1 UNITED STATES DEPARTMENT OF HEALTH AND HUMAN SERVICES + + + + + OFFICE FOR HUMAN RESEARCH PROTECTION + + + + + SECRETARY'S ADVISORY COMMITTEE ON HUMAN RESEARCH PROTECTIONS (SACHRP) + + + + + MEETING + + + + + MONDAY, OCTOBER 29, 2007 + + + + + The meeting convened at 8:30 a.m. at the Sheraton National Hotel, 900 South Orme Street, Arlington, Virginia, Samuel J. Tilden, M.D., J.D., L.L.M., Chair, presiding. SACHRP MEMBERS PRESENT: SAMUEL J. TILDEN, MD, JD, LLM, Chair ELIZABETH A. BANKERT, MA, Member MYRON GENEL, MD, Member LISA LEIDEN, PhD, Member PATRICIA A. MARSHALL, PhD, Member DANIEL K. NELSON, MS, CIP, Member NEIL R. POWE, MD, MPH, MBA, Member JAMES H. POWELL, MD, CPI, Member FRANCINE C. ROMERO, PhD, MPH, Member DAVID H. STRAUSS, MD, Member 2 EX OFFICIO MEMBERS PRESENT: MAGDA BARINI-GARCIA HOWARD L. BRADLEY, Social Security Administration KATHRYN LYNN CATES, MD, Department of Veterans Affairs PATTY DECOT, Department of Defense SARAH F. GOLDKIND, MD, MA, Alternate, Food and Drug Administration PETER T. KIRCHNER, MD, Alternate, Department of Energy MARY LEINHOS, PhD, Centers for Disease Control and Prevention JOANNE R. LESS, PhD, Food and Drug Administration WARREN E. LUX, MD, Environmental Protection Agency PATRICK J. McNEILLY, PhD, Alternate, AHRQ AMY P. PATTERSON, MD, National Institutes of Health JOAN P. PORTER, DPA, MPH, Alternate, Department of Veterans Affairs JEFFERY W. RODAMAR, Department of Education DAVID SHORE, NIH Representative HHS PARTICIPANTS: ANAND PAREKH, MD, MPH, Acting Deputy Assistant Secretary for Health (Science and Medicine) IVOR A. PRITCHARD, PhD, Acting Director, OHRP, Acting Executive Secretary, SACHRP KEVIN A. PROHASKA, DO, Captain (USPHS), Acting Executive Director, SACHRP KELLEY K. HILL, OHRP 3 SACHRP SUBCOMMITTEE MEMBERS PRESENT: LAURIE FLYNN, SIIIDR Co-Chair FELIX A. KHIN-MAUNG-GYI, PharmD, MBA, Subpart A Subcommittee Co-Chair GARY CHADWICK, Subpart A Subcommittee PUBLIC COMMENTERS PRESENT: ALAN TRACHTENBERG, MD, MPH, Acting Research Director, Indian Health Service Research Program TERRY VANDENBOSCH, PhD, University of Michigan 4 T-A-B-L-E O-F C-O-N-T-E-N-T-S Page Welcome: Opening Remarks. . . . . . . . . . . .4 Samuel J. Tilden, M.D. SACHRP Chair Report of Issues/Remarks. . . . . . . . . . . 11 Ivor Pritchard, Ph.D. Acting Director, OHRP Remarks and Swearing In of New Member . . . . 16 Anand Parekh, M.D., M.P.H. Acting Deputy Assistant Secretary For Health (Science and Medicine) Report of SIIIDR Subcommittee . . . . . . . . 27 David Strauss, M.D. Laurie Flynn SIIIDR Co-Chairs Report of Subpart A Subcommittee. . . . . . .136 Felix Gyi, M.B.A., Pharm.D. Dan Nelson, M.S., CIP SAS Co-Chairs Public Comment Period . . . . . . . . . . . .301 Wrap-up Discussion and Adjourn. . . . . . . .302 5 1 P-R-O-C-E-E-D-I-N-G-S 2 8:40 p.m. 3 CHAIR TILDEN: On the record. 4 Good morning. 5 WELCOME: OPENING REMARKS 6 CHAIR TILDEN: I believe it's 7 time to bring the meeting to order. I want 8 to thank everyone for attending this, the 9 14th meeting of SACHRP or the first meeting 10 without Bernie Schwetz. However, you want 11 to think about it. 12 But, of course, this morning I 13 wanted to introduce a number of new 14 individuals as we get started for the 15 meeting. First of all, we are under new 16 leadership at OHRP and also at SACHRP and 17 I'd like to welcome Ivor Pritchard who is 18 the Acting Director for OHRP and for our 19 purposes is the Acting Executive Secretary 20 for SACHRP. And Ivor has a long history of 21 working in Human Subjects Protection and he 22 I noticed has a PhD in Philosophy, I 6 1 believe, from Boston University and he wore 2 his Boston Red Sox's cap this morning. So 3 for us Rockies fans he really rubs it in. 4 Congratulations to the Red Sox. But Ivor's 5 also been working -- has worked a long time 6 in Department of Education, is published in 7 the area of Ethics and Research Ethics and 8 has been with OHRP, I believe, since around 9 2004 and now is serving as Acting Director. 10 In addition to that, we also had 11 a change over in that Cathy Slatinshek who 12 was the Director for SACHRP, Administrative 13 Director, has departed the Agency and acting 14 in her capacity now -- in the capacity of a 15 director is Kevin Prohaska. And Kevin was a 16 physician. He's in Family Practice and has 17 worked in the Commission Corps with OHRP 18 and, I believe, FDA, but I'm blanking on 19 that for the moment. But he has been with 20 the Agency for several years and he is 21 willingly and graciously committed to 22 serving as our Director so that the SACHRP 7 1 can move forward. 2 In addition, as most people know, 3 for the audience, SACHRP for the last couple 4 of sessions has been working with ten 5 members and there's been a vacancy and we've 6 been going through the process of appointing 7 an additional member. And I'm happy to say 8 that we have gotten approval of appointment 9 for Elizabeth Bankert who is currently 10 Assistant Provost for Research at Dartmouth 11 College since January of 2006. Liz has 12 previously been the Director of the IRB at 13 Dartmouth for over 12 years and is Past 14 President of the Applied Research Ethics 15 National Association or ARENA and serves as 16 a faculty member for public responsibility 17 in medicine and research. She's well known 18 in the IRB community and is a co-editor of a 19 book, IRB Management and Function, and has 20 also worked in initiating this IRBNet which 21 is a web-based tool for communication for 22 IRB professionals, sponsors and 8 1 investigators. So we would like to welcome 2 Liz to the Committee. 3 Also I notice that we have some 4 ex officios that may be not new to SACHRP in 5 precisely those terms but may be new as 6 having some sort of formal relationship with 7 SACHRP. So I would like to mention Patrick 8 McNeilly who's now with AHRQ and, of course, 9 I've just found out that this morning 10 because I went over to talk to him to find 11 out how he was doing thinking he was still 12 with OHRP. So congratulations I guess on 13 the new appointment, new position, Patrick, 14 and you tell me you were going to serve in 15 what capacity now for SACHRP? 16 DR. McNEILLY: I'll be serving as 17 alternate for Francis Chesley who's the ex 18 officio member for SACHRP. So I'm his 19 alternate representing AHRQ. 20 CHAIR TILDEN: Great. Thanks and 21 it's good to have you aboard and I think -- 22 Are there any other new individuals? Joanne 9 1 Less from FDA. And how will you be 2 connected to SACHRP? 3 MS. LESS: (Off the microphone) 4 CHAIR TILDEN: Well, welcome. 5 It's good to meet you. Are there any other 6 individuals who I've missed? Okay. 7 MS. LEINHOS: Hi. I'm Mary 8 Leinhos from the Centers for Disease Control 9 and Prevention, Acting Manager for the Human 10 Research Protection Office there. 11 CHAIR TILDEN: Okay. Great. 12 Okay. 13 MS. BARINI-GARCIA: Good morning. 14 I thought I would just say my name is Magda 15 Barini-Garcia over here. 16 CHAIR TILDEN: Yes. 17 MS. BARINI-GARCIA: I'm sitting 18 in for Denise Geolot, the Center for Quality 19 at HRSA. 20 CHAIR TILDEN: Great. Okay. So 21 I also would just to start off again in the 22 relevant part review the function of SACHRP 10 1 that comes from the charter for anyone who 2 is not familiar with it. So SACHRP will 3 advise the Secretary on matters concerning 4 the protection of human subjects with 5 particular emphasis on special populations 6 such as neonates, children, prisoners, the 7 decisionally-impaired, pregnant women, 8 embryos and fetuses, international studies, 9 identifiable samples, investigative conflict 10 of interest and OHRP activities. 11 Now before we move on to having 12 the report from Dr. Pritchard, I'd like for 13 us to consider the minutes and see if we can 14 approve the minutes and you should find the 15 minutes at tab J. And I would after you get 16 to tab J and look at it and refresh your 17 memories entertain a motion to approve the 18 minutes. 19 DR. GENEL: So moved. 20 CHAIR TILDEN: Okay. Second. We 21 have a second. Any discussion? 22 (No verbal response.) 11 1 CHAIR TILDEN: So all those in 2 favor of approving the minutes. 3 (Show of hands.) 4 CHAIR TILDEN: And no 5 abstentions? No nays? Okay. So the 6 minutes are approved unanimously. 7 At this juncture, I should say 8 that we are expecting Dr. Anand Parekh, is 9 Parekh the correct pronunciation, I hope, 10 correct me if I'm wrong, to visit us. As 11 you remember last time, Dr. Agwunobi who was 12 Assistant Secretary of Health made it a real 13 routine of his to visit each SACHRP meeting 14 and make some comments and Dr. Agwunobi 15 shortly after, about a month or so after, 16 our last meeting decided it was time for him 17 to make a career move and he left and 18 resigned as Assistant Secretary of Health to 19 take another opportunity in the private 20 sector. 21 Dr. Parekh has assumed the 22 responsibilities for Dr. Agwunobi and he 12 1 will be visiting us sometime this morning. 2 At that point, he'll make some remarks. 3 We'll also have a swearing in ceremony for 4 Dr. Bankert as part of her appointment 5 process. And so I think when he comes in 6 we'll move on to him at that time. 7 In addition to the agenda today 8 after Dr. Parekh and the swearing in, we'll 9 have two reports, one report from the 10 Subcommittee on the Inclusion of Individuals 11 with Impaired Decision-making in Research 12 Subcommittee. That's co-chaired by Dr. 13 David Strauss and Laurie Flynn. Following 14 the presentation, we'll have a break and 15 then we'll have questions and answers. Then 16 we'll have lunch and in the afternoon we 17 will have the report from the Subpart A 18 Subcommittee which is co-chaired by Dan 19 Nelson and Felix Gyi. Following that which 20 I wouldn't be surprised would be a fairly 21 intense session, we'll have public comments 22 and then wrap up for today. 13 1 Tomorrow we'll have our panels, 2 two panel discussions, one related to the 3 Clinical Translational Science Awards and 4 Human Subjects Protection. That will be the 5 first panel in the morning and that will be 6 followed by another panel to discuss Human 7 Subjects Protection and Research related to 8 Disasters. 9 So I think I got through that 10 piece fully now and we'll turn it over to 11 Ivor and let him talk to us about -- make 12 his remarks regarding OHRP. 13 REPORT OF ISSUES/REMARKS 14 DR. PRITCHARD: I'd like to start 15 out by saying that I'm excited about working 16 as the Acting Director of OHRP for as long 17 as that happens, particularly excited about 18 working with this Committee. For the last 19 several years, I've been sitting in the back 20 by the coats listening to your deliberations 21 and you have proven your ability to play a 22 constructive role in providing advice to our 14 1 office and I'm looking forward to trying to 2 help you continue to play that role that you 3 have. I would also like to welcome 4 everybody who has appeared today to listen 5 to the deliberations of the Committee and to 6 perhaps comment on the deliberations of the 7 Committee when that point in the agenda 8 happens. 9 A couple of things about what 10 OHRP has been doing lately, we've published 11 in the Federal Register a notice asking the 12 public to give us comments about research 13 involving people who are decisionally 14 impaired and may participate in research. 15 The closing date for that notice is December 16 4th. We are expecting and hoping that these 17 comments are going to inform the 18 deliberations of the relevant subcommittee 19 and excited about the number of questions 20 that we were able to ask to the public to 21 comment on. We're hoping that we're 22 actually going to get some really 15 1 substantial and informative information from 2 the public about this issue. 3 We've also just very recently 4 published a notice about the expedited 5 review procedure, particularly about three 6 issues, one clarifying the interpretation of 7 a category that has to do with specimens 8 that were previously collected for research, 9 one on research purposes because that 10 appears to be posing a conceptual or a 11 problem for the research community in 12 interpreting that category. 13 We've also asked the public to 14 comment on a proposed revision of exemption 15 category 7 arising from the recommendations 16 of this committee. So we are listening to 17 what you recommend that we do and actually 18 looking forward to maybe taking action in 19 response to your recommendations and to 20 comment on the whole expedited review list. 21 In the future, we've now figured 22 out when it is that we're going to be 16 1 sponsoring or co-sponsoring regional fora 2 over the next year. On February 8th, we are 3 co-sponsoring with the University of 4 California Davis a conference on Thinking 5 Outside the Box: Addressing the Challenges 6 of Human Subject Research in 2008. On April 7 4th with the Ochsner Health System in New 8 Orleans, we're going to be co-sponsoring a 9 forum on From the Past to the Future: 10 Protecting Research Subjects as Times 11 Change. And on September 16th, Virginia 12 Commonwealth University is going to be 13 sponsoring with us a conference on Informed 14 Consent and More: Improving Human Research 15 Protections and we hope that all of you have 16 an opportunity to go to one or another of 17 those meetings because I'm sure they'll be 18 very useful. 19 And I think those are the major 20 things that have happened in addition to the 21 changes that are relevant to the functions 22 with SACHRP with Kevin Prohaska now serving 17 1 as the Executive Director to this group in 2 an acting capacity and me now being the 3 Executive Secretary in an acting capacity. 4 That's it, I think. 5 CHAIR TILDEN: And right on cue. 6 I was going to open it up to ask some -- if 7 anyone on the Committee had any questions. 8 But we'll just delay that maybe until after 9 we get Dr. Parekh involved. 10 DR. PAREKH: Good morning. 11 CHAIR TILDEN: Good morning. How 12 are you, sir? 13 DR. PAREKH: Nice to meet you. 14 CHAIR TILDEN: Nice to meet you. 15 Perfect timing. 16 DR. PAREKH: It is. Did you plan 17 it that way? 18 CHAIR TILDEN: Well, I can't say 19 we did. But we tried. 20 Our next presenter and more, I'm 21 pleased to introduce Dr. Anand Parekh who is 22 the Acting Deputy Assistant Secretary for 18 1 Health and Science and Medicine in the 2 Office of Public Health and Science for the 3 Department of Health and Human Services. In 4 this capacity and previously a senior 5 medical advisor, he provides oversight, 6 direction and coordination of activities 7 pertaining to a range of emerging public 8 health and science issues, a continuum of 9 medical research including clinical science 10 and health sciences research and issues 11 requiring expert medical analysis and advice 12 particularly those concerning policy 13 planning, formulation and presentation of 14 public health issues affecting the 15 Department. 16 In particular, I should say that 17 it sounds like Dr. Parekh has a lot of ties 18 to Michigan and Johns Hopkins. It could be 19 worse. You could be from Notre Dame this 20 year and really be losing at football. At 21 any rate, it's really that Dr. Parekh has 22 assumed for Dr. Agwunobi. I believe that's 19 1 the best way to say this and SACHRP as a 2 committee reports through Dr. Parekh to the 3 Secretary with our recommendations and 4 thoughts which then if accepted will move 5 onto OHRP. 6 So it's really a pleasure to have 7 you here. I know Dr. Agwunobi was a strong 8 proponent of attending SACHRP meetings and I 9 think brought a lot of information to SACHRP 10 and informed it and helped energize it, I 11 think, because of his interest in our 12 activities and process and I certainly hope 13 from our discussions previously, I'm hoping 14 and certainly been led to believe that you 15 will be just as effective. 16 Again, thank you and we're glad 17 to have you here. 18 REMARKS AND SWEARING IN OF NEW MEMBER 19 DR. PAREKH: Thank you, Dr. 20 Tilden. I'm very happy to be here today 21 representing the Assistant Secretary for 22 Health Office as well as the Secretary of 20 1 Health and Human Services, Secretary 2 Leavitt. Thank you for that kind 3 introduction and also bringing up my 4 Michigan roots as well as Hopkins roots. 5 I'm actually an internist. Actually sitting 6 right here next to Dr. Powe who probably 7 doesn't recall, but I trained at Hopkins and 8 actually met with Dr. Powe several years ago 9 when I was in my training program. So it's 10 good to see familiar faces here. I'm very 11 happy to be here. 12 I want to thank Dr. Kevin 13 Prohaska and Dr. Ivor Pritchard for their 14 leadership also and support of the 15 Secretary's Advisory Committee for Human 16 Research Protection as well as their work in 17 the Office of Human Research Protections. 18 They are working very diligently on a 19 variety of critical issues, difficult 20 issues, when you talk about how you define 21 research and how you separate research from 22 public health practice, issues involving 21 1 equivalency of human subjects research 2 protections when you go from country to 3 country. So they are critical issues that 4 the Office is working on and I thank Dr. 5 Pritchard right now in acting capacity 6 taking over for Dr. Schwetz and doing such a 7 superb job. 8 I'm very happy to be here at this 9 meeting. I want to thank Dr. Tilden for his 10 leadership on the advisory committee as well 11 as all of your support. The work you do is 12 really, really important. It's absolutely 13 critical for the Department, for the 14 Secretary's office, for the Secretary, 15 particularly your focus on vulnerable 16 populations and ensuring that individuals 17 with vulnerable populations are included in 18 the clinical research enterprise. By 19 focusing on vulnerable populations and 20 ensuring their protections as human subjects 21 in the clinical enterprise, you're really 22 fostering their inclusion in these studies 22 1 and by fostering their inclusion and making 2 sure that they are in clinical research 3 studies, you're really enhancing the 4 external validity and the generalizability 5 of clinical trials and making sure that the 6 patient population in these trials are more 7 representative of the general population. 8 So the work you do is very important. 9 You are a prolific committee as 10 well in terms of your recommendations. We 11 have ten advisory committees under the 12 Assistant Secretary for Health and I must 13 say with your six series of letters of 14 recommendations to the Secretary and the 15 approval of those letters you all do a lot 16 of work, not only good work, but you're 17 prolific in your recommendations and these 18 recommendations are not for not. They are 19 seen. They are read. They are studies. 20 Obviously, the Office of Human Research 21 Protections follows them very closely really 22 as noted with the recent, I think, Federal 23 1 Register notice asking for public comments 2 on the need for additional regulations for 3 individuals with impaired medical decision 4 making. So your work is certainly well 5 known to the Secretary's office and I thank 6 you for that. 7 You're right, Dr. Tilden. There 8 has been a change in leadership. 9 Unfortunately, the Office of the Secretary 10 lost Dr. Agwunobi to the private sector a 11 few months ago and currently his successor 12 has not been named. We hope that a 13 successor will be named very shortly. But 14 over the last several weeks, I've filled in 15 the best that I can as Acting Deputy 16 Secretary for Health in Science and Medicine 17 for the Office. 18 I want SACHRP to be confident 19 that even with Dr. Agwunobi's departure you 20 have the full backing of the Assistant 21 Secretary for Health's Office as well as the 22 Office of the Secretary's Office and you 24 1 have obviously the full backing of the 2 Department which views your work with the 3 upmost respect. So I want to make sure that 4 even with Dr. Agwunobi's department that you 5 all know that. 6 I won't be able to stay 7 unfortunately for the whole meeting, but I 8 understand that you all have two good days 9 of meetings planned, today focusing on 10 Subpart A issues and exemptions under the 11 Common Rule and then also your SIIIDR 12 subcommittee focusing on impaired decision 13 making and tomorrow I understand you have 14 two very good panels that the second of 15 which we've had conversations about the 16 importance of research during public health 17 emergencies. 18 You know, it's interesting when 19 you think back about Katrina. You think 20 about the wildfires right now. I did quite 21 a bit of work in bioterrorism in public 22 health emergency preparedness when I first 25 1 came into the Department. There is a wealth 2 of information that can be learned during a 3 public health emergency, both in the 4 behavioral health research arena as well as 5 the clinical research arena and if you think 6 about it, unless we have the appropriate 7 mechanisms there, it's rather difficult for 8 an investigator in the midst of an emergency 9 to think of an idea or a research topic, to 10 put down a research protocol or an 11 algorithm, to have an IRB quickly evaluate 12 it, to implement the research and to 13 actually do the research. By the time all 14 of that happens, usually the emergencies are 15 over and that window of opportunity to gain 16 valuable information in a variety of a 17 research realms is lost. So it's very 18 important as we think about research during 19 a public health emergency not only how we 20 can expedite IRB processes and such but how 21 we can expedite the whole process from 22 thought to implementation while ensuring 26 1 ethically that human subjects are protected. 2 So I think I'm happy that SACHRP is looking 3 into that area and I look forward to hearing 4 about the thoughts of the panel members. 5 I think with that I want to thank 6 all of you for your service and dedication. 7 Your work is certainly something that is 8 looked at very closely by the Secretary and 9 thank you for your leadership. 10 CHAIR TILDEN: Thank you very 11 much. Do you have time to take one or two 12 questions before doing the swearing in 13 ceremony? 14 DR. PAREKH: Absolutely. 15 CHAIR TILDEN: Does anyone have 16 any questions? For some reason, Dr. Genel 17 has a question. 18 DR. GENEL: Well, I realize that 19 things are in transition. But let me remind 20 you that three years ago this committee made 21 recommendations regarding harmonization of 22 the Privacy Rules with the Common Rule and I 27 1 had pointed this out to Dr. Agwunobi who 2 indicated that he would look into getting 3 this expedited. I understand it's at the 4 Office of Civil Rights. So I would hope 5 that perhaps that you could make an inquiry 6 and just find out if we are likely to see 7 some progress at this. Three years is a 8 pretty long time. 9 DR. PAREKH: Sir, can you just 10 repeat? It was the harmonization of? 11 DR. GENEL: Harmonization of the 12 HIPAA Privacy Rule with the Common Rule and 13 there is an extensive report that this 14 Committee sent to the Secretary in September 15 of `04 which reminds pending. There is an 16 acknowledgment from the Secretary, I 17 believe, a few months later indicating that 18 it had been assigned to the Office of Civil 19 Rights. 20 DR. PAREKH: Thank you. I will 21 definitely look into that and see where that 22 is in the process. 28 1 DR. GENEL: Thank you. 2 CHAIR TILDEN: Any other 3 questions for Dr. Parekh? 4 (No response.) 5 CHAIR TILDEN: Okay. As I said, 6 I'm really glad that you were able to take 7 time to come and visit us and talk to us 8 because I know your schedule has to be so 9 complicated now with these additional 10 responsibilities. So thank you very much 11 again for visiting with us and updating us 12 and I hope that you plan to come back and 13 regularly. 14 DR. PAREKH: Absolutely. Thank 15 you, Dr. Tilden. 16 CHAIR TILDEN: Okay. So I think 17 at this point I'm going to ask Kelly maybe 18 or Kevin to try to organize this swearing 19 in. We have a swearing in ceremony and some 20 pictures to get performed. 21 So at the swearing in ceremony, 22 we'll have pictures of Dr. Bankert and then 29 1 we'll have a group picture. 2 (Swearing in of Elizabeth 3 Bankert) 4 DR. PAREKH: Well, it's my great 5 pleasure to do this, the swearing in 6 ceremony for Elizabeth Bankert, Assistant 7 Provost at Dartmouth College and we are very 8 happy. SACHRP is very happy to have you on 9 board and this is a short swearing in 10 ceremony and if I can ask you to raise your 11 right hand and place your left hand on the 12 Bible and repeat after me. 13 I'm sorry. There's probably a 14 better way. Hopefully, we usually should 15 have a flag. We might be able to help you 16 out here so you're not doing such a -- 17 MS. BANKERT: It's a good 18 stretch. 19 DR. PAREKH: If you could repeat 20 after me. 21 I do solemnly swear -- 22 MS. BANKERT: I do solemnly swear 30 1 -- 2 DR. PAREKH: -- that I will 3 support and defend the Constitution of the 4 United States -- 5 MS. BANKERT: -- that I will 6 support and defend the Constitution of the 7 United States -- 8 DR. PAREKH: -- against all 9 enemies, foreign and domestic -- 10 MS. BANKERT: -- against all 11 enemies, foreign and domestic -- 12 DR. PAREKH: -- that I will bear 13 true faith and allegiance to the same -- 14 MS. BANKERT: -- that I will bear 15 true faith and allegiance to the same -- 16 DR. PAREKH: -- that I take this 17 obligation freely -- 18 MS. BANKERT: -- that I take this 19 obligation freely -- 20 DR. PAREKH: -- without any 21 mental reservation or purpose of evasion -- 22 MS. BANKERT: -- without any 31 1 mental reservation or purpose of evasion -- 2 DR. PAREKH: -- and that I will 3 well and faithfully discharge the duties -- 4 MS. BANKERT: -- and that I will 5 well and faithfully discharge the duties -- 6 DR. PAREKH: -- of the office of 7 which I am about to enter. 8 MS. BANKERT: -- of the office of 9 which I am about to enter. 10 DR. PAREKH: So help me God. 11 MS. BANKERT: So help me God. 12 DR. PAREKH: Congratulations. 13 MS. BANKERT: Thank you. 14 (Applause.) 15 MS. BANKERT: Thank you very 16 much. 17 DR. PAREKH: Thank you. Thank 18 you very much. 19 CHAIR TILDEN: I think we're 20 going to get a picture of the whole 21 committee here, the latest composition of 22 it. 32 1 (Pause for pictures.) 2 CHAIR TILDEN: I'd like to just 3 make one announcement before we get started 4 and that is that your packets have a lot of 5 materials that didn't make it into the book. 6 So you might want to take a minute while we 7 get set up for the first subcommittee 8 presentation to look through your packets 9 and see if you get them into the tabs, if 10 you prefer. But I just wanted to make sure 11 that everyone was informed of that as we 12 move forward with our subcommittee reports. 13 In particular, I think the report and the 14 handout for the first subcommittee report 15 we're going to have which is going to be the 16 SIIIDR Subcommittee Report is in your 17 handouts. 18 So let's move forward to begin 19 our subcommittee reports with David Strauss 20 and Laurie Flynn. 21 REPORT OF SIIIDR SUBCOMMITTEE 22 DR. STRAUSS: Good morning and 33 1 thank you, Sam. I want to say thank you to 2 SACHRP and also thank you to the staff folks 3 at SACHRP who have been extraordinarily 4 helpful in keeping SIIIDR activities moving, 5 flowing, keeping the SIIIDR flowing if you 6 will and a special thanks to the OHRP staff 7 liaison who have really been very helpful to 8 us providing us with necessary information 9 and guidance where necessary and all others 10 who've contributed. 11 We've reported to SACHRP 12 previously. I think the Committee has made 13 some strides in the last several months. 14 I'd like to share with you our current 15 thinking. Both Laurie and I will be 16 presenting, taking turns. 17 So what I'd like to do this 18 morning is review our charge just by way of 19 reminding all what we're looking at and what 20 we're considering. I'd like to spend a few 21 moments describing our strategy and review 22 progress. 34 1 Strategy, I think, is critical in 2 this endeavor. We've talked here before 3 about the many efforts that have proceeded 4 ours to provide guidance and to regulate in 5 this area and the many efforts that have 6 proceeded us which have failed to have a 7 significant impact. Our strategy as we've 8 talked about before is one that we hope will 9 be more successful and our efforts have been 10 to carefully consider the historical 11 precedent, to rely upon clinical and 12 empirical information to guide us in our 13 thinking and also to try to solicit 14 information from key stakeholders in the 15 field. We've concluded and we've discussed 16 here before that prior failures in this 17 arena may have a reason in part from an 18 inability or a failure to take into account 19 some of these variables. 20 We'd also like to spend a bit of 21 time today, we hope, discussing with SACHRP 22 a question which is how can SACHRP and 35 1 SIIIDR in particular most effectively 2 advise, consult and make recommendations in 3 order to "improve functions within the 4 authority of HHS on the specific matter of 5 the legally authorized representative." 6 We've talked here before and we've called it 7 a regulatory dead end. What we'd like to do 8 today is talk about some options that SIIIDR 9 has been considering and get your weigh-in 10 on how we can best proceed in thinking about 11 this notion of the legally authorized 12 representative and how it can play a 13 critical role in moving this field forward. 14 Just by review, Sam mentioned 15 this earlier today, the idea for the SIIIDR 16 Subcommittee is really embedded in the 17 SACHRP charter. It asks specifically that 18 special emphasis be placed on special 19 populations such as the decisionally 20 impaired. The SIIIDR charge specifically 21 asks the question of the group to develop 22 recommendations for consideration by SACHRP 36 1 about whether guidance and/or additional 2 regulations are needed for research 3 involving individuals with impaired decision 4 making capacity and as we've presented here 5 before, the conclusion and early consensus 6 of the subcommittee based on preliminary 7 research that we did is that the answer to 8 this question is absolutely yes. 9 And that yes in large part is 10 based on a number of factors. But let me 11 review them in the context of this 12 opportunity statement and the context is 13 that we in this field of human research 14 protections emerged some 30 years ago from a 15 period in which research with captive, 16 incompetent and vulnerable populations was 17 commonplace. 18 Ironically, one might say, in 19 spite of that fact, efforts on the Federal 20 level to craft specific protections for 21 those who are unable to consent have not 22 been successful. And so we would argue that 37 1 where the most vulnerable subjects are 2 concerned, we don't provide a framework of 3 regulations and guidance to guide the 4 ethical conduct of research. I'll talk more 5 about that in a minute. 6 As a result of this void, there 7 lacks regulatory coverage where pressing 8 research questions involving those most 9 vulnerable subjects are at issue. And then 10 finally, while the specific consequences of 11 this void have not been well documented, 12 clear opportunities exist to advance the 13 ethical conduct of research through our 14 activities. There are two possible 15 implications of this failure to act in a 16 regulatory framework or to provide necessary 17 guidance. 18 One complication or one possible 19 effect, of course, is that research is being 20 conducted absent proper guidance and we're 21 placing individuals at risk in ways that are 22 inconsistent with good ethical practice. We 38 1 may be we could argue involving people in 2 research without their consent when that may 3 not be appropriate. We don't know that as 4 fact. It's an implication of the fact that 5 there aren't clear regulations and guidance. 6 The other critical issue and I 7 think maybe this is more of a critical issue 8 today in 2007 than it was in the late 1970s 9 when the first efforts were made in this 10 regard is that the science of the mind has 11 advanced significantly and therapeutics of 12 disorders which impact the brain have 13 advanced significantly. And we may now be 14 confronting genuine need to understand 15 better the causes, diagnosis and prevention 16 of disorders which may impact people's 17 ability to make decisions. And so to not 18 address how best to include such individuals 19 in research may be to deprive those 20 populations of medical progress or the 21 advances of medical science. 22 So we have two great concerns 39 1 that drive this process. One is that on the 2 ground IRBs don't have adequate direction 3 and guidance on how to proceed in thinking 4 about research with the decisionally 5 impaired. And the possible consequence of 6 that lack of guidance is either that 7 research is not being conducted that ought 8 to be, that must be conducted, or perhaps 9 that research is being done when it should 10 not be done and that's the tension and the 11 balance that we need to address. 12 MS. FLYNN: Thank you. Before I 13 go forward and discuss a little bit more, I 14 also want to thank the staff. It's been 15 remarkable the amount of support and 16 progress we've been able to make during what 17 we know is a time of transition and change. 18 So I want to thank everyone for the help and 19 support we've had. It's been really quite 20 extraordinary. Also thank my co-chair David 21 who has really been the strong leader in our 22 effort and I think gives us a lot of 40 1 confidence that we're going to be able to 2 make some substantial progress here. 3 So you've heard a little bit 4 about the background and why the significant 5 issues we've discussed are so important at 6 this point. Let me talk a little bit now 7 about what we've been trying to do in order 8 to move forward as a group. 9 We certainly decided early on 10 there is a problem. We want to provide some 11 specific help to the field and, to do that, 12 we want to engage not only with the 13 community here at SACHRP but also 14 importantly with folks on the ground in the 15 research enterprise as well as key 16 stakeholders across the board. 17 To that extent, we've been 18 delighted to see the issuance of the RFI. 19 We are watching with interest and beginning 20 to get some response. We're certainly 21 hoping and expecting that as the December 4 22 deadline for comment arises and approaches 41 1 that we'll see a lot more information. 2 We've been fortunate to get these comments 3 as they come through so that we can 4 incorporate them into our deliberations. 5 We're also seeking a spectrum of 6 input from across the stakeholder community, 7 looking to hear not only from IRB 8 professionals, but also from academic and 9 professional societies that deal with these 10 issues and that address the conditions that 11 give rise to these problems as well as key 12 patient groups and others. We're beginning 13 to do that outreach. I would ask any of you 14 here who have some suggestions for 15 individuals or organizations you think we 16 might wish to connect with to please let us 17 know. We are very much eager to engage all 18 the relevant commentary. 19 So there is a framework for this 20 work and I want to say that it is a 21 framework that you've seen before and we are 22 addressing some key issues as we look at the 42 1 activities and the results we're trying to 2 achieve. First of all, we're trying to 3 describe and define how do IRBs and 4 investigators identify who are the special 5 populations, the vulnerable populations, if 6 you will, that require protection. This was 7 a point that was discussed earlier and 8 perhaps bears again just a little bit of 9 repeating. 10 For a very long time, the field 11 has been hung up on thinking that most of 12 the folks who are decisionally impaired or 13 vulnerable as we've traditionally thought 14 about research have been overwhelmingly seen 15 as people with psychiatric illness and 16 indeed they are a part of this population. 17 But as we've heard from a variety of experts 18 over the past year, this is a population 19 that is far broader and indeed is of growing 20 concern. 21 It includes people who are 22 struggling with traumatic brain injuries, 43 1 something that's becoming more frequent as 2 we see the results of the Iraq War. It also 3 includes people who are struggling with the 4 aftereffects of stroke or other neurological 5 conditions, certainly the growing population 6 with Alzheimer's and dementia, people who 7 are suffering severe pain, people who may be 8 semiconscious for an extended period or even 9 who are comatose. All of these and others 10 fall into this category and indeed we are 11 trying to continue to understand carefully 12 how that group is defined and who indeed may 13 be or is judged to be decisionally impaired. 14 We are also then looking at how 15 do we decide amongst these individuals who 16 may be vulnerable, how do we decide, who may 17 be provide consent, who may serve as a proxy 18 or surrogate for those individuals who are 19 unable to provide consent for themselves and 20 as you've heard, as we looked at this and 21 surveyed the territory, looked at state 22 regulation, examined carefully the results 44 1 of past efforts at the Federal level, it's 2 clear that there is a gap and it's clear 3 that practices across the world of IRBs may 4 vary considerably. 5 We're also looking then at how do 6 we define what is reasonable risk for this 7 population in research when the ability to 8 provide consent is limited or is absent, 9 what level of risk is acceptable in 10 research with those individuals for whom a 11 surrogate or proxy consent must be given, 12 how do we balance the risks and benefits and 13 how do we judge that we have an appropriate 14 and ethical set of standards being applied 15 in the individual research enterprise. So 16 it's a complex set of issues. They do 17 interrelate and taken together they really 18 form the basis for the ongoing work that our 19 SIIIDR Subcommittee is engaged in. 20 Do you want to make any other 21 comments? Okay. 22 So how have we been addressing 45 1 this work? How have we practically been 2 trying to struggle with these major issues 3 that as you've heard have really been out 4 there in the field and increasingly 5 significant as we go forward with research 6 with populations that may have decisional 7 impairment? So we've developed three 8 working groups to address these issues and 9 they are focused on who is the population 10 and how do we identify them, what are the 11 criteria, how do we look at the risk/benefit 12 calculation and then the significant issue 13 of dealing with this problem of how is the 14 legally authorized representative and how 15 might that person be effectively and 16 ethically employed. 17 David Strauss and I have been 18 meeting weekly to keep up with the work and 19 provide guidance and leadership to the work, 20 take a look at the products as they come 21 along and continue to refine our strategy. 22 We've just instituted a monthly 46 1 teleconference which I must say was really 2 quite an exciting event. You know, when you 3 don't see people and you're working at a 4 distance and you're mostly working through 5 email, you don't really know how engaged 6 people are you can't really see between 7 meetings how much they've gotten 8 accomplished. But if liveliness of the 9 discussion is any way to judge, we certainly 10 have an active group. We really had a very 11 useful first teleconference and we intend to 12 have these on a monthly basis to continue to 13 keep our work flowing. 14 More significantly, we are 15 planning a two-day meeting early in 2008 16 which will be a working session. We expect 17 to come to this meeting from each of the 18 subcommittees with fairly well-polished 19 drafts as a result of their initiative. We 20 will consider those, debate and discuss 21 those, do some further work in small groups 22 and we're hoping to bring forward to SACHRP 47 1 in the first quarter of 2008 some 2 recommendations. 3 This is the group. You've seen 4 them before. Here they are, just as good 5 looking as they were the last time and now 6 you see them in their special settings with 7 their partners in the work. John Oldham up 8 at the top of the triangle on what would be 9 -- Is that your far left? John Oldham is 10 the chair of the work group that's looking 11 at the populations and how they are defined. 12 He is joined by his colleagues that you can 13 see across the board. There is a work group 14 led by Anne Donahue looking at the legally 15 authorized representative and you see there 16 we again have tried to balance these work 17 groups so there are folks who have some 18 substantive knowledge of the regulatory 19 background, the context in which these 20 issues are being discussed, as well as 21 individuals who have a more practical set of 22 experiences or bring the research 48 1 perspective to the table. So I think we've 2 done a pretty good job here of trying to 3 balance each work group to get a full range 4 of ideas. And then the third work group 5 looking at the risks of benefit equation and 6 the approval criteria as we try to apply 7 these issues in real research settings. 8 So we have a terrific group. 9 We've had really very good productivity so 10 far and I think we're feeling quite 11 optimistic that we're going to be able to 12 bring forward some useful work products 13 early in 2008. 14 Looking again at the SIIIDR 15 charge, what is it that we're ultimately 16 dealing with as we grapple in our work 17 groups with these issues and debate and 18 define further the shape of our product, 19 again the subcommittee was charged with 20 developing either one or both of the 21 following products: recommendations on the 22 interpretation of the Subpart A provisions 49 1 that would enhance protections for this 2 population, that is to say guidance, and the 3 second potential product, recommendations 4 for a new subpart under 45 CFR 46 that would 5 provide additional regulatory protections 6 for the population or more practically 7 speaking the recommendation that there be 8 drafted new legislation or regulation to 9 extend these protections. Those really are 10 the choices that we have. Those were the 11 charge that we were given and currently we 12 are working down both pathways and thinking 13 very hard about how to prioritize our work 14 given that we do have an ambitious schedule 15 and given that we want to provide helpful 16 guidance to SACHRP. 17 We certainly have agreed in 18 discussion here as well as with our fellow 19 subcommittee members that guidance to the 20 field really is critical. The more we talk 21 to people, the more we hear how confusing 22 this is, how difficult these issues are in 50 1 the absence of guidance and we've also heard 2 how seriously guidance is taken when it 3 comes from OHRP. People do look to that as 4 the best practice. People do want to 5 conform to guidance when it is issued. 6 At the same time, we continue to 7 feel that on the longer term for clarity and 8 consistency as this population at risk 9 becomes more and more a focus of important 10 clinical research, more and more a larger 11 percentage of our total population, it may 12 be that at the end of our work we will also 13 articulate a belief that regulatory action 14 may indeed be the ultimate answer for these 15 problems. 16 DR. STRAUSS: When I was on the 17 Subpart A Subcommittee, we spoke often about 18 the low-hanging fruit and that we would 19 focus our initial efforts at picking those 20 fruit. In some cases, it was clarification 21 of language of the regulations. I think 22 there is no low-hanging fruit in this 51 1 particular domain that we're involved at 2 this point. And so the committee has worked 3 hard to embrace the topic as a whole and 4 then decide how we might best proceed to 5 make an impact. 6 Part of the argument is that 7 absent any clear direction at this point 8 it's not too hard to make an impact with 9 guidance of some sort and that there are 10 many aspects of the current language of the 11 Federal regulations of Subpart A and we've 12 discussed those here that might readily lend 13 themselves to some guidance or 14 interpretation. For example, Subpart A 15 makes reference to the words "mentally 16 disabled." We don't know what that means 17 exactly. We don't know to whom it's 18 referring. 19 Subpart A makes reference as well 20 to individuals likely to be vulnerable to 21 coercion or undue influence. Again, there 22 too we have little guidance on how to 52 1 characterize that population. 2 Subpart A makes reference to the 3 requirement for additional safeguards for 4 certain vulnerable populations. But there's 5 no guidance which might inform IRBs about 6 what kinds of additional safeguards may be 7 warranted or may be necessary in particular 8 kinds of consideration. 9 Subpart A also makes reference to 10 legally effective informed consent and the 11 requirement for understanding language 12 understandable by the research subject. And 13 yet how one goes about assessing or if one 14 goes about assessing whether or not there is 15 understanding is also something not captured 16 by the regulations or by current regulatory 17 guidance. 18 So as we've begun to think about 19 this, we've arrived at a kind of framework 20 or structure for our process and this is 21 just organized according to each of these 22 three working groups. But it's been our 53 1 interest in reviewing historical, clinical 2 and empirical background involving research 3 with those who are decisionally impaired. 4 We've been seeking input and we've had a 5 number of people both who came and presented 6 at this group and also to SIIIDR, people who 7 represent the interests of specific patient 8 populations, for example. 9 As we've begun to proceed, we've 10 outlined the necessary principles which 11 would guide our thinking. The next step 12 would be to identify key elements that would 13 lend themselves to guidance, OHRP guidance, 14 then to draft that guidance. In the process 15 of doing this what may emerge and I think 16 will likely emerge is a structure for a 17 regulatory subpart. We're not there yet, 18 but we imagine that as we become clear on 19 the necessary structure to informed practice 20 the specifics of that subpart may make 21 themselves evident. And then finally, we 22 may move forward and draft language for this 54 1 new regulatory subpart. 2 We're going to try to accomplish 3 this all at the same time. You see the Xs 4 of what we've finished and everything else 5 is in progress or not yet started. The LAR 6 issue is one that I think is extremely 7 complex and we'll talk a little bit about 8 that today. But I think we've begun to make 9 some headway in other areas. 10 The population working group has 11 been thinking a good deal about how we can, 12 I'm going to just back off here a second, 13 advise IRBs and institutions and others 14 perhaps to begin to think about who are the 15 subjects of concern here. I mean, how does 16 -- how will the regulations define this 17 population that requires additional 18 safeguards and really more to the point how 19 does an IRB and then an investigator 20 actually identify those individuals? 21 I think one of the real 22 challenges of this process for SIIIDR is 55 1 that we're not just operating here on the 2 level of big concept. I think that we need 3 to take those big concepts and those 4 principles and make sure we translate them 5 so that those who do the research and those 6 who oversee the research at the IRB level 7 are clear who we're talking about and what 8 we're talking about. This is ultimately a 9 practical enterprise that we're involved 10 with and I think that one of the strengths 11 of SIIIDR is that our membership is really a 12 membership that includes folks who are 13 involved in the daily activities of IRB 14 function, institutional oversight, clinical 15 research and empirical research on research 16 ethics. So we are paying close attention to 17 what we think are the practical issues and 18 the issues that we'll need to ultimately 19 deliver to the community in the form of 20 guidance. 21 We struggled a lot with whether 22 or not we wanted to consider both disorders 56 1 which affect decision making and 2 circumstances which might affect decision 3 making and we've talked here before about 4 the many different dimensions of impaired 5 decision making and in that we included 6 circumstances that involved, for example, 7 acute stress or highly stressful 8 circumstances. We talked about problems 9 with voluntariness and how that may impact 10 consent and free choice. 11 But as our first cut, we decided 12 to restrict our deliberations to intrinsic 13 problems, if you will, disorders, medical 14 conditions, etc. which affect decision 15 making. We know we have a Subpart A 16 Subcommittee who may be thinking and is 17 thinking about informed consent in broader 18 terms. We thought that we could have the 19 largest impact in thinking about capacity, 20 understanding and comprehension and its 21 impairments rather than the broader 22 requirements or preconditions for consent. 57 1 And it's been said by two of our 2 subcommittee members, Paul Appelbaum and 3 Laura Roberts, both of whom know a thing or 4 two about research in this area that we 5 actually have a relatively scarce body of 6 knowledge about voluntariness; whereas, the 7 empirical basis for our understanding of 8 limitations and comprehension and 9 understanding is far more significant. So 10 in practice, we're thinking about defining 11 the population in terms of these intrinsic 12 disorders which affect decision making. 13 And again, just to just 14 characterize it one last time and as Laurie 15 pointed out, this is in no way congruent 16 with mental disorder and at this committee 17 we heard I thought a very poignant and, in 18 my view, worrisome presentation from John 19 Luce, one of our subcommittee members, about 20 the intensive care unit and we could imagine 21 that and other critical situations where you 22 and I want to make sure we're going to be 58 1 advancing knowledge and doing so rapidly 2 before we take our turn in the intensive 3 care unit. So we're not disorder specific. 4 We're looking at all the disorders which may 5 affect decision making. 6 We talk about individuals with 7 impaired decision making. But rather than 8 thinking of that as a characteristic of the 9 individual or a particular disorder, we want 10 to think about impairment in capacity as an 11 impairment in a specific task and that task 12 is making a consent decision about research. 13 It doesn't make sense to speak about an 14 individual or a population of individuals as 15 having impaired decision making. The 16 capacity that we're interested in 17 understanding is the capacity to consider a 18 consent decision with regard to a particular 19 research protocol at a particular point in 20 time and any practical guidance that we 21 provide to the field needs to be aware and 22 mindful of that and needs to implement 59 1 practice in a way that's consistent with 2 that. 3 We do not want to cast a net so 4 wide that we essentially take autonomy from 5 individuals who have the ability to consent 6 for themselves. We neither want to enter 7 people in a research who can't make 8 decisions for themselves nor do we want to 9 deprive those who can make decisions for 10 themselves of the ability to make those 11 decisions. 12 I said this. Impairment refers 13 specifically to the capacity to make a 14 particular research decision and, as I said 15 again, such impairment occurs in a wide 16 range of conditions. 17 We don't know how you go about 18 identifying these individuals unless in some 19 fundamental and across the board fashion 20 some form of evaluation of capacity is 21 required whenever there's consent. I think 22 that this is an idea that may be understood 60 1 to mean that we're going to require or would 2 recommend the requirement of some formal 3 assessment of capacity. That's not what 4 we're talking about. We're saying that in 5 all circumstances in which a subject signs a 6 consent form that it's the obligation of the 7 researcher to perform some form of 8 assessment. It may be an intuitive 9 assessment. It may simply be noting in the 10 interaction that the subject understands the 11 decision that's being made. But we don't 12 believe that an appropriate first step is 13 the assumption of competence. 14 We could imagine a scenario in 15 which IRBs most familiar with the population 16 at hand, the population being enrolled in a 17 particular study, will be asked to tailor 18 the assessment to the particular needs of 19 the study. It would be tailored both to the 20 population of subjects to be enrolled in the 21 study we would assume but also to the level 22 of the risk of the study. 61 1 In some instances, we would 2 imagine that a formal and elaborate system 3 perhaps using some instrument, an interview 4 of some sort, would be required by an IRB. 5 In other instances, we may simply want the 6 investigator to document his or her 7 assessment that capacity is present. 8 There are many implications for 9 this kind of rule, but I think that they are 10 important implications and as you think 11 about the practicalities of it, it gives 12 rise to other opportunities for guidance or 13 at least notions of good practice and, for 14 example, even in a study which we may not 15 see as involving significant risk, we want 16 to be careful who is the person who's making 17 the determination that the perspective 18 subject does not have capacity. It's a 19 violation of their rights we could argue for 20 someone to determine that they don't have 21 capacity and have someone else make a 22 decision on their behalf and we want to make 62 1 sure that the qualifications of the 2 individuals who are making that 3 determination are appropriate. And again, 4 we don't believe that there's a role at the 5 Federal level or even in guidance to 6 proscribe those kinds of characteristics. 7 But there may be a role in Federal guidance 8 to recommend that IRBs are cognizant or take 9 into consideration those kinds of 10 qualifications in their recommendations. 11 We focus so much on who is going 12 to get into the research study that I think 13 it's important to remember that people who 14 are unable to make decisions for themselves 15 are vulnerable even after that moment in 16 which they sign consent; whereas, you or I 17 or someone who has capacity may decide as 18 the study goes on, for example, that they 19 are not happy with the actual risks and the 20 actual benefits that are being accrued and 21 you could decide to drop out. 22 But how does that work with 63 1 someone who's enrolled by someone else in 2 the research study? Does an IRB require 3 that there be an ongoing advocate for that 4 person who's been enrolled in the study? 5 Well, this is an example of where there are 6 no rules and no guidance and I think that we 7 need to be thinking about what kind of 8 longitudinal involvement. This is really 9 about risk minimization. But it's also 10 about ongoing assessment of capacity, 11 consent and assent. 12 The committee also agrees that 13 there are groups of individuals. There are 14 individuals really for whom consent can be 15 enhanced. It normally won't occur by simply 16 giving someone a 15-page consent document 17 and saying, "read it" or "even read it 18 again." But there is a valuable and growing 19 empirical literature on ways to enhance 20 consent and enhance capacity and SIIIDR 21 believes that at least encouraging the field 22 to consider such enhancements, enhancements 64 1 of autonomy, are a critical part of guidance 2 which will be developed. 3 The risk/benefit criteria working 4 group is earlier on in its thinking. I 5 think probably there is no more difficult 6 question that we'll face than what is 7 acceptable risk for people who cannot make 8 decisions for themselves and I think we are 9 proceeding slowly here. But there are some 10 principles which have already begun to 11 emerge and which will guide us moving 12 forward. 13 The first is that we believe that 14 with appropriate protections, the inclusions 15 of individuals who are unable to consent for 16 themselves, is essential as it will permit 17 access to novel and investigational 18 treatments and advance understanding, 19 diagnosis, prevention and treatment of 20 conditions which impair decision making. 21 Like I said earlier, while we have little 22 documented evidence of this, most of us have 65 1 some anecdotal recognition of the fact that 2 IRBs and investigators and perhaps others 3 are staying away from certain research 4 because the approvability of that research 5 is in question. We'll talk about that more 6 when we talk about the LAR issue. 7 But we believe with appropriate 8 protections we need to do research. We 9 believe that there are circumstances and 10 conditions which cannot be investigated 11 without the enrollment of people who are 12 unable to make consent decisions for 13 themselves. 14 And then this last point, 15 practical and clinical meaningful approaches 16 to risk/benefit assessment, are of paramount 17 importance in order to protect the 18 individuals and promote necessary medical 19 progress. The concepts of risk and benefit 20 get more and more complicated the more that 21 you think about them. As words, at the 22 level of the regulations, they make some 66 1 sense to us. But for those IRBs and IRB 2 members on the front line, these notions are 3 extremely complex and I think they're even 4 more complex when you talk to research 5 subjects and what counts as benefit in the 6 research study, what counts as risks, how we 7 can meaningfully weigh risks and benefits is 8 extraordinarily complex and we want to make 9 sure whatever calculus or algorithm we 10 arrive at to determine what is acceptable 11 risk is one that doesn't give short shrift 12 to the complexities of risks and benefits in 13 research participation. And maybe if 14 there's time later, we can talk more about 15 that. 16 MS. FLYNN: Okay. So you see a 17 little bit now the levels of conversations 18 and discussion and debate that we're having 19 and the kinds of issues that we're grappling 20 with. So really at the core of this is the 21 question of how can SACHRP most effectively 22 indeed carry out that charge to advise, 67 1 consult and make recommendations in order to 2 improve the functioning under the authority 3 of HHS on this very specific matter of the 4 legally authorized representative. 5 We really would like some 6 feedback and some discussion of this issue 7 today. We'd like to get your thoughts on 8 this as we are at an earlier stage in this 9 work group than in the other two and yet 10 this has potentially the most immediate and 11 far-reaching kind of impact if we can make 12 some effective action take place. 13 We certainly are going to be 14 informed and look forward to continuing to 15 hear from colleagues in the field as the RFI 16 comments come in. We are looking forward to 17 hearing about these issues at the December 18 meeting in Boston of PRIM&R. But again, we 19 very much would like to have some 20 conversation today on these issues. 21 The definition. What do we know 22 from the regulatory definition who is a 68 1 legally authorized representative and this 2 is really something the IRBs struggle with 3 and the investigators as well. What we have 4 currently is the following language. "The 5 legally authorized representative means an 6 individual or judicial or other body 7 authorized under applicable law to consent 8 on behalf of a perspective subject to that 9 subject's participation in the procedures 10 involved in research." That's what we have. 11 That's the definition that we work with. 12 But certainly IRB struggled to implement 13 that in the real world of research. 14 State and institutional rules as 15 they work forward from that definition do 16 not address or inconsistently address a 17 whole range of key areas of concern. We 18 know that there are not definitions that 19 deal with this in the context of research- 20 specific rules. Some places they sort of 21 work from the definition of who can make 22 surrogate consent or proxy consent for 69 1 medical treatment and sort of back into it 2 from that direction. But clearly we believe 3 there should be something crisper and more 4 specific to research. 5 We see that there is an issue 6 around who may provide consent for those who 7 are unable and again often in practice we 8 hear it's next of kin, it's the family, 9 again borrowing from the literature and 10 practice in terms of medical treatment or 11 critical care treatment. But here too that 12 may not be exactly the right way to think 13 about this. The issues around research with 14 those who are vulnerable or decisionally 15 impaired are significantly different enough 16 that they may need some special focus. 17 What's the scope of the covered 18 research activities? Are we talking only 19 about surrogate consent for research 20 activities that provide direct benefit? Are 21 there certain things that we would not under 22 any conditions think that surrogate consent 70 1 should be allowed for? How do we develop 2 some understanding of what the scope of that 3 process may include? 4 What in fact is the definition of 5 the population who are unable to consent and 6 here we've had a lot of conversation about 7 this. But it's going to be important that 8 we keep that at the center of all of this 9 discussion so that we respect the autonomy 10 of the individual and remember that consent 11 does occur, rather vulnerability to 12 decisional impairment does occur on a 13 spectrum and is indeed task specific, not 14 disability specific. 15 We also want to look at the 16 reasonable or acceptable risk when a 17 surrogate is employed. How do we think 18 about what someone else can agree should 19 happen to an individual whose direct consent 20 cannot be obtained? How do we weigh the 21 benefits? How do we weigh the risks? How 22 do we think about this in a way that 71 1 provides protection to individuals who are 2 unable to speak on their own behalf, again 3 remembering that this is a growing 4 population, that it is a population that 5 occurs across the age spectrum and that it 6 is a population about which many medical 7 advances are needed. These are individuals 8 who can contribute an ethically developed 9 research enormously to the development of 10 better interventions and treatments for some 11 of the most disabling conditions and 12 devastating circumstances that could befall 13 any of us. But we don't want to move 14 forward without always looking for the 15 individual protections that must be there 16 before research advances can take place. 17 As we've discussed in previous 18 meetings on the subject of the legally 19 authorized representative, we have a 20 regulatory dead end. As you've seen, 21 Subpart A requires that the legally 22 effective informed consent be obtained from 72 1 the research subject. But for those who 2 cannot consent for themselves, Subpart A 3 permits consent by the legally authorized 4 representative to the procedures used in 5 research. However, as we've seen, Federal 6 regulations do not define the LAR. There is 7 no definition and this is left to 8 "applicable local and state law." 9 As we've seen and we've had quite 10 a bit of work in looking over what is really 11 going on, the states with rare exceptions 12 have not defined the LAR for research and, 13 as I've mentioned previously, this leaves 14 IRBs and investigators as well as vulnerable 15 individuals in really a kind of a limbo that 16 we think can be dangerous to the populations 17 and detrimental to the conduct of important 18 research. 19 DR. STRAUSS: So IRBs and 20 institutional officials when they're working 21 hard at this are left to play the game 22 called "Find the Applicable Law." And it's 73 1 a difficult game to play because by and 2 large IRB members, IRB chairs, and even the 3 institutional officials are not very good at 4 searching through the rules, statutory 5 rules, state regulations, various agency 6 rules. It's a difficult game to play and 7 one that I think IRBs often play 8 unsuccessfully. 9 IRBs may also not be so good at 10 understanding this concept of procedures 11 used in the research. And so, for example, 12 if there are state rules which permit 13 clinical surrogate consent of a certain 14 kind, then it's up to the IRB to make a 15 determination about whether those state 16 rules can also be applied to research and 17 when those procedures that are in the 18 research are covered by those state rules 19 and that's a hard call to make. 20 But there are many situations 21 across the country, New York State is one of 22 them, Connecticut is another, in which there 74 1 are no rules about surrogate consent except 2 in some circumstances, for example, a court 3 appointed guardian, a clear advance 4 directive. But those are rare. They rarely 5 occur and they rarely lend themselves to the 6 research context of research decision 7 making. So by and large, IRBs have to 8 figure out whether or if surrogate consent 9 of any sort is possible. 10 And one of the things that's 11 quite odd as we think about it is not only 12 are we playing the "Find the Applicable Law" 13 role but we also need to think about how one 14 goes about conducting the quite common, 15 multi-center, multi-state research activity 16 these days and really what kind of barrier 17 there would be to a multi-site study that 18 was interesting in enrolling people who are 19 unable to make consent decisions for 20 themselves. I mean, we had one case that we 21 know we've discussed at this committee 22 before. OHRP was involved in the ARDSnet 75 1 study from -- I think it was in 2002. 2 So the questions that we want to 3 ask and consider with you today are is it 4 consistent and national approach required, 5 is it possible, and the question about 6 whether it's possible is I think a 7 particularly difficult one again because by 8 and large the definition of who may provide 9 consent for the range of circumstances is 10 not ordinarily one that's part of Federal 11 process. Those decisions are ordinarily 12 left to the states to decide. 13 Is there a role for OHRP guidance 14 in this area? What could OHRP guidance 15 accomplish if we were to craft such guidance 16 with regard to helping IRBs navigate the 17 rocky shoals of the LAR issue? Are there 18 clues or rules to "Find the Applicable Law" 19 game that we may help IRBs with? 20 Similarly, is there a role for 21 Federal regulations in this area? Again, we 22 have to consider a range of possible 76 1 scenarios in both guidance and regulations. 2 If there is a state law that addresses 3 surrogate consent, what would be the 4 interaction between Federal guidance and 5 that state law and, if there is none, what 6 standing or what authority with Federal 7 guidance or regulation have? 8 In thinking about all these 9 options, one option that the subcommittee 10 has spent a good deal of time talking about 11 and seeking input and consultation from HHS 12 counsel on is the question of whether 13 there's a role for SIIIDR and SACHRP in not 14 crafting model state legislation but finding 15 a way to promote or advise on the 16 development of model state legislation and 17 that's one of the things we want to talk 18 about here today as well. 19 This is the last slide and I just 20 want to show this slide to make the point 21 that it's a long and complicated path 22 between the ethical principles and practice 77 1 and really the SIIIDR group is looking at 2 all the different steps here because we 3 think it's necessary to look at all the 4 steps here and all the players as we 5 consider how best to effect practice. 6 I used the word "ironic" before and I'll 7 make the point again that we have enormous 8 regulatory interpretation with regard to how 9 one conducts continuing review, for example. 10 We've looked at that here. Subpart A sought 11 to streamline that to make it more 12 effective. There's a single statement in 13 Subpart A about annual review or yearly 14 review and from that has emerged an entire 15 set of rules and obligations for IRBs and 16 investigators about how to go about doing 17 that and to how to be compliant with that. 18 And yet where an issue as critically 19 important as how one goes about including 20 people who can't make decisions in research 21 for themselves is involved, we say nothing. 22 So SIIIDR is intent on providing 78 1 some guidance to this committee. Our goal 2 is to have something probably on the 3 populations front for SACHRP at your next 4 meeting. But we're hoping today that we can 5 entertain questions and discussion and 6 feedback to SIIIDR on any of the points but 7 with specific reference to LAR problem. 8 Thanks. 9 CHAIR TILDEN: Thank you very 10 much for a very nice presentation. I think 11 the issues you bring up could probably take 12 up three or four hours worth of discussion. 13 I think we set up an hour. So it would 14 probably be best right now if we took our 15 break for our 10 or 15 minute break and come 16 back and then address these issues in order 17 because I think what you presented is quite 18 substantive and there will be a lot of 19 discussion and a lot of feedback. Is that 20 okay? All right. Off the record. 21 (Whereupon, at 10:09 a.m., the 22 above-entitled matter recessed and 79 1 reconvened at 10:29 a.m.) 2 DR. TILDEN: So I think we can 3 reconvene from our recess here and open up 4 the discussion from the subcommittee report. 5 I have just one comment to get 6 started. David, are you going to have your 7 slide presentation available up on the 8 screen while we do the discussion? Okay. 9 Particularly in terms of the grid 10 you presented, which is on page three of the 11 handout. Yes, I really would think to 12 simplify things that the subcommittee and 13 SACHRP in terms of its scope and charge 14 really isn't in the business of drafting 15 guidance or drafting language for a new 16 regulatory subpart, in that it may be more 17 from an economy and efficiency standpoint, I 18 think you hit it right on the head where you 19 identified the key elements for guidance, 20 rationale and basis. But you don't have -- 21 to draft a guidance may take a lot of time, 22 and deny you the opportunity to really focus 80 1 in on what the issues are and what should be 2 addressed in a guidance, rather than 3 developing the guidance itself. 4 And it may just be semantics. I 5 just wanted to point that out. 6 Similarly, for drafting language 7 for a new regulatory subpart or drafting a 8 law even, I think I would say that our time 9 would be better spent in focusing on what 10 should a regulatory subpart address, a new 11 regulatory subpart, not try to actually 12 draft a subpart. And that may be what you 13 meant, but I just wanted to clarify that, 14 and similarly for a model law, I know we 15 have a couple of examples of model laws 16 around the country, and the issue may be, if 17 those model -- not model laws, we have a 18 couple of laws around the country that are 19 specific to research-related issues, and 20 that one could move forward looking at those 21 laws, and it may be that they are 22 incomplete, insufficient, or otherwise 81 1 considered not proper, and from that 2 template identify what content a model law 3 should address, but not to focus on actually 4 drafting a law; they got people who do that 5 for a living, and usually it's a lot of 6 them. 7 So that's just one comment. That 8 may help in terms of focusing the 9 subcommittee's activities in getting down to 10 the nitty-gritty, which is not the structure 11 of the law necessarily; it's what the law 12 says, what the content of it is, that I 13 think is important. 14 So I hope that might be helpful. 15 Okay so I guess we'll go around 16 the table and make comments. And you wanted 17 to focus on the LAR issue and addressing 18 that I think, and where one should -- what 19 the committee sense is. Is that fair to 20 say? 21 MS. FLYNN: That is, and just to 22 respond quickly to your comment, indeed, you 82 1 have articulated better than we did I think 2 what our understanding of what our charge 3 is. And we have had some very helpful 4 guidance to make sure that we provide SACHRP 5 with information and content that can be 6 most helpful. 7 So we do recognize the difference 8 between identifying the elements and 9 drafting the actual language. 10 DR. TILDEN: Thanks. And the 11 staff here has asked that we speak 12 distinctly into the microphone when we make 13 our comments. 14 Dan? Do you have any comments? 15 Questions? 16 MR. NELSON: David, you referenced 17 our discussions with the subpart A 18 subcommittee to attempt to identify the low- 19 hanging fruit, not always successful. And I 20 think you and Laurie and your subcommittee 21 continue to reaffirm our wisdom in sending 22 you off to pick fruit from a different tree. 83 1 Because clearly you're bringing a thoughtful 2 approach to this in a way that we couldn't. 3 And I think the existence and charge of your 4 subcommittee is entirely justified, and we 5 look forward to seeing the work as it 6 proceeds. 7 Just to reiterate, although it 8 sounds like you are already in agreement 9 with Sam's comments, certainly his comments 10 are consistent with what we tried to do with 11 our recommendations from subpart A to 12 provide key elements and talking points as 13 opposed to drafting the actual guidance or 14 the regulations themselves, with maybe one 15 exception out of the 40 or 50 regulations, 16 where we actually got down to the what we 17 thought the guidance ought to say verbatim. 18 We tried to follow that approach, 19 and that seems to work well. 20 I'm going to put you on the spot, 21 but then leave you an out, because I don't 22 think we'll hold you to your answer. But 84 1 I'm wondering where your committee stands 2 today on the question of whether a new 3 regulatory subpart is warranted as opposed 4 to guidance or interpretation that is going 5 to be easier to achieve? 6 DR. STRAUSS: We haven't really 7 completed our discussions about that. But 8 the thinking so far is that they represent 9 short and long term goals; that we recognize 10 that the timeline for affecting practice 11 through regulatory guidance is reasonably 12 foreseeable. We can imagine that we can see 13 an impact to that kind of information, and 14 as I said before, I think any addition will 15 be helpful. 16 So we're very eager to get that 17 piece moving. At the same time we've had 18 discussions, and I think there is generally 19 the recognition that this is an important 20 enough area that more prescriptive 21 regulatory elements may be of value. And so 22 regulations themselves may be warranted. 85 1 But we are not quite there yet. 2 MS. FLYNN: I would just add, 3 echoing what David has said, we really do 4 want to follow I think a both/and kind of 5 strategy here. And just speaking from the 6 standpoint of a patient advocate, I think I 7 will feel, and I suspect there will be 8 others on the committee who will feel, we 9 have not adequately really addressed the 10 issue as fully as it demands if ultimately 11 we don't see some additional regulation. 12 We do believe guidance will be 13 enormously welcome and helpful in the short 14 run. 15 DR. TILDEN: Okay, so Dan, from 16 your perspective, is that -- do you come 17 with any opinion regarding national versus 18 state versus guidance versus new regulation? 19 Or for David and Laurie's benefit, or is 20 that about where you think we ought to be 21 right now? 22 MR. NELSON: What you said. The 86 1 last part. 2 DR. STRAUSS: Sorry, Dan, were you 3 talking specifically about the issue of LAR? 4 Or were you talking in more general terms? 5 MR. NELSON: More general, I mean 6 general, and I accept your response. I 7 think it's very rational and reasonable. 8 I think obviously guidance will 9 be forthcoming much sooner, and the devil is 10 always in the details. And pushing ahead 11 for full blown regulations if you will, then 12 I know we've had SACHRP members in the past 13 who've cautioned us, be careful what you ask 14 for, because as soon as you get a regulatory 15 structure, then you've really got it locked 16 in so to speak in a way that is less 17 malleable than guidance. And I know you're 18 well aware of that. 19 So Sam, I accept their response, 20 and don't know that I'm the one to say yea 21 or nay on it, but look forward to seeing 22 where you go. 87 1 DR. TILDEN: Lisa, I'm sorry. 2 DR. LEIDEN: Well, as a member of 3 one of your working groups, one of my 4 questions is that if in fact we depend upon 5 the state laws, which it sounds like we do, 6 on IRBs, could we not put together an 7 inventory of what those state laws say and 8 present them somehow or have them as part of 9 our working groups? 10 Perhaps we do, and I don't know 11 about it. But it would be very helpful to 12 me, and perhaps to other people from a 13 descriptive standpoint, to know what they 14 say. If in fact one of our charges is to 15 advise or otherwise promote the development 16 of model state legislation, and it's at a 17 level that's important, could we not begin 18 to at least call the states that do have 19 that? 20 I don't know the numbers of the 21 states that have regulations like that. 22 Am I throwing you off base on 88 1 that one? I don't mean to. 2 DR. STRAUSS: No. Certainly there 3 are those who have assembled compendiums of 4 relevant state rules of different sorts. 5 But remember what may be applicable state or 6 local law may not be in the form of a 7 statute or regulation. It could simply be 8 in the opinion, for example, of an attorney 9 general. It could be an agency level rule 10 within a state. 11 And so it's a very murky field. 12 The other problem is there's no 13 uniformity in terms of which elements or 14 aspects of the problem the various state 15 rules address. So for example, you know, 16 California which has a modern rule surrogate 17 based research, hasn't addressed -- what 18 they have defined quite clearly is the order 19 of priority of those who may provide consent 20 for research. They haven't, for example, 21 addressed in any way notions of acceptable 22 risk, and they haven't really gone very far 89 1 in defining what it means to be decisionally 2 impaired, or how you go about identifying 3 that person. 4 So I think that providing 5 information is something that a number of 6 people have tried to do. Actually Ellen 7 Saks, who presented to SIIIDR back in May is 8 about to have an article published in 9 January of her review of state rules. 10 Others have done the same. And I think a 11 couple of the independent IRBs have 12 assembled lists, including Western and 13 Schulman. 14 DR. TILDEN: James. 15 DR. POWELL: I'll admit that I 16 have a limited to no experience in dealing 17 with any research that involves legally 18 authorized representatives, from my 19 perspective of working with the 20 pharmaceutical industry. 21 But I do have two sort of 22 thoughts that seem to be in conflict. My 90 1 one is from the perspective of the 2 pharmaceutical industry, I think that the 3 efficiency of the process of developing new 4 products would be enhanced by a consistent 5 approach nationally, meaning being able to 6 do or have some kind of approach that we can 7 apply across the entire country. 8 But it's in conflict with my 9 concern that there may be regional or 10 cultural or other kind of applications that 11 may be different from place to place with 12 respect to what's appropriate to do in terms 13 of a legally authorized representative. 14 But I still favor the efficiency 15 of the process of clinical research, and 16 there should be some guidance, some approach 17 to guidance, how that is applied may be 18 diverse with respect to the regions in which 19 you would apply it across different 20 communities. 21 So I think, in considering this 22 problem, I would prefer that some guidance 91 1 be applied, that it's national, whether it's 2 guidance or new regulations I'll leave it to 3 people who are much more experienced in that 4 area than I. 5 DR. STRAUSS: You're referring to 6 specifically with regard to LAR? 7 DR. POWELL: I was referring to 8 LAR, yes. 9 DR. TILDEN: Patty. 10 DR. MARSHALL: Thank you for your 11 excellent presentation. Can you all hear 12 me? I've got a little bit of a cold today. 13 I have two questions actually. 14 One is a very broad question, and perhaps 15 there is no answer today, but what would new 16 regulatory elements provide, what would be 17 better about going in that direction 18 eventually as opposed to just providing some 19 serious guidelines, some serious guidance, 20 to the existing regulations? That's one 21 question. 22 And another question has to do 92 1 with, during your presentation you talked 2 about the importance of evaluating capacity, 3 that it should be required in all cases of 4 consent. And would that be different from - 5 - I'm not sure if I can articulate my 6 question very well -- I'm concerned 7 personally about issues related to 8 expressions of autonomy in the informed 9 consent process. 10 So would your evaluation of 11 capacity for decisionally -- someone who 12 might be decisionally impaired, would that 13 be a separate concern than it would be for 14 anyone? 15 How would you address the issue 16 of evaluating capacity? And would that also 17 be associated with some assessment of 18 comprehension after the consent process, if 19 it was someone who was capable of assent? 20 DR. STRAUSS: Those are both very 21 hard questions. 22 DR. MARSHALL: They're big 93 1 questions. They may be rhetorical. 2 DR. STRAUSS: The first question 3 is, what's better about regulations? 4 DR. MARSHALL: Yes, as opposed to 5 guidance. 6 DR. STRAUSS: And I mean I think 7 that certainly with regulations come a 8 mandate. They have more teeth. 9 I think that guidance is -- 10 should -- or we recommend. And by and large 11 I think the issue for this field is, as I 12 see it, is the framework that we're going to 13 recommend significantly different from what 14 exists that a separate subpart is required. 15 We may, and again I don't want to 16 speak to what will happen, but it's possible 17 that in thinking about the kinds of 18 guidance, or the key elements of guidance 19 that we'll recommend, that we may feel that 20 a slightly different structure from what 21 subpart A -- what exists within subpart A -- 22 is required. And I think again, I don't 94 1 know how to make this. This is all about 2 feelings at this point. I don't think we 3 have any evidence. 4 But my sense is that the 5 authority of a regulatory subpart is 6 substantial, and of course the -- in its 7 relationship to the rest of the regulations 8 and the mandate that comes with it is 9 significantly different. 10 MS. FLYNN: Can I just add a 11 thought there too? While completely 12 agreeing with where David is, again, from 13 the standpoint of being an advocate for this 14 longer range stronger approach, at its core, 15 making this an issue of regulation for this 16 most vulnerable decisionally impaired group 17 sets a value for us as a society. It 18 articulates a value for the research 19 enterprise and for all those who are part of 20 it, that we will make our progress with 21 these most disabling difficult conditions, 22 and at the same time we will always protect 95 1 to the fullest extent, we will require that 2 protection in order to go forward. 3 So it has real practical impact. 4 It's the force of law, and you'll do it or 5 you'll be in big trouble. But it also 6 states something very positive about the way 7 in which we want our research enterprise to 8 go forward, and what's at the core of our 9 value around the participants in research. 10 DR. STRAUSS: On the second 11 question, and I think I understand what 12 you're asking, but we're saying that rather 13 than the assumption that competence or 14 capacity is present in research consent, we 15 think that there has to be some affirmative 16 step taken by the investigator to determine 17 that the person with whom you've discussed 18 consent and is signing the consent form is 19 engaged in the process, and has made a 20 decision with understanding to agree to the 21 research, to consent to the research. 22 So don't think that it's simply - 96 1 - that there needs to be some give and take, 2 and the investigator ought to attest to his 3 or her assessment that the subject has 4 understood what's involved in the research. 5 That's what we're talking about. 6 DR. MARSHALL: Thanks, David. 7 I believe that you might consider 8 that issue for anyone who is being 9 consented, and that is not specific to 10 someone who is, or might be decisionally 11 impaired. 12 DR. STRAUSS: Absolutely, and 13 that's what we're saying, that it's a 14 fundamental precondition in a sense, and 15 that where there may be a higher likelihood 16 of impairment, circumstances or disorders, 17 then an IRB might recommend a different 18 approach to that assessment, for example. 19 But it should occur in all cases 20 of consent is what we're saying. 21 DR. TILDEN: Mike, do you have any 22 comment? 97 1 DR. GENEL: Well, one of the risks 2 of not being first is that the first 3 questions I had have already been asked. 4 DR. TILDEN: It's harder. 5 DR. GENEL: So I will now ask 6 questions that the rest of you can't ask. 7 DR. TILDEN: You can pass if you 8 want. 9 DR. GENEL: No, I think one of the 10 more difficult parts of this and one of the 11 compelling reasons I believe to try and get 12 some order in this chaotic field is the need 13 to have some uniform standards that would 14 permit multi-institutional research trials 15 to go forward. 16 And we'll hear a little bit about 17 this tomorrow in terms of the CTSA panel, 18 because one opportunity that does exist and 19 will only become greater as the CTSA program 20 expands is the capacity within nationwide to 21 actually conduct meaningful studies. 22 It seems to me as I split the 98 1 components of your diagram, your panel, that 2 one could probably develop coherent guidance 3 on two parts of that; that is, defining the 4 population and the approval criteria. And I 5 think I can rationally say that one could 6 develop coherent guidance that would handle 7 those aspects. 8 But the LAR problem is a much 9 more complex one that is going to not be 10 done so quickly in terms of standards. And 11 there I would think you need to get help 12 from the legal brains that are available. 13 Now at the last meeting we did 14 pass a motion requesting that you get a 15 compendium of the various laws and so forth. 16 Have you received any of that material yet? 17 DR. STRAUSS: Yes. 18 DR. GENEL: Has that been helpful? 19 Or has it just made clearer how difficult 20 it's going to be to get this done? 21 DR. STRAUSS: I think the latter. 22 But we did have an opportunity subsequent to 99 1 the last meeting to work with counsel to try 2 to understand the relationships of the 3 federal rule and state rules, and the 4 federalism issue, and the kind of barriers 5 that exist to the ready implementation of 6 guidance or regulations in this area. 7 DR. GENEL: Well, my suspicion is 8 that to really effect change here is going 9 to require some sort of real effort to 10 energize the national community, either 11 through the state legislators, or through 12 Congress, to get anything done. And absent 13 that I think we can only try to identify the 14 magnitude of the problem, highlight it, and 15 offer recommendations for solutions. 16 But it's going to be very 17 difficult, absent some sort of legal action, 18 to accomplish anything. 19 Now how, I mean that's a massive 20 effort, and perhaps the advocacy 21 organizations can assist us in making the 22 point that there is a need for this sort of 100 1 coherent national policy in order for 2 meaningful research to go forward. I think 3 that would be the direction I would look 4 for. 5 MS. FLYNN: If I could ask you 6 some follow up, thank you, would you then 7 feel that we might serve well to identify 8 the elements that might be addressed in 9 regulation should such action be recommended 10 and adopted further down the road? In other 11 words going beyond cataloging the problem, 12 which we will certainly do; but also to 13 address what might be the elements? Is that 14 -- 15 DR. GENEL: At the minimum. I 16 mean, at a minimum. But I think where I 17 think SIIIDR and SACHRP can perhaps provide 18 some benefit is by bringing clarity to the 19 issue and the need for specific action, 20 particularly in the LAR issue. 21 Because I think the other aspects 22 of what you're dealing with could be handled 101 1 nicely and easily through guidance. 2 DR. STRAUSS: You know I think 3 that there is an interaction between these 4 three elements, and it's one of the reasons 5 we made that picture and triangle with 6 arrows connecting them. 7 Because you know what I imagine 8 is that if there is a strong statement, and 9 if the field recognizes for example the 10 guidance that we would create on population 11 and risk-benefit analysis, then we've 12 created a framework within which states 13 might frankly be more at ease addressing the 14 question of LAR for research, because there 15 now is a structure within which that 16 research can comfortably be done. 17 Right now, there is a void in my 18 estimation. This is not -- regulating 19 research is not something that states do 20 often. They have no compliance programs in 21 that regard. So it may be that if there is 22 a federal structure for at least two of the 102 1 three components that states would be more 2 likely to do the third. And then perhaps 3 there is a way that we can suggest a sample 4 for what that third piece might look like, 5 it'd more likely be promoted. 6 DR. GENEL: And I would not 7 underestimate the resistance that's out 8 there to doing any of this. 9 DR. TILDEN: Elizabeth. 10 MS. BANKERT: In my interactions 11 with IRBs all over the country I think you 12 have hit the exact problems, and that is 13 that there is this void, and so they fall 14 back on their state laws. They have to; 15 they don't have anywhere else to go. 16 So I think it's fabulous to go 17 with a national guidance, because then they 18 won't have the excuse that there is no 19 guidance out there, so they have to go to 20 their state laws. 21 But there will be roadblocks; no 22 question. But I would suggest moving 103 1 forward with it. And I really, the 2 population working group ideas would be 3 really very helpful for IRBs, as soon as 4 possible as you can get the guidance going. 5 So I think this work has found 6 all the issues IRBs confront everyday, and 7 so we'd just really highly recommend moving 8 forward. It's great. 9 MS. FLYNN: The LAR thing, we're 10 part of a compilation, and found the exact 11 same thing that you guys have; it's not that 12 helpful. Rather, we need this guidance on a 13 national level. 14 DR. STRAUSS: Again, the tricky 15 business is the relative authority of 16 federal and state rules in this domain, and 17 where there is no state rule, versus where 18 there is, I think will have different 19 abilities to act. 20 MS. BANKERT: But even so, in the 21 IRBs that I have interacted with, the 22 attorneys tend to use OHRP guidance as 104 1 regulations. And so then comparing that to 2 the state laws they have to do as well. But 3 since there is no guidance, then they have 4 to fall back on state law. And exactly 5 what you're saying I've heard over and over 6 again, that this type of research is not 7 being done because the state doesn't allow 8 it. And that will still be a roadblock, 9 but this would be helpful. 10 DR. STRAUSS: One of the things 11 that we've discussed previously is that I 12 think one of the reasons that this endeavor 13 is more likely to succeed at this go-round, 14 one of the many reasons is that I think the 15 whole institutional IRB culture has changed 16 dramatically in the last six or seven or 17 eight years, and I think there is a real 18 infrastructure where people do in fact pay 19 attention, and are keen to understand the 20 regulations and OHRP guidance and those 21 interpretations. I think there is a whole 22 infrastructure that permits that now. I 105 1 think that was less the case, we had a less 2 invigorated IRB system, eight, nine years 3 ago. 4 DR. TILDEN: Francine, you have 5 any comment? 6 DR. ROMERO: I just wanted to 7 commend the group. They're doing a 8 wonderful job and being as inclusive as they 9 can of individuals that they are advocating 10 for, and I really do appreciate that. 11 Just wanted to I guess to make a 12 suggestion to the group to really look at 13 the state models that exist, and even though 14 they may be limited in their applicability, 15 or in their usefulness, to really look at 16 them, to incorporate some of the aspects 17 that they are mentioning. Because I think 18 if we do go with the national regulatory 19 approach, it's good to work within the 20 capabilities of the state, and just their 21 kind of adherence to these sorts of 22 regulations that might be occurring. 106 1 And then I missed the SACHRP 2 meeting, so I don't know if in our packets 3 we have gotten a couple of the RFI? Did we 4 get that at all? Because I'd be curious to 5 see some of the language if that's possible, 6 and then possibly in the next updates, to 7 the SACHRP committee, to just hear what some 8 of the public comments are, I'd be very 9 interested to see some of those as well. 10 You're doing a wonderful job. I 11 do appreciate all the work. 12 DR. STRAUSS: I think the group 13 should certainly look at the RFI. I think 14 it was really carefully crafted, and I think 15 the folks who were involved, I know it was a 16 long hard -- hard to deliver product. It 17 was done quickly, and I think really did 18 address many of the concerns that were 19 voiced at many of the SIIIDR meetings. 20 So we are hoping that we'll get 21 some helpful response. 22 DR. TILDEN: Kevin's writing down 107 1 that right now, Francine, so the committee 2 will get a copy too. 3 Neal, you have any comment? 4 DR. POWE: I could just say, I 5 think most of what I was going to say has 6 been said. But let me just comment on how I 7 feel about this issue. 8 I wanted to commend the 9 subcommittee for laying out their process 10 early, allowing us to see the process, and 11 have some input into the process before the 12 result comes. 13 I do believe that there should be 14 consistent principles that can be used 15 nationally for I think the same reason that 16 Dr. Genel mentioned, that it's exceedingly 17 important for multicenter, multi- 18 institutional research for especially for 19 rare conditions where investigators need to 20 amass a large number of research subjects to 21 make progress in an area, and where, 22 particularly for some of the areas of 108 1 vulnerable subjects in these areas, I think 2 we could learn a lot by doing more multi- 3 institutional research. 4 I share some of the concern about 5 how far -- how far we go on this issue. I 6 think the approach to define the key 7 elements first is important. What are the 8 key elements? What principles should be 9 laid out? 10 But I think for it to go much 11 further, there's going to have to be 12 compelling evidence that -- about how far to 13 go, and whether that requires regulatory 14 reform or not. 15 So I would urge to lay out those 16 key elements, and if there is compelling 17 evidence, to proceed to reform the 18 regulations, then I think that may be 19 appropriate. 20 But I think to say right now 21 that's where we are, I would urge some 22 caution.