guarantee you, you've got something like close to 50 13 independent IRBs, almost every one of them, if not 14 every one of them, would be at this conference. 15 And your central IRBs, you could have 16 representation from them as well, so you know, I don't 17 see that as a problem. I think we're going to get a 18 lot of people to come to this because I think it's 19 important to look at alternative review models that 20 can enhance protection of human subjects, reduce 21 regulatory burden and you know, get the buy-in from 22 institutions who are reluctant, you know, to move in 288 1 that direction. Okay? 2 So before we -- before we move further in 3 terms of a recommendation, I would -- we haven't had 4 an opportunity to think about this as much as the 5 sponsors have, obviously. So I'd like to see what 6 Susan and Lynn and Amy have to say about what they 7 think the direction ought to be that we move in. 8 Susan, maybe beginning with you. 9 MS. ELLENBERG: Well, Ernie, I was delighted 10 to hear what you proposed. I did now know what you 11 were going to propose -- 12 CHAIR PRENTICE: Neither did I. 13 MS. ELLENBERG: -- before you said it and 14 that is what I think. I think it's critically 15 important as to what comes first, the focus sessions 16 or that national conference, that the national 17 conference come first in order to be seen as, and in 18 fact to be moving forward with this issue in a way 19 that many can observe. 20 The second thing, I think, is that I also 21 share your enthusiasm for having some didactic 22 presentations, panel discussions, followed by small 289 1 group discussions so that we can begin to address the 2 education issue and the mis-information as I believe 3 it is, about liability and accountability. I think we 4 need to walk up and shake hands with the fact that if 5 an institution is the site of a study that it can't 6 relieve itself of responsibility no matter what we do. 7 That's just how the world works, and so I hope that we 8 can -- I hope that SACHRP will endorse the concept of 9 moving forward with the national conference to be 10 succeeded by then focus groups that come out of the 11 conference. 12 CHAIR PRENTICE: All right, great. We'll 13 continue with Amy. 14 DR. PATTERSON: Well, I'd definitely like to 15 support the concept of an open public conference. I 16 think that's very critical from our perspective. I 17 also think that a great deal of thought needs to go 18 into articulating when everybody goes home at the end 19 of that conference, what will be the tangibles, what 20 will we be holding because a comment that happened 21 after this past workshop was, "Well, we've heard all 22 these things before, what's new? We've heard the 290 1 various expressions of opinions". 2 So I think speaking of metrics and outcomes, 3 I think we have to very crisply articulate what the 4 questions are going to be and as Susan and others have 5 already voiced, I think, tackling the issue of 6 liability and accountability and potential solutions 7 there, as difficult as they may be, is going to be 8 central or else we're just going to have repeats of 9 these dialogues over and over again. So I think 10 that's our perspective. 11 CHAIR PRENTICE: Okay, thank you. Lynn? 12 DR. CATES: I agree with everyone so far. 13 I'm delighted that you proposed a public meeting as 14 the next step. I think that is the best way to go. 15 I think that we do need to do this to keep up 16 momentum. We need to provide education. We also need 17 to listen to more people. So having a meeting that's 18 open to all, I guess I would assume that lots of 19 people would come. I think it will be an excellent 20 meeting. 21 I agree with Amy that we do nee to pay 22 attention to not only what the outcome in tangibles 291 1 will be from this public meeting, but also what is 2 beyond that because I don't want us to lose momentum. 3 I feel like we got a lot of momentum in November. I 4 think if we could have a public meeting relatively 5 soon, I would encourage that we not only look to the 6 public meeting but beyond to what we need to do to 7 make this a part of our new AAHRPP culture. 8 CHAIR PRENTICE: Thanks, Lynn. We also, I 9 just found out we have the senior policy analyst from 10 ASCO, would you like to say a few words? Great. 11 ASCO REPRESENTATIVE: Thank you, Dr. 12 Prentice, and I just want to on behalf of ASCO thank 13 the entire committee, Dr. Schwetz and the planning 14 committee. We've had a tremendous interest in this 15 issue since ASCO passed a policy statement in November 16 2002 supporting central review because of, as people 17 have mentioned, Dr. Gyi mentioned, this is a real 18 issue in oncology trials, many of which are multi- 19 center and we saw doing review at multiple 20 institutions as being potentially something that would 21 serve as a hindrance to efficient access for patients 22 especially to quality clinical trials. And so we have 292 1 -- I just wanted to reiterate our profound continued 2 interest in this and continuing to be a partner. 3 And I just wanted to echo, too, Amy and 4 Lynn's comments about the need to think about what the 5 next steps will be, too, because I think a real value 6 of this workshop was, as Dr. Schwetz mentioned, 7 getting folks to actually talk to each other. And he 8 did an excellent job of setting the stage for that and 9 I think talking about next steps and real tangibles is 10 very important. ASCO, we've started this by getting 11 together a round table at our offices with just 30 12 people looking at oncology trials and we're pleased 13 that it's grown to that and now people are really 14 looking at it with all due attention. 15 And so I think, thinking about what the next 16 steps are and what alternatives are and ways to 17 address either real or perceived barriers that are out 18 there is going to be really important to move it to 19 the next stage, so thanks a lot and we really 20 appreciate your time and attention. 21 CHAIR PRENTICE: Okay thank you. All right, 22 can I assume that SACHRP will recommend that there be 293 1 a national conference along the lines we've discussed 2 to be followed by targeted workshops? I mean, it's 3 not something we've got to vote on. Does anybody 4 object to that? Okay. We are running a little late. 5 Before we move into the public comment period, Bern, 6 could you say a few words about the IO initiative that 7 you started and the AAHRPP meeting in Phoenix and what 8 you plan, and then we'll move into the public comment 9 period? 10 SECRETARY SCHWETZ: Thank you, Ernie. As 11 you recall, I don't remember what the date was of the 12 meeting when SACHRP had a panel of institutional 13 officials but I wanted to bring this issue back to 14 SACHRP for further thought and discussion because a 15 couple of things are happening. One of them is a 16 priority of mine for this year, to reach out beyond 17 the IRB community and beyond investigators to reach 18 out to the signatory officials and other institutional 19 officials. 20 Parallel to that, institutional officials 21 who were part of the panel at SACHRP have begun to 22 move out into their community and talk about their 294 1 need to talk to each other and at that AAHRPP meeting 2 that we just had a few weeks ago in Phoenix, I had 3 requested of Marjorie Speers that I would have the 4 opportunity to talk to institutional officials and 5 signatory officials. 6 So we had more than 40 of them together for 7 a breakfast where we could talk about the status of 8 what's going on with institutional officials in the 9 context of the research enterprise. And I've had a 10 couple of other meetings with institutional officials 11 to begin to help me understand how can I get them 12 together, how can I help them? How can we help them 13 improve in subject protection by working with them? 14 So the two things that are going on, this has become 15 a priority for me and the other one is that they're 16 interested in organizing. And I think that if 17 institutional officials and signatory officials and 18 find the means where they could gather and talk to 19 each other and if some of us could be there and learn 20 from them and to help answer questions, we might be 21 able to make some progress here. 22 So let me show you on this diagram why I've 295 1 concluded that this is a very high priority for me. 2 And everything in the blue is what the research 3 institution holds. So we've got a sponsor and OHRP on 4 the outside here. And I haven't thought this through 5 from the FDA perspective or other sponsors. I'm 6 thinking mostly of OHRP's relationship to this 7 simplification of what I showed earlier as the 8 research enterprise that some of you saw. 9 So OHRP's only real direct connection into 10 the institution is with the signatory official and 11 it's been made clear to me that if I am talking about 12 signatory officials, I shouldn't be talking about 13 institutional officials because they're two different 14 things. So we have not been very crisp about that 15 from OHRP. So our connection is to the signatory 16 official who signs the FWA. So that's our leverage 17 into effecting any impact over -- effecting any impact 18 over an institution. But in addition, there's a whole 19 other set of people in the administration of the 20 institution who are important in this. So then the 21 signatory official has responsibility for the IRB 22 structure and its components and others in the 296 1 institution have responsibility over the investigators 2 and the teams of people who are responsible for 3 carrying out the research. I've put a dotted line 4 here to remind me of the sometimes antagonistic 5 relationship that exists between investigators and 6 IRBs and that becomes important in our efforts from 7 OHRP to reach the investigators when this is not a 8 very good conduit between IRBs and the investigators 9 over whom they have oversight responsibility. 10 Now, if you look at where has OHRP been 11 focusing its efforts for education, the size of these 12 bands is not absolute and it's not quantitative. It's 13 just to give you an impression that there is a 14 difference here. Most of our effort has to do with 15 informing the IRB structure, the meetings that we 16 have, the educational conferences, the guidelines 17 that we put out pretty much largely geared toward the 18 IRB community, a lot less to investigators and their 19 staff in terms of we hold a meeting and who comes, 20 it's the IRB community, not the investigators. 21 Two to three percent of people at our 22 conferences are investigators. The rest are all 297 1 essentially all IRB folks. And an even smaller 2 connection of education between us and the signatory 3 officials, a very weak connection that we have there. 4 Now, when you ask the question where are the risks to 5 subjects -- the colors don't mean anything here 6 either, they're just two different colors, the most 7 immediate risk to subjects is in the hands of the 8 investigators. There's pretty much agreement in all 9 the audiences that I talk to that that's the group who 10 has the most immediate and the last opportunity to 11 prevent harm to subjects. 12 So I put that bigger than the others. The 13 IRB structure, obviously, has some responsibility here 14 in protecting human subjects, not just institutions 15 but so the signatory official. So the risk to 16 subjects is greatest out here where our band of 17 connection is relatively small. We have no direct 18 control over the investigators but we do have direct 19 control over the signatory official who under the 20 terms of their -- the conditions of getting an FWA, is 21 that the institutional -- the signatory official 22 assumes responsibility for the culture of the 298 1 organization. They also have the responsibility for 2 the training of investigators and the behavior of 3 investigators, which signatory officials don't 4 necessarily like to hear the last one because that's 5 almost impossible to carry out, be responsible for the 6 behavior of all their investigators. 7 So my reason for wanting to reach the 8 signatory officials is because they have that 9 responsibility over the investigators. So by virtue 10 of us reaching out and communicating with signatory 11 officials, we reach all of the investigators at that 12 institution, if we can convince the signatory 13 officials to create a culture of responsibility and to 14 be responsible for the behavior of the investigators, 15 as well as their training. 16 So here we are working over here when at 17 this point I'm trying to enhance our connection to the 18 signatory officials so that we leverage the connection 19 to the investigators. So now the good thing that's 20 happening parallel to this is that David Wines from 21 the University of Iowa and Dick Bianco, from the 22 University of Minnesota, are providing some loud 299 1 voices of, "Hey, guys and gals, why don't we get 2 together"? In the over an hour discussion that they 3 had at breakfast in Phoenix, one of the points that 4 Dick made was that, "Hey, look back over the last 5 hour, we've got a lot to about and we ought to have 6 been meeting on a regular basis". So, I'm encouraging 7 that they would meet at a national level or in a 8 regional level, however they can get together, because 9 we can go to them and talk about their issues and help 10 them. 11 Obviously, they're responsible for a much 12 wider cut than just accreditation or just human 13 subject protection. So there are a lot of things that 14 they need to talk about, but I am looking forward to 15 the opportunity to interact with them in a more 16 organized way and I just wanted to say these few words 17 to allow SACHRP the opportunity to comment on this. 18 CHAIR PRENTICE: Okay, yeah, thanks, Bern. 19 It's my understanding that actually David and Dick are 20 meeting in Washington on Thursday to discuss this 21 particular issue and think about developing some kind 22 of an organization or association for IO's. So 300 1 undoubtedly some time in the future, we would be able 2 to get a report about their efforts. 3 Do any members of SACHRP have any questions 4 with regard to this? 5 MEMBER SELWITZ: I just think it's great 6 approach. I think it's overdue. I'm blessed with a 7 signatory official that truly understands these issues 8 but I don't think that's true across the board and I 9 think this is excellent. I think there are a number 10 of existing organizations as well, that have ready 11 access to these individuals like AAMC, like COGR, as 12 ell, okay, what is it Government Council on Government 13 Relations but there are existing organizations. Many 14 -- excuse me, I don't want to say IO's, SO's also 15 attend PRIM&R and ARENA and there's been an increase 16 in that over the last few years, wouldn't you say, 17 Susan, so that's another resource, but I think this is 18 a great direction to go in. 19 CHAIR PRENTICE: Okay, yeah, Neil. 20 MEMBER POWE: Yeah, I would just echo that, 21 that I think the idea that this probably ought to come 22 from -- not from the government, but groups outside 301 1 the government getting together, some group like the 2 AAMC sponsoring the start of such a group. I'm not 3 sure that the government can do this. The government 4 can attend it. Whether the government can actually 5 cause it to happen, I'm not sure. 6 CHAIR PRENTICE: Felix? 7 MEMBER GYI: You know, I do think that the 8 time has come for us to leverage the signatory 9 officials' roles but I would ask us to be inclusive of 10 non-institutional -- the traditional institutional 11 models. There are many, many research sites that 12 receive federal funds that are not under an 13 institutional umbrella that probably ought to get the 14 message because right now you'd be preaching to the 15 choir in the way that makes sense but whether there 16 could be a potential larger number of harm that could 17 be done resides in those other areas as well as 18 within, as you have mentioned before, the independent 19 IRB community as well. So I would encourage us to 20 think a little bit outside the box along those lines. 21 CHAIR PRENTICE: Okay, great, listen, we 22 really have to move on if that's acceptable. We have 302 1 a number of people who have signed up for the public 2 comment period and they've been very patient because 3 we're over times. So I would like to begin with Linda 4 and Cheryl Ann. I understand you're kind of a dual, 5 both of you are coming up at the same time; is that 6 right? Okay, that' great. Just for the record, you 7 know, state your name and affiliation, okay? And you 8 need to go up to the microphone. 9 MS. EHLER: Hi, I'm Linda Ehler, I work for 10 the National Institutes of Health, Division of -- 11 National Institute of Allergy and Infectious Disease, 12 Division of AIDS, Regulatory Affairs Branch, and I'm 13 just speaking on behalf of my own personal observation 14 as a member of the Regulatory Affairs Branch of the 15 Division. We have a lot of interest in multiple -- 16 alternative multiple IRB review models because we do 17 a lot of multi-site trials that are conducted all over 18 the world and we hear complaints from investigators on 19 sites about the issues involved with multiple IRB 20 reviews. 21 So I applaud the group in convening a 22 workshop in the fall discussing this issue. However, 303 1 if the group does go forward and have targeted 2 workshops or a national audience conference, I really 3 think you need to take into account inviting members 4 of the international IRB community. I think their 5 input would be very valuable. And also the group also 6 needs to remember that many of our international -- 7 many of the countries that we interface with the 8 division, the Division of AIDS, they have national 9 IRBs and/or industry help or the Medical Control 10 Councils in South Africa that also weigh in and have 11 to provide review and approval of any research that's 12 conducted within the country. So that needs to be 13 kept in mind as well. Thank you. 14 MS. MATHIAS: And I'm Cheryl Ann Mathias and 15 I also am at the Division of AIDS at NIH, NAID and I 16 am speaking not on behalf of the agency but my own 17 personal thoughts. I want to applaud the group for 18 looking at the 60-day rule. And once again it's in 19 reference to international settings. In our 20 international settings the flexibility of having that 21 additional time would probably be extremely helpful 22 because one of the barriers in those settings is 304 1 communication. They don't have e-mails as readily 2 available. They send letters, they send couriers and 3 during the rainy season, it's hard to get to the IRB 4 centers. 5 Also they meet at not always monthly so -- 6 and it's also been my experience since I spend a lot 7 of time now in international settings that the 8 institutions and the IRBs in those instances actually 9 do ask lots and lots of questions of their 10 investigators and there is a lot of dialogue that does 11 go on between the ethics boards and the investigators 12 and that flexibility of time would probably be 13 extremely helpful. So I would just like you to keep 14 that into your thoughts as you deliberate. Thank you. 15 CHAIR PRENTICE: Thank you both. Are you 16 both going to be able to be here tomorrow for our 17 international panel? Okay, great. Let's see, Kammy. 18 FEMALE PARTICIPANT: Thanks, Dr. Prentice. 19 Actually, I'll be here tomorrow as well, so perhaps 20 I'll just save my comments till tomorrow. It's 21 awfully close to the dinner hour. I'll talk to you 22 tomorrow. 305 1 CHAIR PRENTICE: Well, hold on a minute. 2 Yes, we do have a public comment period tomorrow at 3 1:00. Would you like to hold your comments till then? 4 FEMALE PARTICIPANT: I'll hold my comments. 5 CHAIR PRENTICE: Okay. I don't know if John 6 Mather is going to be quite so gracious. 7 FEMALE PARTICIPANT: Let's take John and get 8 it over with. Just kidding, John. Just kidding. 9 MR. MATHER: It's too close to supper. John 10 Mather of Chesapeake Research. I just wanted to make 11 a brief comment and comment on the significance of the 12 Under-Secretary of Health being here spending the 13 amount of time here and the remarks he made. I think 14 it's something that obviously, Bern, with the 15 additional comment you made about what he said after 16 he left, is something this committee ought to 17 capitalize on in two ways. 18 One is there are various recommendations 19 that have been put forth, whatever can be done to 20 nudge him to use his good offices to move those along 21 is very important. The other thing I'm aware of is 22 the challenge that you have, Bern, in getting, you 306 1 know, the kinds of things done with the staff that you 2 have. And I know there have been certain actions that 3 have been taken to sort of freeze the hiring process 4 that's effected your office. I would encourage you 5 and particularly you, Ernie, to get to him now and to 6 raise the issue very seriously about opening up those 7 positions in OHRP, because more and more there's 8 clearly to me a lot of work that has been done but yet 9 can be done and it's going to take some horsepower to 10 get that done. 11 So here's an opportunity that he sort of 12 gave us and gave both of you, so I would encourage you 13 strongly to push on those. 14 One last pont he did not raise and we didn't 15 raise in his presence, and that was the issue of the 16 significance of accreditation and what is the 17 accreditation process. You brought it up again here 18 in the opportunity you had down there in Phoenix to 19 talk to some signatory officials, and maybe this needs 20 to be brought particularly to his attention. So my 21 last thought is, you know, here's an opportunity to 22 capitalize on it. 307 1 CHAIR PRENTICE: Thanks, John, for those 2 comments. We've had three letters now accepted by the 3 Secretary and the proof of the pudding is the 4 implementation of our recommendations and we can, you 5 know, spend all day developing recommendations but 6 they mean nothing unless they're implemented. The 407 7 recommendations, of course, were implemented in a 8 timely way and I feel the same way you do. I really 9 want to encourage OHRP and I understand the limited 10 staff and the problems that they have at the moment, 11 but in any way possible to try to, you know, get those 12 recommendations that we've made accepted by the 13 Secretary, implemented as soon as possible. 14 So thank you for that, John. Okay, we're -- 15 unless somebody has anything else they would like to 16 add, we are going to adjourn and we will reconvene at 17 8:30 in the morning, so thank you, everybody. 18 (Whereupon, at 5:05 p.m., the above-entitled 19 matter recessed, to reconvene at 8:30 a.m. on March 20 15, 2006.) 21 22