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 83 1 usually involve the Informed Consent. And the thing 2 is, during the consent process and the life of the 3 study, our personal journey is more important to us 4 than just what's happening in that room with the 5 research team. Our relationship with the research 6 team is one little part of what's going on in our 7 entire family. So, for example, there may be support 8 systems in place when a family member has a 9 catastrophic diagnosis. The neighbors will be cooking 10 food for your family every day for two months, grandma 11 comes to live with you so that you can be at the 12 hospital with the sick child. Someone takes a leave 13 of absence from work to help support the family. This 14 is wonderful support mechanism for the beginning of a 15 medical crisis, but these things change, so at the 16 moment when we are consenting or agreeing to be in 17 research, we may have things in place that change over 18 the life of the study. Someone had to go back to 19 work, grandma had to go home and water her plants, the 20 neighbors are tired of cooking for us, and so our life 21 situations become complicated in ways that the 22 research team don't understand. And even when we want 23 to participate and cooperate with the research, our 24 resources are challenged in other ways, in other parts 25 of our lives that we don't feel the research team 84 1 understands, or acknowledges. 2 So what do these crazy, emotional families 3 and potential subjects want? We have an interesting 4 perception, I think, of the consent process. 5 Sometimes, and of these 812 families, you would think 6 that there were just two different kinds of research 7 they were involved in, because their consent processes 8 usually fall into two different categories. One is, 9 the consent form is not very important. They just 10 have a lot of verbal discussion with their doctor, and 11 at the end of this discussion, they sign the last 12 page. They don't really go through the form at all. 13 And the other category is where the research team goes 14 through every line of the consent form, like it's a 15 legal contract, and they're scared out of their wits 16 when they finally sign that last page. So it's two 17 different categories. 18 It depends on where they are. They're not 19 exactly sure what role the consent form even plays in 20 their participation with research. A lot of them sign 21 the form and go home and put it in the back drawer, 22 and they never look at it again. Other people, who 23 are a little more involved, or I was going to say anal 24 retentive, but then I wasn't going to say anal, like 25 me, I took my consent form with me to every single 85 1 clinic visit because I wanted to track exactly what 2 drugs they were putting into my kid. All right. That 3 was me. Other people, I was astounded to find that 4 once they signed it, they never looked at it again. 5 What happens is months later, years later, 6 without fail the families that I work with look back 7 on their experience with research, and they say I 8 didn't know what I didn't know, and so I didn't ask 9 the right questions. Without fail, that's the theme, 10 that's the underlying theme of every conversation 11 we've had about research in my organization. 12 Okay. So what do they want? These 13 emotional people who are really trying to understand 14 a new body of knowledge, and these people who really 15 want to be participating in clinical research, they 16 want help. All right? And the things that they want 17 are a description up front that describes their role 18 in research, not as it relates to the particular 19 study, but just in general. I'm a high school teacher 20 in my old life, and I think that there is a 10th grade 21 health class that is required for every high school 22 student in the country, and there should be a chapter 23 on clinical research, so that these young people are 24 exposed to the basic tenets of research way early in 25 their life, so that it's not a surprise, or it's not 86 1 a novel concept, if in the - I don't want to say 2 probability, but high likelihood at some point in 3 their adult life they will be asked to participate in 4 research. This vocabulary and these concepts should 5 become part of the general public education so that 6 when you are faced with this sometimes traumatic 7 experience, you're not struggling to learn a whole new 8 idea at the point when you're making medical 9 decisions. 10 Yes, simple language, please, and simple 11 format would be great. Also, as a teacher, let me 12 just say something about eighth grade readability. 13 The ability to decode eighth grade language is not the 14 same as the ability to comprehend at an eighth grade 15 level, and so consent forms that are written at eighth 16 grade readability, it's ludicrous to use them as 17 assent forms for an eighth grade aged child. 18 I think what my families would love is 19 that consent form or format that Dr. Dickler talked 20 about, the three parts, A, B, and C. We often don't 21 know what's important and what's not. The consent 22 forms today are a mishmash of important information, 23 research ideas, risks, and then there's all these 24 sections on liability, and who's going to own the 25 product afterwards, and how much compensation if 87 1 you're injured, and what's your financial 2 compensation. So separating the important things from 3 the unimportant would be very helpful for lay people 4 to try to get their brain around the study concepts. 5 I co-presented at a PRIMR workshop a 6 couple of years ago, and the gentleman that I was 7 presenting with was studying ways to evaluate if 8 subjects understood what was going on in research. 9 And he wanted the subjects -- he proposed that the 10 subjects take a test, a factual test on the research 11 and pass it before they be allowed to participate. 12 That brought up a lot of red flags in my mind, because 13 I work with children, and because I think those -- 14 these minor subjects aren't able to understand a lot 15 of what's going on in the research, and so someone 16 else needs to decide. But I also think that maybe a 17 more humane thing to do would be have a checklist that 18 tests the process of consent, not the factual 19 understanding. So, for example, if before somebody 20 was consented, if they were given a list of things, 21 and the doctor would say we're going to go through a 22 consent process. Here are the questions you should be 23 thinking about as we talk about the research, then 24 that primes the subject as to what they should be 25 considering as they go through the process. 88 1 Then they go through the consent process, 2 and as the end, literally hand them a checklist, have 3 them test themselves. Did this process work for me? 4 Did I get to do all these things? Did I consider all 5 my questions? Were they answered? Do I understand 6 these important things? And that test - then the 7 subject can kind of test themselves, and take their 8 pulse about how they feel about the consent process. 9 And how about offering a peer mentor? 10 This is one of the things that We Can does. When a 11 family is diagnosed, when their child is diagnosed 12 with a brain tumor, we match them with a volunteer who 13 has been through a similar situation with their own 14 child. We match them according to tumor type, and 15 treatment option, and life situation, and side 16 effects. And we don't offer medical advice, but what 17 we do is we help them come up with a framework, with 18 a mindset, with a list of questions that they can use 19 in their relationship with their doctors. 20 I think that researchers should have a 21 stable of volunteers of mentors, of people that they 22 could say to a potential subject, would you like to 23 talk to somebody who's been through this before? And 24 not just any old person, you have to train them, and 25 they have to understand the parameters of the support 89 1 they can offer, but it would be a huge benefit, and I 2 think an emotional benefit to your potential subject. 3 What do subjects want from the 4 researchers? We want tools. We want tools. For 5 example, We Can developed a spreadsheet. It has the 6 10 most commonly asked questions about a brain tumor 7 that a child has, and then there are columns. And 8 each column has an accurate age-appropriate response, 9 so here are the 10 questions, the first column is how 10 you would answer a preschool child. The second column 11 is the answers you would give to a school-age child. 12 And the third column is the answers you would give to 13 a teenager. So each answer in every column is 14 accurate, but they're age-appropriate. We give this 15 tool to the parent so that when they go home, they can 16 talk to their children about what's going on with 17 their brother, sister, or with the child, themselves. 18 The thing that's so interesting is we 19 found out that parents were using these for 20 themselves. The parents needed to go home and read 21 the baby answers first. And then once they could 22 understand the baby answers and they were okay with 23 that, then they read the school-age answers. And now 24 they felt that they understood a little bit more, and 25 they felt more in control of the concepts, and then, 90 1 finally, they were able to read the teenage answers, 2 which are pretty close to an adult response. So what 3 we learned was that when first exposed to this 4 traumatic situation, they needed some basic 5 information in easy to digest bites. And then as time 6 went on, they were able to handle more sophisticated 7 information. 8 Researchers, I'm sure, will tell you, 9 their subjects become more sophisticated as the study 10 progresses. Well, what our families would like is 11 halfway through the study, go through the consent 12 process again, please, because now I understand the 13 concepts, now I can say Medulloblastoma or 14 Astrocytoma. Now I know how to have an intelligent 15 conversation. And maybe two months or three months 16 into the study, I will have more important questions 17 to ask, more intelligent questions to ask, and maybe 18 I'll be ready to understand the answers. 19 The other thing our families would like is 20 an exit interview. We would like to meet with the 21 research team when the study is over, and have them 22 explain to us here are the things you need to watch 23 out for the next few years because your child has had 24 these certain drugs. Here are the kinds of people who 25 might be contacting you for further information. Here 91 1 are the kinds of studies you might look to to see if 2 they would help you or your child. That would be 3 helpful, because we don't feel any sense of closure. 4 We feel that we have invested our time, and our 5 family, and our goodwill in this research, and nobody 6 ever sends us a report on what happened with the 7 study. 8 An interesting thing happened. My son 9 diagnosed 12 years ago with aggressive brain cancer, 10 and we did a clinical trial. And he's doing very 11 well, he's 17 now, but he has significant disabilities 12 from his treatment. Now that I'm on an IRB at UCLA, 13 I was assigned to review, by fluke, the latest 14 incarnation of the trial that he was enrolled in 12 15 years ago. And I had mixed feelings about that, 16 because I remember 12 years ago what my mindset was, 17 what my family was going through. Here I am now 18 reading this consent form with very educated eyes, and 19 I have to tell you, I was appalled. I realized that 20 12 years ago, I did not know what I was consenting to. 21 That 12 years ago when they said loss of IQ points, 22 they meant mild retardation. That 12 years ago when 23 they said in three words in the consent form, mild 24 hearing loss, what they should have said was 25 possibility of significant hearing loss, and your 92 1 child will need hearing aides for the rest of their 2 lives. They never talked about neuropsychological 3 testing 12 years ago, or growth hormone, or the toll 4 that would be taken on the family to go through this 5 research. 6 Well, I brought this up to my committee, 7 and they said wait a minute, Gigi, 12 years ago you 8 weren't consenting to what happens after the research, 9 you were just consenting to the study itself, for 10 those 12 brief months. Well, they're right, except 11 that 12 years ago, I didn't know that. And so all 12 these years I've had this sense of being betrayed, 13 almost like I was tricked into doing something that 14 was awful. And they say to me, I have good friends, 15 they said well, Gigi, the doctors saved your kid's 16 life. And I said well, yes, they did, but that 17 doesn't make me feel any better, because now that the 18 cancer battle is over, we have a lifetime of problems 19 ahead of us dealing with the long-term side effects, 20 mental retardation, quality of life. And my son has 21 a great and wonderful life, but I think that while I 22 am grateful, and while the families I work with are 23 grateful to the researchers, you, as a community, the 24 research community would have a better loyalty from 25 us, and a better relationship if there was some 93 1 follow-through. Someone should have sent me a report 2 that said here's what we learned from your kid. 3 Now what I found out was 12 years later 4 they did learn some things from my kid. There's a 5 whole paragraph now in the new consent form about 6 hearing loss. There's a much more detailed 7 explanation about what IQ loss means. They recommend 8 neuropsychological evaluation on a regular basis, so 9 they learned these things from my kid, except I found 10 out by accident. And the other thing is, because the 11 people in our group talk a lot to each other, I know 12 that kids 10 and 12 years later have developed other 13 brain tumors from the radiation they received when 14 they were a young child, so I've been waiting for my 15 letter. No one, no one has sent me a letter saying, 16 Mrs. McMillan, 12 years ago your son had brain 17 radiation of this many rads. You should have him 18 checked for benign tumor growth. I'm still waiting 19 for my letter. 20 I even brought it up to my Committee, and 21 I still haven't gotten my letter. So there's not been 22 any follow-up, which I think is -- it's a huge 23 disservice. If you're going to invite these subjects 24 to give part of their lives into this research 25 endeavor, then you need to make the most advantage of 94 1 it, and help them feel more like a participant. 2 So the recommendations from my families, 3 and from the people that I've talked to over the 4 years, are how about a checklist, which I think Dr. 5 Dickler referred to, a way - in Part C of his three- 6 part thing, as a way of evaluating the process of the 7 consent. 8 I would love to see somebody offering some 9 peer mentors. Parents want a chance to revisit the 10 information. They go through a big battle, a long 11 battle learning these words, learning these concepts. 12 Two months and a third of the way in, or at least 13 halfway through the study, go back and revisit the 14 important parts. 15 Tools, we need tools, words for children. 16 We especially need to know how to talk to our kids 17 about it. An exit interview, please. And then, 18 finally, we would like a report. We'd like to know 19 what you learned when we were working with you. Thank 20 you. 21 DR. TILDEN: Thank you very much. The 22 final presenter at the panel will be Dr. Alan 23 Fleischman. 24 DR. FLEISCHMAN: Thank you, Professor 25 Tilden. It is an honor and a privilege to speak 95 1 before this group, and to be part of such a 2 distinguished panel. While we set up a bit of this 3 technology, I want to tell you a little bit about the 4 National Children's Study, and its attempt to answer 5 some of the concerns and questions raised by each of 6 our three speakers. 7 Our thinking at the National Children's 8 Study is that the regulations are not a problem, that 9 the regulations don't preclude good practice. Our 10 view has been that local practice has resulted in the 11 problems discussed, and that we can, if we are smart, 12 develop methods to increase consistency, increase 13 understanding, and enhance Informed Consent. 14 The National Children's Study made a 15 strategic decision not to create a Central IRB, but to 16 make attempts to enhance the process of consistency 17 across the probably 1,000 IRBs which will look at, in 18 some sense, the National Children's Study. 19 What I'm going to do this morning is tell 20 you a little bit about the study, so you'll understand 21 our Informed Consent process, and then I'm going to 22 show you snippets from a 25-minute video, one of the 23 consents that we have for the study. 24 The National Children's Study is a bold 25 study, and its approach to Informed Consent is bold 96 1 and innovative. The goal of the study is to provide 2 information that will lead to improvements in the 3 health, development, and well-being of all children. 4 The study will investigate the separate and combined 5 effects of environmental exposures, as well as gene 6 environment interactions on pregnancy outcomes, child 7 health and development, and precursors of adult 8 disease. This is an ambitious project. 9 It is the largest and most ambitious long- 10 term study ever conceived or implemented in the United 11 States. It is longitudinal in nature, will involve 12 100,000 children from across the country, as well as 13 their families, and their environments. The 14 participants will begin with women pre-conception, and 15 in early pregnancy, and will study their pregnancies, 16 and then their newborns for 21 years. 17 Environment is defined broadly, chemical, 18 physical, biologic, behavioral, social, and cultural 19 environment in which the women exist, and the children 20 are brought up. We will examine a wide range of 21 common environmental exposures, and less common 22 outcomes, and evaluate the impact of environment on 23 genetic expression. 24 This study was authorized by the 25 Children's Health Act of 2000, when Congress asked the 97 1 NICHD in collaboration with other federal agencies to 2 plan, develop, and implement a prospective cohort 3 study to answer hard questions about children's 4 health. I'm pleased to say today that in the fiscal 5 year 2007 budget, the study is fully funded, and has 6 good prospects for funding in the future. In fact, as 7 the study is now conceived and planned, we will begin 8 recruitment in the year 2008, and an IRB near you will 9 be seeing this project soon. 10 The priority exposures are these for the 11 study, and the priority outcomes range from the 12 outcomes of pregnancy, all the way through to 13 precursors of adult important diseases, and the 14 epidemics of childhood that are listed here. 15 The study will have a probability sampling 16 methodology in 105 locations throughout the United 17 States, which represents the face of America's 18 children in a national probability sample. Seven 19 sites who are enumerated here have been given the 20 privilege of being vanguard or pilot centers, and are 21 beginning the process of planning and implementing the 22 study, as we speak. 23 There will be about 14 face-to-face visits 24 at these times, but between visits there will be large 25 amounts of data collection by phone, computer, and 98 1 mail. We will also look at environments outside the 2 home, inside the home, and at sites where children 3 spend as much as 30 hours a week. 4 I was asked to advise the study on ethical 5 concerns, and did this small list of ethical issues 6 that needed to be dealt with. This group could easily 7 list this list, as well as other issues. Today, we'll 8 talk about one of those, Informed Consent. 9 There are many individuals who will 10 participate in this study, and many aspects of 11 Informed Consent. What I will show you today are 12 snippets from the pregnancy Informed Consent, which is 13 the largest and most complex part of the Informed 14 Consent process. We have completed the pre-pregnancy 15 Informed Consents, pregnancy, and the father or 16 partner's Informed Consent is in the completion phase 17 for August. 18 Our approach is an interactive electronic 19 video consent with research staff available during 20 this Informed Consent video. It will include all 21 elements of Informed Consent. There are English and 22 Spanish versions already developed, translators will 23 be available for other languages, and in any site with 24 an extraordinary number of Mandarin speakers, or 25 Samoan speakers, or Dominicans, there will be other 99 1 versions available, which is easy to do in this video 2 construct. 3 There was concern for health literacy, 4 cultural sensitivity, and diversity in the construct 5 as it was developed, and there was also concern that 6 we assess understanding as we go, without the 7 complexity of post-testing, but actually as part of 8 the process of informing, and I'll show you how we do 9 that. And, also, the obtaining of an electronic 10 signature in this bold new approach. 11 We believe that an electronic approach can 12 improve understanding, and that we can assess 13 understanding, that it includes in the electronic 14 approach inclusiveness, so that subjects or 15 participants can, in fact, see in the video people who 16 look like themselves and their families, that there's 17 transparency, and that there's standardization, that 18 the Informed Consent process will be the same 19 throughout the United States, or very similar between 20 sites. 21 We think we can improve understanding 22 using visuals, easy to understand colloquial language, 23 and we can assess. We think inclusiveness, by 24 picturing people from diverse communities. We think 25 we can enhance or improve transparency by making it 100 1 clear to the public how the study was explained during 2 the Informed Consent process, and we think we can 3 increase standardization by ensuring that everyone has 4 the same things explained to them, and that they get 5 an adequate time to question, and answer the 6 questions. 7 In our first phase, in 2008-2009, as part 8 of a pilot study, we still ask some research questions 9 about this video Informed Consent process, and we will 10 compare it to a very sophisticated, slick written 11 Informed Consent, which a study of this size and 12 complexity would have created if it was going to 13 create a written consent process. So we will study 14 the eConsent versus a written consent, to look at 15 differential understanding and retention, differential 16 respondent rating of materials, differential 17 enrollment, and differential attrition rates. 18 The hypothesis of this pilot study is that 19 there will be enhanced understanding. There will be 20 ratings by participants that the video engages them, 21 and is helpful, but there will be decreased enrollment 22 in the study. 23 This is a very serious problem for the 24 researchers, and this group of research epidemologists 25 are concerned that if we explain accurately what this 101 1 observational study will be, and the moderate burdens 2 it will provide, that people might not want to be part 3 of it. This is open for evaluation, and it's 4 empirical question. We hope the hypothesis is wrong. 5 We do believe, however, that the video may increase 6 continuity and retention because of the honesty with 7 which the subjects will understand their 8 participation. 9 So what I'm going to do now is run the 10 video and show you some of the technology that is part 11 of this process. This is a prototype. It is not the 12 final video. Actually, the final video will be in my 13 hands in about three weeks, and then will be in IRBs 14 hands thereafter. 15 Okay. As you can see on this form, we 16 have both the pregnancy and the pre-pregnancy, or pre- 17 conception videos available to this laptop at this 18 time, and we have them in English, and in Spanish. 19 And we will begin, hopefully - do we have the audio? 20 (Video played.) 21 DR. FLEISCHMAN: Now, I'm going to pause 22 here to show you a bit about the technology. It's not 23 just the content, but the technology that's been 24 developed through the National Children's Study. 25 As you can see, we can play or pause, we 102 1 can replay, we can change the volume, for the hearing 2 impaired we have captions, but some people like to 3 have the captions available even when they're 4 listening to the video, so we can have the captions on 5 or off, and that's the participant's decision. We can 6 exit at any time, and a few questions are asked of the 7 person who's exiting at the time they are exited. And 8 at the top, I show you that we've actually been 9 concerned about the elements of Informed Consent, so 10 that we can go back to your role, or talk about 11 benefits or risks, or compensation. And then there's 12 a Q&A that we have. And you will see how we've 13 embedded some of the questions in the midst of this 14 video. 15 (Video played.) 16 DR. FLEISCHMAN: Now I'm going to go to 17 the next part. 18 (Video played.) 19 DR. FLEISCHMAN: Again, I'm going to flip 20 forward. 21 (Video played.) 22 DR. FLEISCHMAN: There's a pause until 23 there's an answer. 24 (Video played.) 25 DR. FLEISCHMAN: So the assessment is both 103 1 an assessment and a reinforcer of the essential 2 elements. 3 (Video played.) 4 DR. FLEISCHMAN: We're now on "Your Role". 5 (Video played.) 6 DR. FLEISCHMAN: Now I'm going to go 7 forward to the "Benefit" section. 8 (Video played.) 9 DR. FLEISCHMAN: I'm going to move to 10 "Risks" now. 11 (Video played.) 12 DR. FLEISCHMAN: I'm going to move then to 13 the last Q&A. 14 (Video played.) 15 DR. FLEISCHMAN: I'm going to stop here. 16 We've spent probably about 10 minutes, or 12, on the 17 video itself. It goes about 25 to 30 minutes. The 18 last part of the questions pauses and says, "Now if 19 we've not answered any of the questions that you still 20 have, please ask the research assistant who is with 21 you", and it pauses the video, and has to be actively 22 moved then toward the consent document and signature, 23 but first, there's a formal request for questions, and 24 a comment about, "If you're not ready to consent, you 25 may wish to show this video to your family, your 104 1 spouse", et cetera. 2 Thank you very much for your attention. 3 DR. TILDEN: Thank you, Alan. I think at 4 this point we're going to take about a 10-minute 5 break. Right there, exit. And then we built-in, the 6 way the agenda worked, we built-in the ASH to be this 7 afternoon, and he came this morning, so we can -- if 8 we take about 10 minutes and come back, we'll do our 9 discussion. And then we'll get to lunch at noon, or 10 a little thereafter. 11 (Whereupon, the proceedings went off the 12 record at 11:12 p.m., and went back on the record at 13 11:25 p.m.) 14 DR. TILDEN: Well, we're ready to 15 reconvene. I see all the panelists are seated up 16 front, and are ready for questions. And so I don't 17 see any reason to change, I believe everyone probably 18 has some questions, so we'll just start with James, 19 and move on. And if you don't, you can yield. 20 MR. NELSON: I suspect each of us will 21 want to thank you for a great set of presentations. 22 I've had the privilege to work with each, I think, of 23 the four of you previously, so I know the hardcore 24 academics in the group won't take it as an insult when 25 I say perhaps the most articulate presentation was 105 1 that from the lay person in the group. And you can 2 see why Gigi is such a valued member of our Subpart A 3 Subcommittee. But that doesn't take anything away, 4 certainly, from each of your presentations, which was 5 each very informative. And thinking from the 6 perspective of the Subpart A Subcommittee, we're very 7 interested in turning your observations, your comments 8 into concrete recommendations that we might then bring 9 back to SACHRP. And I would leave that as an open 10 question, if there are things -- there are already 11 some tidbits in your closing comments on each of your 12 slides that I see room to turn into discrete 13 recommendations. 14 But I think my opening comment is actually 15 for Alan, with regard to the National Children's 16 Study. We are privileged to be one of the 17 participating sites, as a vanguard site, and so I'm at 18 least personally aware of the work that your group has 19 done to lay the groundwork for this, and to get people 20 on board, and to get input up front. But thinking 21 where the rubber meets the road, and when you go out 22 and start recruiting all of these sites, how are you 23 going to approach the IRBs who will each want to have 24 a foothold on this, or a say in this, a part in the 25 review process, what happens when one says well, we 106 1 don't do electronic here, or we have our own consent 2 template, and we'd like to rewrite the whole thing 3 because that's what we're really good at. And I'm 4 sure you -- I know you're anticipating that, and I'm 5 wondering what plans are in place. 6 DR. FLEISCHMAN: Well, we believe that 7 3,000 flowers do bloom in this country. We have 8 engaged the vanguard or pilot centers in this process 9 of development of this video, both through inviting 10 the IRB chairs, or research administrators to central 11 core discussions, as well as we have a group of IRB 12 liaisons from each of the centers which have worked o 13 this process. So our hope is, at least at the first 14 seven centers, that this process will go well. 15 We have embedded in the video what my 16 technology colleagues call hooks, and we will give 17 honest recognition, that if an IRB insists on adding 18 additional information to the video, it may. We're 19 not going to encourage that, but we will actually 20 provide the technology to put it up so that it is 21 esthetically pleasing and consistent. And at four 22 different places we have hooks for logos, local 23 pictures, and institutional identity, so that we will 24 have our technologists do the work with the local 25 sites, both in terms of the esthetics, as well as the 107 1 -- in terms of additional points. 2 The rubber will hit the road if someone 3 disagrees with some of the principles that have been 4 developed here about things like revealing findings, 5 storing samples, genetic testing and assessment, and 6 these are substantive issues which we've thought a lot 7 about, and gotten some expert help on. But when it 8 happens, we'll know about it, and we hope to write 9 about it academically so that we can teach others 10 about it. 11 DR. TILDEN: You're ready to ask a 12 question, James? 13 DR. POWELL: Yes, I found my notes. 14 DR. TILDEN: Okay. 15 DR. POWELL: Again, thank you. I enjoyed 16 the presentation, as well. My question comes from my 17 experience in pharmaceutical development, in that we 18 often in the company conflicted between the desire to 19 have a shortened consent form, and the issues of our 20 legal staff wanting to put everything in there to make 21 sure that we've told everybody everything. How much 22 of that - I'm speaking primarily to Dr. Dickler - how 23 much information have you seen where the desire for 24 industry sponsors to include such legal information 25 has driven the length and the complexity of consent 108 1 forms? 2 DR. DICKLER: There's no question in my 3 mind that the industry consent forms will be the 4 toughest nut to crack, and probably will only be 5 crackable when we've demonstrated proof of principle 6 in other venues. So that's why the game plan to go to 7 the academic center pilot institutions and use 8 investigator-initiated protocols as a first step. 9 I'm one of those who believes that the 10 signs in the garage that tell you that they're not 11 responsible if your car gets broken into are simply 12 there to prevent you from suing. They have no legal 13 status whatsoever. And that language, the exculpatory 14 language in the document has no legal bearing 15 whatsoever. They can sue the company and win, despite 16 that language being there, so it may make the company 17 lawyers feel better, but it's not actually 18 accomplishing any purpose other than intimidation. 19 DR. TILDEN: Okay. Jeff. 20 DR. BOTKIN: My thanks, too, to the panel. 21 It's hard to over-emphasize the importance of this 22 whole domain. I just think this is critical. 23 I have sort of a large background question 24 that actually may want the panel to get back to later, 25 probably, which is going to be, what do you think 109 1 SACHRP ought to do? What would be your 2 recommendations for SACHRP and how we can help move 3 this whole process forward? 4 In the meantime, I had sort of two more 5 specific questions. First, for Dr. Dickler - I very 6 much like the idea presented in terms of Part A, Part 7 B, Part C sort of idea. So fairly specific question 8 here - I couldn't find the specific language, but it 9 says Part A includes all of the essential elements. 10 What do you mean by "essential" there? Are we talking 11 about all the required regulatory elements there, or 12 essential in terms of what you believe to be important 13 for subjects to understand the research? Along with 14 that, do the participants sign each part at the 15 inception of their participation? 16 DR. DICKLER: Well, when I said the 17 "essential elements", I was referring to the 18 regulatory required elements, so getting the form down 19 to what's required, and putting it in language that 20 people can really understand. I think the answer to 21 your question really depends on the complexity of the 22 research, the depth of the emotional situation that 23 the research is taking place in, so in the situations, 24 for example, described by Gigi, everybody needs a lot 25 more information than you can possibly put in Part A. 110 1 And they'll need a lot more supplementary materials, 2 and a lot of formats, and a lot more time, so this is 3 not one size fits all. 4 The rubber really meets the road, the 5 panel felt, so the Part A, Part B, and Part C, was the 6 Committee, it wasn't me, they get credit for it. And 7 the rubber really meets the road in what you put in 8 Part A versus what you put in Part B. But the goal 9 should be understandability of the Informed Consent, 10 so they need to understand that it's a research 11 question that's being addressed. That's what they're 12 consenting to. And they need to know the difference 13 between standard of care, and the research. But 14 that's why we're going to have to work on model 15 templates for different kinds of complexity of 16 research, and this is not easy going. It really takes 17 a lot of talent, a lot of creativity, and so the whole 18 purpose of having templates is that so every 19 institution, and every IRB won't have to reinvent the 20 wheel, so that they have really something to hang 21 their hat on that they can use on a practical basis 22 day-to-day as they craft individual consents. 23 DR. BOTKIN: And is the idea then that 24 once somebody is ready to sign on, that Part A is what 25 they sign, and then Part B is available for their 111 1 consultation at their leisure sort of thing? 2 DR. DICKLER: That's the concept, but you 3 can do it any variety of ways. Part C was to test 4 whether they really had understanding in some fashion, 5 teach-back or one of the many tests that's been 6 developed. Gigi's list was a great list to test 7 whether or not people really understood all the things 8 that they needed to understand. I think if somebody 9 goes through that list and they keep that list with 10 them, I don't know that you need the signature. 11 DR. BOTKIN: Sam, can I ask another one 12 while I've got the floor? 13 DR. TILDEN: Yes. 14 DR. BOTKIN: Question for Gigi. One of 15 the things that we've thought about a bit, and I think 16 other institutions have probably used is participant 17 advocates, people who are supposed to have an 18 intermediary role between the clinicians and the 19 potential participants, or participants, sort of sit 20 through the process, help explain it, be a resource 21 person, et cetera. Is that an additional complicating 22 factor in this, or do you think that's a beneficial or 23 helpful sort of practice? 24 MS. McMILLAN: I think it's a very 25 complicating factor, but I think it would probably be 112 1 the very best thing to do. That's exactly what I was 2 talking about, and you called it a research advocate. 3 My experience is that these kinds of advocates, 4 although institutions get nervous about it, actually 5 in the long run makes everybody's job easier, because 6 then you will have a more informed, and efficient, and 7 functioning subject, as well as somebody who can get 8 back to the institution and give them a head's up if 9 there's some problems. But it is a scary process. I 10 think that people are afraid of lay people, and we're 11 like going to cause trouble, and badmouth the doctors, 12 and refer people to other places. If you have a well- 13 trained advocate on your team, it would be a very good 14 thing. Immensely complicated, though. 15 DR. TILDEN: Mike. 16 DR. GENEL: This was an extraordinarily 17 stimulating panel discussion, and it's sort of pushed 18 me in a somewhat different direction, more 19 philosophical than anything else. Particularly, 20 Jonathan and Gigi's presentations. There's an 21 enormous amount of symbolism in the words that we use, 22 I think as Jonathan pointed out. And I think by 23 labeling something as research, which is, I suppose, 24 better than an experiment, we sort of imply that 25 medicine is scientific. And in reality, it's a 113 1 probabilistic science, if anything. And I think that 2 perhaps some of the difficulty, Gigi, that you 3 conveyed is this sort of impression that we provide, 4 that we can reduce things to quantitative answers, 5 where it's really very much judgmental. 6 Oftentimes, going through discussions with 7 families, the final question I'm asked is well, 8 doctor, if this were your child, and so forth. And I 9 think it's - the very nature of this is it's very, 10 very hard to reduce these things so that you can put 11 them in precise scientific terms. I think that's -- I 12 don't know how one gets around this. I'm sort of 13 struggling with this, but I think this is part of the 14 problem in the communication, which is what I'm 15 hearing. This is a problem in communications. We're 16 coming at it from somewhat different perspectives. I 17 don't have -- no answers. I just raise those. 18 MS. McMILLAN: I just want to comment on 19 that, briefly. One thing that I think is that we are 20 pretending that, as you said, that the consent form is 21 it, that we can actually solve this problem. And the 22 fact is, we can't. And I would say from the subject's 23 perspective, then be honest with me. The fact is, we 24 can't give you all the information, and we aren't 25 going to know everything that's in your future. We are 114 1 asking you to agree to this particular part of the 2 process, and I think there needs to be some respect on 3 the part of the researchers for the subject to be that 4 honest, because our sense later on, much later on that 5 there's things they knew that they didn't tell me, 6 that sours any kind of value or much of the value that 7 we thought we had gained during the process. I would 8 love to know what Dr. Moreno thinks. 9 DR. MORENO: Well, the Radiation 10 Experiments Advisory Committee did a subject interview 11 study that you might recall, and actually used some of 12 these terms, presented some of these terms, 13 "experiment", "research", "study", "test", "trial", 14 and it was very clear that they had different 15 emotional valancies, so to say that you're going to 16 experiment on me, no thank you, but you're going to -- 17 and we also asked if it was an experiment, or a test, 18 or a study, or so forth, how much would this help you? 19 So an experiment, that doesn't sound like it's going 20 to help me. A test, you're going to kind of test 21 stuff out on me. Yes, that's good. That probably 22 means it's going to help me. So you're absolutely 23 right, the language is critical. And as I said, as 24 the language changed, very noticeably after the 25 introduction of randomized controlled trials in the 115 1 early 50s, the language clearly changed to be more 2 formalistic, and perhaps more reassuring. And yet 3 words, guinea pig and experiment still persist in the 4 culture, which I think is quite interesting. 5 The other thing I wanted to mention about 6 Gigi's remarks and her talk about the way that people 7 actually use the forms. We also found in the subject 8 interview study a dozen years ago that - and this, I 9 think, complements what you said - people don't read 10 the form, or don't feel that they really understand 11 the form, don't really feel they get a lot out of the 12 form in the beginning. And sort of in a qualitative 13 follow-up, it was found that people carry the form 14 around with them. When they go see their doctor 15 again, they pull it out of their briefcase or purse, 16 and they kind of -- it's only when your microwave 17 stops working that you look at the manual. Right? 18 And so that sort of - I'm not sure I'm getting the 19 program here, then I go back to look at it. So, 20 although, many of us are form bashers, nonetheless, 21 they are really important, not initially, but perhaps 22 as - particularly in a longer term study, as the thing 23 goes on, they're really important for people to have 24 as a reference point. 25 DR. GENEL: If I may comment further, Sam. 116 1 I would strongly endorse Mrs. McMillan's plea for 2 follow-up on the results of research studies. The 3 problem is institutional and systemic. The problem is 4 there are no incentives for any of us to spend the 5 time or the energy, other than altruism, in doing 6 this. And I think that's something, perhaps another 7 part of -- it's a systemic issue that perhaps we ought 8 to really look at. The incentives are -- in fact, 9 there are disincentives rather than incentives for 10 doing this. And that's, I think, more likely why it 11 never happens. 12 DR. TILDEN: David. 13 DR. STRAUSS: Thank you all. I thought it 14 was a really very interesting and informative panel. 15 I have a comment, and then I have a question. 16 So we talk incessantly about Informed 17 Consent being a process, but we really -- we don't 18 know what the process is to look like. We don't 19 really know the extent to which subjects want certain 20 kinds of information, or use certain kinds of 21 information. We know even less, it seems to me, about 22 how one goes about doing permission and assent with 23 children; in other words, what actually happens on the 24 ground. And so I think that perhaps the Subpart A 25 group that's looking at Informed Consent can help the 117 1 field think a little bit about process, and what that 2 should entail. And it seems to me a really critical 3 starting point is where Gigi commented earlier in 4 talking about orienting people to the Informed Consent 5 process to begin with, that the process is really 6 alien to most subjects. 7 Across the table from the doctor, they're 8 not asked in normal circumstances to make the kind of 9 choice that the eConsent form begins with. You have 10 to make a decision, you have to make a choice, we want 11 to help you make that choice, is really what - we talk 12 about consent. We're talking about informed choice, 13 really. And, again, I think one of the required 14 elements of consent ought to be some kind of 15 fundamental orientation to what the expectations of 16 the subject, perspective subject in that context. So 17 that's my comment. 18 My question is, first of all, I think all 19 these are really terrific approaches. I'm curious 20 about what the eConsent Form costs now, and what they 21 imagine it might cost some day when they can share the 22 template and let us all insert our text and voice- 23 overs, but that's for another time. 24 The final common pathway is about the 25 interaction between the investigator or research 118 1 assistant. And we've gone from this model 100 years 2 ago, where we thought it was harmful for people to 3 know too much about what the doctor was going to 4 decide for them, to one now where we, frankly, create 5 this myth of complete autonomy on the part of 6 subjects. And truth is somewhere in-between. Some 7 subjects really want you to help them make a decision, 8 they really do, and they need that. So my question 9 for the group is, how do we best educate investigators 10 and research staff as to how to go about discussing 11 the choice to participate in a research study with 12 research subjects? What's the role for education 13 here? 14 DR. FLEISCHMAN: I just wanted to tell the 15 Committee about an activity that's going on at the NIH 16 that I'm not involved in, but I'm aware of, and that 17 comes out of the Office of the Director, with the help 18 of the Bioethics Division of the Clinical Center, the 19 development of a Bioethics Curriculum for high school 20 students. And it's broad-based bioethics, but one of 21 those curricula elements and days is about research 22 and Informed Consent. And I think Gigi's idea, which 23 is an important one, not a new one, but an important 24 one that's not yet ever been well-implemented in this 25 country, might actually come out of this process 119 1 that's being begun through the NIH, and will then be 2 disseminated through the United States. So my hope is 3 that we can begin where we need to begin, and that is 4 much earlier than the day after the diagnosis of a 5 serious problem. 6 DR. MORENO: I want to talk about how 7 clinical investigators are trained. A few years ago, 8 I heard a presentation by an FDA officer that 9 indicated that there had been a dramatic increase in 10 the number of people doing clinical trials from around 11 the mid-90s to about 10 years later. And it raised 12 very interesting questions about how those people 13 learned how to do clinical trials, so it's a larger 14 question than just training about Informed Consent. 15 My experience suggests that many people 16 learn how to be clinical investigators from research 17 nurses, from experienced nurses who are older, and I 18 won't say wiser, necessarily, but have been in the 19 field for a while, and having taught a course, an NIH- 20 funded course nationally for research nurses for 21 several years, I've heard a lot of stories from them 22 about how the young people who are - young physicians 23 who are starting to work as investigators really 24 didn't know anything. And so I think you've raised a 25 good question, but there's a larger problem, and I 120 1 think the American Society of Clinical Investigators 2 has been working on this question. Maybe other people 3 on the panel know about this, Dr. Dickler does, I 4 gather, but I think there's really a question here 5 about, I won't say licensure, that's a dirty word, but 6 certification of clinical trialists, so that these 7 skills should be part of that process. 8 DR. DICKLER: So I'll take that on. But 9 the basic answer to your question is it's very 10 important. It's a skill that they must have, I would 11 say must have. And as has been pointed out by 12 Jonathan, this is a much larger question, and that is 13 how should clinical investigators be trained. And the 14 AAMC had a whole task force on it, the report is up on 15 our website. It outlines a series of principles on 16 how best to attract, train, nurture, and support these 17 individuals. And what the task force concluded is 18 that we are now in a different era of science, that 19 the science of doing clinical and translational 20 investigation is much more complex than it ever was, 21 and the people doing it need to have formal training 22 in science, which would include this kind of training. 23 They felt at least a Master's degree with a thesis, 24 and I can tell you that many of the CTSA programs that 25 are being evolved are aiming for Ph.D.s, not for 121 1 Master's degrees. 2 In addition, they felt they needed a 3 legitimate full post doctoral experience of 4 approximately three-years duration, in which they got 5 progressive independence, and superior expert 6 mentoring in how to conduct investigation. And the 7 goal for this is not only that they be competent, but 8 that they'll survive as investigators once they reach 9 the faculty level. The great problem is that the 10 people that Jonathan talked about, who were taught by 11 the nurses, they don't make it as researchers, because 12 they don't get the support from the institution that 13 will allow them to devote their time to investigation, 14 and allow them to actually build careers. 15 Institutions will not invest in individuals unless 16 they have the background and the credentials to 17 justify that, so it's a whole package that has to come 18 together to make it work. But the end result is 19 somebody who will be able to do, and will be able to 20 train their assistants to do the right kind of 21 education. 22 DR. STRAUSS: Let me just -- I think in a 23 way that's an answer to the other thought that I had, 24 or worry that I had. You spoke out incentives to get 25 investigators to write good consent forms, and conduct 122 1 good consent processes. And you're saying you can't 2 carve it out, it needs to be part of a fundamental 3 approach. 4 DR. DICKLER: My own prejudice, by the 5 way, on writing Informed Consents is that we'd be far 6 better off if every institution had an Informed 7 Consent writing group, where people who were trained 8 in the science of literacy, that they understood the 9 principles, and they had templates to work with, and 10 they took every protocol, and they wrote the consent, 11 because it really is something where experience pays 12 off, and you'll get much better consistency. But 13 that's a step down the road. 14 DR. STRAUSS: I couldn't agree with you 15 more. I think it would be wonderful if someone would 16 do a cost analysis and show that it's also cost- 17 effective for the institution to do that. 18 DR. DICKLER: I think it would be cost- 19 effective. If you just take the time involved in 20 going back to the IRB four times because your consent 21 is lousy, it would be enormously cost-saving. 22 DR. TILDEN: Neil? 23 DR. POWE: I'd like to thank the panel for 24 their lucid, and I should say informing presentations, 25 and for really ushering, helping us to usher in the 123 1 future of proper Informed Consent. 2 I'd like to just -- just a question that 3 just came up about training, since I'm involved in 4 training. I actually had training 20 years ago from 5 two experienced research nurses, and fortunately, I 6 survived. 7 (Laughter.) 8 DR. POWE: Survived so much that, in fact, 9 I run training programs actually to train people 10 formally in Master's and doctoral degrees in clinical 11 research, so we have a much formal process. In fact, 12 this summer, took a group of medical students after 13 the first year through an exercise in creating a 14 consent form, and talking to patients about Informed 15 Consent, so we're trying to do that in a way that's 16 more formalized, and that includes all the important 17 components, many of which all of you have laid out. 18 I have a couple of questions. The first 19 is something that David started on, but no one really 20 addressed, which is the resources and cost that might 21 be associated with bringing in this era of proper 22 Informed Consent. I applaud the National Children's 23 Study for using modern media technology, but I also 24 look at my institution and I see individuals who do 25 small studies, 10, 20 subjects, sometimes hundreds of 124 1 subjects, let alone sometimes in a few cases thousands 2 of subjects. To create a video like that, and 3 software like that would be a considerable resource 4 that they would have to bear, or let's say the 5 institution would have to bear, that come out of the 6 direct cost of research, or the indirect costs that 7 funders pay for infrastructure. And Ms. McMillan 8 talked about having lay advocates, which brings up 9 another issue of cost and resources for those 10 individuals. And then the training that we just 11 mentioned, to do that training is also costly. So my 12 first question to the panel is, do they have any 13 opinion about how we can do these things more 14 efficiently to get to where we need to be? And who in 15 society -- what part of society should bear the cost 16 of proper Informed Consent? Should that be on the 17 back of institutions, on the back of researchers, on 18 the back of the public? 19 MS. McMILLAN: I have a couple of ideas. 20 First of all, with regards to multimedia tools for the 21 consent process, certainly there are some just 22 components or discrete bodies of information that 23 could be pre-produced. So, for example, if I went to 24 UCLA to enroll my son, and I was told my son should be 25 in a trial, they could hand me a CD that explains 125 1 clinical trials. At least that I could take home with 2 myself, and repeatedly watch it with my husband and my 3 family, until I really understand what the process of 4 a clinical trial was. Then when I came back to talk 5 to the doctor, I could be more specific about the 6 treatment, or what they're recommending for my son. 7 So I think there's, within even the realms of say of 8 certain diseases, pediatric brain tumors, there could 9 be a CD that has general information about pediatric 10 brain tumors, and treatment, and the kinds of trials 11 that are generally available. So even if I have those 12 two pieces of information, probably relatively, I 13 won't say inexpensively produced, but not to 14 exorbitantly expensive, those would be helpful, so not 15 study-specific, but pieces of information. 16 And the other thing is regarding the 17 research advocates, I think you -- in general, people 18 underestimate the need for subjects to give back, to 19 finish their experience with the research. So, for 20 example, everything that my family has learned, or 21 everything the families I work with, everything they 22 have learned as their child has gone through treatment 23 for their brain cancer, the final part of their 24 healing is when they can volunteer and give back to 25 somebody else. You would have -- we have no lack of 126 1 volunteers to become these one-on-one mentors that we 2 provide; that is, the training is not expensive, and 3 it comes from the heart, but quality control is key, 4 but I think you could have volunteer research 5 advocates. Somebody on staff, somebody at the 6 institution would have to monitor that, clearly. 7 DR. FLEISCHMAN: Just to be clear, the 8 cost for the National Children's Study's innovative 9 approach is basically done on a federal contract owned 10 by the federal government, and will be available and 11 disseminated free once it is owned. So it does have 12 the potential then, the infrastructure has the 13 potential to be disseminated. The videos then, of 14 course, would -- there are some generalizable videos, 15 and some that would be specific to studies. 16 I think this is an evolving technology, 17 and as such, is going to need some investment in 18 innovation, initially, and will then become much less 19 expensive for duplication. 20 I think there's an interesting concept 21 here about cost. I am not a dean, I've not been a 22 dean, but some of my best deans are friends, and they 23 don't talk about the indirect cost recoveries with any 24 kind of clarity or accuracy, so that anybody in the 25 research infrastructure understands what that actually 127 1 covers. So I guess it's part of the deanly penumbra 2 to keep that secret, so I -- the deans are all 3 laughing. But I do understand the responsibility both 4 of the funders, and the major funder responsible for 5 indirect cost recoveries is the NIH, and the 6 institutions as they distribute those indirect cost 7 recoveries over a whole host of very important things. 8 I don't for a minute think that the things they are 9 paying for aren't important, but they do make hard 10 choices across those varying things. I mean, the 11 take-home message is we shouldn't start with a pie 12 that can't be divvied up in different directions, when 13 we have a very important, critical part of the future 14 of the research enterprise. 15 MR. DICKLER: Well, I have been a dean, so 16 the answer is differential cost. Are the things that 17 we're suggesting going to cost more than we're already 18 paying? And I would argue that maybe they'll even 19 cost less, but they certainly will not cost more. I 20 think if you had -- if you did Informed Consents 21 right, and had a committee that wrote them, you would 22 save your institution hundreds of thousands of dollars 23 a year, if not millions, in the cost of personnel who 24 are spinning wheels, and not getting anywhere. 25 I think if we do training of clinical 128 1 investigators in the right way, and I know how heavily 2 you're involved in that, and I know you know what the 3 right way is, that those people will succeed at having 4 careers, as opposed to being lost to private practice, 5 in which case we've lost hundreds of thousands of 6 dollars on each one who decides to go into private 7 practice. We're already spending those dollars, and 8 if we do it right, then we won't lose that dollars. 9 So the important thing is to make sure that the 10 dollars we do spend are spent well. 11 And then, of course, the last thing is 12 that one size doesn't fit all. If you're going to 13 draw a blood sample, I don't think you need a video 14 like Alan is creating. So I think there's all sorts 15 of answers to that question, but the basic answer is, 16 we have to not spend more money, but spend the money 17 smarter. 18 DR. POWE: May I ask one more question? 19 DR. TILDEN: Alan, I think, has just a 20 comment or question real quick, and then you can go 21 ahead, Neil. 22 DR. FLEISCHMAN: Just a quick comment on 23 the topic of PI training and resources. The comment, 24 DNA Advisory Committee that oversees human gene 25 transfer research or gene therapy research developed 129 1 a number of years ago an Informed Consent resource 2 that was developed out of the observations that Pis in 3 that arena were having time and time again, the same 4 difficulties in developing sound Informed Consent 5 documents, overstating the positive benefits of 6 research, presumptive use of the first person pronoun 7 and so on, and developed a resource that's on our 8 website now that is actually probably the most 9 frequently visited portion of our website for all the 10 resources that we offer to that community. 11 At present, the NIH program on Clinical 12 Research Policy Analysis and Coordination is taking 13 that resource as a starting point, and now developing 14 it into a richer set of web-based tools for reviewing 15 such issues as description of risk, description of 16 benefits, modes of communication, samples of Informed 17 Consent language that are both well done, and perhaps 18 problematic, and so on, again by means of just 19 offering a broader resource to the community. And 20 it's something that as we develop it, that we're going 21 to put out for broader input and comment, but I just 22 wanted to make folks aware of that. 23 DR. TILDEN: Neil. 24 DR. POWE: Ms. McMillan, you've raised a 25 very important issue that I've had to grapple with, 130 1 and that's getting Informed Consent among individuals 2 that are newly diagnosed with a disease, versus later 3 in the course of the disease. I've done a lot of work 4 in chronic kidney failure, and patients who develop 5 kidney failure going on to dialysis, and trying to 6 enroll them into studies at the time that they've been 7 diagnosed with end-stage renal disease. And a lot of 8 information about the disease, the clinical context of 9 treatment are coming at them at the same time that 10 researchers want to enroll them into either 11 observational studies, or clinical trials. And so I 12 just wanted to see if you had any insight. You did 13 say something about letting this process go longer, 14 the process of Informed Consent going longer in such 15 individuals. Researchers love to capture the 16 individuals when they develop the disease so they can 17 learn about when a disease is initiated, how it should 18 be treated early. But I don't know if you have any 19 other thoughts about how we can pay more attention to 20 that area, because I think it is a difficult area, but 21 one that needs to be addressed. 22 MS. McMILLAN: Someone once asked me if a 23 young couple had a baby diagnosed with terminal brain 24 cancer, should they ask that young couple to enroll 25 their child in research, and everybody in the room 131 1 expected me to say no, are you kidding? Stay away 2 from those folks. And, actually, what I said was 3 please, give them the chance to make that decision. 4 It may be a way they can honor their child's life, and 5 they need to be the one to choose that or not, so 6 please offer it to them. But you have to offer it in 7 a very compassionate way, and you would approach them 8 differently than you would an adult who has had some 9 experience with the disease, and is now maybe as a 10 more knowledgeable potential subject going to make 11 some decisions. So what I would say is, it is most 12 respectful to offer the chance to be involved in 13 research. That is the most respectful thing you can 14 do, is offer them the chance. How you offer it, I 15 mean, that's where we get to the problem. And I think 16 using a research advocate or a lay mentor would be a 17 good tool. 18 Also, you can provide a subject with a 19 handout, even one page that says you've just been 20 diagnosed with A, B, C. Here are some things that I'm 21 probably going to want to talk to you about in the 22 next few weeks, just like a head's up. But right now, 23 let's talk about your medical issue. But later on, 24 there might be some research that we'll talk about. 25 But, I mean, it's another way of introducing that 132 1 idea, that there are other things on the horizon. 2 I think it's all in the manner that you 3 approach them, but I would say definitely approach 4 them. 5 DR. DICKLER: I should mention with regard 6 to your question, that the Children's Oncology Group, 7 which is dealing with many of the same issues that 8 Gigi was talking about, their task force designed 9 Informed Consent as a two-stage Informed Consent, 10 which starts with the education, and then down the 11 road gets to the actual consent. And this is all on 12 their website, COG, Children's Oncology Group. Eric 13 Cassell, writing this for a long time, as you probably 14 know, and there are some studies, also, besides Eric's 15 experience, to suggest that, as you know, that it 16 seems almost impossible in the acute phase to overcome 17 hope as the guiding standard for agreeing to be in 18 research. It seems almost impossible to overcome 19 that, but it does seem that as people get more 20 experience and kind of settle in to this life-changing 21 event, that they are able to evaluate the reasons to 22 stay in. 23 The subject interview study, again, was 24 done a dozen years ago, indicating that when people 25 who are in a clinical trial for a while, were asked 133 1 why they got into it, they said because I hope it will 2 help me. Well, were you told that this was not 3 designed to help you? Oh, yes. Well, why did you 4 agree to be in it? Because I hope it will help me. 5 So there doesn't seem to be, and I'm not sure we want 6 to overcome that. I mean, that's a human response. 7 So then the question was well, why are you 8 still in it? Do you still think it's helping? They 9 said no, I don't, but maybe they can learn something 10 from me. So that does kick in, as you go on, but it 11 takes a while. And that doesn't mean that asking 12 somebody, as Gigi said, is not right in the acute 13 phase, it just really puts a great moral burden on the 14 person who is doing the asking, because of the 15 vulnerability. 16 DR. TILDEN: So last comment from Dr. 17 Schwetz before we adjourn for the morning. 18 DR. SCHWETZ: This was a very informative 19 panel, and thank all four of you for being part of it. 20 I want to revisit the conversation that occurred 21 between Jeff and Gigi as it relates to a distinction, 22 at least in my mind, between a research advocate and 23 a subject advocate. 24 The GCRC, and I distinguish this on the 25 basis that a research advocate is one who is 134 1 advocating for research, primarily, and not 2 particularly focused on the interaction with subjects, 3 and being able to help them make a decision. In 4 contrast, the subject advocate is someone who is not 5 advocating for research for a population, or for an 6 institution, but they are there to really help the 7 subjects know how to make decisions about being a 8 subject. 9 The GCRC has had a requirement for a 10 research subject advocate, which is a hybrid between 11 the two. And as I have talked and discussed this 12 issue with quite a number of them, I have learned that 13 in some cases, the research subject advocates from the 14 GCRC did, in fact, interact with subjects, but not 15 very many of them, and not very much of the time. 16 They were training investigators, they were 17 interacting with IRBs, they were doing a lot of things 18 that indirectly would be helpful to the subjects, but 19 they're not necessarily spending time talking to 20 subjects to find out how things are going. So my 21 question of you, Gigi, is what is the - and this, I 22 would hope, will come back to the Subpart A 23 Subcommittee with some distinction on this - what is 24 the real need for a subject advocate, versus the 25 research advocate? 135 1 MS. McMILLAN: Darn, you ask good 2 questions. 3 (Laughter.) 4 MS. McMILLAN: A potential subject who 5 maybe has just received a diagnosis is reeling from 6 the emotions that I described, and from the feeling of 7 not knowing enough to do a good job as they make 8 decisions on their behalf, or on behalf of their 9 family member. The interaction with somebody who has 10 been in that place before, who has been in that 11 situation before, relieves an incredible amount of 12 burden. Instead of feeling isolated and alone, and 13 I'm the only one in the world dealing with this 14 particular issue, to have an experienced lay mentor 15 who understands what it's like to be in that 16 situation, and who can serve as a model of someone who 17 has come out at the other end of the process, and is 18 in tact, that opens up all kinds of doors for greater 19 functionality. 20 I would say that a subject advocate would 21 help a potential subject get their brain around their 22 participation in the research, and would be a 23 barometer, could serve as a barometer for, is this 24 person missing something? Does this person need more 25 tools? Actually, would have to use - the advocate 136 1 would have to use their judgment about what kind of 2 tools to offer to the potential subject. And I think 3 that the advocate would help the potential subject 4 realize that they have rights, that there are 5 questions, and just encourage them to participate on 6 their own behalf. 7 Many times a new subject sits in the room 8 and just listens. They don't realize it's an 9 interactive process, so an advocate actually models 10 the appropriate behavior for the subject, models a 11 mind set, models a way of thinking, models actual 12 behavior, and serves, like I said, as a barometer, 13 what kind of tools need to be offered to that subject. 14 So you could see my thought is kind of clarified there 15 at the end, because that was a very good question. 16 That's very different than someone who is 17 advocating for research. And thank you for bringing 18 up that distinction. 19 DR. TILDEN: Okay. Well, I would like to 20 add my appreciation to the panel. I've gotten more 21 positive comments about this panel than I have any 22 other panel for this past year, so I guess you can 23 take that with you. And so, thank you very much for 24 this very informative session. We will adjourn and 25 reconvene at 1:10. Thank you. 137 1 (Applause.) 2 (Whereupon, the proceedings went off the 3 record at 12:16:45 p.m., and went back on the record 4 at 1:15:44 p.m.) 5 DR. TILDEN: Let's see. We've got a 6 quorum? Yes. All right. Good afternoon. We're here 7 to have our second panel of today's meeting, which is 8 on the subject of Diversity of Ethnic and Racial 9 Representation in Clinical Trials, and I'll read the 10 charge. 11 "How well do the subjects of clinical 12 trials and other research studies involving human 13 subjects represent the population whom the research is 14 intended to serve? Despite known differences in 15 safety and efficacy of certain drugs between ethnic 16 groups, minorities are often under-represented in 17 clinical trials. NIH requires applicants for federal 18 funding to provide a strategy for inclusion of people 19 of diverse racial and ethnic origin in clinical 20 trials. FDA enacted guidance to standardize 21 collection of race and ethnicity data for clinical 22 trails that will be submitted to FDA for review. 23 However, FDA does not require diversity of ethnic and 24 racial representation in clinical trials submitted to 25 the agency. What can we learn from the experience of 138 1 NIH, FDA, and others about the diversity of subjects 2 in clinical trials? Are additional steps needed to 3 further enhance the racial and ethnic diversity of 4 subjects in human subjects research? And, if so, what 5 additional steps should be considered?" 6 Our panelists today to discuss this topic 7 are - we have four distinguished panelists. And 8 instead of doing, the first time where I introduced 9 everyone at once, I'll just introduce each one 10 individually as they come up to prepare for their 11 talks. So our first speaker today is Dr. Giselle 12 Corbie-Smith, who is an Associate Professor of Social 13 Medicine and Medicine at the University of North 14 Carolina at Chapel Hill. She completed medical school 15 at Albert Einstein College of Medicine, and trained in 16 -- did a residency at Yale University School of 17 Medicine. 18 Her interest in minority health issues, 19 especially access to care and the influence of 20 culture, race, and ethnicity, and social class on 21 health dates early from her academic career. 22 Since joining the faculty at UNC in 2000, 23 she has continued her research on the appropriate 24 engagement of communities of color in research with 25 funding from a wide array of federal agencies. Dr. 139 1 Corbie-Smith is also the Co-Director of the Program on 2 Health Disparities at the UNC, Cecil G. Sheps Center 3 for Health Services Research. Most recently, she 4 served on an Institute of Medicine committee examining 5 ethical issues in housing hazards research, and also 6 has served as a member of the National Children's 7 Study Federal Advisory Committee since 2005. 8 DR. CORBIE-SMITH: Thank you. It's truly 9 an honor to be here, and address the Committee on this 10 topic. And as was noted in our charge, my comments 11 are going to stay sort of along the lines of diversity 12 as it pertains to race and ethnicity in clinical 13 research. And I was asked to sort of paint with broad 14 strokes the landscape of what kinds of things we need 15 to be thinking about, and the kinds of issues that are 16 raised as we think about diversity in clinical 17 research. And given who I'm having the honor of 18 addressing today, I thought I would sort of talk about 19 some of the ethical, as well as practical 20 considerations in diversity. 21 So, first, how did we arrive at mandated 22 inclusion? For, unfortunately, many years there have 23 been public reports of ethical misconducts that raises 24 this issue of vulnerability in research. The 25 Nuremberg Trials with prisoners, the Willowbrook Study 140 1 with vulnerable children, the Jewish Chronic Disease 2 Hospital studies in elderly, and the U.S. Public 3 Health Study at Tuskegee, which Tuskegee would rather 4 you call it around racial and ethnic, as well as socio 5 economic disadvantage. 6 The Belmont Report reinforced the need to 7 protect groups considered vulnerable by these 8 characteristics, by physical, mental, social, and 9 economic circumstances. And so, for many years, there 10 was little public pressure to enter clinical research 11 due to this perception of being a high risk endeavor 12 with very low benefits for participants. However, in 13 the early and mid-1980s, HIV/AIDS epidemic became 14 really a pivotal event in research participation. 15 This is one of the first times where we 16 saw potential participants picketing in the streets 17 to gain access to clinical research. Research was 18 seen as offering the best and least costly hope to the 19 victims of this epidemic, and AIDS victims campaigned 20 to gain admission to clinical trials. There was 21 picket signs that said, "Research is treatment, too." 22 Sort of -- I need to find that photograph, because I 23 think it really sort of points to how this incredible 24 shift in the perception of research, where research 25 was being considered previously, this risky burden 141 1 that was imposed upon individuals, and now a prized 2 benefit from which no one should be excluded. 3 So in 1993, the National Institutes of 4 Health started mandating the inclusion of minorities 5 and women in clinical research through the NIH 6 Revitalization Act. We know that clinical research 7 drives advances in medical care, and this was sort of 8 the basis for this mandate. And that participation of 9 racial and ethnic minorities in clinical research is 10 critical for understanding and eliminating racial and 11 ethnic disparities. This is some of the language 12 that's in the mandate, with the goal to better 13 understand disparities in health, and to improve the 14 generalizability of research findings to a greater 15 population. 16 This issue of diversity in clinical 17 research raises all kinds of questions, though. And 18 while those were the goals of the mandate, many 19 questions end up coming up. First of all, what is 20 race? And because of - and as I'll go into a little 21 bit later - because of this issue of mandated 22 inclusion, we now are asked to enumerate who we're 23 engaging in our research. How do we count people? 24 How do we ask people to identify themselves? Is this, 25 in fact, an appropriate variable upon which we should 142 1 be conducting analyses? How should we collect data on 2 race? And what are the implications of this variable 3 in understanding differences in health, and should we 4 continue to use racial classification to assess the 5 role and consequences of race in our society? 6 Some other things that this diversity 7 mandate raises are what are the consequences of single 8 race clinical trials? The Bedell example sort of 9 looms large in that regard. And what is appropriate 10 representation? The language in the mandate asks for 11 appropriate representation of racial and ethnic 12 minorities, and women in clinical research. How do we 13 operationalize that? 14 When we're asking individuals from diverse 15 backgrounds to engage in research, do we need to re- 16 examine the application of some of the ethical 17 principles as it pertains to communities of color, and 18 to communities that are under-served? And when 19 investigators are engaging under-served communities 20 and communities of color in research, what other 21 obligations do they have as they recruit these groups? 22 So the great debate on the use of race has been 23 looming large for many, many years, and it's been this 24 longstanding debate about the use of race in research, 25 whether to use this variable, and whether it's a 143 1 biologic or a social construct, or some other 2 combination of these ideas. 3 Certainly, the debate has been heightened 4 by advances in genetic research. Every time you turn 5 around, there's another sort of attempt to try to 6 explain differences in health using genetic markers. 7 The NIH mandate has sort of pushed this issue forward 8 in terms of, particularly in federally-funded 9 research, and then in the year 2000, we had changes in 10 the OMB categories of race and ethnicity. And those 11 are the categories that we need to use when we're 12 reporting the recruitment into our studies. However, 13 the OMB categories acknowledges the absence of 14 scientific considerations in its classification, and 15 doesn't define the concepts of race and ethnicity. 16 There are sort of two ways to think about 17 whether to use race, this variable of race in 18 research. Some would say that research using the 19 concept of race actually perpetuates the negative 20 consequences of thinking in racial terms. That, in 21 fact, this way of thinking about research reifies race 22 as a biologic construct, obscures other determinants 23 of health that need to be considered as we're looking 24 at differences in health. Where some would say that 25 measuring differential experiences, treatments, and 144 1 outcomes across racial categories is, in fact, 2 necessary to track disparities, and to inform policy 3 to achieve greater social justice, you can make 4 disparities disappear by stop -- by ceasing to measure 5 those differences in health by race and ethnicity. 6 And, in fact, not measuring race may actually 7 contribute to racial prejudice. 8 Obviously, many of us, probably all of us 9 are familiar with the problems of this variable. 10 There is lack of conceptual clarity, or agreement on 11 what we are measuring when we collect data on race. 12 There's questionable meaningfulness to respondents, 13 and the terminology and concepts of membership may 14 differ across groups, particularly groups that are 15 newly immigrating to this country. There's a lack of 16 reliability, internal as well as external validity 17 problems. Across person, with shifting identities, 18 you can -- there are many studies that have documented 19 in infant mortality studies, how the race of the child 20 has changed in the one year from birth to death. And, 21 certainly, there's all sorts of anecdotal reports 22 across shifting identity within one person. Certainly 23 across time, as our census illustrates, people are 24 categorized differently, can be categorized 25 differently every 10 years. And then across place, 145 1 even within the United States, and certainly if we're 2 doing transnational studies, where there are problems 3 with comparison across data sets and across countries. 4 So even if we were to -- even if we feel, 5 as many of us feel comfortable with this uncertainty 6 and this variable, how do you then operationalize this 7 mandate? I can tell you that at the time that this 8 mandate was proposed, and then enacted, there was a 9 lot of consternation amongst investigators actually in 10 the scientific literature about what does appropriate 11 representation mean? There was an uncertainty due to 12 the lack of clarity on what the actual goals were. 13 And several of us thought that we would actually try 14 to puzzle through what could the goals be, and how 15 then would you operationalize it? So, for example, we 16 saw that there are at least three possible goals to 17 minority inclusion in clinical research that was put 18 forth by this mandate. 19 Goal one would be to test hypotheses about 20 possible differences by race and ethnicity. Again, 21 this is adherent to what the overarching goal of the 22 mandate put forth, and then you would need to do your 23 power calculation so that you had adequate numbers of 24 whatever racial or ethnic group that you chose to 25 include in your studies. And oftentimes, it would be 146 1 on a one-to-one ratio, if that was your primary 2 hypotheses. 3 Another goal would be to generate 4 hypotheses about possible differences in race and 5 ethnicity. And there, you could look at national 6 parity. It's unlikely if you use census data by which 7 to sort of have national parity that you would have 8 adequate numbers to test hypotheses, but you could 9 then generate hypotheses. 10 And then the third goal, if the goal is 11 sort of just an equitable distribution of risks and 12 benefits, sort of pointing to social justice and 13 distributive justice, then you might actually want to 14 include amongst your group, say if the study was about 15 diabetes, you might actually want to include racial 16 and ethnic minorities in a proportion that was 17 parallel to the prevalence of the disease, or the 18 outcome that you were studying. 19 We felt that investigators should be 20 explicit about what goal that they were trying to 21 adhere to in any proposal that they submitted to the 22 NIH, and state which goal that they were selecting, 23 and why they chose that goal. 24 So just to think a little bit more about 25 justice in clinical research, this, to me, answers the 147 1 question, to whom will these results be applied, and 2 is the population represented in such a way that the 3 results can be generalized? That's sort of, to me, 4 the bottom line. And oftentimes, it's thought of in 5 terms of a fair distribution of benefits and risks of 6 research participation throughout a population with 7 the idea that risks are going to be minimized, and the 8 benefits are a value maximized for individual subjects 9 and society. 10 In the National Academy's Institute of 11 Medicine Panel that I was privileged to be a part of, 12 we sort of started thinking about the research that's 13 happening within communities, and whether we need to 14 re-examine some of these ethical principles, the 15 ethical principles that so much research is being 16 based upon, primarily due to social, historical, and 17 economic context, that are going to infiltrate and be 18 a part of any research relationship that you're going 19 to ask individuals to engage in. And we felt that a 20 relationship paradigm actually needs to be 21 superimposed on these ethical principles. So, for 22 example, respect for persons. Informed Consent may, 23 in fact, need to be examined if participants are 24 vulnerable in many ways, and live in communities that 25 lack economic and political power. So if you're 148 1 engaging communities that under-served, you may need 2 to think very carefully about what respect for persons 3 means in how you operationalize Informed Consent. I 4 think the dialogue this morning was a really wonderful 5 base on which to start, to think more broadly about 6 what Informed Consent could look like, and what are 7 all the ways that people can be vulnerable. 8 In terms of beneficence, participants and 9 community representatives might have a markedly 10 different assessment of the benefits and risks of 11 research than researchers or IRBs, and their voices 12 need to be heard. As part of the National Children's 13 Study, I know that there is that attempt, but I would 14 expect that any investigator or investigator 15 partnership needs to think about how to engage their 16 communities to make sure that the risks and the 17 benefits that they see are, in fact, the ones that 18 participants see, as well. 19 And then justice often focuses on sort of 20 equitable selection of subjects. Again, we need to 21 think about the multiple ways that people could be 22 vulnerable, and add into that relationship framework 23 issues of power, responsibility, trust, context, and 24 history that need to be considered to round out what 25 that relationship you're asking people to engage in 149 1 could mean to them. 2 So in the midst of this, we have Bedell 3 that sort of pushed the envelope and pushed us to 4 think even more about what it means in terms of 5 diversity in clinical trials. We know that in terms - 6 - this is sort of one of -- this is the first race- 7 specific drug that's been approved by the FDA. And 8 it's sort of been seen as the forerunner for 9 pharmacogenetics kinds of research. And so, to me, it 10 brings up all kinds of issues, and others have written 11 about this, as well. We know that this field of 12 trying to elucidate the genetic basis for drug 13 efficacy and toxicity is sort of growing 14 exponentially. And really builds on breakthroughs and 15 mapping the human genome, and attempts at 16 understanding genetic variation. 17 This technology relies on high throughput 18 sequencing, technology and routine ubiquitous 19 population genotyping that we don't have yet. So, 20 therefore, has sort of come to rely secondarily on 21 easily identifiable populations, often using race as 22 a proxy for genetics. 23 Pam Sankar and her colleagues in their 24 JAMA article sort of spoke to this paradox of focusing 25 on genetics and disparities research, and I think it's 150 1 particularly germane when it comes to pharmacogenetics 2 and single race clinical trials. 3 First, they suggest that this over- 4 emphasis on genetics may, in fact, divert attention 5 from research on social, economic, and political 6 issues that lead to health disparities. They also 7 suggest that it fosters the misconception that 8 disparities will be easy to solve, that you'll be able 9 to take your pill twice a day, and you will fix 10 whatever ails you in terms of congestive heart 11 failure. And, in fact, may support the tendency to 12 attribute poor health to genetics, thus fostering the 13 idea of genetic determinism. And, lastly, they 14 suggest that, in fact, this focus on genetics and 15 pharmacogenetics in health disparities research 16 reifies racial categories, and can, in fact, 17 concretize biologic basis of race, and, therefore, 18 reinforce the stereotypes. 19 So one quote that I pulled out of here in 20 my attempt to try to shorten my presentation was from 21 a participant that I had in a focus group, who his 22 words will always stay with me. He said, "If I do all 23 of this, and it benefits society and everything, how 24 is it going to help me? How is this all going to come 25 back and help me?" And it reminded me of the comments 151 1 this morning. So every participant expects benefit 2 from their participation in some way. And Nancy King 3 describes the different kinds of benefit that can be - 4 - that we can think about, the potential direct 5 benefits of receiving a particular intervention in a 6 clinical study, collateral benefits of study 7 participation, such as free medical care, closer 8 monitoring, et cetera, and the sort of squishy 9 societal benefits that accrues to others in the 10 greater society that we never hold investigators feet 11 to the fire about, or at least we don't have a good 12 mechanism for holding it. And so, coupled with 13 Nancy's work, and this participant's comments, I 14 started thinking about this idea of societal benefits, 15 and, particularly in the frame of community-based 16 participatory research, and where there's an explicit 17 expectation that research benefits are going to accrue 18 to the population that you're engaging. 19 We know that disparities in health are at 20 least, in part, determined by social environmental 21 inequities, and I would suggest that we need to 22 consider ways to affect these socio economic factors. 23 And some of them can be just very simple, creating 24 capacity amongst community leaders to participate in 25 a meaningful way in research, creating opportunities 152 1 for employment and training, building and supporting 2 existing infrastructures within communities, as well 3 as providing the results of research or study findings 4 back to communities. And I think Gigi really very 5 eloquently put that this morning. 6 There's certainly been all kinds of 7 efforts that have been -- that are models on which we 8 can build, the HIV/AIDS trials in resource poor 9 countries, the National Bioethics Advisory Committee 10 Guidelines on Conducting Trials in resource poor 11 countries, and then other nation's, such as New 12 Zealand and their Maori, who are their indigenous 13 groups, where explicit research transfers in terms of 14 economic, financial resources are expected to be left 15 within that community. 16 I think we need a deliberate and a multi- 17 dimensional approach. And this is one of the themes 18 that I heard this morning, was about trust, and 19 building trust. And part of it is demonstrating the 20 trustworthiness of the research enterprise, that where 21 as this sort of body of investigators and 22 administrators are worthy of having our population's 23 trust be put in us. It's a way to close the circle 24 between this inclusion and diversity in clinical 25 research, and disparate health outcomes. And so that 153 1 research participation is not yet another example of 2 the inequity so evident in our society. 3 So just in summary, I actually think that 4 this, for me, this mandate of diversity actually 5 raises more questions than it does in terms of 6 solving. How and whether to use race as a variable, 7 the goals of diversity in clinical research, and how 8 do we meet the expectations of benefit in under-served 9 groups? I'll just end there. Thank you. 10 DR. TILDEN: Thank you. Our next speaker 11 is Dr. Vivian Pinn. Dr. Pinn is the Director of 12 Office of Research on Women's Health, an appointment 13 she's held since November 1991. Since 1994, she was 14 also named Associate Director of Research on Women's 15 Health at NIH. Dr. Pinn came to NIH from Howard 16 University College of Medicine in Washington, D.C., 17 where she had been professor and Chair of the 18 Department of Pathology since 1982. Dr. Pinn has been 19 invited to present the ORWH's mandate programs and 20 initiatives to many national and international 21 organizations with an interest in improving women's 22 health, and the health of minorities. Her recent 23 focus has been to raise the perceptions of the 24 scientific community about the importance of sex and 25 gender factors in basic science, clinical research, 154 1 and healthcare. Dr. Pinn. 2 DR. PINN: Thank you very much, and I'm 3 delighted to have an opportunity to tell you about 4 what we're doing at NIH in terms of inclusion of women 5 and minorities with a focus on minorities in our 6 clinical research studies. I'm glad I followed Dr. 7 Corbie-Smith, because she's covered much of the 8 background, and much of the basic information, and I'm 9 going to dwell mostly on how our process works at the 10 NIH, and how it came about, and what we're doing, and 11 then end with some of the individual institute 12 efforts, and some of the issues that remain for us. 13 The attention to inclusion in clinical 14 research at NIH really grew out of the very start of 15 the most recent women's health movement, when the 16 Public Health Service Committee on Women's Health 17 Issues was set up in the mid-1980s by Ed Brandt when 18 he was in the Office of the Assistant Secretary for 19 Health, and this committee was taking a look at what 20 data existed related to women's health, and what the 21 different agencies in the Public Health Service, as we 22 referred to it then, were doing on women's health. 23 And as a result of that, NIH's focus being research, 24 began to pay attention to whether or not women were 25 being included in clinical studies, and what you heard 155 1 most about, and still hear most about are studies of 2 heart disease, cardiovascular disease in women, in 3 which women were not necessarily included to a degree 4 that studies could be -- that there could be 5 determinations of where there were differences. 6 This is sort of a brief summary time line. 7 I apologize. Copies of my talk are being passed out 8 because I'm going to go rather quickly, but you will 9 have copies of these, if you don't already. But this 10 is sort of the time line going from the beginning up 11 until sort of present time. 12 Following that committee, Public Health 13 Service Committee looking at women's health issues, 14 NIH developed, or put into place, what was then an NIH 15 policy, that was actually published in the NIH Guide 16 to Grants to Contracts in 1987, that urged the 17 inclusion of women. And following that, there was -- 18 questions were raised about why not also address the 19 issues of minorities in clinical trials, so later that 20 same year in the NIH Guide to Grants and Contracts, a 21 policy was also published encouraging the inclusion of 22 minorities in the NIH Guide. 23 It was in June 1990 when the Congressional 24 Caucus on Women's Issues called for the General 25 Accounting Office look at or audit of the NIH to see 156 1 whether or not women were being included in clinical 2 studies at that time, saying okay, you say you have a 3 policy. What are you doing about it? And, actually, 4 although this - what we hear most about in terms of 5 this GAO report was the issue related to women in 6 clinical studies, this GAO audit actually also looked 7 somewhat, not to the same degree, but also looked 8 somewhat at the inclusion of minorities in clinical 9 research studies funded by the NIH at that time. 10 So following that, and the Congressional 11 concern, again mainly focusing on the inclusion of 12 women, NIH responded with the establishment of the 13 Office of Research on Women's Health, which I now 14 head. And, actually, that office was really put into 15 place to ensure members of Congress and the advocacy 16 communities that NIH was going to make sure that women 17 were included in clinical studies. But with that, 18 obviously, we made sure our policies, as we 19 strengthened them in `91 and `92, also referred to the 20 inclusion of minorities, as well as women. And you 21 really can't separate the two when you're looking at 22 data, you're collecting data for male, female, and 23 looking at the different racial and ethnic groups. 24 Well, we thought we had in place guidelines that would 25 allow us to then require, we said we were requiring 157 1 the inclusion of women and minorities, but in 1993, as 2 you've already heard, as part of the NIH 3 Reauthorization Act, in that Revitalization Bill, 4 there was a section that called for, put into law, the 5 requirement that women and minorities be included in 6 clinical studies. 7 Following that, we revised our guidelines 8 based on the law. And following that, we've not had 9 an audit related to inclusion of minorities, but we 10 have had audits related to analyses by sex and gender, 11 and we have continued to update and pretty much 12 clarify our policies as we go forward. 13 And so, what we saw, really based on the 14 kind of discussion you've already had, and that you 15 heard in the previous presentation, was how do we put 16 in policies when we're getting the shift from 17 exclusion for protectionist reasons to now a 18 requirement for inclusion? How do we do that, still 19 preserving the policies of protection? And we had 20 many debates related to this in the early 90s, as we 21 drafted the implementation plan of that new law back 22 in `93, `94. This is the law, and it was a section in 23 that Act that was entitled, "Clinical Research Equity 24 Regarding Women and Minorities". As far as I know, 25 we're the only country in the world, at least that 158 1 I've been able to identify, and from talking to people 2 from other countries, where there is actually 3 something in law that does require inclusion of women 4 and minority populations in clinical trials, or in 5 clinical research, I should say. 6 A number of other countries have pursued 7 what we have in our policies, and how we implement 8 them, and are looking at issues, but there are, 9 obviously, various issues related to whether or not 10 there are governmental central funding of research 11 studies, so that such a requirement can be 12 implemented. 13 In any case, with the NIH Revitalization 14 Act of 1993, what was put into that statute was pretty 15 much what NIH was already doing, with the exception of 16 four major things. One, it indicated that the 17 Director of NIH at that time must ensure, in 18 consultation with the Director of the Office of 19 Research on Women's Health, and what was then the 20 Office of Research on Minority Health, that women, and 21 minorities, and their sub-populations are included in 22 clinical studies funded by the NIH. And that term 23 "sub-populations" was added by then Congressman from 24 Texas, who was concerned about making sure that many 25 of the different segments of different, what we then 159 1 called racial groups, or ethnic groups, were 2 addressed. Also, to ensure, because we had heard, and 3 many who said they were including women and minorities 4 in their studies, but if you looked for differences, 5 or to what you'd call analyses to see if there are 6 differences, there usually were not enough included, 7 so the statute indicated that there must be included, 8 women and minorities must be included, such that a 9 valid analysis of differences could be accomplished. 10 And if during the question and answer period, you 11 don't understand how we got to valid analysis, let's 12 just say it was much better than the original 13 language, which was requiring a statistical 14 significant difference, because we probably would have 15 not been able to get studies underway if we'd had to 16 have those large populations. 17 Also indicated cost could not be an 18 acceptable reason for including these groups and, 19 finally, that there must be outreach efforts to 20 recruit these groups into clinical studies which to us 21 indicated that an investigator who was seeking NIH 22 funding for research, for clinical research, should 23 have included or should include in their plan in their 24 grant submission their plans for and how they're going 25 to recruit and to retain both women and members of 160 1 minority populations in their studies. As we 2 implemented the law, we did allow for compelling 3 rationale and justification if certain groups or women 4 were excluded and these are reviewed as part of the 5 process. 6 The intent as the language was designed 7 then and as we heard from members of Congress and from 8 the advocacy communities was to make sure that 9 research was available -- that the benefits of 10 research were available to all members of the public 11 and also to understand or to try to clarify whether or 12 not the interventions under study would differ in 13 their response based upon either sex or gender or 14 based upon race or ethnicity. 15 That's sort of the history bringing up to 16 date without going through all the specific changes we 17 put into place. But I'd point out and I'll show you 18 in a second a report that really summarizes everything 19 probably in more detail than you wish, but we get so 20 many questions and so many who are interested in the 21 policies and what we've done that we have them all 22 summarized in a report that we update every year. 23 But in order to maintain and to monitor 24 this, the adherence to our policies based on statute, 25 we have an NIH-wide tracking and inclusion committee 161 1 which is based in our office. Angela Bates is here 2 who also serves as our staff liaison, Carl Roth who 3 serves as my co-chair from the National Heart, Lung 4 and Blood Institute which has had an excellent record 5 in terms of ensuring both women and minorities in 6 clinical studies for many years, and representatives 7 from across the NIH, and from this committee, we 8 pooled with representatives from each of the 9 Institutes and Centers. 10 We put together data. We worked together 11 for consistency and reporting consistency and 12 monitoring consistency and how this policy is applied 13 across studies across all of the NIH, and we put out 14 annually a report on monitoring adherence which is 15 aggregate data. We don't try to break it down in this 16 report. It would be such a huge tome, but each of the 17 institutes have individual data and the Office of 18 Extramural Research does maintain that data through 19 its computerized tracking system. 20 But we put it together in a report that 21 not only provides the narrative of the history of this 22 and what changes have been implemented but also gives 23 the data. And I want to just give you a taste of 24 that, but the copies of this report are in the back. 25 If you didn't get one, I encourage you to do that 162 1 because it's going to be impossible to read the 2 numbers on the screen as I show you. I really want to 3 just show you trends. 4 In addition so that this doesn't get 5 thought of -- and I should also add that while this 6 did come about through law, that our major challenge 7 in implementing the language of the statute was to 8 take what was law and which some felt, especially at 9 that time was just being politically correct, but once 10 we had the law to make sure that we were, in fact, 11 implementing it based in science and so that we wanted 12 to come up with ways -- and I hope we did a pretty 13 good job of coming up with ways of implementing that 14 law so that we were preserving scientific concepts in 15 the design of research. 16 One of the other things was that the law 17 did require that advisory councils should monitor each 18 of the Institutes in terms of how the Institute was 19 adhering to or being in compliance with the law and 20 the policies. So we have a report we do every other 21 year, report for Congress, that reports on that with 22 statements from each of the advisory councils for each 23 of the Institutes which have to review all the grants 24 before they become funded, and I like that concept 25 because it, again, puts it back, the focus, on science 163 1 and within each of the Institutes to pay attention to 2 this. 3 In our report, we have many tables, more 4 data than I think anyone would want to see, but we 5 know that you cannot, I mean, it's possible to over 6 interpret the data as we have it and we feel that it's 7 better if we present it and then give what conclusions 8 we feel can be drawn hoping that will guide people to 9 not over interpret it. You'll also notice that in our 10 reporting we have tended over the last few years to 11 separate. We present aggregate data, but we also 12 separate domestic data from foreign population data 13 because NIH funding is not only domestic but also many 14 times goes out to other countries and, of course, 15 questions are raised not only similar to what you've 16 just heard in the previous presentation about race and 17 ethnicity but certainly questions about whether or not 18 this needs to be addressed in foreign populations. 19 The answer is yes. We're told that when the law was 20 drafted there were no exceptions allowed for foreign 21 populations. But, in addition, it's all self 22 identification. That's how the identification by race 23 and sex are derived or supposed to be derived. 24 And so we want to make sure that the data 25 doesn't get skewed. One year we had a huge number of 164 1 Asian women in studies, and it turned out there was a 2 breast cancer study being conducted in China with 3 something like 300,000 being observed and, of course, 4 it really sort of skewed the data when you looked at 5 it for that year. So we've tended to present the data 6 as aggregate and also look at that. 7 Now trends are interesting, but I'm also 8 going to show you some problems with trends for those 9 who are interested in what's happening with studies. 10 Now here is looking at trends of enrollment by sex as 11 well as looking at minorities and non minorities. And 12 you can see, as you would expect, that as clinical 13 trials and clinical research increase, we see an 14 increase and we've begun to try to monitor the 15 differences. 16 But, of course, looking at trends in both, 17 and we include in this both extramural and intramural 18 research meaning research being done at the clinical 19 center and the NIH-based studies versus those in the 20 extramural community, we really can probably while we 21 have the numbers and we think they're fairly accurate, 22 I think trends are probably the most important thing 23 to look at in terms of the data, and we can see from 24 `95 to 2006 that there was a great increase in 25 minority enrollment. But I'm going to show you some 165 1 issues or problems we have in dealing with that data 2 and that is what you've already heard the change in 3 OMB categories for race and ethnicity. 4 You see at the top of this form that we 5 were nicely collecting data related to the old way 6 that OMB prescribed that we look at race and with the 7 major categories of American Indian, Asian Pacific 8 Islander, Black, Hispanic, White, and unknown or 9 other. Of course, with the changes in the OMB 10 requirements, it required us to set up categories to 11 look at race and ethnicity, Hispanic or non Hispanic, 12 and then looking at the different racial categories 13 within the different -- the two categories of 14 ethnicity which then has affected our data collection. 15 So don't try to read these numbers. If 16 you want to see them, they're in the report. But if 17 you look, we have to now collect data for those 18 studies that started prior to the implementation of 19 the new way of utilizing OMB, the OMB format. We have 20 to collect it using, continue collect it using the old 21 format and then we have to look at those studies that 22 have started since the change and how you collect data 23 using the new format which means that Angela Bates who 24 does most of this calculation has a great time trying 25 to deal with this data and for us to try to put it 166 1 together recognizing we have some restraints in what 2 we can do. But we do present it as best we can. 3 Here is the old form showing this is just 4 for total aggregate extramural and intramural research 5 using the old form for those studies that were studied 6 prior. And we still have a number of studies with 7 fairly large enrollments that are still continuing 8 that were funded prior to the change in the format. 9 There are some trends we can talk about, but this is 10 looking at all clinical research and we tend to look 11 at both all clinical research versus Phase III 12 clinical trials which are the ones for which most of 13 the analyses are done. But we do see, for example, 14 more females than males and, again, for minorities, 15 more minority females than males and looking at the 16 fact that about 43 percent in the aggregate research 17 are classified as U.S. minorities. Looking at race 18 and all of these, they will be in the handout that you 19 have and they're in the report and this is again 20 looking at all total research and, of course, as you 21 might expect, I'm not sure whether it's good. I won't 22 give a value judgment, but as you might expect, for 23 looking at the breakdown that we don't get a good 24 number of breakdowns for those who identified 25 themselves as Hispanic but in the new form of data 167 1 collection. 2 And here we have, I guess, similar data 3 related to those in Phase III clinical trials, again 4 using the complicated format of Hispanic versus non 5 Hispanic with racial breakdowns and then, of course, 6 looking at the old form and the new form. We have 7 similar data or similar trends that we can identify 8 related to looking at both males and females, more 9 females than males, and I must say this has brought a 10 lot of concerns from the men's health community about 11 whether or not we were excluding males. But that's 12 not the case, and I'll say just a bit since we're 13 really focusing on ethnicity and race. But, in fact, 14 if you eliminate gender-specific studies that as one 15 would expect or one would hope the balance between 16 males and females in studies or conditions that affect 17 both are pretty much level or about the same. So it's 18 not a real disparity in terms of including males in 19 clinical trials. 20 And, of course, looking at race in Phase 21 III clinical trials, the smallest identified racial 22 minority group for those who are included are American 23 Indian and Alaskan native and then looking at the new 24 standards, the smallest racial minority is Hawaiian- 25 Pacific Islander with far less than one percent, a 168 1 very small group. Then looking at ethnicity, again 2 about in the new -- looking at comparisons for the old 3 and the new standards, I shouldn't say standards, ways 4 of classification, that again we have difficulty 5 identifying breakdown for those who identified 6 themselves as Hispanic. 7 So as we look at race and ethnicity data 8 comparing old form and new form, we find we really 9 can't add them up. So I'm going to show you a series 10 of charts that I'm going to go through very quickly, 11 and they're in the handout, but to show you how we 12 have difficulties. People want to see the exact 13 numbers because they really can't be considered 14 additive because the data collection format is 15 different. 16 Here, for example, looking at American 17 Indian and Alaskan Natives, the red line on this is 18 showing and you can see the numbers are collected by 19 the old form and then when you see the new form data 20 which are here represented in yellow, don't feel we 21 can actually add those numbers. I think in your mind 22 you can pretty much add them assuming that people have 23 identified themselves appropriately. But this doesn't 24 take into account looking at Hispanic/non Hispanic and 25 how do we really reconcile that. So we have ways of 169 1 doing that, but that's sort of to show you sort of the 2 trends. 3 The same for black and African American. 4 You can see similar -- so it's not really a decrease 5 in the numbers that are included. It's just that 6 we've got pretty much a level line and where there 7 might be an increase because on the new form the data 8 is collected differently we can assume that's 9 additive, but we can't be sure. So we've not added 10 here Asian Pacific Islander, Hispanic, not White and 11 again, you see the same thing. Those who classified 12 themselves as Hispanic earlier and then with the new 13 way of collecting data with the new form which we 14 implemented in 2002, it looks like it's level but 15 probably is an increase if you were to add them. But 16 we don't feel we can really do that. 17 And here is the data showing males versus 18 females in sex-specific studies when you exclude sex- 19 specific studies to show that it's about even for 20 males and females. 21 As part of that mandate for NIH to go on 22 to investigators is that there must be outreach, 23 meaning they have to both demonstrate they're going to 24 include women and minorities and also demonstrate how 25 they're going to reach out to include these 170 1 populations in clinical studies to be funded by the 2 NIH. So we developed back in the early `90s and it 3 was recently revised as so called "Outreach Notebook" 4 which has frequently asked questions that addresses 5 issues of inclusion but also gives information to 6 those who feel they don't know how to reach out to 7 recruit or retain women or minorities in studies or to 8 find out about implementation of policies, this 9 directory, and I think we sent a few copies here if 10 you're interested. But they're all, all of these are 11 online and it helps to address some of the problems 12 that investigators have. 13 For example, one of the questions that 14 often gets raised is if you have a multi-center study, 15 do you have to have all populations represented in 16 each center? And the answer is no. If it's a multi- 17 center study that's tied together and the SWAN study 18 which is a study of women's health across the nation 19 is an example where you can see the different 20 populations get focus in different centers, and the 21 mechanisms like that for meeting the mandate of the 22 policy are described in that outreach. 23 Now I think I've talked longer than I 24 should have. So I'm going to have to go even a little 25 bit quicker over this to point out to respond to some 171 1 of the questions that we often get asked which is how 2 do we ensure that the inclusion policies are met and 3 there are a number of ways in addition to our 4 monitoring of the committee. 5 First of all, I'll point out that if an 6 applicant to NIH does not meet the requirements for 7 inclusion of women and minorities, that application 8 should not be funded and should not go forward. It 9 gets what we call a bar to funding. How do we monitor 10 that? Each one applying to the NIH who's going to be 11 doing clinical research has to both indicate target 12 data as part of the initial application, in other 13 words, what populations are intended to be included 14 and a breakdown in terms of sex, gender, racial/ethnic 15 groups, and how they're intending to do that. 16 Now often we hear questions and we often 17 see our data evaluated and being looked at in terms of 18 census data. But we have to point out that census 19 data should not be used in general to draw conclusions 20 about the numbers of minority populations or women for 21 that matter that are included in NIH funded studies 22 because the way we adapted the law or implemented the 23 law taking into consideration scientific basis for 24 implementation is that the inclusion in a clinical 25 study really depends, the breakdown for the target 172 1 data of what is intended to be included, should be 2 interpreted on the basis of the prevalence of the 3 condition under study in the population to be studied. 4 So it's going to vary in terms of which population, 5 how many males or females, as well as which ethnic 6 groups based upon the condition to be studied, and 7 that is a very important point because that is the 8 basic message for our design and how we evaluate the 9 target populations for studies for grant applications 10 that come in. 11 Each investigator must include information 12 related to subject selection, who they're going to 13 have, how many, what their plans are for outreach and 14 to be held responsible for making sure that they 15 recruit and retain in the studies and actually study 16 the numbers or approximate numbers that they put 17 forward in their target data when they put that 18 forward. 19 Our program officials at the NIH, the 20 scientific officials, are responsible for monitoring 21 this, for approving target and planned enrollment, for 22 looking at that to see does the number or proportion 23 of women versus men or different racial groups 24 correspond to the population characteristics of the 25 disease. Is there good justification for exclusion of 173 1 certain groups or exclusion of women or men, etc.? 2 And that is what must be considered and that must be 3 entered as part of the scientific score for funding 4 decisions. 5 If an application does not meet that 6 requirement, they should not be funded. They should 7 have a bar to funding and actually if it's felt to be 8 good science, the program officers can discuss with 9 the investigator, and they must revise their plan if 10 they want to go to council to get funding. 11 And with this, let me see. This is just 12 to show you the way that the data is collected, both 13 in terms of target data versus also reporting accrual 14 data so that we have a way to follow that even from 15 the application to the progress report. So we see 16 complying with the NIH inclusion policy as really 17 being a responsibility in many areas and all the way 18 from our PIs who submit the applications to members of 19 the NIH staff as well as members of the public who are 20 volunteers in these clinical studies. 21 With the new Revitalization Act that was 22 passed last year reauthorizing NIH, there were no 23 exclusions allowed, and exclusions for foreign 24 populations were not addressed. So the original 25 interpretation continued and the requirements from the 174 1 original Revitalization Act continue. There were no 2 changes made. 3 I want to just mention a joint portion and 4 there are flyers for you on the table related to how 5 we're trying to address some of these issues and while 6 the focus is mainly on sex and gender, it also 7 addresses the policies in a format that we hope helps 8 to get the word out to the general scientific 9 community and that is a web-based course that we 10 developed with the Office of Women's Health at the 11 Food and Drug Administration. It's really to focus on 12 why we need to do sex and gender analyses, but also we 13 are focusing on other issues. It's an online course, 14 but in looking at the first chapters that we have in 15 this course, there is one section that deals with the 16 legislative process framework and I'm not going to say 17 much about this because Dr. Sacks is here. So he'll 18 be talking about FDA. 19 But I wanted to point out the difference 20 in that NIH actually has the law that applies and has 21 language and statute. The FDA does not. The language 22 for inclusion is part of the NIH Revitalization Act. 23 So it does not apply to other portions of DHHS or to 24 industry, and FDA, in fact, has in its guidance its 25 provisions for inclusion mainly addressing sex and 175 1 gender inclusion. But in 1998, the guidance for 2 industry on collection of race and ethnicity data 3 which it requests, and I won't say anymore about that. 4 I think I want to just end if I can take 5 about two more minutes and just show you some examples 6 from some of our Institutes. I should point out that 7 everything related to inclusion is not only on our 8 office website in a section on inclusion of women in 9 research, but also is available on the NIH general 10 website as well as the Office of Extramural Research 11 website. 12 Now that we have clinicaltrials.gov, we 13 went to look just to see if you wanted to search for 14 clinical trials are specifically recruiting different 15 minority populations and I'm not going to show them 16 all, but if you search according to different racial 17 and ethnic groups, you can see that they are listed. 18 There were not a lot for Alaskan Natives. Most of 19 them or many of them should be looking at diversity of 20 populations. But if you look, you can go and search 21 to see which ones are specifically looking at certain 22 racial breakdown populations and then you can also 23 look, going to the NIH CRISP registry, and see studies 24 that are being conducted that are currently funded 25 that are being conducted on different racial and 176 1 ethnic groups. I thought it would just be interesting 2 to show you some examples of some of the different 3 studies and that you can go and search that. 4 And many of our Institutes wanted to just 5 convey some of the special outreach efforts they are 6 conducting like NIDA and many of our Institutes have 7 brochures in different languages to reach out. The 8 Clinical Center often gets overlooked in this 9 discussion because those are intramural clinical 10 trials. It's a little harder to monitor and to do the 11 general inclusion because most of those are extremely 12 rare diseases that are being studied at the NIH and 13 often have to deal with -- while there are lots of 14 recruitment efforts, nationally you know the issues of 15 sending your patients to NIH and not general studies. 16 They are mostly very rare diseases. 17 NIAID, just to show you a breakdown again 18 of looking at NIAID, one particular Institute's 19 breakdown for minority inclusion and you can see the 20 breakdown here for different racial groups which is 21 how they reported as well as ethnicity from their 22 studies and, of course, looking at NIAID, you can see 23 again the largest number being, the largest percentage 24 being black or African American and the smallest 25 percentage Hawaiian/Pacific Islander. 177 1 NIDCD, comparing, seeing how those who are 2 registered as minority or considered minority that 3 we've seen an increase over years. NICHD has raised 4 the issue, another issue, we're not discussing today, 5 at least I hope not, and that is the issue related to 6 inclusion of children in the policies because NIH has 7 a policy, not based on law, but a policy requiring the 8 inclusion of children. But the policy of inclusion of 9 children does not exclude the need to address the 10 other issues of male and female as well as ethnic 11 backgrounds. 12 NIMH has pointed out specifically that 13 they're seeing in research, their funding, some 14 difficulty in addressing Hispanic population in some 15 of the efforts they're doing. 16 And, of course, the Cancer Institute which 17 we could talk about all day. 18 I want to end with just another aspect of 19 something that really hasn't been announced. I think 20 it's being announced today or maybe it got posted 21 yesterday and it's not research specific. But there 22 is the Ruth L. Kirschstein T-32 Training Programs in 23 the Chemical Biology of Cancer which is a program, 24 it's a training grant program. 25 When we talk about inclusion of 178 1 minorities, one of the things we sort of take it to is 2 looking at diversity, not only of those in clinical 3 trials, but those who conduct clinical trials and 4 those who are scientists and researchers. And that 5 particular issue in this particular program is going 6 to announce an enhancement of this program looking for 7 recruiting trainees from racial and ethnic backgrounds 8 similar to what we talk about in terms of clinical 9 research. I think it's just interesting just looking 10 at some of the questions which I think are posted, may 11 not yet even be posted, but to show some other areas 12 of focus. But here showing a focus of how this 13 program will look, and I'm sure Dr. Kirschstein's 14 going to be very pleased about this to look at 15 diversity of participants to participate in this 16 program. 17 So with that, I have on the back table a 18 chapter that we wrote really describing. If you don't 19 want to read that whole big, thick report, there's a 20 nice summary and update. This is a revised chapter in 21 John Gallon's book on clinical research that again 22 summarizes our policies and what some of our issues 23 are and as you heard in the previous presentation we 24 continue to monitor and require the inclusion of 25 minorities because that is what we have for law. But 179 1 I'm constantly being challenged by many who feel that 2 we should not be looking at race and the whole 3 question about race and ethnicity versus genetic 4 inheritance. But right now, all I can do is say that 5 as long as we have the law and until the law is 6 changed, it is a requirement, and we do hold 7 investigators to that. 8 So thank you very much. 9 CHAIR TILDEN: Thank you. Our next 10 presenter is Dr. Leonard Sacks. Dr. Sacks has worked 11 for the FDA for the past nine years and currently 12 holds a position in the Office of the Critical Path 13 Programs. He holds an M.D. degree with specialty 14 training in infectious diseases and has practiced both 15 in the V.A. system and in Johannesburg, South Africa. 16 He's here today to discuss the FDA's approach to 17 diversity in clinical trials. 18 DR. SACKS: Good afternoon. Thanks very 19 much for the introduction and for the invitation to 20 participate in this meeting. My remarks are going to 21 be very brief compared to the other speakers. 22 Perhaps I should just preface what I'm 23 going to say by indicating that my discussion revolves 24 around registrational trials for drug products at FDA, 25 and that constitutes a very small subset of the full 180 1 spectrum of clinical trials. Obviously, many other 2 trials take place in different communities regarding 3 disease pathogenesis, mechanisms of disease, 4 epidemiological studies and so on, and that is not the 5 purview of the FDA. 6 So having said that, let me move ahead 7 with my first slide which basically summarizes my 8 sense of the ideal world of clinical trials and in 9 this setting, clinical trials would be very large. 10 They would be a large representation of all subgroups, 11 and remember that subgroups are a very important 12 component of how we understand the results of our 13 trials, and the important ones I've listed there 14 include gender, which we've heard plenty about, age, 15 race and ethnicity which is the focus of my talk, the 16 severity of the disease upon enrollment, concomitant 17 treatments that patients are taking at the time they 18 are enrolled to the study, the presence of underlying 19 diseases, for example, things like diabetes, 20 hypertension, etc. 21 In the ideal world of clinical trials, one 22 would have the ability to detect very rare adverse 23 events which is obviously an area of great concern to 24 FDA, and probably some of you are aware that adverse 25 events of concern may occur at rates of one in 30,000, 181 1 one in 40,000, severe adverse events. These are in 2 practical terms impossible to predict with the current 3 structure's clinical trials. 4 Finally, ideally we would have the ability 5 to customize dose for maximum safety and efficacy in 6 all the different subgroups of clinical trials and 7 that in the current system is not possible. 8 What about the real world of clinical 9 trials? Well, I think the things we have to bear in 10 mind are that participation in clinical trials is a 11 voluntary process. It's influenced by culture. It's 12 influenced by education, by convenience, by personal 13 beliefs and suspicions. So we cannot force 14 participation in clinical trials. 15 Remember that trials are performed in 16 communities where the disease is easiest to study. 17 One has to be pragmatic. For example, 18 immunosuppressive drugs are studied in transplant 19 centers and not in community hospitals. Anti-malarial 20 drugs are by and large studied in Africa where the 21 representation of participants is pretty much limited 22 to one or two racial groups. 23 In practice, infinitely large trials 24 cannot and really should not be performed and 25 therefore, we can never include adequate numbers of 182 1 all the subgroups to achieve statistically significant 2 results in those subgroups just on the limitations or 3 the availability of patients and the availability of 4 other resources. 5 Now I just want to contrast that with the 6 reporting of ethnic information in clinical trials. 7 Reporting is a different story. This is just 8 recording information, and FDA recognizes the 9 importance of ethnic and racial information in 10 reviewing the data. The nature of racial and ethnic 11 information required is often specific to the 12 application or to the drug, and I'll expand on that 13 slightly. 14 During the drug review process, FDA does 15 assess the adequacy of information on race and 16 ethnicity which is based on the population who is 17 likely to use the drug, likely differences in drug 18 metabolic pathways between different ethnic groups and 19 likely differences in racial co-factors, for example, 20 food, nutrition, presence of other diseases. And then 21 upon review, if a racial concern is identified that 22 has not been adequately addressed, the drug may not be 23 approved. Also systematic exclusion of certain racial 24 groups would undoubtedly raise concern and might 25 result in non-approval. So this is the reporting of 183 1 racial information in clinical trials. 2 I just want to change emphasis a little 3 and discuss the scientific perspective on racial 4 differences in drug development. I think it's 5 important to realize that generally the genes that 6 determine the color of our skin or the features of our 7 faces are not those that determine different responses 8 to drugs. The reason different races may respond 9 differently is partly due to breeding within groups 10 resulting in different frequencies of genes that are 11 unrelated to the racial characteristics I mentioned. 12 Many of these important genes are well 13 recognized and can be tested for specifically, and the 14 ones I refer to are the P450 group of enzymes in the 15 liver that are responsible for drug metabolism, 16 specifically the CYP2D6 enzyme which may result in 17 differences in drug metabolism, things like G6PD which 18 is an enzyme, the deficiency of which results in 19 hemolysis or anemia in patients using certain drugs. 20 So there are specific tests looking for genetic 21 responses or likely genetic responses to new drugs. 22 Just to continue the same theme, in racial 23 terms, we're a lot more similar than we are different. 24 Definitions of racial differences are often social, 25 and they may not be medically meaningful, and I think 184 1 this has already been referred to. I've just listed 2 a string of racial terms just to indicate really how 3 nondescript our understanding of this is, and you will 4 recognize a lot of these as Asian, African, European, 5 Hispanic, Pacific Islander, American Indian, 6 Aboriginal, White, Black, Mixed, Caucasian, Negroid, 7 Mongoloid, Bushman, Aryan and Semitic. 8 Without dwelling on the differences, the 9 next point I wanted to make was that the most well- 10 recognized racial differences in responses to drugs 11 are really very few. We recognize differences in the 12 distribution of this important enzyme, CYP2D6, the 13 supposed racial differences in the distribution of the 14 G6PD phenotypes. There are differences in 15 distribution of sickle cell genes and there are 16 thoughts that beta blockers and that angiotensin 17 converting enzyme inhibitors are -- at least the 18 responses to these drugs are different in different 19 racial groups. 20 I think more important other medically 21 important subgroups of patients have a much more 22 serious impact on drug responses. We've heard a lot 23 about gender, and gender is a very important 24 determinant in differences in the responses to drugs. 25 It carries with it a whole lot of other concepts 185 1 including hormonal differences, pregnancy, the types 2 of diseases that men and women get, the distribution 3 of body fat, the presence of menstruation, etc. And 4 an example would be thalidomide which is probably one 5 of the most egregious failures in medical drug 6 development where the drug was perfectly safe in men, 7 but disastrous when it was used in pregnant women. 8 As far as age goes, another cofactor, age 9 obviously affects the maturity of the kidneys and of 10 the liver. It affects immunological responses and 11 hematological responses and an example of a drug which 12 is dealt with very differently in adults and children 13 would be aspirin which is very safe in adults, but in 14 children may cause Reye's Syndrome. 15 And finally, the overwhelming importance 16 of concomitant medications and the example I've given, 17 the cisapride which was a drug that was used for 18 gastroesophageal reflux which was very toxic when it 19 was used in conjunction with inhibitors of the P450 20 enzyme system and resulted in deaths from cardiac 21 arrhythmias. I think the points that race has a small 22 impact, but by and large, there are many other more 23 important cofactors that we do have to look at, at 24 least, subgroups that we have to look at in clinical 25 trials. 186 1 So I guess what I'm advocating is a 2 practical approach. It's more practical to address 3 racial differences on a case-by-case basis than having 4 a blanket approach to this. First, we characterize 5 new drugs in the test tube and in animals. We look at 6 receptors. We try to understand the targets for new 7 drugs. We try to understand their mechanisms of 8 action. Then we figure out how the new drug is 9 metabolized, how it is distributed in the body, and 10 how it's excreted from the body. 11 Drugs metabolized by the enzyme I 12 mentioned CYP2D6 may raise some race-specific 13 concerns. Drugs likely to affect patients with 14 abnormalities that are common in certain racial and 15 ethic groups may raise race-specific concerns. For 16 example, sickle cell anemia is differently represented 17 in different racial groups, G6PD deficiency porphyria 18 and these may have impacts on how drugs are tolerated. 19 And then just to conclude the concept, one of our most 20 promising tools is genomics which allows us to look at 21 the actual genes that are determining these responses 22 to drugs without having to make distinctions between 23 people just based on physical appearance. 24 Once a race-specific concern is 25 identified, how many subjects from each racial group 187 1 are needed, and we've heard a little bit of discussion 2 on this before. In the realm of safety, if a gene of 3 concern is present at a very low frequency in one 4 racial group and absent in another, it would be best 5 to enroll most of the study participants from the 6 racial group for the gene of concern so that you can 7 see what it's impact is. If a condition is more 8 prevalent in one racial group, it makes sense to study 9 the drug in that group because those are the ones who 10 are most likely to be taking the drug. And finally, 11 if a disease manifests differently in different racial 12 groups, the study of a drug for that disease should be 13 powered to reflect efficacy in each racial group. In 14 other words, if you think that people do respond 15 differently in different racial groups we should 16 examine the difference, and hypertension may be one 17 example of a condition that seems to be somewhat 18 influenced by racial characteristics. So I guess the 19 bottom line there is one size does not fit all, and we 20 have to tailor our recruitment numbers according to 21 scientific principles. 22 So my general conclusions are, first of 23 all, our overarching societal goal is the availability 24 of safe and effective medical products for all who 25 need them. Race and ethnicity should be addressed in 188 1 a practical way, employing emerging technology that 2 promotes efficient drug development and obtains 3 pertinent information about the subgroups. Scientific 4 principles should be the ones that should be used to 5 optimize the study of racial and ethic concerns in 6 drug development. And finally, modern tools, for 7 example, pharmacogenomics should be used to expedite 8 the study of drugs in different populations. 9 Thanks very much. 10 CHAIR TILDEN: Thank you. So our final 11 presenter today is Dr. Barbara Pence. Dr. Pence is 12 professor of pathology at Texas Tech Health Sciences 13 Center in Lubbock, Texas and currently serves as 14 Associate Vice President for Research and Associate 15 Dean for the Graduate School of Biomedical Sciences. 16 She's been involved in a project entitled 17 "Eliminating Disparities in Clinical Trials" and in 18 the practical implementation of dealing with 19 disparities in clinical trials. So with that, I turn 20 it over to Dr. Pence. 21 DR. PENCE: Thank you very much. First of 22 all, I would like to tell you just a little bit about 23 my background and why I feel a little qualified to 24 talk about clinical trials and diversity and also IRB 25 issues. 189 1 As the Vice President for Research, I 2 oversee all the research in our institution, 3 especially a very large division of clinical research. 4 I, myself, do clinical research. I'm a certified 5 clinical research professional and in the graduate 6 (audio system malfunction). It's back. It was taking 7 a brief break I presume. 8 But what I'm going to talk to you today 9 about is a project that I have become involved with 10 during the past year called EDICT, Eliminating 11 Disparities in Clinical Trials. First of all, I would 12 like to thank Dr. Corbie-Smith for her introduction to 13 the issues and also for Dr. Sacks and Dr. Vivian 14 Pinn's presentation on what the government is doing in 15 terms of both FDA and especially the NIH with regard 16 to the representation of minorities and women in 17 clinical research. 18 However, one of the things I want to point 19 out and where EDICT kind of picks up some of the slack 20 is that in terms of the clinical research in this 21 country, a recent piece of data from a new book by 22 Howard Brody called Hooked: Ethics, The Medical 23 Profession, and the Pharmaceutical Industry which was 24 published in 2007 actually says that our federally- 25 funded clinical research comprises only about 25 190 1 percent of what's going on in this country. So we 2 have a lot of it that really cannot necessarily come 3 under the NIH requirements. 4 So that's one of our concerns is that 5 minority and under served participation is still a 6 major concern. In fact, I do a lot of reviewing for 7 the National Cancer Institute and I was really 8 surprised to hear that in the cancer clinical trials 9 alone 88.8 percent of the participants are still 10 white. They are not members of minority groups or 11 ethnic differences. This led to the development of 12 the EDICT project. We're not just dealing with race 13 and ethnicity but also with issues of the elderly and 14 the general under served in terms of participation in 15 clinical trials. 16 There it is. Okay. Now what is EDICT? 17 Again, I said it is a collaboration between Baylor 18 College of Medicine and the Intercultural Cancer 19 Council. However, our efforts are directed 20 specifically just to cancer clinical trials or asthma 21 clinical trials. We started out focusing on that, but 22 all clinical trials. 23 And it addresses problems and solutions 24 that are related to improving the participation of 25 minority and the under served. I live in an area of 191 1 West Texas where being rural is part of being under 2 served, tremendously under served. If it weren't for 3 Texas Tech School of Medicine that's spread all over 4 West Texas it would be like the Outback of Australia. 5 So it truly is under served because of geography. 6 And the project is a four year project, a 7 collaboration again Genentech and being funded 8 Genentech. We first met last year in Houston at 9 roundtable to discuss these issues of eliminating 10 disparities in clinical trials and there were many 11 academic, research, government and minority community 12 leaders that all met to work on this issue. 13 So we have come up with a credo that 14 formalizes our beliefs in terms of this project. The 15 first one is all individuals have the opportunity and 16 necessary support to participate voluntarily in 17 clinical trials for which they are eligible. 18 Participants and researchers will understand and 19 promote the benefits of diversity in clinical trials. 20 And results from clinical research will benefit the 21 participants, communities and society at large. 22 Now a great deal of our efforts are 23 focused on policy research. That's what I'm primarily 24 working on and my team or group that we're working 25 with which I'll explain in a few minutes how the 192 1 project is organized. The goal of our policy research 2 is to increase knowledge of the processes involved in 3 developing and implementing health policy, impacting 4 the three R's of clinical research, recruitment, 5 retention and the return of minority and under served 6 patients to clinical trials. 7 So this organizing framework known as The 8 Three R's involves, first of all, recruitment. In 9 addition to the issues of active recruitment, this 10 also includes issues of access to clinical trials. 11 One of the things we are finding in talking with our 12 colleagues who do a lot of cancer clinical trials is 13 that many times minorities and the under served are 14 never even asked by their health care providers to 15 participate in cancer clinical research. So this is 16 just one of the aspects of access. 17 Retention. We all know that retention of 18 all participants in clinical research can sometimes be 19 a difficult challenge especially with minorities and 20 the under served. So keeping participants satisfied 21 and on protocol and in the study is one of our focuses 22 in terms of one of the three R's. 23 And finally, return, giving back to our 24 participant populations. 25 Now with regard to recruitment, the 193 1 current literature shows a significant under- 2 representation of minorities, elderly and under served 3 in clinical research. In terms of access, minorities 4 as I said have been shown as very willing 5 participants, not unlike any other group, to 6 participate in clinical research. However, they are 7 just not asked as often. 8 Retention may also take special efforts 9 which is another focus of the EDICT project and the 10 return, giving back, involves being able to more fully 11 access the safety and efficacy of the drugs that are 12 used on all members of the U.S. population that is 13 often not ever tested on those who will actually be 14 prescribed these drugs. 15 It's very similar to the situation with 16 children in the past where children were very often 17 excluded from any kind of clinical research because of 18 safety concerns. Now that has all changed with new 19 efforts to recruit children if at all possible to 20 clinical research. However, they were being 21 prescribed drugs and still are that have never been 22 tested formally on children. 23 So this is how the continuum works. It is 24 a cycle of recruitment, retention and return, all of 25 which we are focusing on in terms of the EDICT project 194 1 that involves increased participation of minorities 2 and the under served clinical trials. 3 Now what are some of the objectives our 4 efforts on policy research? And again, the emphasis 5 in EDICT is the emphasis on policies. We are going to 6 assess policy issues related to under represented 7 populations participation in clinical trials. Much 8 information is being gathered by our research team in 9 looking at areas which you will see when I outline the 10 teams. There are many aspects of addressing these 11 issues on the participation from recruitment and 12 retention to policy level at the highest points in our 13 government. 14 We are also planning to organize and 15 conduct a national policy development summit meeting. 16 And finally, we plan to conduct dissemination 17 activities involving policy education and advocacy 18 relating to minority and under represented 19 participation in clinical trials. 20 Now these are the Opportunity Teams. This 21 is the basic organizational structure of the large 22 number of people who are actually working on this 23 project. Opportunity Team 1 is going to focus on the 24 allocation of research funding proportionate to case 25 fatality and how practical this may or may not be in 195 1 terms of designating participating in clinical 2 research. Opportunity Team 2 will focus on assuring 3 health care coverage in clinical trials. Opportunity 4 Team 3 will deal with education and training, both at 5 the institutional level and at the professional level. 6 Opportunity Team 4 is going to focus on education and 7 training at the public level, the interface with the 8 public, and especially with patients. Opportunity 9 Team 5 will focus on fostering community input and 10 involvement and those relationships that are relevant 11 to clinical research in minorities and under served. 12 Opportunity Team 6 will deal with patient and 13 participant navigation. Opportunity Team 7 is going 14 to deal with pharmaceutical relationships and 15 partnerships. Opportunity Team 8 publication related 16 policies regarding participation in clinical research. 17 And finally the one that I chair is Opportunity Team 18 9, Regulatory Oversight and Enforcement which explains 19 why I'm here today. 20 One of the things that we are working on 21 as additional projects are two projects called CLAS- 22 ACT and the EDICT Backpack projects. Now all of us in 23 this room probably are aware of the National Standards 24 for Culturally and Linguistically Appropriate Services 25 or CLAS. What we have done is we have combined that 196 1 with And Clinical Trials and come up with a term 2 called CLAS-ACT. 3 CLAS mandates all current federal 4 requirements for recipients of federal funds. They 5 are recommended by the Office Of Minority Health who 6 is a partner with us in this project for adoption of 7 this mandate by federal, state and accrediting 8 agencies. These are predominantly for health care 9 organizations and they are recommended for voluntary 10 adoption by health care organizations. However, we 11 are proposing them in terms of clinical research. 12 One of the things we do at Texas Tech is 13 we require all of our consent forms at our El Paso 14 campus where our patient population is predominantly 15 Spanish, I mean, about 90 percent and all of our 16 consent forms have to be in both English and Spanish. 17 Also the Backpack Project is another one 18 which is going to be a collection of recruitment best 19 practices, as it were, existing evidence-based and 20 promising practices to support those addressing the 21 elimination of disparities in clinical trials and this 22 will involve government, private and nonprofit 23 entities. We will also look at what goes on at 24 exemplary sites in terms of recruitment of minorities 25 and under represented participants and also the review 197 1 process. 2 So what we need is a culture change. That 3 is the underlying premise for my being here today. 4 What was the original impetus for the current 5 legislative and regulatory environment for clinical 6 research oversight? The most immediate concern is 7 safety and protection from exploitation. The Belmont 8 Report also has a clear emphasis on equity and 9 justice. However, today's oversight bodies are 10 generally more concerned with participant safety. 11 This is what they have been trained and told to do. 12 However, some see justice and equity to be completely 13 outside the purview of human subjects research 14 oversight. Most IRB members would tell you this is 15 not our concern. We are concerned with safety of the 16 subjects. 17 So while it's most immediate concern, or 18 IRBs' most immediate concern, was the concern for 19 patient safety on the heels of such tragedies such as 20 thalidomide and exploitations such as the Tuskegee 21 Project, the Belmont Report does have a very clear 22 emphasis on equity and justice in both allocation and 23 the burdens and the benefits of clinical research and 24 I think Dr. Corbie-Smith has already addressed that. 25 So we are pushing for a need for change in 198 1 this thinking. We propose that a significant culture 2 shift is in order to rehabilitate the original intent 3 and impetus of human subject research oversight in 4 this country. What this might look like is 5 accountability and enforcement of enrollment for 6 equitable inclusion in clinical trials. 7 Research design takes into account not 8 only equitable participant accrual, but also 9 differential plans for the retention of under 10 represented populations. We review these at the NIH 11 scientific review level, but most IRBs do not really 12 address these issues specifically in their IRB review. 13 Now would this look like in terms of this 14 culture change? First of all, investigators and 15 sponsors regardless of whether they're with 16 pharmaceutical, private sector or NIH or other Federal 17 Government are held accountable for equitable 18 inclusion with the inclusion policies and regulations 19 that are bolstered with real oversight and enforcement 20 power, not just the NIH. And that research design 21 would not only actively address issues of literacy, 22 language and socioeconomic barriers to enrollment, but 23 will also formulate differential plans for retaining 24 minority participants in clinical trials. 25 Now inclusion policies cannot summarily 199 1 exclude those with disabilities or co-morbidities that 2 don't significantly heighten the risk to participants 3 or that don't compound the science. This is a key 4 issue. Many times patients with co-morbidities are 5 excluded from participation in clinical trials simply 6 because it's just easier to design a trial that way 7 and your data might be a little cleaner. 8 But the real world is not like that. Most 9 patients are on more than one prescription drug and to 10 exclude them from participation in a clinical trial 11 may not actually test what's going to happen to that 12 drug in the large populations after that drug is 13 approved by the FDA. Perhaps the CFR is amended to 14 require IRB composition to be more representative of 15 the community in which the trial is to take place. 16 And, finally, consent forms and 17 instructional material as well as interpretation 18 services should be made available in all the area's 19 major languages, perhaps any language spoken by at 20 least ten percent of the area's population. 21 So what would this look like further? 22 Researchers would have to include the disabled and 23 those with co-morbidities and especially the elderly 24 in their design for their clinical research with an 25 accompanying budget. If we amend the CFR to require 200 1 IRB composition to be 20 percent perhaps community 2 representatives, that might approximate the 3 predominance of racial and ethnic groups in the 4 institution service area. 5 And finally, IRBs in institutional 6 research offices require that consent forms and 7 instructional material as well as interpretation 8 services be made available so that there is no reason 9 not to ask participants who don't speak English. 10 Another project that is part of the EDICT 11 overall project is a field demonstration research arm 12 that is designed to test the effect of various 13 interventions on participant accrual and retention in 14 cancer and asthma trials when it's applied to under 15 represented populations as compared to no 16 intervention. 17 So what we will actually assess is what 18 interventions are successful in increasing 19 participation of minorities and the under served in 20 clinical trials. This is the basic study design. 21 This is ongoing at Baylor College of Medicine. The 22 two arms are develop the protocol and obtained the IRB 23 approval and this would be a historical data 24 collection as is usually done without specific 25 intervention. 201 1 But the intervention group is going to 2 actually test a number of these ideas and best 3 practices that we are collecting to develop 4 intervention tools that will look at the differential 5 recruitment of minorities and the under served in 6 clinical trials. This is going to start with cancer 7 in minority trials, but certainly can be expanded to 8 all types of clinical research. 9 With that, I'll close. Thank you very 10 much. 11 First of all, I'd like to mention also 12 there is a handout I put back on the table back there 13 and it's "Cancer Clinical Trials: Preparation by Under 14 represented Populations" and it's put out by the 15 Intercultural Cancer Council and it's available. 16 CHAIR TILDEN: Okay. Thank you. In the 17 interest of time, I was hoping that we could just move 18 right into the panel discussion and avoid a break 19 because of travel schedules, etc. I would like to 20 maintain the maximum benefit of the panel. So if the 21 panelists would come up, we could get started with 22 questions. 23 (Pause.) 24 CHAIR TILDEN: James, do you have any 25 questions or comments for the panelists? 202 1 DR. POWELL: I think I'd like this chair, 2 the end chair. I get to go first every time. 3 CHAIR TILDEN: Every time. That makes me 4 last every time. 5 DR. POWELL: I have a lot of questions, 6 but I'll focus only on one since I've been involved in 7 drug development for some time. First of all, I think 8 the presentations were very good and I really enjoyed 9 them. I appreciate everyone coming to share this very 10 useful information. 11 The one thing I would like focus on is 12 I've been involved in drug development and I know that 13 a lot of time we use these tools such as enzymes to 14 develop new drugs to try to identify what's going to 15 happen in humans and quite often we learn a lot of new 16 things when we actually put them in place, put the 17 trials in the field and we find out things don't work 18 quite as they did in the laboratory and in our smaller 19 scale clinical trials. Obviously, that's the reason 20 we do large clinical trials to be able to understand 21 how most of the population might react to a particular 22 product. 23 But what I want to focus on is one 24 particular situation that caused me, one of the 25 reasons that we began this discussion about 203 1 harmonizing the regulations with respect to NIH and 2 with the FDA and the particular example that comes to 3 mind is the large mortality trials that one might 4 conduct with a new, say, pharmaceutical product and we 5 may without a straight issue to include adequate 6 diversity. Many times those trials will be conducted 7 without a good understanding of what happens in 8 diverse populations. We may get an overall response, 9 but what happens in smaller or in African American or 10 in minority groups may be unclear at the end of those 11 trials and that, of course, does not allow adequate 12 instruction to physicians on what's best to do. 13 Although we still make assumptions and move ahead with 14 how we might treat a patient on the basis of those 15 trials. 16 One of my questions that I would like the 17 panelists to address is do they feel it consistent -- 18 one of my concerns is, is it consistent with the 19 Belmont Report, a beneficence that any one patient in 20 those trials who at the end of the study don't get a 21 result that really has implications for that part of 22 the population. Is that in a sense meeting the 23 requirements of beneficence or justice in that we 24 don't have information on how to actually use the 25 product in the part of the population of the community 204 1 from which that particular individual comes? 2 So I don't know if -- Hopefully, you get 3 the point of the question meaning that we really want 4 those trials to be applicable to everyone in the 5 population and sometimes we get to the end of those 6 studies and we are left wanting with respect to how to 7 really use a product in a particular part, a minority 8 part, of the community and that to me does not 9 necessarily fit within the construction of the Belmont 10 Report. Comments. 11 DR. PENCE: They're all looking at me. 12 CHAIR TILDEN: We'll let Giselle organize 13 the group here. 14 DR. PENCE: Okay. In my opinion, I think 15 it is a social justice issue. I think it's also a 16 medical issue in the same way that treating children 17 with a drug that's never been tested on children and 18 assuming efficacy and safety for children just because 19 you may have ratcheted the dose stand a little bit or 20 whatever you've done. So I think there are two issues 21 there and I do agree that it is a social justice issue 22 and not consistent with what we are expected to do in 23 terms of the Belmont Report. 24 DR. CORBIE-SMITH: I am -- I struggle with 25 this question and I struggle with it -- I guess I 205 1 should say I feel the most comfortable addressing the 2 question around the issue of distributive justice and 3 making sure that those who are most likely to benefit 4 from the drug, device or what have you, or participate 5 in the studies in a manner that speaks to their 6 distribution or the prevalence of the disease and so 7 on. 8 And let me just say that I struggle with 9 your comment because it supposes a physiologic 10 difference between races and that's the part that has 11 me uncomfortable. And so it's a fine line that, I 12 think, your comment and your question walks because I 13 think there are ethical reasons to make sure that 14 there is diversity within clinical research that do 15 speak to the issues of justice and appropriate 16 distribution of risks as well as benefits and value. 17 But I do struggle with this issue of an 18 underlying assumption that we're going to see 19 differences based physiology or genetics or etc. 20 because I think that ends up being a very slippery 21 slope that we have to be very careful about in terms 22 of supposing that there are genetic differences 23 between races. 24 DR. SACKS: Perhaps I can just add to 25 that. Actually, I agree with the comments of Dr. 206 1 Corbie-Smith. Our experience has really been that, at 2 least in the realm of drug approval, ethnic 3 differences haven't made a major contribution to the 4 way drugs work. I did distinguish in my talk between 5 approval of drugs versus utilization of drugs, 6 programs, I guess, regimens we use, etc. which really 7 fall into the realm of medical practice and may be 8 affected by many other social co-factors. But in 9 terms of the actual genetic structure of trial 10 participants, I don't think that race has that much of 11 an implication, except, for example, some partitioning 12 or, at least, unequal distribution of certain genes. 13 I don't know if that -- 14 DR. POWELL: Yes. Interestingly enough, 15 in my work in drug development, I haven't found that 16 many differences that were ethnic differences either 17 because when we've seen them and we've explored them 18 more thoroughly, we've found other reasons why one 19 part of the population, the minority population, 20 appeared to respond differently and I can tell you a 21 little story about a study that we thought, a drug 22 that we thought, showed a difference in the Japanese 23 population only to find out when we explored 24 carefully, it was a difference due to the smoking 25 habits and the exposure to smoke. 207 1 And we've seen many cases where we've done 2 a trial in a diverse population and we've seen one 3 part of the population responding differently. It did 4 not turn out to be a genetic difference. It turned 5 out to be something else associated with that 6 particular part of the population. So we've seen that 7 a number of times and we've seen that in drugs that 8 are in the marketplace where in fact we later find out 9 there's a difference, an ethnic difference but later 10 on determine that there's something else with the way 11 the drug is administered in a part of the population. 12 The point is if we don't study a diverse 13 population and we assume certain things of how people 14 respond, then we won't know and that's the reason why 15 we think, I think, it's important that we have 16 diversity in clinical trials. 17 DR. CORBIE-SMITH: I would completely 18 agree with your last comments and say that often times 19 people actually don't go to that next step. They find 20 a difference and assume that there's some biologic 21 basis and that's -- We're all a product of the society 22 we live in and I think what I would ask is that we 23 continue to ask people to push beyond simple 24 explanations for complex problems. 25 CHAIR TILDEN: David, you wanted to ask 208 1 questions. 2 DR. STRAUSS: Certainly. I just wanted to 3 follow up on that specific point because there's an 4 enormous ethical mandate, I think, to address health 5 care disparities and to improve therapeutics for all 6 groups and especially those that have been under 7 served and under represented before. 8 But the question for me as a policy one is 9 does it make sense to promote across the board 10 diversity in all studies all the time, which may have 11 a downside to it as I see it. It may send the message 12 that we need to fill our slots with people and I think 13 the risks, of course, have to deal with recruiting 14 people who aren't seeking access to experimental care, 15 but people who, for example, might obtain clinical 16 care through research, right, because they can't 17 afford clinical care otherwise as opposed to an 18 approach that might be more, let's say, scientifically 19 or rationally based in which there's targeted and 20 mindful attention to the kinds of research that James 21 is talking about, research which would at some points 22 cast a wide net to identify possible associations 23 between race and physiological differences and then 24 narrow in. 25 The question is, is the approach to 209 1 mandate diversity in every clinical trial. Is that 2 the best approach for us as a society? 3 DR. PINN: I think the answer to your 4 question is no as an absolute, but in fact, go back to 5 how we've tried to implement the policy at NIH which 6 is to look at the populations that are affected by the 7 disease or may be affected by the medication under 8 study or by the intervention that is being studied and 9 to make sure and to then use that as a scientific 10 basis for deciding which populations should be 11 included in clinical studies which is why we have, at 12 least at NIH, have concerns about so often just seeing 13 data and how comments are being made simply looking at 14 inclusion numbers based upon population data rather 15 than looking upon effected populations for what's 16 under study. So I think the answer absolute as you 17 asked it is no, but in specifics in terms of looking 18 at diversity of clinical trials that we do have an 19 obligation to consider including the diversity of 20 those populations that are affected. 21 And going back to the previous question, 22 I'm glad I didn't really have to answer that, but I 23 guess I should make a comment and I'll start by saying 24 long before you went to FDA and long before I went to 25 NIH when I was a private citizen and I was President 210 1 of the National Medical Association and this was in 2 the `80s, so it was over 20 or about 20 years ago and 3 I was leading a delegation to ask why minorities 4 weren't being included in clinical studies, in 5 clinical studies I've since learned, I've been 6 educated, at that point we were asking why minorities 7 were not in clinical studies of the FDA. I now know 8 that FDA doesn't really per se do them. They really 9 come from industry. But I remember sitting in that 10 room and being told clearly there were no differences 11 between races in response to drugs. I didn't know at 12 that time I was going to end up handling this issue 13 for NIH, but it's also made me much more tolerant and 14 patient when people come to ask me similar questions 15 about NIH. 16 But I think as I think back that was 20 17 years ago. We're really talking the same question 20 18 years later. I hope we have a better and a broader 19 perspective but it still comes back down to does race 20 matter. I like to -- I was so pleased you talked 21 about the BiDil controversy, the racial controversy, 22 because we hear a lot of that in terms of our policy 23 and as I think some of you know, there have been a 24 couple of papers published suggesting that authors 25 should not use race in describing their patient 211 1 populations. 2 But I sort of go back and I've forgotten 3 which author it was but the one of the editorials of 4 policy pieces in The New England Journal in response 5 to the BiDil controversy ended up saying and what Ann 6 Taylor who was the lead author on the BiDil paper have 7 both said which is until we have definite 8 determinations for differences that race may serve a 9 purpose as a surrogate marker for other conditions 10 that may affect the outcome of an intervention. That 11 may be not an exact quote, but I know the word 12 "surrogate" was used and that is how I have sort of 13 approached this issue as we go forward. 14 When someone replaces on my driver's 15 license African American or black with my genotype or 16 something else, then I can relate to not looking at 17 race. But as long as that's how I'm characterized, 18 then I'm really going to have concerns about how I and 19 people like me and maybe we won't be different but it 20 is the best, it is the most, I won't say the best, it 21 is the most commonly used surrogate marker, but it may 22 help us distinguish other contributing biological or 23 social factors that are the determinants for our 24 outcomes. 25 CHAIR TILDEN: Other questions? Dan? 212 1 MR. NELSON: Thanks from me as well for 2 all of your presentations including my own department 3 colleague from UNC. You would think two faculty in 4 the small department wouldn't have to come up here to 5 see each other but we're all busy people. So thanks 6 to you all for speaking to us. 7 My mind jumps rapidly ahead from the 8 conceptual and ethical issues that have been laid out 9 very clearly to ask what practical recommendations we 10 should be considering to address these issues. In 11 other words, how do we operationalize this beyond what 12 we're already doing? So I guess the question is if 13 you had a direct pipeline to a group that could impact 14 federal regulation or interpretation or guidance which 15 happens to be the chairs we're sitting in right now 16 with, at least, the opportunity to consider 17 recommendations and pass them forward to the 18 Secretary, what would they be? 19 I heard, at least, one quite concrete 20 recommendation or suggestion toward a mandated 21 percentage of IRB members considering studies. That 22 immediately starts to raise some practical operational 23 issues if we say 20 percent which is good in concept, 24 difficult in application as so often these things are. 25 If we say 20 percent of the IRB membership, well, if 213 1 you have an IRB with 10 or 15 members that we're 2 talking two people to represent the community and then 3 it's fleshed out by all the scientific expertise 4 needed to look at things and if you think about an IRB 5 in the middle of a large city, you might have 20 6 groups represented in a few square miles. How do you 7 really put -- how do you satisfy that requirement and 8 make it meaningful at the same time we satisfy it? 9 But I guess that's not to discount that 10 suggestion and I'm wide open to anything that we might 11 consider and then pass along through the approval 12 pipeline for recommendations. 13 DR. PENCE: I think in terms of concrete 14 recommendations, one of the things that I think our 15 group would like IRBs to consider is just what we've 16 been talking about today is specifically trying to 17 recruit those people who have been under represented 18 in clinical trials for whatever reason because I 19 remember my first experience in doing clinical 20 research which was with the tamoxifen breast cancer 21 prevention trial why back in the early to mid `90s and 22 basically most of the people we ended up recruiting 23 were white college graduates and in Lubbock, Texas, 24 even that was a mismatch and there was no insistence 25 or no requirement that we tried to recruit Hispanic 214 1 women of which our population is 25 percent in 2 Lubbock, Texas. 3 So I think one of the things that we 4 really want to promote is that this becomes something 5 that IRBs look at because of the issues of leaving 6 them out. It's a justice issue if they don't get the 7 opportunity to even be asked to be in clinical 8 research. So I think that is why we are proposing 9 that at this level. 10 DR. CORBIE-SMITH: I would -- In terms of 11 responding to your comment, Dan, I would suggest that 12 and not having served on an IRB before and I'm not 13 necessarily requesting to serve on an IRB either. 14 MR. NELSON: There's a vacancy coming up 15 back home. 16 (Laughter.) 17 DR. CORBIE-SMITH: I would suggest that 18 there might be ways to have ad hoc members for 19 particular projects so that while the standing 20 membership might need to be fixed, say, at the 20 21 percent or whatever proportion you choose, that ad hoc 22 members to review particular protocols, specifically 23 ones that might be race specific or single race 24 studies, might be a way to sort of round out the 25 perspectives of different groups and have them come 215 1 into bear on the review. 2 DR. PINN: A couple of things. One, and 3 correct me if I'm wrong, Joan, but I believe when the 4 law was first passed and we were trying to deal with 5 who was going to monitor the studies early on I 6 remember the directive that was sent out or it wasn't 7 really a rule, but you might go back and take a look 8 at the original language that was given to IRBs about 9 their role in monitoring and looking at studies that 10 come before them because I know there was a lot of 11 concern by IRB chairs about taking on this new 12 responsibility and was it really the role of the IRB 13 and, as I recall, there was a directive from this 14 office that suggested that it wasn't a direct 15 responsibility but that it was a role that there was 16 a value for the IRB to assume. Then I remember we had 17 a couple of major meetings with IRB chairs to address 18 the issue and their role in helping to implement this. 19 But it might just be worthwhile. 20 Actually, that's buried somewhere in my laundry room 21 that original language from back then. Hopefully, you 22 have somewhere in your files. I actually would like 23 to see it again because I'm thinking it's been 24 questioned whether or not we should go back to IRB 25 chairs and address this issue again and get a take on 216 1 it this many years after it was passed. 2 But the other issue is related to, that I 3 think is important that we hear a lot from our 4 investigators, the fact that NIH has a requirement, a 5 policy based in statute, that requires inclusion of 6 women and minorities, but that that policy does not 7 relate to the pharmaceutical industry and many 8 investigators have funding, both federal funding from 9 NIH and have funding from pharmaceutical companies, 10 from industry, and as you've heard earlier perhaps a 11 greater amount as our dollars shrink, even a greater 12 amount from industry and yet in trying to review 13 studies and requirements for investigators who have 14 dual funding, how to resolve those issues of what's 15 required, what must be, what may not be, when you 16 you're dealing with both industry and NIH funding. 17 And I don't -- we often hear -- you probably know more 18 about this than I do, but we hear a lot of concern 19 about that from investigators about that issue and 20 about it also being a concern in dealing with IRBs. 21 So perhaps somebody can define it better 22 than I have, but as you look at this issue related to 23 inclusion and IRB roles and industry versus federal 24 funding and those implications, I think that may be an 25 area that could some further examination. 217 1 DR. SACKS: Can I just make a comment I 2 guess in an attempt to disentangle a couple of 3 concepts which I think we haven't separated here? The 4 question being what is the purpose of including 5 diversity or addressing diversity in clinical trials 6 and, in fact, there are two different aspects that 7 have to be thought of. 8 The one is the bearing that ethnic 9 diversity has on the results and I think we've spoken 10 about that at some length and, in general, the 11 consensus is that race, for example, doesn't have a 12 big bearing on how people respond to drugs. The other 13 thing is access to clinical trials and a fair 14 consensus of clinical trials are superiority studies 15 where potentially there is a benefit within the 16 clinical trial to the actual participants and in that 17 setting, I think, access to clinical trials for 18 minorities is important to address. I think they are 19 two different concepts which perhaps we haven't 20 separated yet. 21 DR. BOTKIN: I have two questions. One 22 was more specific and then the second a little bit 23 more general and the first one has to do with 24 resources that would be available for helping in this 25 effort and I think one of the things that I would say 218 1 our IRB tends to see is that recruitment is across the 2 board. Folks will recruit anybody who shows up in 3 clinic who meets the inclusion criteria including 4 minority groups, etc. But yet frequently there's not, 5 in those circumstances, a specific recruitment plan or 6 resources targeted at minority populations or 7 specifically, Spanish-speaking populations unless the 8 study is particularly targeted to those particular 9 groups. 10 I guess my assumption is and I'm looking 11 at Drs. Pinn and Sacks here, from agencies' 12 standpoints that the agencies would be open to funding 13 additional resources at the application phase to help 14 specifically recruit individuals in minority 15 populations. I don't know how often that shows up 16 within the application or how the applications are 17 necessarily designed to foster that. But we 18 frequently find as an IRB when we turn to 19 investigators and say "What is it that you're going to 20 do to help recruit Spanish-speaking individuals," it's 21 "Well, we don't have money for translation." The IRB 22 used to pay for translations, but we can't afford that 23 any longer. So sometimes simple resources may not be 24 available. 25 So would it possible for the NIH and the 219 1 FDA to foster particular attention to the additional 2 resources necessary to adequately recruit these 3 individuals and should IRBs be specifically looking at 4 resources that are available within the context of a 5 trial to say "Are these folks serious about recruiting 6 these folks or have they simply just said their 7 inclusion criteria include minority groups and we're 8 happy with that as a sufficient nod to justice?" 9 DR. PINN: Well, the short answer is yes, 10 but no, in that I don't want to make commitment for 11 NIH in putting out lots of funds. But if you look at 12 the law and what it says, when you apply to NIH for a 13 clinical study, clinical research or clinical trial, 14 you are required to include populations and you are to 15 include an outreach effort as part of your description 16 of your plan of how you -- meaning that you should be 17 including as part of your grant application your plan 18 for how you're going to obtain those individuals to be 19 part of the study. 20 When I first went to NIH, when the office 21 first started and before the Revitalization Act was 22 implemented in `94, the first moneys, our first 23 budgetary moneys in the Office of Research and Women's 24 Health were spent as supplements to fund investigators 25 who said we have studies with men. We need money to 220 1 help recruit women. After the law was passed, I 2 didn't do those supplements anymore because it was a 3 requirement. If you were going to be funded by NIH, 4 you were supposed to include both women and men. So 5 it should have been part of your basic research 6 application and the same here. 7 Now I can't say that if people have -- I 8 mean costs -- The law says costs cannot be a factor. 9 So I can't say other than that because that's what the 10 law is. The reality is we're looking at funds and 11 we're looking at budget and budget cutbacks. But that 12 should not be a reason to -- I mean if someone is 13 looking and describes that as part of an application 14 and it's justified, it should not be a reason to cut 15 that out of the budget. So I don't know that that 16 happens. Maybe it does and I'm not aware of it. 17 So the basic answer is that it is at least 18 by law that is expected and should be done. Now we do 19 know that we see that often people build in or maybe 20 they don't build in a request for minority recruiters 21 or for outreach for certain populations and I know 22 that both the National Center for Health Disparities 23 and many of the Institutes have outreach. 24 But just look like what I showed you for 25 that Ruth Kirschstein Award we're seeing hopefully and 221 1 I made a list, I didn't try to present it, of many of 2 the studies where there's particular outreach to 3 minority populations if we can still use that term 4 where built in as part of the grant is a plan for how 5 to do that. Now I'm not saying it's always done and 6 perhaps there needs to be more focus on it, but the 7 answer is by law, yes, that should be part of the 8 original budget and it shouldn't have to be added on 9 as an additional expense. Practically, how it's 10 working, you'd have to tell me. But from our vantage 11 point, that should be part of it. 12 DR. PENCE: I can address the issue of we 13 do look at that and it's part of the budget. It's not 14 a particular -- It doesn't stand out. It's just that 15 if they are going to specify a minority population 16 that they are planning to recruit they have to outline 17 specific recruitment strategies to address that 18 population. 19 DR. SACKS: Just the FDA onus is a very 20 simple one. We don't pay people to do clinical 21 studies. In fact, we get paid by people who do the 22 clinical studies to review them. So really the only 23 impact we can possibly have on recruitment is in the 24 situation where it becomes an approval issue where 25 there's a concern about a particular racial group or 222 1 a subgroup and we have the prerogative not to approve 2 the drug or to request for the information. But 3 funding is not really within our purview at all. 4 DR. BOTKIN: Well, it sounds to me from 5 that response that it may not be unreasonable for IRBs 6 to hold investigators' feet to the fire to a greater 7 extent to say "Show us the resources that you're going 8 to allocate to do the recruitment that you say you're 9 going to do" as opposed to again, I think, a lot of it 10 tends to be somewhat passive which is "We're going to 11 recruit everybody who walks into this clinic with this 12 diagnosis" and then it may get passed to the IRB to 13 say "Well, tell us what that means in terms of your 14 Spanish-speaking patient population or potential 15 participants. 16 Second -- 17 DR. PINN: Or at least it should be part 18 of the plan and remember there that you're required to 19 submit target data of which populations you're 20 planning to study. So there should be described some 21 outreach activities to the different -- if there are 22 different needs related to recruiting and retaining 23 different segments of the population that are 24 described in terms of the target population. Yes, 25 that should be described and I think it would be 223 1 certainly reasonable to hold investigators' feet to 2 the fire to make sure they really are committed to 3 what they're putting on paper they're going to do. 4 DR. BOTKIN: Yes, and, I guess, as a study 5 section member, too, I would say what I tend to see is 6 that if you're anticipating ten percent of the 7 population that's going to be recruited is Hispanic 8 that that description per se ends up being perhaps a 9 satisfactory recruitment plan as opposed to having 10 more substance to say "Well, tell us about that ten 11 percent and how you're going to make special 12 accommodations to make sure that those folks are 13 accommodated within your research." 14 DR. PINN: But isn't that often what we 15 see makes the difference between a study that is 16 successful in recruiting diversity of populations 17 because they've thought it through and understand what 18 it might take as opposed to those who list what they 19 think they should list and then flounder in terms of 20 bringing in populations. 21 We have had some major studies where we've 22 met with -- Our office has been co-funders along with 23 the Institutes where we've met with investigators from 24 certain centers who had a commitment to bring in 25 certain segments of the population that represent 224 1 diversity especially from multi-center sites and where 2 they were not going well and where they knew that 3 their funding may not continue and we've seen all of 4 a sudden a scurry-up and all of a sudden they become 5 smart in how to reach out to those populations when 6 there is a threat of losing, not a threat, but it's a 7 reality. If they don't meet by accrual what they've 8 indicated they're going to do and what's looked at in 9 terms of a multi-center trial in terms of meeting 10 diversity, funds may be pulled. But it's too bad 11 because we should have that concern right up front in 12 terms of commitment to populations in the study. 13 DR. BOTKIN: My question, I guess, sort of 14 relies to this as well which is I think a lot of the 15 discussion is how is that investigators and perhaps 16 sponsors can do a better job in this regard. But I 17 think what we know about why people agree to 18 participate in research has a whole lot to do with 19 trust and if there isn't trust in the community with 20 the research enterprise then recruitment is going to 21 be a real challenge. 22 What opportunities or what strategies 23 might you comment on to help enhance trust within 24 minority communities in order to enhance the research 25 collaboration? 225 1 DR. CORBIE-SMITH: I would say actually 2 that I would ask you to sort of flip or at least 3 change the perspective a little bit and think about 4 what the research enterprise can do to demonstrate 5 their trustworthiness rather than going out to try to 6 gather a little trust because the onus then is on the 7 participant as if there's something wrong with the 8 potential participant and frankly, I don't think we've 9 done a good job of demonstrating our trustworthiness. 10 I mean, the earlier panel, I think, just 11 even letting the families know what happened in that 12 study to me would have engendered a tremendous amount 13 of trust. You know, the panel this morning just 14 really demonstrated how important it is to keep that 15 circle going. I think Barbara's work in terms of 16 returning results back to communities so that people 17 understand what their participation means could go a 18 long way. I think the reality is that the trust in 19 medicine and research has eroded tremendously in the 20 last several years and we have to do a much better job 21 of demonstrating that we are, in fact, trustworthy. 22 CHAIR TILDEN: Okay. Mike? Neil? 23 DR. GENEL: Well, I've been struggling 24 with some of this and let me just throw out a basic 25 premise and invite your comment. To paraphrase a 226 1 former member of the Administration, it strikes me 2 that there are clinical research trials conducted in 3 the health care system and the society we have rather 4 than the system in society we would like and that to 5 some extent, the mandates are really a substitute for 6 an aspirational goal rather than any way to correct 7 the problem and just an observation and I invite your 8 comments on this. 9 DR. PINN: I'll just say that, yes, it is 10 aspirational and I guess my feeling is as James has 11 said, as Barbara has said, as others have said, that 12 just as we hope to address all segments of the 13 populations address health disparities, that as we 14 look at research where it's conducted and what the 15 possible outcomes are, that we can only hope that by 16 looking at issues related to inclusion of diversity of 17 populations that we are somehow bringing information 18 from and to those segments of the populations that may 19 not have access to all these fine things we're talking 20 about. So I guess we do build hope into what research 21 and diversity and participation in clinical research 22 can bring and the benefit that can be gotten. 23 But you are right. It's sort of theories 24 are sort of built on what we aspire to instead of what 25 we have. But if we don't work towards it. We may not 227 1 ever have it. I don't know if that makes sense. In 2 my mind, it makes sense. How I said, it may not, but 3 I have to agree with what you said. Barbara, you look 4 like you want to say something. 5 DR. PENCE: I think, yes, it is 6 aspirational. But if we don't try, we won't change 7 anything. So maybe that's idealistic. I think there 8 are ways we can do the experiment, do the study, make 9 the effort and see what the outcomes are. 10 DR. GENEL: I can't -- I won't argue. I 11 can't argue with that. It's just that I think the 12 problems we're talking about are not problems of our 13 clinical trial system. They're problems of our health 14 care system and problems of our society. 15 DR. PENCE: Absolutely. 16 DR. CORBIE-SMITH: I would actually say 17 they're problems in our society. 18 DR. GENEL: Yes. 19 DR. CORBIE-SMITH: That are reflected in 20 our health care system that are reflected in clinical 21 research. 22 DR. GENEL: The other is a little more 23 pragmatic. Just your recommendation, Dr. Pence, 24 regarding the role of IRBs, I'm just wondering how 25 that might be -- how that might work in what we're 228 1 hearing about about multi-center trials and trials 2 that are conducted and that would require the 3 engagement of multiple IRBs. I can imagine that some 4 of the things that you've suggested would be 5 problematic in that type of a scenario. 6 DR. PENCE: If they use a central IRB for 7 the trial which we do not use at our institution, but, 8 in that regard, that IRB would have a lot of, I guess, 9 clout as it were to basically evaluate the recruitment 10 plan and the minority distribution or the under served 11 distribution or the efforts to recruit the under 12 served in clinical research and if they're using local 13 IRBs like we do at our institution for all of the 14 trials, many of which are multi-centered, then 15 individual IRBs could take that on. 16 For instance, one of the things that 17 really irritates me is something that will be approved 18 by the IRB where one of the exclusion criteria is does 19 not speak English. I mean, we're in Texas. Give me 20 a break. That should never be an exclusion criteria. 21 And IRBs should make an effort to really look at these 22 things. 23 I mean, I can remember when the IRBs in 24 our institution always said, "It's not our issue to 25 pass judgment on scientific merit." Well, then it 229 1 became apparent that it is their responsibility 2 because research is not going to go anywhere. By its 3 very nature, it's unethical. So I think there are 4 ways for individual IRBs to deal with that. We always 5 have input into the recruitment in our own patient 6 area, even though study site number 451 for a certain 7 pharmaceutical company. 8 DR. POWE: I just want to thank each of 9 the panel members for coming and discussing this 10 delicate but important issue with us. I have a 11 question for Dr. Pinn and then I have one for the 12 whole panel. 13 NIH has been collecting now a lot of data 14 about minority enrollment in studies and it makes me 15 think that we could learn more from that experience. 16 For example, they collect data on targeted enrollment 17 as well as then actual enrollment achieved and I 18 wonder do those forms that I send in ever meet up and 19 does anyone ever hold me accountable to my plan. I 20 mean as a researcher if I think about it and I have a 21 plan and I actually say I'm going to do something, am 22 I more likely to actually achieve that and then what 23 goes to that, if you don't have any oversight like 24 that and you're in a non NIH trial, do we have any 25 evidence that actually an NIH-funded trial achieves 230 1 better recruitment goals than an industry sponsor? Is 2 it really evident for that? 3 I began to think about this and you could 4 look at an investigator-initiated grant like an R- 5 mechanism versus a cooperative agreement like U- 6 mechanism where there might be a more heavy hand by 7 the NIH than in an investigator-initiated one and are 8 there differences in meeting recruitment goals between 9 those types? What this would argue is if, in fact, 10 the teeth being there help us achieve this that, in 11 fact, maybe we should put more teeth into this? A 12 good example might be what Dr. Pence talked about of 13 should we now require information on retention, not 14 just targeted enrollment and achieved enrollment, but 15 actually who is being retained in studies? 16 So that's my first question as to whether 17 -- What can we learn? 18 DR. PINN: And not an easy question. Let 19 me see if I can answer this briefly. One thing and 20 one thing I guess that does concern us is that when 21 we're talking about data and we're talking about 22 things that it helps, at least it helps us, if it's 23 distinguished, if somehow we've distinguished between 24 what is NIH funded versus industry funded, instead of 25 lumping all the data together, because there are 231 1 different requirements or lack of requirements, etc. 2 But let me come back because actually I 3 think you posed an interesting question that is does 4 an NIH requirement maybe affect what's happening in a 5 site that's getting part funding from NIH where 6 there's a requirement and part funding not. I'm not 7 sure about that. 8 You asked the target data. We haven't 9 really published the target data because we have eased 10 into that. You can't imagine or maybe you can imagine 11 what a complicated process it is trying to collect 12 data on the numbers of women and minorities and men 13 who are included in studies and then with the change 14 in OMB classification, differing categories, and then 15 trying to monitor, etc. So we haven't even thought 16 about how we're going to start reporting. We've 17 thought about it, but we haven't come with an answer 18 about how we would report that to you in data like the 19 data charts I have for inclusion. 20 But we've seen a transition into including 21 target data and having it be evaluated and, actually 22 just a few months ago, we had another training session 23 of all the NIH program people who must handle NIH 24 grants to both explain the inclusion policy, what it 25 means and what expectations are which included then 232 1 and hopefully will have a better recognition of the 2 importance of not only evaluating target data in the 3 initial consideration of a grant for funding but also 4 in looking at the accrual and comparing it with target 5 data in terms of progress reports for continued 6 funding. 7 So, yes, the data that you enter as target 8 data and then when you enter your accrual data is 9 supposed to be considered. One of the slides that I 10 showed, showed where we have the chart that you fill 11 it in. You know. For those who don't you fill in 12 what your target data was and what you have accrued 13 and whether accrual and retention, I mean, if you were 14 bringing people in and then you're losing people, your 15 accrual data should reflect that because you're not 16 supposed to just report who brought you in. But 17 actually what our data is looking for is the number 18 who are enrolled in NIH clinical studies in the year 19 in which we are reporting. So we aren't looking at 20 how many you've recruited over 50 years, but how many 21 are in the study this year. 22 And that is supposed to be the role of the 23 project officer at NIH in the Institute in evaluating 24 the progress reports and the info that comes in. So 25 from our vantage point, yes, it should make a 233 1 difference. It's supposed to be making a difference 2 and I have to hope it is and what the NIH Institutes 3 report to us is that it is. 4 We do know that there are instances as I 5 referred to a few minutes ago where the recruitment or 6 where the retention has not been where it is and where 7 we've had to deal with where, at least in those where 8 I've been involved anyway, we have gotten back to 9 investigators to indicate you have to assure of what 10 you're doing or your funding won't continue. 11 Is it universally being held to? I don't 12 know. I'd like to know if there are examples where 13 someone experiences that. I just found a grant that 14 got through that had a male only population because 15 they came to us to ask for money to be able to add 16 women. Should never have gotten through the review 17 process. That will be a topic of discussion at our 18 next tracking meeting of how did this happen. We'll 19 be addressing that, but if there are issues we find 20 out, we'll do what we can to shore it up. 21 I'm not sure I can answer how that really 22 should affect -- I don't think I can really tackle the 23 industry issue because I'm not involved in there. I 24 hope that gives you a response. Bottom line is, yes, 25 it should make a difference. It's supposed to and 234 1 from what we're told and from what we tell those who 2 handle grants it is to make a difference and if it 3 isn't, then we need to know about it if you have 4 experience that it's not being looked at. 5 And as for reporting that data, I have no 6 idea how we're going to report it because it should be 7 looked at in terms of an individual study rather than 8 aggregate kind of data. 9 DR. POWE: My second question is for the 10 panel as a whole. Most of you as I understand don't 11 believe that drug efficacy or maybe even safety to 12 some degree is affected by race or ethnicity and that 13 it might not be a reason to mandate, have the same 14 kind of mandates that the -- the same mandates at the 15 FDA as at the NIH. 16 But what would you say to my colleagues 17 who have a new drug and say "Show me that it works in 18 the patients I treat" or my patients who say "Show me 19 that drug works and is safe in people like me" 20 regardless of whether race or ethnicity has anything 21 to do with, in actuality, efficacy or safety? 22 DR. SACKS: Certainly, I'll take a quick 23 stab at that. I think one of the reasons we do 24 clinical trials really is to get an aggregate of data 25 and not to concentrate on the individual. So really, 235 1 I think, it's very difficult to say to any given 2 individual that you're going to have the following 3 response that was shown as a result of the trial. In 4 other words, if there was an 80 percent success rate 5 in the trial, the response in the individual is not 6 going to be an 80 percent response. He's going to be 7 a success or a failure. So I think it's impossible to 8 tell the individual that he's been fully represented 9 in the trial. But, obviously, through the aggregate 10 of data and the information that we know about racial 11 differences, the likelihood that that patient is going 12 to be off the norm is very small. 13 I did also want to mention one other thing 14 which may not pertain directly to what you've been 15 saying, but I know that it perhaps adds a different 16 flavor to what people think about industry-sponsored 17 trials for new drugs at FDA. A large percentage of 18 the data that we review is foreign data. It comes 19 from depending on the stating of the disease minority 20 groups. It comes from European trials. It comes from 21 South American trials. So I think in some sense the 22 data we see is probably more eclectic than most people 23 assume. Anyway, that's my comment. 24 DR. PINN: I'm trying not to talk too 25 much, but I spend so much time on this. Two comments. 236 1 One, just to comment back on the foreign data, that's 2 an issue that we've had deal with. I mentioned it 3 briefly. You may not -- Maybe I shouldn't have 4 because you may not have raised the issue. But it's 5 been a concern because we've had NIH program officers 6 reflecting the opinion of many investigators who apply 7 to NIH who because they are conducting their research 8 in other than the U.S. feel that they should not have 9 to indicate race and not adhere to that. But as I 10 said, in order to get clarification, talk to some of 11 the people who wrote the law and there is no 12 exception. 13 I want to just -- In response, I don't 14 have an answer, but I'm thinking of two things in 15 response to your question. One, at the time that I 16 was a private citizen who raised that question it was 17 because the black cardiologists felt that they saw 18 differences in how some of the hypertensive medicines 19 worked in their black patients as opposed to other 20 patients and raised the question back then and so that 21 was one of the areas like heart disease drove 22 inclusion of women in clinical studies. I think 23 hypertensiveness kind of drove the push to look at 24 differences in medications by race. 25 And then coming back to studies and what 237 1 does it mean, I'm sure many of you may remember, maybe 2 some of you don't, the controversy around mammography 3 and the question about changing the age for requiring 4 or recommending mammography and the push to change was 5 really based on, at least that was when Klauser was 6 still at NCI, there was that consensus panel and the 7 thrust was really that based on a Swedish study and I 8 can remember that there was African American woman, 9 after African American woman, after African American 10 woman at the mike and on the phone and calling saying, 11 "If you're going to raise the age for recommending 12 mammography, tell me and that Swedish study that 13 you're basing this decision on, were there women who 14 looked like me?" 15 Now we can say in science that we should 16 not be making medical decisions based on looks and 17 that gets back into the whole philosophical argument. 18 But I can sympathize with your question 19 even if you weren't looking for sympathy. I can 20 sympathize that I know we had to address that for the 21 mammography issue and for other issues when people 22 want to know when you set those medical standards, 23 were there people like me who were shown to benefit or 24 not benefit from what you're now saying should be the 25 change in standards of practice. 238 1 That's more an observation to reinforce 2 that we do need to address that scientifically and by 3 policy. I'm not sure I know what the answer is. 4 CHAIR TILDEN: Dr. Corbie-Smith had to get 5 a flight. So she had to leave right now. Are there 6 any other comments or questions? David? 7 DR. STRAUSS: I'm sorry that Dr. Corbie- 8 Smith had to leave, but I had a couple questions for 9 Dr. Pinn. First of all, does your office simply look 10 at accrual numbers or do you also look at the extent 11 to which study hypotheses were examined by race and 12 ethnicity? 13 DR. PINN: The reports that we do are 14 within the Office of the Director and to be honest, 15 our accrual reports, and if you look at that thick 16 report and all the data, to me rather than looking at 17 the individual numbers represents trends and 18 demonstrates that at NIH we are monitoring inclusion 19 and looking at numbers. The actual, I wouldn't try to 20 report because, in fact, looking, it really has to be 21 done at the individual trial level. The data that we 22 put in that report comes from the extramural computer 23 system and we have some people here who are the reps 24 within the Institutes who then are reporting what is 25 generated within the Institute. 239 1 So the answer is twofold. There are two 2 aspects to respond to your question. One, the data 3 that we give you is aggregate data that really the 4 major point from that data is that we're showing that 5 we have a system in place beginning with each 6 individual grant review, going through the councils, 7 going through the institutes and then coming through 8 extramural and coming through intramural research to 9 show that we have a system in place to monitor and to 10 track adherence to the inclusion policy, all aspects. 11 But the level of specific detail that you're asking 12 about is actually done at the individual grant level 13 by the program officers who are overseeing the grant. 14 So overall it should work and we wouldn't 15 begin in our office to try to monitor the thousands of 16 grants individually. But putting together an active 17 report that that is hopefully reflecting what is 18 happening within the Institutes and within each 19 division and program office. 20 DR. STRAUSS: Right. So my question 21 specifically then is does the law that you've referred 22 to, one that requires that funding decision, for 23 example, take into consideration the extent to which 24 the investigator proposes or is powered to both look 25 at scientific questions by race and ethnicity. Does 240 1 the law address that? In other words -- 2 DR. PINN: The law. Okay. I think I have 3 your question. Before I give a long answer wrong, 4 tell me. Say it again. 5 DR. STRAUSS: I'll say it again. 6 DR. PINN: Yes. 7 DR. STRAUSS: There's been so much focus 8 on accrual and I guess I just want to make sure that 9 we're not just talking about accrual for accrual sake. 10 But I want to make sure that if IRBs or institutions 11 and NIH is asking to do this that we're doing it with 12 an outcome in mind which is essentially the scientific 13 analysis of data by race. 14 DR. PINN: Yes. There again, I can give 15 you two parts to the response. Yes, the law requires 16 that there be inclusions such that a valid analysis of 17 differences by the language says gender should be sex 18 or by race can be performed. So that is a 19 requirement. And so in looking at the numbers to be 20 included up front, it should be that you're looking to 21 make sure that numbers are being included such that a 22 comparison can be done and in looking at one of the 23 questions, I guess the slide I took out, I had too 24 many, but part of the instruction to those reviewing 25 the data as it's reported in the progress report is 241 1 what is the progress and are there going to be enough 2 participants to conduct that analysis that is proposed 3 or that is required by law. 4 Then we get to the other phase which is 5 something that we've tried to deal with and I must say 6 it's been addressed more in terms of sex/gender 7 reporting than of race, but it gets down to even if we 8 require this analysis and require it as part of the 9 final progress report to NIH, if you look at the 10 literature, the likelihood of seeing it by race is 11 even less than that of seeing it by sex and we know 12 that by sex many journals we don't see those reported. 13 So we have a disconnect between what is required by 14 law so that NIH has to require it in terms of the 15 conduct of the study and how much of that actually 16 gets reported. 17 We don't know. We encourage. We can't 18 require because we do not dictate editorial policies 19 and what happens with journals. But we ask for that 20 analysis. In the final report to NIH, we request, we 21 encourage, investigators to submit those analyses by 22 sex and race in their manuscripts when they're 23 submitted to journals. That's as far as we can go. 24 It has been up to editorial boards and 25 reviewers for what actually gets published and gets in 242 1 the literature to evaluate whether or not this 2 inclusion really is having an impact on how we 3 evaluate interventions in terms of what gets in the 4 literature and what gets out there for use in 5 practice. 6 DR. PENCE: If I could make one comment 7 with regard to that as well. I think scientifically 8 that the inclusion of different groups may not be 9 enough for our primary endpoint analysis, but 10 certainly it can be hypothesis generating, if not 11 hypothesis testing. 12 DR. PINN: You all don't ask easy 13 questions. 14 CHAIR TILDEN: Do you want to do a follow- 15 up? 16 DR. POWELL: Yes, I do want to. Well, not 17 specifically that one, but to something that Dr. Sacks 18 mentioned if I may. In my previous experience, at the 19 IND stage we looked at the epidemiology of the disease 20 and say, "What is the population impact?" It's 21 similar to what you're talking about looking for a 22 target population. What do you see as the barriers to 23 FDA at the IND stage requiring that kind of 24 information especially since you already have guidance 25 regulations that require an analysis by race and 243 1 ethnicity in clinical trials? 2 DR. SACKS: Sorry. I'm not quite sure 3 that I understood. We do have regulations that 4 require that you report that data and we look at that 5 data. But barriers to -- Can you just express that? 6 DR. POWELL: Barriers to targeted 7 inclusions similar to what the NIH requires and given 8 that you are going to analyze these data, one of the 9 questions was how do you use that data. I mean, we do 10 know that there are differences in therapeutic 11 outcomes even we say that race and ethnicity don't 12 affect drug efficacy. We do know that there are 13 therapeutic outcomes that are different in different 14 parts of the population. So the question is what do 15 you see as the barriers to a targeted population 16 approach at the IND stage for new drugs that are 17 entering into development. 18 DR. SACKS: Well, I guess it's a difficult 19 question to answer. I don't believe there's a 20 specific barrier. In other words, FDA would look at 21 the information they were provided with. The question 22 is what conclusions they would draw. If a study were 23 reported in one small section of the community and 24 there were reasons to suppose that it could not be 25 generalized, FDA would have to respond appropriately 244 1 either by not approving a drug or by labeling it for 2 a specific use in populations where it's being looked 3 at. 4 But I can't see that there's a barrier to 5 that. I mean, the initiatives come from people who 6 submit information to FDA. We don't prescribe what 7 they submit to us. We analyze it. 8 DR. POWELL: In terms of -- 9 CHAIR TILDEN: I think the question is 10 just that. What's the barrier to require or delineate 11 certain criteria for submission as opposed to just 12 analysis? That's what he's, I believe, trying to ask. 13 DR. SACKS: I still hope I'm getting the 14 question. 15 CHAIR TILDEN: Well, by basically, 16 adopting a similar approach as NIH has had to adopt by 17 law, or I shouldn't say that, that's 18 mischaracterization, that now is required by law 19 because they obviously had policies before that, what 20 is the barrier to FDA taking the same type of 21 approach, if there is a barrier? 22 DR. SACKS: I don't think there's a 23 practical barrier. I mean, again FDA doesn't mandate 24 these things, but I suppose what you're proposing is 25 that they could. 245 1 I guess, in my view, the practical 2 implication is what are you going to do with that 3 data. One of the problems that I sort of tried to 4 highlight in my talk is that there are so many 5 subgroups in the analysis of charges for the approval 6 of a drug that to give any statistical power to the 7 very small nuances of race over and above the hundreds 8 concomitant medications, the underlying diseases, the 9 differences in sex, the differences in renal and 10 hepatic metabolisms and so on, you're very unlikely to 11 end up with a meaningful result and there is a 12 profound difference in terms of racial handling of a 13 drug. So I'm quite sure that in the ways that we look 14 at it that it would lead to a useful result. 15 Perhaps just to clarify something 16 pertaining to a comment you'd made earlier. There are 17 co-factors that go along with race that we're all 18 concerned about as public health professionals. 19 But I do want to remind you that a lot of 20 trials that support drug development are not replicas 21 of the real life situation at all. They have very 22 controlled inclusion and exclusion criteria and we 23 don't look at the real life utility of the drug. So 24 that's something that falls into the purview of 25 practice of medicine and I think needs independent 246 1 attention. It's not what the FDA does. 2 In other words, we try and exclude things 3 which might make the activity of the drug look 4 different. We try and make our community or at least 5 our enrollees look homogenous. We exclude the 6 influence of other medications. We exclude the 7 influence of prior treatment. We exclude the 8 influence of other diseases which may affect the 9 outcome. 10 So again, just bear in mind that the FDA 11 trials are somewhat artifactual. They don't look at 12 all the community factors that might affect the 13 outcome. 14 DR. PINN: If I may comment with my 15 colleague here because we've done a lot of 16 collaboration mainly in terms of looking at women in 17 clinical research. But remind you that the FDA does 18 have the clinical whole rule and actually if you want 19 to see the origin, that's just historical, I'm big on 20 historical and how things involve, there's a four part 21 section back there from an IRB meeting here that 22 Charlie McCarthy is the lead article and Ruth Merkatz 23 was the first head of Women's Health at FDA summarized 24 this clinical whole rule that had to do with inclusion 25 of women. But there is a clinical whole rule in 247 1 addition to the requirements, the Guidance for 2 Industry on the Collection of Data by Race and 3 Ethnicity. 4 But I did ask if there had ever been a 5 study or a drug that had been turned down because it 6 did not meet the requirements of the clinical whole 7 rule and I've not been able to identify that any has 8 and perhaps the difference may be the scientific 9 things that you discussed in addition to which there 10 are no teeth because there is no law. 11 But FDA does, in fact, have a clinical 12 whole rule with an amendment that was put in place in 13 -- it passed in `93, I think, in the histories in that 14 article if you want to just have it for reference that 15 was then updated after that. But it's a matter -- And 16 I think we were requiring it. But once we had the 17 law, I don't know how you could do a law related to 18 industry, though I think that's such a different 19 situation. 20 CHAIR TILDEN: Just as a matter of 21 comment, CMS has proposed a clinical research policy 22 and I don't know how many people are familiar with 23 this. They proposed it. They, I wouldn't say, 24 withdrew it, but in their reconsideration, they didn't 25 adopt it and then 10 days later, they re-proposed the 248 1 clinical research policy again. 2 The second time they kept the same 3 standards for payment in clinical trials and the 12th 4 of the 13 bullets basically adopted the NIH standards 5 in the sense that any clinical trial what would seek, 6 potentially seek, Medicare payment, and by default, 7 possibly Medicaid payment in the sense that if states 8 adopt the Medicare policy which many states do, that 9 there would have to be a written protocol outlining 10 how the research will address outcomes for 11 subpopulations including women. In fact, Dr. Pinn 12 could probably quote it because I'm sure it comes 13 right out the requirement for minority health, but 14 gender, race and ethnicity, the elderly, etc. 15 So in some respects if that policy, and 16 it's to be finalized in about 60 days, if those 17 standards go through, it may actually result in an 18 ancillary mechanism in which any clinical trial who 19 proposes to have designated services paid by a third 20 party which could include Medicaid or Medicare would 21 have to articulate this as a condition of payment. 22 There's a lot of concern about this policy 23 by a number of stakeholders. But it could actually 24 create a situation where even the privately conducted 25 studies -- because it's my understanding although some 249 1 clinical trials are fully paid for by the sponsor, the 2 majority of clinical trials look to the beneficiary 3 and their third party payor to cover standard 4 treatment and diagnostic portions of the trial and 5 have for some time. So there may be in terms of 6 clinical trials and treatment trials may be another 7 ancillary obligation that one would have to assume in 8 order to help to defray the cost of the trial because 9 CMS is looking at this as support for research. 10 Do you have any comments on that? Do you 11 know anything -- I believe the FDA and NIH were and 12 certainly AHRQ were involved in those discussions with 13 CMS. 14 DR. PINN: I have a side comment, but I 15 won't make public ones. That's all. It's good. 16 CHAIR TILDEN: Does that conclude 17 questions? Any other comments? I would like to thank 18 each one of the panelists for their participation in 19 this panel. I think it's very good and enlightening 20 and I hope that the Subpart A Subcommittee as they go 21 through their deliberations can use the information in 22 a constructive and useful way. Thank you. 23 (Applause.) 24 CHAIR TILDEN: So we have two other steps 25 before we get to adjournment and the next step is to 250 1 open the session to public comment. Is there anyone 2 who cares to make a public comment? Okay. Please 3 identify yourself. 4 MR. WEINBERG: My name is Armand Weinberg 5 and I'm the principal investigator of the EDICT 6 project that was mentioned earlier. I'd like to thank 7 the group for hearing a discussion on this topic and 8 I tell you that I think it's like a toe tester in a 9 sense. This is a step in the water that we as a group 10 have been looking at with a great deal of intensity. 11 When it started out, it looked like a very 12 simple question to address. It became very clear that 13 it was very complex and it was going to take some time 14 and a multi-sectorial group to work on it. And we are 15 very pleased that you have taken the step of listening 16 to this. 17 Because I know it's late in the hour and 18 I've been on panels like you're on today, I'll keep my 19 comment really very simple. I think there's a couple 20 of things that I would ask you to also keep in mind. 21 One is there is growing evidence that some 22 of the research that is beginning to look at 23 differences in populations that have been perhaps 24 under represented in trials like those who are older 25 are starting to show that there are some issues that 251 1 are surfacing because we are now starting to have 2 studies that are addressing these things such as age 3 and aging and the differences. I think it is not very 4 good to sometimes forget that the lack of evidence 5 does not mean that there may not be evidence. We just 6 may not have found it yet. So I think it's very 7 important that we keep that perspective. 8 And so just to make my point as I close 9 this quick comment, I promise, is I know one of the 10 things that we've uncovered that seriously deserves 11 attention is the question of availability of 12 information for participants in clinical trials, not 13 just in the consent stage, but in the material stage. 14 And one of the things that I would wonder whether this 15 group might look at is the role of IRB in assuring 16 that in a very simple way. 17 When we looked at some of this we found, 18 for example, and if you could all imagine just in a 19 sense to even close your eyes but not your ears, the 20 availability if you were offered a role in a clinical 21 trial in a language other than yours and you were 22 given the form in the other language. 23 Now in our world today, it's very common 24 to hear people say from the IRB that it's acceptable 25 to provide a short form of a consent form. And a 252 1 short form of a consent form in a second language to 2 me really sort of is like the tip of the iceberg of 3 what this whole discussion has been about. If it's 4 okay to have a short form in Spanish, I'd like to know 5 why we can't have a short form in English because it 6 makes me wonder what we might be missing if we were on 7 the other side of the receipt of this kind of 8 information. 9 So I do think that that just sort of 10 typically -- It's just sort of one of the questions 11 that we've uncovered that we don't have the evidence 12 about. We don't know what the impact of that is, but 13 it may well play out from the point of signing and 14 agreeing to consent to participate in a study versus 15 going through and actually completing a study. 16 I just thank you again for the opportunity 17 to be here and listen to this and I hope you will 18 continue to have this discussion. 19 CHAIR TILDEN: Thank you. 20 MS. ROLLINS: I'll be very brief. My name 21 is Dr. Rochelle Rollins. I'm with the Office of 22 Minority Health within HHS and I just want to put a 23 challenge out there and a hope that the different 24 offices within HHS continue to look at this topic. 25 I'm thrilled that this happened today and I hope the 253 1 conversation continues. 2 I met with Dr. Height a couple weeks about 3 this, weeks ago about this, and she wants to continue 4 the conversation. So if there's a subcommittee that 5 is going to take this on and the FDA is willing to be 6 part of the conversation with NIH, the Office of 7 Minority Health will do whatever it can to help the 8 conversation to continue. Thank you. 9 CHAIR TILDEN: Thank you. I think from 10 what I've heard the big issue is one of access and 11 communication. And it seems like IRBs could be aware 12 of issues like the prevalence of the condition in the 13 community, their community, and in cases, it would be 14 difficult. It's almost like adverse events. When you 15 have multi-center trial, you're just seeing a small 16 subset. So that would be difficult. But in cases 17 where you have large representations of populations 18 which are obviously under represented as you get 19 reports of screening and enrollment, etc., it seems 20 like asking the question "Is there an issue with 21 access" is possible. So I do think that there are 22 some things that would be worthy to look at in terms 23 of what would be reasonable under the IRB regulations 24 and process. 25 I think it was a very productive session 254 1 and I was really glad that we were able to hold it and 2 get information from everybody. Thank you for 3 attending and if there's no other business, I will 4 entertain a motion to adjourn. 5 DR. GENEL: So moved. 6 CHAIR TILDEN: Second. We stand 7 adjourned. Thank you everyone. 8 (Whereupon, at 4:02 p.m., the above- 9 entitled matter was concluded.) 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25