1 UNITED STATES OF AMERICA DEPARTMENT OF HEALTH AND HUMAN SERVICES + + + + + SECRETARY'S ADVISORY COMMITTEE ON HUMAN RESEARCH PROTECTIONS + + + + + MEETING + + + + + TUESDAY, JULY 31, 2007 + + + + + The Advisory Committee met at 8:30 a.m. in the Sheraton National Hotel, 900 South Orme Street, Arlington, VA, Dr. Samuel Tilden, Chair, presiding. MEMBERS PRESENT: SAMUEL TILDEN, MD, CHAIR BERNARD A. SCHWETZ, DVM, PHD, EXECUTIVE SECRETARY CATHERINE SLATINSHEK, MA, EXECUTIVE DIRECTOR JEFFREY BOTKIN, MD, MPH MYRON GENEL, MD DANIEL NELSON, MS, CIP NEIL POWE, MD, MPH, MBA JAMES POWELL, MD, CPI DAVID H. STRAUSS, MD EX OFFICIO MEMBERS PRESENT: HOWARD BRADLEY, SOCIAL SECURITY ADMINISTRATION SARAH CARR, ALTERNATE FOR AMY PATTERSON KATHRYN LYNN CATES, MD, DEPARTMENT OF VETERANS AFFAIRS KELLINA CRAIG-HENDERSON, ALTERNATE FOR SARAH SCHNEIDER DENISE GEOLOT, HSRA SARAH GOLDKIND, ALTERNATE FOR FDA WARREN E. LUX, MD, ENVIRONMENTAL PROTECTION AGENCY JOAN PORTER, DPA, MPH, ALTERNATE FOR THE DEPARTMENT OF VETERANS AFFAIRS JEFFERY W. RODAMAR, DEPARTMENT OF EDUCATION ALLEN SHIP, ALTERNATE FOR AMY PATTERSON 2 A G E N D A REMARKS . . . . . . . . . . . . . . . . . . . . . .5 Samuel J. Tilden, M.D. SACHRP Chair BRIEFING ON FINAL REPORT OF NATIONAL CONFERENCE ON IRBs . . . . . . . . . . . . . . . . . . . . . .7 Bernard Schwetz, Ph.D., D.V.M. Director, OHRP REMARKS BY: . . . . . . . . . . . . . . . . . . . 13 John Agwunobi, M.D. Assistant Secretary for Health PANEL ON INFORMED CONSENT ISSUES . . . . . . . . 47 Howard Dickler, M.D. American Association of Medical Colleges Gigi McMillan, Executive Director WeCan Pediatric Brain Tumor Network . . . . 78 Alan R. Fleischman, M.D., Ethics Advisor The National Children's Study . . . . . . . 94 NICHD Jonathan Moreno, Ph.D. University of Pennsylvania. . . . . . . . .111 BREAK . . . . . . . . . . . . . . . . . . . . . .104 PANEL ON INFORMED CONSENT ISSUES . . . . . . . .105 LUNCH . . . . . . . . . . . . . . . . . . . . . .137 3 PANEL ON DIVERSITY IN CLINICAL TRIALS . . . . . .139 INTRODUCTORY REMARKS BY: Dorothy Height, Ph.D. President Emerita and Chair National Council of Negro Women PANEL MODERATOR: Giselle Corbie-Smith. . . . . . . . . . . .139 Associate Professor of Social Medicine and Medicine University of North Carolina/Chapel Hill Vivian Pinn, M.D. . . . . . . . . . . . . .154 Associate Director for Research on Women's Health Director, Office of Research on Women's Health National Institutes of Health Barbara Pence, M.D. . . . . . . . . . . . .188 Texas Tech University Health Science Center Team Leader, EDICT Project Leonard Sacks, M.D. . . . . . . . . . . . .205 Office of Critical Path Programs Office of the Commissioner Food and Drug Administration PUBLIC COMMENT . . . . . . . . . . . . . . . . .250 ADJOURN 4 1 P R O C E E D I N G S 2 (8:36:29 a.m.) 3 DR. TILDEN: Good morning. I would like 4 to bring the meeting to order. I'd like to welcome 5 everyone here for the second of the two days for the 6 SACHRP committee meeting. 7 This morning, from an agenda standpoint, 8 we'll have a few remarks, and we need to revisit one 9 brief item of business from one of the recommendations 10 yesterday. Following that, we'll have a briefing on 11 the final report of the National Conference of IRBs by 12 Dr. Schwetz. Somewhere between delivering the 13 briefing and probably the full discussion of the final 14 report, we will have a visit from Dr. John Agwunobi, 15 Assistant Secretary of Health, which we'll interrupt 16 our proceedings to welcome him. 17 Following that this morning, we'll have a 18 panel on informed consent issues. And then after that 19 panel, we'll break for lunch, we'll have a break 20 during the panel. And then we'll come back in the 21 afternoon and have a second panel discussion on the 22 Diversity in Clinical Trials. And that will conclude 23 our proceedings. We'll have public comment, and wrap- 24 up and adjourn. 25 So, first, I'd like to revisit our first 5 1 recommendation that we made yesterday, and would like 2 to consider an amendment. It's more of a technical 3 amendment. It doesn't go to what the request for 4 advice in terms of legal options of SACHRP, but the 5 recommendation that we approved was that SACHRP 6 request HHS legal counsel to provide the subcommittee 7 a summary of legal options to address a roadblock, et 8 cetera. And we would like to consider an amendment 9 that states, "SACHRP requests OHRP to provide the CDER 10 Subcommittee with a summary of legal options to 11 address a roadblock", et cetera. Okay. And it makes 12 it more -- it clarifies the issue, and allows CDERs to 13 get the information they need without stumbling over 14 some legal issues. So I'd like to propose a motion 15 that we consider making that amendment to the initial 16 recommendation. 17 PARTICIPANT: So moved. 18 DR. TILDEN: Okay. Motion. Second? And 19 discussion? Okay. So all in favor? 20 (Vote taken.) 21 DR. TILDEN: Okay. So that amendment to 22 the first recommendation is passed. 23 I think that takes care of all the remarks 24 I had planned, so next item, we'd move into our 25 report, briefing on the final report of the National 6 1 Conference on Alternative Models to IRBs. Bernard. 2 DR. SCHWETZ: Good morning to all of you 3 on this second day. Actually, I'm not going to go 4 through the -- but to summarize the contents of the 5 report of this conference. What I want to summarize 6 is what steps, what discussions have we had since the 7 report came out that represents the follow-up to some 8 of the action items that were actually in the report. 9 So just to refresh your memory, and for some of you 10 who weren't on SACHRP at the time this unfolded, I 11 would remind you that there was an earlier 12 recommendation of SACHRP that OHRP and others would 13 look at the question of why central IRBs, 14 specifically, the Adult Oncology Central IRB of NCI 15 isn't used more widely in the community for which it 16 was intended. And that under-utilization has been of 17 concern from the standpoint of the efficiency and the 18 effectiveness of the community doing this kind of 19 research, so we had this discussion at SACHRP, and the 20 recommendation was there should be a conference to 21 explore this under-utilization of Central IRBs, the 22 primary Central IRB that existed at that time. 23 As a follow-up, so that it wasn't just a 24 question of why aren't we using the NCI Central IRB 25 more widely than we are as a community, we broadened 7 1 it a little bit to look at alternative models of IRBs, 2 with the intent being that there isn't just one model 3 of IRB that could be used for certain types of 4 research. And, in fact, there may be some form other 5 than the local IRB that might be beneficial, 6 particularly in today's world of multi-center/multi- 7 site trials, where there is an inefficiency of having 8 every institution repeat the work of every other one. 9 So we had a workshop in November of 2005, a group of 10 some 40 or 50 people, to structure the framework for 11 what our National Conference might look like, and who 12 should be invited, and how should it be organized, 13 what should the topics be? 14 Well, that conference happened in November 15 of 2006, and that was the National Conference on IRBs. 16 And utilizing an IRB model choice that was best suited 17 for the kind of research that was being reviewed. And 18 many of you attended that conference, so I know you're 19 familiar with the outcome. But I want to go over, 20 just very briefly, who the sponsors were, and who were 21 the co-sponsors, because this represents the audience 22 that we had intended to reach in the National 23 Conference. So the Association of American Medical 24 Colleges, and OHRP, NIH, the Association - I'm sorry - 25 the American Society of Clinical Oncology, and the 8 1 U.S. Department of Veterans Affairs were the sponsors, 2 but then we selected a group of representatives of 3 organizations from the community that we wanted to 4 have at the conference, and I'll read those; American 5 Association of Universities, Council on Governmental 6 Relations, Consortium of Social Science Associations, 7 the U.S. Department of Defense, National Association 8 of Colleges and University Attorneys, and Public 9 Responsibility in Medicine and Research, PRMR. So 10 these people all have input on what this conference 11 would look like, and how would we reach out to the 12 proper part of the enterprise so that we had the 13 people there who actually made the decision about what 14 model of IRB might be used in their particular 15 institution. 16 So the final report was made available a 17 few months ago, and this is the site. This is an AAMC 18 website address, but there are links from our other 19 organizations, so that if you want to find it by going 20 to our website, you can, but this is the one site at 21 which it is located. We chose not to have every one 22 of our agencies have a primary website address for 23 this, because of the possibility that some changes 24 might be made by somebody, and there would be 25 different versions of it in different places. So this 9 1 is the authentic. You have a copy of this report at 2 Tab M in your books. 3 Okay. Now the follow-up activities. The 4 activities that I will be talking about here briefly 5 are based on the meetings that have continued of that 6 sponsor group, so we have continued to talk about the 7 follow-up to the report, what are the action items, 8 how are we going to address them, how do we prioritize 9 them? So one of the things that was recommended in 10 the report itself was that there should be further 11 guidance from OHRP, FDA, and NIH to clarify the 12 responsibilities that the local IRB has, and if there 13 is an additional IRB that's involved in the review of 14 the protocol and the follow-up activities, that while 15 FDA and OHRP have made it clear that other than -- 16 IRBs other than the local IRB is perfectly acceptable 17 to us under certain conditions of documentation. We 18 have no problem with a non-local IRB serving as the 19 IRB for studies. 20 This request was that we would provide 21 additional guidance beyond just the fact that it's 22 okay to use some form other than the local IRB. And 23 that's something that we will be discussing between 24 NIH, and FDA, and OHRP, what that might look like, and 25 how can we come out with some guidance that would be 10 1 consistent between us, that would be advice on further 2 structuring how you might use an IRB beyond your own 3 local IRB. 4 We also thought it was important that we 5 might target the future discussions. Up to this time, 6 the discussions that we've been engaged in involve 7 anybody who wants to come from the enterprise, from 8 the institutions who are doing research. And that's 9 a relatively non-targeted approach, as we tried to 10 inform people about what the issues were, what the 11 options are. So we asked ourselves, what are the 12 types of research that are the highest priority for 13 engaging in a non-local IRB? And that's an activity 14 that we are looking at right now, with the intent that 15 when we identify those areas of research, we should be 16 able to target them with further communication to them 17 directly, to make sure that they understand what the 18 options are that are available to them. 19 Also, the opportunity or the need to 20 communicate with sponsors and advocacy groups. In 21 terms of an example within our federal structure of a 22 sponsor, the Office of Extramural Research of NIH has 23 two regional meetings every year, one on the east 24 coast, and one on the west coast, generally, where 25 they bring together a group of institutional officials 11 1 to talk to them about whatever they want to talk about 2 in terms of research, and funding from NIH. This is 3 an opportunity for some of us who are involved in this 4 discussion about models of IRBs to get in front of a 5 large number of institutional officials standing with 6 NIH to open up a dialogue with these -- it's another 7 route to institutional officials. And as I've talked 8 to institutional officials now in many different 9 sites, one of the things that they really engage in as 10 a discussion is models of IRBs, because they have had 11 this question brought to them, and they want to know 12 more about it. Well, this is an example of another 13 opportunity with a funding agency for us to be talking 14 about models of IRBs. 15 From the standpoint of advocacy groups, we 16 want to identify organizations that represent specific 17 patient groups where the research that they might be 18 engaged in would be multi-site research for which an 19 alternative model might be appropriate. Again, an 20 effort to target the audience for discussion, and we 21 have also found that the people who represent these 22 patient groups are very interested in how effectively 23 their patients can be enrolled and engaged in 24 research. 25 We talked about this one in the context 12 1 that, Sam, this might be something that would come 2 back to SACHRP at some time as a panel, a panel of 3 individuals representing some of these patient groups 4 where multi-site research is going on. And they may - 5 - not to talk about them as advocates for a disease 6 population of patients, but as a discussion of what 7 types of IRB models would be most appropriate for 8 them, and how do they move up on taking advantage of 9 that? So that would be another opportunity to have 10 this discussion with a group of people who are 11 directly interested in the outcome. 12 As another topic, we've also talked about 13 developing a tool kit to provide -- so that everybody 14 doesn't have to reinvent the wheel at every turn. 15 IRBs are good at this, but we're trying to avoid the 16 need for institutions and IRBs to start from scratch 17 every time, every place. So the thought was, there 18 are model agreements out there, the kind of agreement 19 that exists between a local institution, or a local 20 IRB and an alternative IRB, that defines who is 21 responsible for what. And the crispness of that 22 agreement is what either makes it successful, or less 23 than successful if there are problems. And nobody 24 seems to have, in this agreement, who is responsible 25 for some particular points in the work. So model 13 1 agreements could be in this tool kit that would be 2 available electronically, so the people could see what 3 one of these agreements looks like. One that has been 4 considered to be a good one. 5 There could be SOPs for this process, and 6 it would give information of how to work this decision 7 process through, and to get agreements in place. And, 8 also, it could be a place to collect best practices, 9 best practices as they arise from those of you who are 10 engaged in doing this work. And it would be helpful 11 to the rest of the community to be able to get to this 12 website and see model agreements, to see SOPs, how 13 these flow in the institution, and some of the best 14 practices that have evolved from that. 15 We have also written a Points to Consider 16 - we, it doesn't include me, there were folks from NIH 17 who put a Points to Consider document together 18 related, again, to the conference issues, the 19 information in the report, but the report is long, and 20 there's a lot of structure information in there that 21 related to the conference. Well, this is kind of an 22 extract of all the information in that report in a 23 manner that, in just a few pages, would give you all 24 the points that you would need to know as you consider 25 these alternative models of IRBs. So this document, 14 1 again, is something that would be made available on 2 the website, and would be of assistance for people who 3 didn't necessarily want to start off by reading the 4 lengthy report, but would read just two or three pages 5 of very succinct information about what's in the 6 larger report that came out of the conference. 7 There was also a discussion about grants 8 being made available for empirical research, and for 9 the functions and performance of IRBs. And that's 10 something that we have all been asking for. There was 11 a specific recommendation for OHRP to have grants in 12 this area. Well, OHRP doesn't have grant authority, 13 and we're such a small office that for us, even if we 14 had the authority to add the number of people it would 15 take to administer our grants program and a study 16 section review process, that it's just not feasible 17 with the small number of people that we have within 18 OHRP. So, again, I have talked to NIH, and to other 19 organizations. There are other federal agencies that 20 do support this kind of research. 21 The people who are interested in these 22 grant opportunities are not necessarily familiar with 23 where that money is, and how to access it. So that's 24 another opportunity for better communication, as we 25 make it known what federal agencies do have grant 15 1 money available, or contract money, or cooperative 2 agreement money available for this kind of empirical 3 research. 4 We also discussed reaching the 5 investigator community. And a focus of this 6 discussion has been the Clinical and Translational 7 Science Awards, the CTSA of NIH, the replacement for 8 GCRCs. This, for those of you who aren't familiar, 9 there are 12 sites right now that have this award, and 10 it's going up with more awards this year. And over 11 the next few years, heading up to 60 institutions that 12 have these awards, and this award process creates the 13 infrastructure for large numbers of organizations then 14 to be able to communicate, and cooperate, and 15 collaborate through the consortium that would be 16 created by the CTSAs. 17 Just last Friday, Anthony Hayward and 18 several of the people from his office came over to 19 talk to us at OHRP about what the CTSA really is, in 20 the context of needs for human subject protections, 21 and issues that relate to the regulations. And it was 22 a great discussion. I see this as a wonderful 23 opportunity for OHRP to have a network through which 24 we can communicate with the audience that we want to 25 be able to talk with through all of these institutions 16 1 that are now engaged in a network to do research. 2 And I'm very happy to have Elaine Collier 3 here from that part of NIH today, to engage in this 4 discussion, if you want to have further questions 5 about CTSAs, and how it relates to human subject 6 protection. Elaine is here to be part of that 7 discussion. 8 So with that, I will close, and just say 9 that I would welcome further discussion from SACHRP 10 about how SACHRP might continue to be involved in this 11 process of looking at models of IRBs. I mentioned one 12 possible connection in the future, having this panel 13 of patient advocacy groups to talk about IRB models. 14 But if you have other suggestions, we would welcome 15 them. 16 DR. TILDEN: Thank you, Bern. Sam, if you 17 would prefer - I would be happy to give up the floor 18 to Dr. Agwunobi, if you'd like to do that. 19 DR. SCHWETZ: I was thinking, since we 20 sort of planned for this, and this worked out to be 21 perfect timing, so I think what we'll do is have Dr. 22 Agwunobi address us, and then we'll pick up the 23 discussion after that. 24 DR. TILDEN: Okay. 25 DR. SCHWETZ: I'm pleased to introduce Dr. 17 1 John Agwunobi, Assistant Secretary of Health, I say 2 who we report to, but he tells me he works for us, so 3 we're pleased to have you here today, John. Thank you 4 very much. 5 DR. AGWUNOBI: Thank you, Sam. Sam and I 6 speak fairly regularly. He calls me, we have 7 conversations between meetings, an attempt, I think, 8 to have Sam begin to translate what's going on in the 9 meetings into action within the departments. And, Mr. 10 Chairman, I applaud your willingness to work well 11 beyond the confines of this particular room to make 12 sure that the work of SACHRP is translated into 13 action. 14 Speaking of translated into action, I'm 15 going to start with that which fills up the largest 16 part of my heart today; and that is, some of the -- 17 and I would urge all of you to join me in this. I 18 wish to express my deepest gratitude to Bern Schwetz. 19 Bern has, as many of you are probably aware, this is 20 his last SACHRP meeting. Despite our begging and 21 pleading, my tears in a private session with him, Bern 22 has refused to change the date of his retirement, and 23 is expected to retire from a long and illustrious term 24 in the federal government, ending with SACHRP, and 25 OHRP, in September. 18 1 I know, because I get the phone calls, and 2 the emails, and the whispers from scientists across 3 the community that there is great concern. Everyone, 4 I think, is beginning to feel the same angst that I 5 feel about the loss of Bern. Everyone recognizes that 6 filling his shoes will be extremely hard to do. 7 I know how much of your life you've put 8 into this, I do. I know that this has been something 9 very important to you, the penultimate project of your 10 entire career. Getting us to this point could never 11 have been done without you. 12 Out of respect for you, personally, our 13 friendship, and out of respect for the work that 14 you've done, and the dedication of your team and 15 SACHRP, I commit to all of you to making sure that we 16 do our utmost best to find a replacement who carries, 17 picks up your standard and carries it forward towards 18 the goals that you've set and beyond. 19 The process, so that everyone understands 20 how it works, this is not a political appointment. It 21 is a very important role within my office, and within 22 the Department of Health and Human Services. The 23 Director of OHRP, it's a regulatory role, in that the 24 person is responsible for assuring a certain quality 25 of IRBs and research work overall across out nation. 19 1 But it's much more than that, it's also an educational 2 and, hopefully, vision-setting role, a role that is 3 supposed to prevent and assure quality through 4 education, through communication, through 5 collaboration with the science community, the research 6 community of our nation. 7 Although it must never compromise on the 8 quality, on protecting human research participants, 9 and must never allow slippage in terms of the 10 standards that are expected by our citizens, it must 11 also focus on collaborating. It can't be a blunt 12 instrument that's used to beat the system into 13 submission. OHRP must be a collaborating office, one 14 that understands, works with, and helps nurture the 15 research community towards those goals. These are all 16 qualities Bern had, and that's why replacing him is 17 going to be tough. He understood this. But I do 18 commit to searching for someone that understands those 19 premises, so who gets it, to replace you. 20 Our Human Resource process, we work for 21 the federal government, is a little slower than it 22 might be in other settings. There will be an open and 23 transparent search for Bern's replacement, with a full 24 panel-type interview, and a selection of the best 25 candidate possible based on the qualifications that 20 1 I've just described, and others. Bern has helped us 2 over the years detail in the job description the kind 3 of quality, the kinds of experience and education that 4 an individual should have. 5 I recognize that the Human Resource 6 process, although I hadn't intended this, I fully 7 intended to have someone in place two weeks before you 8 left so that you could do a little training. I fully 9 expect that it is possible that the Human Resource 10 process might force me to name an acting individual, 11 just the way it works, for that short period of time 12 in the interim. However, I also recognize that the 13 acting individual has to be able to carry the ball, 14 and hand it off effectively to the permanently 15 selected individual when the time comes. And it can't 16 be someone that sets us back. 17 I will, in the next - this month, I will 18 be looking at my Plan B, so to speak, just in case, 19 and I will be doing so very diligently. I recognize 20 that even an Acting Director has to be selected with 21 great care. I'm going to handle it personally, and 22 make sure that it is done appropriately. And I'll do 23 it in consultation with Bern to make sure that we have 24 the right kind of person. 25 All right. If you would, before I 21 1 proceed, if you'd join me in applauding Bern for his 2 service to the nation. 3 (Applause.) 4 DR. AGWUNOBI: Mr. Chairman, if I might 5 just add a thank you, once again, to all of you, the 6 members of SACHRP. I recognize that you do this from 7 a place of patriotism, loyalty, and support of your 8 fellow citizens, and to your professions, and to your 9 love of research, and your love of human research 10 subjects, your desire to protect them. 11 I understand that today you were supposed 12 to later on this afternoon, or this morning, rather, 13 hear from Dr. Height, Dr. Dorothy Height, a leader in 14 the African-American community. No, a leader in our 15 nation, who has long been an advocate for the African- 16 American community, an individual who, I think, 17 everyone recognizes as a part of our history in terms 18 of her role in the fight for equality, and in the 19 fight for minority communities and women around the 20 world, quite frankly. 21 I'm told that she, unfortunately, took ill 22 a few days ago. I'm comforted to hear that she's 23 actually doing quite well in hospital, but recognize 24 that she won't be able to attend today. I understand 25 you were going to be discussing the special issues 22 1 related to minority communities in research today, and 2 I hope that although the conversation will go on, that 3 you will consider at some point in the future having 4 her come in and speak to you. I can't speak on her 5 behalf, but I recognize, having met with and spoken to 6 her in the past, that her perspectives put things in 7 perspective. She has this personal experience of 8 having been a part of a much larger fight. And I 9 think her insight and her words will, I think, add 10 considerably to any discussion on the subject of 11 protecting minority research subjects. 12 I will continue to serve you, SACHRP, 13 through these transitions that we've described and 14 beyond. This is the only Advisory Committee that I 15 asked to attend every single time it meets. It's a 16 personal privilege to be here, something I'm 17 particularly interested in. But I also recognize that 18 you have a very -- that your role is one that can't be 19 duplicated, it can't be diminished, or neglected. 20 I run the Public Health Service, and I'm 21 told that in the past, the Public Health Service was 22 involved in experiments like the Tuskegee event. We 23 have a history of having made mistakes alongside 24 others, and I feel personally obligated to not only be 25 here when you need me, but to also listen to the 23 1 recommendations that you come forward with, to make 2 sure, more importantly, that the Secretary of our 3 Department to whom you make these recommendations, 4 sees them, reviews them, has a discussion about which 5 ones we can implement, and responds to them. 6 I recognize that we may be a little tardy 7 with some of our responses to your recommendations, 8 but continue to urge your patience. You will receive 9 them. This Secretary recognizes that when volunteers 10 come together to serve on these panels, that it's a 11 conversation that begins. You don't just write 12 recommendations and stick them in the mail. It's a 13 conversation between him and you that needs to occur. 14 I'll help facilitate that conversation. 15 Mr. Chairman, if your colleagues, or 16 anyone in the audience has questions for me, I'd be 17 willing to take them here, but I don't want to hold up 18 the remainder of Bern's time, if I can avoid it. 19 DR. TILDEN: I think we have one question 20 here. 21 DR. GENEL: Dr. Agwunobi, I think I speak 22 for my colleagues in expressing my appreciation for 23 your candidate update on the process of selecting the 24 new OHRP Director. May I ask how SACHRP, as a body, 25 or as -- or we, as individuals, can assist you in that 24 1 process, both from the standpoint of an Acting 2 Director and a permanent Director for OHRP? 3 DR. AGWUNOBI: I am ill-advised - sorry, 4 ill-advised is the wrong phrase - I am not advised. 5 I don't know, put it that way. I don't know what the 6 HR rules, Human Resource rules, are regarding hires. 7 I recognize that, and I may be speaking a little bit 8 out of turn, Bern, perhaps, can add to this, I 9 recognize that there's supposed to be a panel that 10 selects from across all the candidates. This panel, 11 although I have a role in nominating individuals to 12 sit on this panel, I don't know if it has to be 13 employees of the Department, or if you can involve 14 others from outside of the Department. I'm just not 15 sure, so I'm not going to be able to opine on whether 16 or not I could appoint someone from outside of the 17 Department to serve on the panel. These panels, and 18 the rules around them, are designed all too often in 19 negotiation with unions, and lawyers, and my job is to 20 do what they say, follow the policy. 21 Having said that, I'm also cognizant of 22 the fact that this is a -- it's the only regulatory 23 office in my shop, in the Office of Public Health and 24 Science. And because it's a regulatory shop, I need 25 to be sure that there's an arm's length, even as it 25 1 relates to the administration, that the person needs 2 to be independently selected, and needs to be the best 3 person I can find, so I do have to follow all of the 4 rules. 5 Let me get back to you on whether or not 6 there's some formal role that I might play. I'm also 7 cognizant of the fact that I might not be allowed to 8 share the names of the candidates before the panel has 9 made its selection. I just want to be sure I follow 10 the rules, so I'll have to get back to you on that. 11 If there's an opportunity for me to 12 consult with SACHRP, if it's appropriate, I'd be 13 willing to do so. I just have to follow the rules 14 before I go down that path. I'm being advised. I'm 15 not doing this on my own. 16 DR. GENEL: May I ask just a follow-up? 17 Can you give us some idea of the timing of when an 18 official announcement will be out regarding 19 applications? 20 DR. AGWUNOBI: I can tell you what I know. 21 Five weeks ago, I was informed that the posting would 22 go in the Federal Register the next day. Upon 23 reviewing the write-up for the job description that we 24 were going to post out and publish, it was found that 25 it didn't have all the details it was supposed to 26 1 have, and it went back for drafting. I expect it will 2 be within the next -- it will be in weeks, not months. 3 So I'm surprised it hasn't already happened, quite 4 frankly. 5 One way that you might help, and this I 6 think we can arrange without any problem, would be to 7 review the wording of the posting, perhaps the Chair 8 would consider, to get a sense of whether or not it 9 has everything that you and SACHRP think it needs to 10 have, in order to attract the kinds of people that we 11 want it to attract. I think that might be allowable, 12 given that it's not -- it doesn't have a person's name 13 on it. It's about general qualities related to 14 candidates. 15 DR. GENEL: You would not want to wait 16 until our October for that input, I presume. 17 DR. AGWUNOBI: No, this is something I 18 would discuss with Sam in one of our in-between 19 meetings, in the next day or so. 20 DR. TILDEN: Well, thank you very much. 21 As always, it's special to have you come to our 22 meetings and address the panel, and our Committee. So 23 I just want to personally thank you. And I, also, 24 want to say thank you, because whenever I call Dr. 25 Agwunobi, he answers, and I get to talk to him, and 27 1 that's sometimes not known in the federal system. 2 It's not easy to access individuals, but John's always 3 available for SACHRP business. 4 DR. AGWUNOBI: Sam, I gave you my cell 5 phone for a reason, so that you could call, so that we 6 could have conversations. 7 There is one other thing that Sam and I 8 have been talking about, and I understand that there's 9 an ongoing series of conversations related to the need 10 for us to talk about how we might conduct -- how 11 research in the hours and days following emergencies 12 can be conducted in a way that protects the human 13 subjects involved. 14 With the IRB processes, and the time that 15 it takes to write protocols, and to identify PIs and 16 the like, it almost precludes realtime research in the 17 days, perhaps even in the weeks, following an 18 emergency, like a hurricane, or a 9/11-type event. 19 And so, all of the research that's conducted, 20 especially in the field of mental health, all of the 21 field that's conducted looks back into the days and 22 the hours, and you almost are precluded from 23 researching the acute and transient changes, and 24 symptoms that occur following an event. 25 There's some sense, and Sam and I had this 28 1 conversation, that we might be able to shorten the 2 time to initiation of approved research following an 3 emergency if we did some work ahead of time with IRBs, 4 training, perhaps template protocols and the like, but 5 there's some discussion that needs to occur, I think 6 at this level, first, before we go on. And if I'm not 7 mistaken, the chief scientists at NIH, and at CDC will 8 probably be having a conversation with you, Sam, and 9 perhaps with someone from OHRP, to try and help 10 facilitate where we might take this, and how we might 11 proceed down that path. 12 DR. TILDEN: Well, thank you very much. 13 You're certainly welcome to stay as long as you have 14 time, and your schedule permits. And we'll move on to 15 discussion of this alternative for IRB. 16 DR. AGWUNOBI: Well, thank you. 17 DR. SCHWETZ: Let me just -- 18 DR. TILDEN: You want to make a comment? 19 DR. SCHWETZ: Well, to start the 20 discussion. We want -- those of us who are on this 21 Planning Committee, the Organizing Committee for the 22 conference that we had, don't want to just let this 23 sit there, and assume that it would have a life of its 24 own. So we are trying to figure out how can we keep 25 this discussion going, how can we keep the level of 29 1 interest up, how can we enhance the level of 2 communication? 3 There are barriers that keep institutions 4 from considering options that are available to them, 5 and we would certainly welcome your input on how we 6 might address this issue, and how we might try to 7 increase people's awareness of what options are 8 available to them, under what circumstances, and 9 whether these are educational activities, or whether 10 they are some other nature of activity that needs to 11 be taken. We welcome your input. 12 DR. TILDEN: I wonder if we could have the 13 recommendations, the final couple of slides where 14 you're saying this is the activities we're taking, put 15 back up on the screen. Do you think, Kelly, you could 16 help us with that, just so that we have a reference 17 point. 18 DR. SCHWETZ: If there are other 19 activities that you think we should be engaged in, we 20 would welcome that. This is an informal group of 21 people who are trying to move this forward. We have 22 also discussed in our last conversation, the 23 possibility that if others want to be part of this 24 discussion, it doesn't have to be limited to the group 25 of sponsors that you saw on that second slide. So if 30 1 there are other people who would like to be engaged, 2 either in and out, or on an ongoing basis, that's a 3 possibility, as well. 4 DR. TILDEN: Well, personally, from a, I 5 guess, the perspective of serving as an institutional 6 official, for instance, for the last three or four 7 years, I'm faced with lots of issues related to the 8 "off-site research", the non-simple stuff. It's very 9 easy when you are awarded a grant, the investigators 10 at your institution - straightforward, not necessarily 11 easy, but straightforward - when everything is 12 aligned. On the other hand, for instance, when you 13 out-source a project to another institution, the 14 issues are -- so you become the grant awardee, but 15 maybe a whole piece of a program goes out to another 16 institution. Then there are relationships that need 17 to be generated, because of your position, as maybe 18 receiving the award, yet all the activity, all the 19 research, et cetera, is performed somewhere else, or 20 there's some portions of the project. And I certainly 21 endorse the idea of having a clear articulation of 22 what the roles and -- what the responsibilities are 23 that institutions would need to address in those types 24 of situations. And, also, to have agreements that may 25 be more robust. 31 1 I've had to go ahead and create my own 2 agreement because there's - for instance, reporting. 3 When something happens at another institution, the 4 current agreements that are out there that you could 5 pull off, let's say, the OHRP website, I think they 6 don't really address the issues, if there's a problem 7 at the other institution, where their IRB is reviewing 8 it. What's the reporting relation? How do you get 9 communicated to, et cetera? And these are very 10 important, I believe, issues, because if you're going 11 to be responsible for something, and you don't know 12 about it, and you don't protect the communication 13 piece so that you do know about, so you can intervene 14 in a responsible manner, then I think some of the 15 criticisms, like David Lyons pointed out during the 16 conference, why on unchecking the boxes, et cetera - 17 well, there's a notion we want to preserve this 18 federal-wide assurance, and not subject it to any risk 19 from a regulatory standpoint. But I believe that a 20 lot of that is because we don't know what the 21 regulatory risks are, and how to formulate agreements 22 and relationships that when one would come in, say 23 well, this is a reasonable approach. And that if the 24 process works, that you're able to act in a 25 responsible manner. That's just one area that I would 32 1 definitely support working in. Other 2 questions/comments? Dan? We can just go around. If 3 there's enough interest, we'll just go around. Okay. 4 MR. NELSON: Two observations, Bern and 5 others. I'm glad to see this going ahead, and we've 6 discussed that several times. I think there's a lot of 7 need for this, and a lot of interest in this. And 8 there was a very similar discussion held as long ago 9 as 1998, was my first involvement in it, and probably 10 before that, but in Virginia here, there was a 11 conference with many of the same organizational 12 players, and, in fact, many of the same individuals at 13 the table. A White Paper was produced, identifying 14 many of the same issues. And that, indeed, did lay 15 fallow or lay on the shelf without any real follow-up 16 or impact. And I think the difference, at least from 17 my perception, the difference this time around is that 18 folks like you and others are really taking a 19 leadership role, and want to see this moving ahead. 20 And I think that's what it's going to take to move 21 this ahead. 22 I'll admit, I was rather disheartened 23 after the November 2006 conference, not because of the 24 outcome of the conference. I thought it was very well 25 done, good discussions were had, and there is a head 33 1 of steam behind it. But I left the conference with 2 sort of a sinking feeling, having observed first-hand, 3 again, how much of the discussion, how much of the 4 perception of barriers to alternative models to 5 thinking outside the box, to doing things in a 6 different way, are rooted not in evidence, or 7 realities, or in practical issues, but in plain old 8 human behavior, and human inertia, and human 9 perception or misperception. So very rapidly, people 10 digress back to local IRBs good, central IRBs bad, 11 NIH-funded studies good, industry-funded studies bad, 12 no IRB can protect or is as good as my IRB. And when 13 we each say that, of course, the logic breaks down, 14 but that's what we hold to. And I don't know how to 15 overcome that. 16 I think the practical issues, and to be 17 sure there are real issues, there are agreements to be 18 drafted, and liability concerns to address, and 19 allocation of responsibilities to clarify, but I think 20 the real barrier is just -- is more in the heart than 21 in the head, to be honest, of IRBs and institutions 22 across the country who look at this scenario, and then 23 stay away from it. And I don't know that I have a 24 good suggestion how to address that, but that's my 25 observation. 34 1 DR. SCHWETZ: Dan, I think you're right. 2 And that's one of the reasons why we're trying to 3 sharpen the focus on this, as opposed to being a blunt 4 discussion with everybody who will stand there and 5 engage in the discussion, because some of them don't 6 need to consider a different model, some of them don't 7 want to consider a different model, regardless of the 8 need. And if we can find some ways to target the 9 audiences so that there is a greater likelihood that 10 some part of the audience will benefit from this, and 11 will take advantage of it, that's better than not 12 reaching anybody at all. So part of it is targeting 13 the audience correctly, but as you say, this is a 14 chronic problem, and there aren't very many acute 15 solutions for chronic problems, so I think we need to 16 keep talking about it, and keep moving in the 17 direction. And that's why if we had had the 18 conference with no follow-up, it would have made very 19 little impact, so I think the follow-up is important. 20 Thank you, Dan, for your comments. Jeff? 21 DR. BOTKIN: I've certainly been involved 22 with this issue locally, but not so much with this 23 broader discussion. And as I looked at the report, I 24 guess I would say it's not crystal clear in the report 25 exactly what the problem is that the alternative 35 1 models are designed to solve. And I guess my 2 perception is that it's not primarily a human subjects 3 protection issue, but more an administrative burden 4 issue for investigators, and for sponsors. 5 As such, I guess what seems to me that 6 this is sort of a quality management project, to a 7 certain extent, and what we're lacking at our 8 institutional level, and what I suspect many other 9 institutions are lacking is good benchmarking on the 10 process, good processes by which we can capture data 11 on how the administrative process works. So I'm 12 wondering, to some extent, if -- what would be the key 13 measures we would be looking for if this initiative is 14 successful? What are the administrative measures that 15 we would want to evaluate, and are there opportunities 16 for SACHRP, OHRP, or maybe AHRP to help institutions 17 develop mechanisms by which basic benchmarking data 18 can be efficiently collected, so that we'll know once 19 some of these initiatives mature whether we're being 20 successful or not? 21 DR. TILDEN: Well, that gets into the 22 whole issue of evaluation, and I guess, funding, or 23 taking the time to do these types of studies, quality 24 assurance, or whatever you call them. And right now, 25 I believe there was a recommendation from the report 36 1 that some activities, research activities, or 2 activities to evaluate to get this type of empirical 3 information should be promoted. And even though OHRP 4 isn't a granting agency, or have authorities to 5 provide grants, it would -- it's still possible that 6 that type of evaluation -- the issue is that these 7 types of infrastructure processes are critical for 8 entities to perform the work that they're trying to 9 achieve. And so it has to -- the governors of the 10 entities, the leadership of the entities, that needs 11 to be made clear. Okay? 12 If you want to get from A to B, and 13 there's a roadblock, or a point that's very 14 inefficient, that having data to try to identify what 15 the issues are, would be useful. But we seem to 16 generally just go along, and just -- we take a lot for 17 granted, as you're pointing out, that you'd like to 18 see information, but unless there's an impetus to 19 gather it, it may be years or decades, or never be 20 done at all. 21 DR. SCHWETZ: Just to make a comment that 22 I should have made when I was talking from the slides. 23 The reason for having the CTSA prominent in this 24 discussion is, as we talked to Anthony Hayward, and 25 Elaine, and others from the CTSA staff about what they 37 1 want to see happen, one of the things they want to see 2 happen is to explore these alternative models of IRB 3 function, so that they optimize this network by using 4 the best combination of IRB structures, functions, as 5 they can. So I see that, again, as kind of a 6 controlled situation, where we're going from 12 to 60 7 sites that will be in intense communication with each 8 other. And I think it's a great opportunity to 9 continue to explore what model of IRB review and 10 continuing function is appropriate for the kind of 11 work that's done in this kind of a consortium. 12 DR. TILDEN: Dan, you think that this 13 report should be -- I was thinking maybe the contents 14 of this report should be referred to the Subpart A 15 Subcommittee, and maybe to be utilized or evaluated, 16 particularly maybe by the Assurance Group or 17 something, to see what -- whether, after review, we 18 could come back and maybe endorse, with a view toward 19 endorsing certain of these activities, or all of them, 20 and send that on. Is that something you think would 21 be workable? 22 MR. NELSON: In one word, yes. Indeed, we 23 disseminated it to all of our members at our last on- 24 site meeting, but I believe it became available just 25 immediately before, so it was, at that point, too 38 1 fresh off the press, and really for informational 2 purposes, but I think with the upcoming meeting in a 3 couple of weeks, now that we have a chance to look at 4 the agenda for that, I think that would be entirely 5 appropriate. And right in the middle of things we 6 should be thinking about. 7 DR. TILDEN: Mike. 8 DR. GENEL: Just to follow-up briefly on 9 what Bern mentioned. Yesterday, I received an email 10 regarding a Pediatric Oversight Committee that's been 11 formed within the CTSAs, that's going to be having a 12 web workshop on September 11. Among the items on the 13 agenda is the "Feasibility of a Central IRB Model for 14 addressing some of the issues that are related in 15 collaboration between the CTSAs", which is very much, 16 I think, in line with what Bern just shared with us. 17 DR. TILDEN: Okay. David? 18 DR. STRAUSS: You know, it strikes me as 19 not surprising that it's hard for institutions to get 20 married, so to speak, before they know one another. 21 And where IRB review is concerned, it seems to me that 22 there are a number of options short of official 23 designation of IRBs as the designated IRB, or these 24 official authorization agreements, that could occur, 25 but, again, in my experience, rarely occur, and that 39 1 is some simple or basic collaboration, or 2 communication between IRBs engaged in the review of 3 the same protocol. 4 It's a phenomenon, again in my experience, 5 which is rare, and I'd be interested if there's any 6 data on the extent to which IRBs chairs or staff 7 actually communicate with one another? But it seems 8 to me that it is - there is an opportunity for IRBs to 9 resolve differences, resolve problems, approach things 10 in similar ways, if they were only to speak with one 11 another. 12 In fact, what happens is that IRBs, and 13 the "I", I think, stands for isolationist, tend to be 14 only willing to speak to investigators, so the 15 investigator is the one who's charged with managing 16 communications between IRBs, to the extent that there 17 are any. And so, I guess two questions. One is, what 18 do we know about the extent to which IRBs actually 19 communicate with one another when they're involved 20 jointly in the review of the same research? How can 21 communication actually facilitate, or speed review, or 22 resolve differences? Is this an opportunity, or a 23 mechanism to move things in the direction of ultimate 24 contractual marriage, so to speak? It's always good 25 to date a bit before you tie the knot. 40 1 And really, the question is, what can OHRP 2 do, or what can this Committee do via OHRP, to foster 3 communication between IRBs, or among IRBs, and other 4 review bodies, the SMBs, all involved in the review of 5 a single project? I think that would take us some 6 ways. 7 DR. TILDEN: Neil, you have any? Well, I 8 think that possibly given the comments here, that we 9 should consider a motion to refer this to the Subpart 10 A Subcommittee, maybe to look at the follow-up points 11 that were presented in this presentation. And, also, 12 to address some of the issues that David just brought 13 up in terms of what we know, how could communication 14 be advanced or improved, and what we could recommend 15 in terms of moving to the future. Maybe that could be 16 -- because we have a full agenda today, so I think 17 that -- but we don't want to lose this piece. I think 18 we want to continue to move forward. Does that sound 19 like a reasonable motion? You want to make that 20 motion, Dan, or modify it? 21 MR. NELSON: Sure. 22 DR. TILDEN: Or modify some form of that 23 motion so we could move on? 24 MR. NELSON: That's a welcome motion, 25 because it's already on our agenda, so you'll just be 41 1 affirming what we're already planning to do, so thank 2 you. So moved. 3 DR. TILDEN: Okay. Mike. 4 DR. GENEL: Let me just ask a procedural 5 question. I mean, to what extent does OHRP have the 6 capacity to simply serve the IRB chairs and ask the 7 question? I mean, is this feasible? I mean, we could 8 at least get some answers to some of the issues that 9 David raised. 10 DR. SCHWETZ: Did you say OHRP or AHRP? 11 DR. GENEL: Anybody. 12 DR. SCHWETZ: We're limited in surveys. 13 In order -- if we develop an instrument with more than 14 nine subjects in it, so to speak, then we have to -- 15 DR. GENEL: But some of the entities that 16 are engaged in the human research protection process 17 could conceivably conduct this type of a survey. 18 MR. NELSON: Indeed, some of that is 19 already going on. I know several years ago already, 20 I think AAMC and others reached out through Dean's 21 offices to find out barriers, and to survey people. 22 There's a survey going on right now through all 23 participants in the NCI Central IRB project, to ask 24 some of these same questions, and probe deeper, so 25 some of this is already going on. 42 1 DR. TILDEN: Right. That was David's first 2 question, what do we know? So maybe this Subpart A 3 Subcommittee would be trying to get at it. But it may 4 be that more formal, or additional information is 5 required. 6 Okay. So we have a second. Okay. All in 7 favor? 8 (Vote taken.) 9 DR. TILDEN: Okay. Great. That 10 recommendation passes. It was approved. 11 Okay. So I think now it's time to turn to 12 our first panel for today, and I need the charge. 13 Okay. So the charge for today's first panel on 14 Informed Consent, reads as follows. "The purpose of 15 this panel is to educate SACHRP members about some of 16 the more problematic issues regarding the Informed 17 Consent document and process. The panel will provide 18 different perspectives, and also begin to suggest 19 recommendations that may be considered by SACHRP and 20 the associated Subcommittee. 21 Panel members will be asked to explore 22 their perspective within the perspective within the 23 context of the regulatory framework, and to make 24 recommendations that may be considered within the 25 regulatory framework. 43 1 The four panelists will provide the 2 following: Panel Member One will be asked to review 3 the current concerns regarding the Informed Consent 4 form and process. The panelists will also be asked to 5 explore the rationale as to why some of the problems 6 have occurred. Panel Member Two will be asked to 7 present the theoretical issues and concerns related to 8 the Informed Consent process and form. Panel Member 9 Three will be asked to comment on the practical issues 10 and concerns related to the Informed Consent. And 11 Panel Member Four will present the subject perspective 12 regarding the Informed Consent form and process. All 13 members will be asked to present recommendations for 14 improving the Informed Consent form and process." 15 Today, we're fortunate to have four 16 distinguished panelists to discuss the charge of the 17 Committee, and allow the Committee to think about 18 these issues. I'd like to introduce our first 19 panelist, and I'll introduce all four panelists at one 20 time. 21 We have Dr. Howard Dickler. Dr. Dickler 22 has had a distinguished career as an investigator for 23 the National Cancer Institute, and in the National 24 Institute of Allergy and Infectious Diseases. His 25 sub-specialty is in the area of Immunology. 44 1 In 1999, Dr. Dickler became Associate Dean 2 for Research and Graduate Studies and Professor of 3 Medicine at the University of Maryland School of 4 Medicine. After six years there, he joined the 5 Association of American Medical Colleges in 2005 as 6 the Director for Clinical Research, the Division of 7 Biomedical and Health Sciences Research. And he 8 served as principal staff for a Clinical Research Task 9 Force, too. 10 Our second speaker will be Dr. Jonathan 11 Moreno, and Dr. Moreno needs no introduction to the 12 Medical Ethics community. So I think I would just say 13 that Dr. Moreno currently serves as the David and Lyn 14 Silfen University Professor, Professor of Medical 15 Ethics, and of History and Sociology of Science at the 16 University of Pennsylvania. He's a member of the 17 Institute of Medicine, and he also serves as an 18 advisor to the Howard Hughes Medical Institute, the 19 Bill and Melinda Gates Foundation, and 20 GlaxoSmithKline, and is past president of the American 21 Society for Bioethics and Humanities. He's written 22 numerous books in the area of biomedical ethics, and 23 is highly published in the area. 24 The third speaker will be Dr. Alan 25 Fleischman. Excuse me. The third speaker will be 45 1 Gigi McMillan, and Gigi is Co-Founder and Executive 2 Director of We Can Pediatric Brain Tumor Network. We 3 Can offers information and support to families whose 4 children have brain tumors. And the programs include 5 support group meetings, parent education, guidance, 6 teen groups, sibling workshops, family camps, and one- 7 on-one mentoring by trained volunteers. 8 Gigi is a community member, and subject 9 representative for UCLA Medical Center IRBs, and a 10 patient advocate for the NCI's Pediatric Central IRB. 11 And she also sits on Subpart A Subcommittee for 12 SACHRP. And serves as liaison to the CDER 13 Subcommittee. 14 And then our last presentation will be Dr. 15 Alan Fleischman. And Dr. Fleischman is Senior Advisor 16 at the New York Academy of Medicine, and Chair of the 17 Federal Advisory Committee of the National Children's 18 Study at the National Institute of Child Health and 19 Human Development at NIH. 20 He is a pediatrician, which I'm glad to 21 hear, and has formerly served as Director of the 22 Division of Neonatology. In 1994, he became Senior 23 Vice President for the New York Academy of Medicine, 24 where he was responsible for initiatives in urban 25 health, medical education, public policy, bioethics, 46 1 and public health. 2 In 2004, Dr. Fleischman became Ethics 3 Advisor to the National Children's Study at NIH, and 4 accepted appointment as the Acting Chair, and then 5 became Chair of the Federal Advisory Committee to the 6 study. Consequently, has changed his role at the 7 Academy of Medicine, and he serves as Senior Advisor. 8 So he's published numerous articles in this area, and 9 served on multiple committees on ethical conduct of 10 research in children. 11 So we'll start with Dr. Dickler. Thank 12 you. 13 DR. DICKLER: Good morning. On behalf of 14 the Association of American Medical Colleges, we would 15 like to add our thanks to Bern Schwetz for all he's 16 done over the years. He has worked with us very well 17 on any number of projects, and through his leadership, 18 real progress has been made. 19 Bern has asked me to address three things 20 this morning. The first is, what sort of issues exist 21 in Informed Consents, as documented in the literature? 22 Second, to offer some rationale for why those issues 23 exist. And third, to tell you a bit about a meeting 24 we held a short time ago, whose purpose was to 25 strategize about how to address those issues. 47 1 So the first problem with Informed 2 Consents that the literature talks about is the fact 3 that they often do not contain what they're supposed 4 to contain; namely, the elements required by 5 regulation. This particular study actually parsed it 6 into 22 different requirements that they looked at in 7 a large number of ICFs across medical specialties. 8 You can see the results, less than 10 percent address 9 all of the requirements, only about a third address 10 more than 90 percent, and a full fifth were missing 11 almost half of the requirements, so not a very good 12 record. 13 This is a particularly interesting 14 example, because in this case, it was the same 15 protocol which went through 16 different sites, and 16 16 different broadcasts. And only in three cases were 17 all the basic elements required in the CFR present in 18 the Informed Consent. You can see the number of 19 missing elements present in those that did not contain 20 them all. So even when you start with the same 21 protocol, you wind up with deficiencies. 22 The second problem has to do with the 23 reading level of Informed Consent documents. We are 24 all aware from literacy studies that approximately 25 half of our population in this country cannot read at 48 1 the eighth grade level. And approximately a quarter 2 of them cannot read at the fourth grade level. So if 3 you look at Informed Consents, you can see there's a 4 real problem, because the average Informed Consent is 5 beyond the tenth grade. These are three studies from 6 among dozens, literally, that occurred across 7 different decades, and they all say the same thing. 8 Very few are at the eighth grade level or less, and 9 most are beyond the tenth grade level. 10 Even more interesting is this study by 11 Paasche-Orlow in 2003, in which he looked at the 12 standards that U.S. Medical Schools establish for 13 readability, and 61 websites contain those standards, 14 and they range from the fifth to the tenth grade 15 level. So even though they were aiming for the right 16 place, if you looked at the language in their model 17 Consent forms that were present on the same websites, 18 they did not meet their own standard. In fact, they 19 exceeded it by an average of 2.8 grade levels, and the 20 average score for those readability tests on those 21 sample IRB-approved forms was still beyond the tenth 22 grade. 23 And the third problem is the length of 24 ICFs, which have increased over the years. There are 25 three references here. I know I'm going fast. This 49 1 will be in the materials, and I'd be glad to provide 2 additional details after the session. 3 The problem is, as the document gets 4 longer, the less likely it is that it will be read, 5 both because of time constraints in the Informed 6 Consent process, and because, frankly, it's 7 intimidating. Also, unspoken in many cases is a 8 credibility issue. If the length of the Informed 9 Consent is not consistent with the oral consent 10 process, and the amount of information conveyed, it 11 leads to the unspoken question, what are you not 12 telling me? 13 I'm going to cite a couple of examples of 14 what happens when you make Informed Consents better, 15 or compare them by length. In this case, this was a 16 mock study done in 1969, a long time ago, in which the 17 investigators gave aspirin a fictitious name, and the 18 length of the Informed Consent form was proportional 19 to the amount of detail about the risk that was 20 included in the form. And what the investigators 21 found is that comprehension inversely related to the 22 length of the form. You can see the numbers. 23 Even more striking is, those that read the 24 longest form, two of 22 missed a direct 25 contraindication that they had, and five of 22 missed 50 1 entirely that you could have a fatal reaction. So 2 more detail was counterproductive, greater length was 3 counterproductive. 4 In this particular study, the 5 investigators took a standard industry Informed 6 Consent, and modified it. They removed all 7 information except that required by regulation. They 8 made formatting changes to make it more approachable, 9 and they simplified the reading level from 12.0 to 10 8.7. They had shown significantly increased 11 comprehension of all the key areas that are listed 12 there, so for the 12 questions, if they read the 13 modified form, better than 85 percent of the 14 participants scored on 10 of 12 questions. If they 15 used the standard form, that happened on only 3 out of 16 12 questions. Moreover, even asking them if they read 17 the whole form, 32 percent admitted they didn't read 18 the whole form when they used the industry form, and 19 only 2 percent for the modified form. 20 We convened a meeting on May 30th, and you 21 might ask why the AAMC is interested in this question. 22 There are a couple of reasons. First of all, medical 23 schools and teaching hospitals, which are our 24 constituents, conduct a great deal of the clinical 25 research in this country. And we would all benefit if 51 1 there was greater public trust in the research 2 process, and nothing would enhance that more than 3 transparent and understandable Informed Consent forms. 4 But, also, we have a responsibility to attract people 5 to doing clinical research as a profession, and the 6 easier we can make it, the less regulated we can make 7 it, the better chance we have of attracting the best 8 and brightest into doing that as a career. 9 The participants, including several people 10 in this room, were a balanced group. The only thing 11 that they had really in common was that they all were 12 very expert in human research protections. We had 13 ethicists, IRB chairs, IRB administrators, university 14 counsels, research teams, or Vice Presidents, and 15 representatives of various government agencies, and 16 AAHRPP. 17 We had three presentations on groups that 18 are working to simplify Informed Consents. The 19 Children's Oncology Group formed a Task Force in 2004, 20 and has made significant progress in simplifying 21 Informed Consents. As you might guess, presenting 22 Informed Consent to the parents of a child who has 23 cancer involves many, many pieces of information, such 24 as most children do participate in trials, the 25 standard therapy is very scary, and very destructive, 52 1 but the results are surprisingly good. But it takes 2 an awful lot of education of the patient, and prior to 3 the work of this Task Force, all that information was 4 contained in the Informed Consent form. And so, it 5 became very difficult for the Informed Consent form to 6 do the job that it was designed for, or what 7 regulation asks of it. So the way they approached it 8 was to focus the consent strictly on the research 9 question. All additional information about the 10 research process, what standard treatment was about, 11 was contained in other places. So they developed a 12 handbook, they had a website, and they provided 13 multiple appendices to the Informed Consent. 14 They worked very hard to get simplified 15 language. They used a lot of templates, simple 16 sentences, short paragraphs. And most interesting, 17 they found, now this is a clinical trial group, a 18 cooperative group, they found that they got much 19 better consents if, in essence, they constituted a 20 group of professional consent writers who just by 21 practice, and by doing this repetitiously, they got 22 much better consistency, and much better language in 23 the Consents. 24 A second effort has been made by AHRQ, who 25 have created an Informed Consent and Authorization 53 1 tool kit. This tool kit is designed for Health 2 Services research, which AHRQ supports, and for low- 3 literacy audiences. They approached it by omitting, 4 again, all non-essential information, using shorter 5 words and sentences, a lot of formatting and 6 highlighting to draw the attention of the subject to 7 the right place. And the tool kit, in addition to the 8 Informed Consent form, is composed of teach-back, how 9 to train the person doing the Informed Consent to 10 elicit questions, and certification form that reminds 11 the investigator to cover all aspects of the process. 12 The last example came from a commercial 13 IRB, which has created a one-page Consent Form 14 covering simple procedures research, such as drawing 15 a blood sample. This is one-page long, and it's not 16 gotten there by using six point type. It's gotten 17 there by simplifying. It avoids redundancies, 18 presents only the required information. And, in fact, 19 leaves out some of the "required" elements, because 20 for a very simple thing, you might not require all of 21 them, and that leeway is provided for in the 22 regulations. The wording is very concise, and it's 23 grouped under cohesive headings. 24 So if it's possible, and these examples 25 show that the community does want to do this, and it 54 1 can be done, so what are the obstacles to doing this? 2 I've identified several for you here. I'm sure that 3 you can think of others. 4 It's expensive to do Human Research 5 Protections, and it's an unfunded mandate, so the 6 costs of this fall under administrative costs for 7 academic institutions, and those are capped in federal 8 grants and contracts. And every institution is 9 already at the cap, so every extra effort that you 10 make is at the institution's own expense. 11 The next one has been talked about already 12 here this morning, in that institutions and IRBs feel 13 isolated. They never talk to each other, even when 14 they're doing the same protocol in a multi-center 15 trial. They never talk to each other about the 16 consents, or the process. And they certainly feel 17 isolated from the regulatory agencies. We have a 18 strong expression that they would like positive 19 guidance and templates, and best practices, and tool 20 kits from the regulatory agencies, but the feeling 21 they have is that they only get warning letters and 22 audits. 23 Inertia is probably the biggest. It's the 24 easiest thing, and people always do the easy thing 25 when they're busy, and all these people are busy. The 55 1 easiest thing is to copy the last one that go through 2 the IRB, just changing the specifics, as needed. 3 And it's also difficult to write, simple 4 Informed Consents. And this is a task that's often 5 delegated to the juniorest member of the research 6 team, to the fellow, to the new coordinator. Nobody 7 wants to do it, and so the writers lack the necessary 8 skills and training to really do a good job. 9 And, lastly, the group pointed out quite 10 clearly, there really is no incentive, other than 11 being a good investigator, or a good scientist, for 12 doing this. 13 So the group outlined a potential 14 approach, and that was to treat Informed Consent as a 15 process, and not as a document, so that you could make 16 the document simple by eliminating everything that did 17 not pertain to the research question, and including 18 only the essential elements that were needed for the 19 complexity of that research, and using the language 20 and formatting that made it understandable to the 21 majority of our citizens. Everything else was lumped 22 into what was referred to as Part B, whether that be 23 supplemental handbooks, or websites, or appendices. 24 This is where all the additional information not 25 concerned with the question involved in consent would 56 1 go. 2 And, finally, depending on the research, 3 you might want a verification or a certification 4 process, either a teach-back, or an actual test, and 5 many have been devised, or a certification that all 6 parts of the process were carried out. 7 The next steps, most of the members of the 8 panel agreed to participate in a working group that 9 will have its first conference call in September, to 10 begin to develop model templates for research of 11 differing complexity and risk. 12 OHRP, through Baron, has already agreed to 13 review those materials for consistency with the 14 regulations, and if they're consistent, to endorse 15 them as such. And this is not only for templates, but 16 for best practices and tool kits. And we're hoping 17 that FDA will do the same. 18 There will be a need to develop a website 19 so all of these great materials can be accessible to 20 all the IRBs who need them. And we need to work out 21 where that website will sit, and who will pay for it. 22 And we need to really get this process going with 23 pioneer institutions to implement these changes for 24 those protocols that they control at that 25 institutional level; namely, those that are 57 1 investigator initiated, because we think this is 2 doable. And we think that once you have proof of 3 principle, then the rest of the world will follow. 4 You don't fall off the face of the earth if you prove 5 that the earth is round, and the rest of the world 6 will follow. And then you'll have a good chance of 7 having the leverage to work with other sponsors, like 8 the NIH and industry. And, obviously, they want to 9 liaise with this group. 10 So my last slide is about what SACHRP can 11 do to help enable change. These are just some 12 suggestions, and I hope you will have others. I would 13 argue that a change is needed, and the time is now. 14 We're desperately in need of boosting the credibility 15 of clinical research in this country, and nothing will 16 help better than a transparent and understandable 17 Informed Consent document. 18 The group felt that academic medicine is 19 ready and eager to make these changes if they are 20 supported. And SACHRP can urge that OHRP, and 21 indirectly FDA and NIH, can be positive and proactive 22 in their approach to these issues in the form of 23 guidance and approved templates, practices, and tool 24 kits. SACHRP could support funding to establish and 25 maintain a website to distribute the above materials, 58 1 and they could support funding for pilot projects to 2 show that implementing these changes at some 3 institutions is entirely doable, feasible, and it 4 really works. Thank you. 5 DR. TILDEN: Our usual mode of operation 6 is to have each speaker give their presentation, and 7 then open up for questions for all four. So our next 8 speaker will be Dr. Moreno. 9 DR. MORENO: I'm always delighted when 10 somebody else has to worry about the slides. It's 11 worth the trip just for that. A shout-out to Bernie 12 Schwetz, congratulations and thank you for your 13 service, and hello to the Staff. 14 My understanding is that the OHRP is still 15 under-staffed, and I hope that the journalists in the 16 room, although the OHRP staff themselves cannot say 17 this, will ask the administration representatives why 18 that is the case. If the work of OHRP is so 19 important, as we all in this room believe it is, then 20 I think it's incumbent on the administration to make 21 sure that it is appropriately staffed. And even if it 22 was fully staffed, it wouldn't be enough. And the 23 people who work for it, and the members of this 24 Advisory Committee, I think, can attest to that. 25 Having been impolite in starting that way 59 1 with a protest as a citizen taxpayer, let me say, 2 first of all, that there are at least, by my count, 3 half a dozen people in this room who could give this 4 talk, but paraphrasing Harry Truman, "I'm the only 5 speaker you've got" for the next 15 minutes, so I'm 6 going to do my damnedest. 7 I've been given, of course, the impossible 8 task of talking about the concept of Informed Concept, 9 and making, at least, some references to the forum; 10 although, Dr. Dickler's presentation was excellent and 11 constructive. I may make a historical coda to the 12 forum conversation toward the end of my remarks. 13 When we think about Informed Consent, I 14 guess the standard textbook starts by mentioning this 15 legal case in 1957, which was actually a clinical 16 case, not a research case. And in the Salgo case, the 17 term "Informed Consent", as you can see, was not used 18 by the court, but is used by the American College of 19 Surgeons in an Amicus Brief. Many people are 20 surprised that the American College of Surgeons would 21 use the term "Informed Consent", but, in fact, the 22 actual origins of the term "Informed Consent", and I 23 say that with complete love for my surgical 24 colleagues, but, in fact, the actual origin of the 25 term "Informed Consent" in writing was in the context 60 1 of a research study. And we really only learned the 2 details of this in the mid-90s when I worked for a 3 Presidential Advisory Committee on Human Radiation 4 experiments. 5 As many of you know, there was a series of 6 17 plutonium injections in hospitals in 1945, as part 7 of the Manhattan Project. And after - this is on the 8 web - there's a lot of good stuff about it on the web 9 - and after that, when the Atomic Energy Commission 10 inherited the contracts and most of the 11 responsibilities of the Manhattan Project, they 12 discovered that these secret plutonium injections had 13 taken place as part of the project to develop the 14 atomic bomb. And I should explain that these 15 plutonium injections were conducted, apparently, 16 because Dr. Oppenheimer and others were worried about 17 the exposure of their graduate students to plutonium. 18 It was basically a worker safety problem, and they 19 identified 17 patients around the country who were 20 diagnosed with bone cancer, and gave them injections 21 of various quantities of plutonium in a liquid 22 solution. 23 It turned out that only about two-thirds 24 of those patients actually had bone cancer. The rest 25 of them were misdiagnosed, mistakes will be made. So 61 1 the Advisory Committee for Human Radiation Experiments 2 concluded in 1995 that these patients were not aware 3 that they been injected with plutonium. And, in fact, 4 the word "plutonium" was classified until after 5 Nagasaki, so they couldn't have been told too many 6 details. But the point I want to make is that when 7 the AEC found out about this after the war, they 8 decided, basically, under advice of counsel, to keep 9 it secret, but they advised their physician 10 investigators to whom they were giving radioisotopes 11 for medical experiments, that they should make these 12 their rules. And if you look at these rules, I think 13 it's quite fascinating. 14 This is the first time, so far as we know, 15 the phrase "Informed Consent" appears in writing. 16 And, actually, this is an example of Informed Consent 17 enthusiasm, because they were even going to make the 18 next-of-kin responsible for giving Informed Consent, 19 which we today would consider to be unethical. So, I 20 guess, the point here is that as we go on in the 21 decades and we think about the implications of our 22 ethical standards, we learn more and more about what 23 we really think, and what we ought to think, so as a 24 historical remark, this turns out to be the first 25 time, as far as anybody knows that the phrase 62 1 "Informed Consent" appears in writing. Before that, 2 you hear about voluntary consent or just permission, 3 but not Informed Consent. Informed Consent, when 4 people thought about it, I think, seemed to raise the 5 bar above voluntary consent in terms of how much 6 people understood. 7 So I'm not the only one to have argued 8 that inconveniently, on the whole, the medical 9 profession has not been composed of people who were 10 enthusiastic about Informed Consent, or, at least, 11 have harbored reservations about Informed Consent, 12 whatever that is. And I'll talk about some of the 13 good reasons for those reservations in a moment, but 14 I think part of the kind of knee-jerk tendency of 15 those of us who like to criticize doctors, is to 16 suppose that during the whole medical tradition, that 17 there's been a kind of inherent systematic disrespect 18 of human beings. And I'm not sure that that -- I 19 think that's not exactly right. 20 I think, rather, to a great extent, the 21 reason for the fact that physicians have not been, if 22 you like, consent enthusiasts historically, is partly 23 because it's very hard to tell until you start doing 24 systematic research, particularly controlled trials, 25 it's very hard to tell in medical practice 63 1 historically what counts as standard practice, and 2 what is a deviation from standard practice, that may 3 be innovative, or perhaps experimental. So I think 4 there's a conceptual problem that helps to explain the 5 lack of enthusiasm that physicians have had over the 6 eons for what we would today call Informed Consent. 7 It's not just because they're not respecters of 8 persons, although some of them might have been. 9 The Hippocratic Oath, in particular, of 10 course, is silent on the question of truth-telling. 11 It says a lot about that you shouldn't have sex with 12 patients, and you shouldn't charge your students 13 something that my medical students who are paying big 14 tuition bills find very interesting. But it doesn't 15 talk about -- and the other Hippocratic writings don't 16 talk about telling the truth to patients, and I think 17 there are probably good reasons for that, as well, we 18 can talk about. 19 I love this remark by the 19th Century 20 French physician, Thouvenal, who I use this with my 21 students to sort of encapsulate the ultimate physician 22 paternalist attitude, which is now so much in 23 disrepute. Basically, if you read it, it says that 24 the physicians ought to be running the world, and 25 perhaps they should. Maybe they wouldn't be doing any 64 1 worse, but this does show, I think, the kind of cosmic 2 implications that historically have been thought to 3 reside in the experience of the wise old doctor. 4 Of course, the individual who is the icon 5 of modern human research ethics, Henry Beecher, was 6 himself an old wise doctor, who got to be old, and 7 many in this room are great fans of Dr. Beecher. 8 Beecher, of course, became particularly famous in 1966 9 when he published that landmark in the New England 10 Journal of Medicine on Ethics in Clinical Research, 11 identified nearly two dozen cases of what he said were 12 unethical practices of human experimentation in the 13 published medical literature. Because Beecher was a 14 professor at Harvard, an anesthesiologist at 15 Massachusetts General, he was a blue blood who was 16 within the cloth, and could say things, and get 17 attention for saying these things that other people 18 could not. 19 What is less generally recognized, of 20 course, is that Dr. Beecher, himself, as many people 21 did in the 1950s at Harvard and other major places, 22 was doing experiments in his case involving LSD, as an 23 anesthesiologist, for the Central Intelligence Agency, 24 and was a reporter to the CIA on hallucinogenic 25 experiments, and the possibilities that hallucinogens 65 1 could be used as truth serums to compromise our 2 people. Particularly, perhaps notable physicists who 3 might be made indiscrete if they were giving LSD, and 4 my own view is that Beecher, himself, underwent a kind 5 of change in his thinking as the decade went on, and 6 became an advocate for human research protections. 7 However, he was not an advocate of the 8 rules that this Advisory Committee, and the OHRP are 9 responsible for ensuring are respected. In fact, Dr. 10 Beecher, himself, spoke repeatedly, and wrote 11 repeatedly against laying down rigid rules to govern 12 human experiments, including rules about Informed 13 Consent. I think he was a real Informed Consent 14 skeptic. He was a virtue ethicist, as philosophers 15 like to say. He believed that in the final analysis, 16 what really protects people who are in research is the 17 virtuous investigator, and not all the rules that all 18 of us can envision and write down, and try to 19 implement in long complex forms. 20 Beecher wasn't the only one. His 21 protegee, the late Lou Lasagna, made a marvelous 22 rhetorical statement in 1971, typical of the members 23 of this generation, and these were people who were 24 part of the first generation that was really 25 interested in human research ethics. And I love this 66 1 remark. "For the ethical experience investigator, no 2 laws are needed. And for the unscrupulous, 3 incompetent, no laws will help." So the unscrupulous, 4 incompetents out there are beyond the reach even of 5 Bernie Schwetz, presumably, and OHRP until it's too 6 late. So I think that, in a way, what Dr. Lasagna 7 said was not arguable. I guess the bigger question is 8 whether, nonetheless, it's important for society to 9 create some standards that are at least aspirational, 10 that we ought to hold out for people and say that if 11 you're doing it right, this is the way you do it. And 12 I think that's an important exercise. 13 Nonetheless, one has to give this 14 generation, and virtually all previous generations of 15 doctors their due in their skepticism. There are some 16 reasons for these reservations about all these rules. 17 For example, the Hippocratic Oath is clear, and other 18 Hippocratic writings are clear, that the first 19 obligation of the doctor is to promote best interest, 20 not necessarily to bring the patient into all the 21 details about what he or she wants to do with the 22 patient. Lay persons do have limited abilities, 23 often, to understand medical information. There's a 24 kind of psychological argument that if you tell a 25 patient too much, that you might undermine your 67 1 ability to take care of them well, that you might 2 undermine your Asclepian authority, that you may do 3 damage to therapeutic alliance if somebody knows too 4 much. 5 This sounds old-fashioned, but there may 6 be some psychological truth to this, both in research, 7 and in clinical care. And, as I said before, it's not 8 always clear what counts as an experiment. The 9 deviation from standard clinical care and something 10 that's innovative is not always an easy line to draw. 11 I'll come back to that in a little while. But while 12 people like Beecher, and Lasagna, and others were 13 saying these things about the fact that rigid rules 14 don't really help us with people who want to do bad 15 things, there was a kind of underlying disquiet for 16 many reasons in the 1960s about the way that medicine 17 traditionally had dealt with the problem of engaging 18 people in the research process. So Jay Katz very 19 eloquently referred, and I think accurately referred 20 to a kind of gorilla warfare that's always been the 21 case between doctors and patients. You know, doctors 22 tell patients what to do, and then patients go home 23 and do whatever they damned well please. And that's 24 probably just as true with research subjects, unless 25 they're carefully monitored, as anybody else. 68 1 The frame, I think, here is the question 2 of when, historically, has the discretion of the 3 physician experimenter been subject to external 4 constraints. And that really has been a very recent 5 phenomenon. And, actually, in some respects, 6 involuntary human experiments have long been in 7 disrepute. There are legal cases, even in Medieval 8 Europe about doctors doing experiments and being taken 9 to court for doing these experiments without, at 10 least, the consent of the medical faculty. So, in a 11 certain sense, there's never been any real question 12 that it's a wrong thing to impose an experiment on 13 somebody. But the harder question is, what counts as 14 an experiment, and how much do you have to bring them 15 into the process. 16 So, in the law, for example, it's long 17 been recognized as an Anglo-American law since the 18 middle of the 19th Century, that there is something 19 like bodily integrity. There are different legal 20 theories about what that means, but this has been much 21 harder to translate from the law into routine medical 22 practice. Of course, many people came to be more 23 sensitive to this problem as a result of the 24 concentration camp experiments following the Second 25 World War, when they were revealed at Nuremberg during 69 1 the famous doctor's trial, and the Nuremberg Code, 2 written by the judges at the Nuremberg doctor's trial, 3 after the trial were so concerned about the fact that 4 it was hard to show that the doctors involved in these 5 Holocaust experiments had deviated from standard 6 medical practice, that they actually decided to write 7 their own Code of Ethics, which we know as the 8 Nuremberg Code. And this is the famous first line of 9 the Nuremberg Code. 10 So gradually, I think, after the Second 11 World War, with the advent of controlled trials, and 12 it became a little easier to distinguish between 13 routine clinical care and experiment. In fact, by the 14 way, the word "experiment" drops out of the medical 15 literature in the 1950s. They start to be called 16 "trials" or "research", rather than "experiment." And 17 I think, also, because the word "experiment" began to 18 have a bad odor. It seemed to signify something that 19 you were doing in an unsystematic way, perhaps in an 20 uncareful way. So you will very rarely hear 21 physicians any longer saying that they're doing an 22 experiment on somebody, but you will hear that they're 23 doing a clinical trial, they're doing an 24 investigation. 25 So I think gradually people began to be 70 1 more sensitive about the idea that there was some 2 moral constraints on what investigators, not 3 experimenters, but investigators did with people. And 4 so Paul Ramsey said in the 1970s, "No man is good 5 enough to experiment on another without his consent", 6 part of the changing times of the 1960s that some of 7 us vaguely remember. Hans Jonas, a New School 8 philosopher, New School for Social Research, I think 9 made this very powerful statement that actually 10 includes, I think, the kind of sense of survivor 11 guilt, himself a survivor of the Holocaust, and the 12 sense that we have a special moral obligation to 13 people who are willing to let their bodies used in 14 experiments so that we can benefit from the knowledge 15 that might be attained in that way. The language here 16 is very powerful, and quite a powerful response to Lou 17 Lasagna, who is to be martyred in the service of what 18 cause, and by whose choice? 19 Now you might say this is - the idea that 20 we're martyring our participants in research studies 21 is, perhaps, a little rhetorical, but I think it 22 captures the sense of moral responsibility that people 23 have when they're doing research with human beings, 24 that became more evident to people in the 1960s and 25 1970s. 71 1 Ramsey actually articulated what I suppose 2 is sort of the ideal in some respects, that the 3 subject should be able to identify with the 4 experiment, and that the human subject should be a co- 5 adventurer with the investigator in the quest for 6 knowledge. You know, if the first item were true, 7 then who would we want to see recruited in research 8 studies but our lab partners, which is a no-no these 9 days, as I'm told. So this business of intellectual 10 identification with the research is a double-edged 11 sword. And there may be other ethical reasons that we 12 can't actually buy this proposition. But, perhaps, 13 the ideal, at least the aspiration, that somehow human 14 participants should be co-adventurers in the quest for 15 knowledge is one to which we should still adhere. 16 So what factors have led to these changes, 17 I've alluded to some of them. These tremendous 18 changes in the attitudes about the ethics of research 19 with human beings, and the requirement of Informed 20 Consent, I think it's clearer now when we're doing 21 something that is deviation from routine practice, at 22 least sometimes it's clear. There's obviously a lot 23 more money being spent in research now, greater 24 societal investment, as a result. Society wants to 25 know what people are doing behind closed doors of 72 1 human beings with their money. 2 The consultation room has become a lot 3 more crowded, particularly after the advent of managed 4 care. There are greater concerns about liability. 5 The 24-hour news cycle, obviously, carries headline 6 liability, as one of my former colleagues likes to 7 say. And, of course, this scandals and tragedies with 8 which we're so familiar. Hardly, in my experience on 9 a previous research protections body, one of your 10 predecessors, hardly a meeting went by when somebody 11 didn't talk about the Syphilis Study, or it didn't 12 come up. The scandals and tragedies weigh very 13 heavily on us still. 14 So through the 1970s, 1980s, a body of 15 standards was developed concerning elements of 16 Informed Consent here following Beecham and Childress. 17 Arguably, Informed Consent for research entails higher 18 standards, perhaps somewhat qualitatively different 19 standards than consent to treatment. The National 20 Commission insisted in the Belmont Report on a 21 distinction between research and treatment, a 22 distinction that we know from several studies is hard, 23 even for doctors who are doing clinical trials, to 24 keep in mind. Even doctors and nurses doing clinical 25 trials find it hard, sometimes, to remember what this 73 1 is about. This is really about gathering data and 2 expanding knowledge, not about helping the subjects, 3 not a primary purpose of the study. 4 Healthy, normal subjects may not benefit 5 at all, except perhaps with their pocketbook, or their 6 sense of altruism, or their karma. Preliminary 7 studies, as we well know, may not have therapeutic 8 intent, so that seems to change the whole notion of 9 risk and benefit. And, as Bob Levine has liked to 10 point out for 30 years, we use this very easy 11 distinction between therapeutic and non-therapeutic 12 investigations, but then we have some problems with, 13 for example, vaccine studies, where do they fit in? 14 So Informed Consent for research does seem to reside 15 in a somewhat different dimension than Informed 16 Consent for treatment. 17 So among the many continuing concerns 18 about Informed Consent, which many people in this room 19 I know are concerned about, could make a still longer 20 list, it's amazing that so few people have really 21 dedicated themselves to the empirical side of what 22 counts as adequate consent. A number of people in 23 this room have done that, Applebaum, Blitz, and others 24 have done that, but we sill don't know a lot about 25 indicators of capacity, or lack of capacity to 74 1 consent. We're still having debates about how much 2 research subjects or participants notice that 3 language, also is highly politically charged. They 4 should be able to understand. 5 We know that people have hope, even after 6 rationally they shouldn't have hope, when they're in 7 a protocol. Is that compatible with their 8 voluntariness? Still debates about that. When should 9 the Informed Consent process be repeated? Is Informed 10 Consent, in general, as some of my colleagues have 11 told me, like a Miranda Warning, that is sure to scare 12 the pants off anybody they try -- somebody really 13 understood and read what was in that Informed Consent, 14 why the hell would they sign up, is basically 15 quote/unquote what some of my colleagues have said to 16 me. 17 And I just want to say, in the bioethics 18 world, I'm hearing increasing quiet talk that maybe 19 the bioethics revolution, which has succeeded so well, 20 has over-valued Informed Consent in a certain way. 21 Maybe we ought to go back to worrying more about risk- 22 benefit, and the interests of patient subjects, and 23 maybe we shouldn't be so focused on autonomy-based 24 notions of Informed Consent. And, of course, the God- 25 damned form. 75 1 Then we have problems of innovative 2 procedures. As we all know, procedural innovation is 3 not regulated, unless it involves a new drug or 4 device. There are many innovative procedures, for 5 example, in orthopedic surgery, that entail 6 significant risks to patients, but are not regulated, 7 so I'm going to do a plug here for a book that I 8 published with a colleague, Angie Reitsma, last year, 9 in which we tried to explore the problem of innovative 10 research in the context of surgery, not picking on the 11 surgeons, particularly, who were very cooperative, I 12 must say, with this study, and are very aware of the 13 problem. 14 What do we do about innovative procedures 15 that don't seem to rise to the level of a clinical 16 trial? What are the earmarks of innovative procedure? 17 This is, it seems to me, still a great unchartered 18 territory for the most part. 19 Just some historical remarks about the 20 forum. Dr. Dickler's presentation was very rich, and 21 there's not much I can add to it, except perhaps an 22 historical note. I'm sure all of you in this room 23 know who this is, because you're all students of the 24 history of human research, so this is Walter Reed. 25 Walter Reed was the youngest graduate of my former 76 1 medical school, University of Virginia. He was 16 2 years old when he graduated from UVA Medical School in 3 1867. Reed, as many of you know, did a research study 4 on Yellow Fever in Havana, Cuba in 1900, including a 5 number of these young soldiers in the study, and he 6 developed, for reasons that are still not clear, and 7 may never be entirely clear, the first consent form. 8 And I sometimes go through an experiment, as it were, 9 with my medical students. I have them look at the 10 form and tell me what they think about it, and it's 11 kind of a fun exercise, perhaps, for IRBs, as well. 12 This is the Spanish language version of the form, 13 since he also recruited a number of the local men to 14 be in his Yellow Fever study. And this is the English 15 language version of the form. 16 Speaking of simple consent forms, they 17 wouldn't have called it a consent form, of course. It 18 was probably called a contract in those days. This is 19 one page. It's in words of not more than a couple of 20 syllables. It's very clear. It, perhaps, does over- 21 promise, as many consent forms do. It says we're 22 going to give you excellent care for your Yellow Fever 23 if you take the bit from this female silverback 24 mosquito, and if you get the disease. Of course, 25 excellent care in those days meant basically watchful 77 1 waiting, and hoping that you survive. And it also 2 makes a monetary offer. It says we'll give you $100 3 in gold if you take the bite from the mosquito, and 4 we'll give you another $100 in gold if you get sick. 5 And if you die, the money will go to your family. 6 The soldiers, apparently, by the way, 7 declined the money, which I think is interesting. So 8 this is a simple consent form, but even a simple 9 consent form, obviously, may not be acceptable for 10 other ethical reasons. And it's only, as I say, in 11 simple English on one page. 12 So there, of course, continuing concerns 13 about consent forms, whom do they serve? I remember 14 that when we looked at the consent form at the 15 Hastings Center 23 years ago for the first heart 16 transplant, heart implant I should say, artificial 17 heart implant, it was, as I recall, and maybe Mike 18 Genel or others who are around may remember this, I 19 believe it was a 14-page single-spaced form. And we 20 said well, that's the craziest thing we ever heard of. 21 Well, now there are a lot of 14-page single-spaced 22 consent forms, and you know, you have to wonder who 23 are they being written for, clearly. Are they being 24 written for the institution, are they written for the 25 participants? 78 1 So Dr. Dickler talked about literacy 2 level. I also want to mention numeracy level. Carrie 3 Kelpridge, an oncologist at UVA, taught me that 4 numeracy is also a problem, so that many people are 5 unable to know that one out of ten is the same as 10 6 percent, something we don't always, I think, refer to 7 as much as literacy. 8 Who controls what goes in? Are there 9 other ways of doing these presentations? There have 10 been some creative ways of figuring out how else to do 11 consents. And, of course, we always like to say 12 consent is the process, not the form, but you have to 13 wonder when you actually see the way things are done. 14 So I'm going to leave it there, and thank you for your 15 apparent attention, and look forward to the discussion 16 with the panel. Thank you. 17 DR. TILDEN: The next speaker will be Gigi 18 McMillan. 19 MS. McMILLAN: Good morning. I'm going to 20 speak today from personal experience, and also on 21 behalf of the hundreds of families that I have worked 22 with in the past 10 years. I'm going to put you in 23 the mind of the subject, just for a little bit. 24 In my work with families whose children 25 have brain tumors, we do a lot of different programs, 79 1 one-on-one support when they're newly diagnosed. We 2 follow them, or help them through the issues that 3 their families deal with during treatment, and also 4 long-term recovery. So most of these children have 5 been involved in clinical trials, so over the years, 6 over the past 10 years, I've been able to be with 7 these families as they have gone through considering 8 research, actually going through the consent process, 9 and then going through the lives of these studies that 10 they participate in. 11 What's interesting to find is that as we 12 all talk among ourselves, we are telling many of the 13 same stories. You would think that out of, I think I 14 did the counting, about 812 families, that there would 15 be maybe 812 different stories. But, actually, when 16 we speak to each other about our experience with 17 research, we are always talking about the same few 18 categories of concern, the things that bother us, the 19 things that we like, and so I want to share some of 20 those with you today. 21 I just want you to know that all of these 22 parents and these children, these family members, 23 these subjects, they want to understand what the 24 researcher is telling them. They want to understand 25 what the research is about. They desperately want to 80 1 understand enough to make a good decision; and, yet, 2 we are all short-circuited by the circumstances in 3 which we find ourselves. We are emotional, we are 4 medically uninformed, and most of us at this moment, 5 the moment before we walk into the room with the 6 research team, we don't understand what a clinical 7 trial is. So we feel at an extreme disadvantage, and 8 I need to spend just a few moments explaining to you 9 what is going on in our heads. 10 With these emotions, we are maybe in 11 shock, or we're afraid, we're frustrated, we're 12 desperate, and there's this noise, like white noise in 13 the back of our minds. And parents have told me that 14 they see the mouths of their doctors moving, but they 15 don't hear a word. All they hear is their own voice 16 in the back of their head saying oh, my God, oh, my 17 God. This is a moment when they know that they need 18 to be at their very best so that they can make a good 19 decision on behalf of their children; and, yet, these 20 highly educated people cannot round up the discipline, 21 or the calmness, or the sense of self to be quiet in 22 their mind and listen to what the research team is 23 telling them. 24 There are, for example, my own husband who 25 was a wonderful attorney, was going to take the lead 81 1 in a discussion with our research team. And he had 2 his legal pad, and ultimately, he became so 3 overwhelmed during the discussion that he had to write 4 the questions on the pad and hold it up for us to 5 read, because he couldn't speak. This is a highly 6 functional man, who in the moment when he really 7 needed his brain and his skills to do something 8 important on behalf of his family, he was unable to do 9 that. So we are emotional often at the point when we 10 need to be making decisions about clinical trials. 11 We are medically uniformed. For us, it's 12 like being dropped into a foreign country, and we 13 don't speak the language, we can't read the signs, we 14 don't know which side of the road to drive on. We 15 don't have a map, we don't know where we're going. 16 And, yet, you, the research team, you know exactly 17 what's going on, you know exactly what you want from 18 us, you are going to try to explain things to us, and 19 we don't even have the vocabulary with which to have 20 an intelligent conversation. That is demoralizing. 21 We lose our confidence, and we, again, feel at a huge 22 disadvantage. 23 The other thing is that we don't know 24 about clinical trials. We hear these scary words that 25 the previous panelists referred to, experiments, 82 1 guinea pigs. We've read the stories. There's always 2 stuff in the newspaper about the poor subjects who die 3 because of the drug, or there's something going on 4 kind of tricky at different institutions. We hear 5 that, we hear those things. And, yet, a doctor that 6 we trust is suggesting that we consider research, so 7 we don't know how to get our brains around this. We 8 hear things, we don't really know what the process is, 9 we don't know what the facts are, and yet, somebody 10 that we are supposed to trust, that we desperately 11 want to trust, is suggesting that we consider 12 research. So, as I said, we are at a disadvantage, 13 and we're a mess, frankly. 14 We want to ask questions. We know that 15 we're repeating ourselves sometimes, because maybe 16 we've asked the question, and we've been told the 17 answer, and we couldn't absorb it. So we began to 18 feel that we're going to look stupid, or we're going 19 to insult the researcher. 20 What happens is, because we are in -- we 21 have no confidence, we began to feel that it's us 22 versus them, that we are the person who doesn't know 23 what they're doing, and the other people are the 24 experts. And we don't know how to get around that. 25 Our first contacts with the research team