1 UNITED STATES DEPARTMENT OF HEALTH AND HUMAN SERVICES + + + + + SECRETARY'S ADVISORY COMMITTEE ON HUMAN RESEARCH PROTECTIONS + + + + + MEETING + + + + + MONDAY, JULY 30, 2007 + + + + + The Advisory Committee met at 8:30 a.m. in the Sheraton National Hotel, 900 South Orme Street, Arlington, VA, Dr. Samuel Tilden, Chair, presiding. MEMBERS PRESENT: SAMUEL TILDEN, MD, CHAIR BERNARD A. SCHWETZ, DVM, PHD, EXECUTIVE SECRETARY CATHERINE SLATINSHEK, MA, EXECUTIVE DIRECTOR JEFFREY BOTKIN, MD, MPH MYRON GENEL, MD DANIEL NELSON, MS, CIP NEIL POWE, MD, MPH, MBA JAMES POWELL, MD, CPI DAVID H. STRAUSS, MD EX OFFICIO MEMBERS PRESENT: FRANCIS D. CHESLEY, JR., MD, HEALTHCARE RESEARCH AND QUALITY HOWARD BRADLEY, SOCIAL SECURITY ADMINISTRATION KELLINA CRAIG-HENDERSON, ALTERNATE FOR SANDRA SCHNEIDER KATHRYN LYNN CATES, MD, DEPARTMENT OF VETERANS AFFAIRS WARREN E. LUX, MD, ENVIRONMENTAL PROTECTION AGENCY SUZANNE FITZPATRICK, ALTERNATE FOR FDA JOAN PORTER, DPA, MPH, ALTERNATE FOR THE DEPARTMENT OF VETERANS AFFAIRS JEFFERY W. RODAMAR, DEPARTMENT OF EDUCATION DAVID SHORE, MD, ALTERNATE FOR AMY PATTERSON 2 TABLE OF CONTENTS Welcome: Opening Remarks, Samuel J. Tilden, M.D., SACHRP Chair. . . . . . . .3 Report of Issues/Remarks, Bernard Schwetz, D.V.M., Ph.D., Director, OHRP. . .4 Report of SIIIDR Subcommittee, David Strauss, M.D. and Laurie Flynn, Co-Chairs . 12 Report of Subpart A Subcommittee, Felix Gyi, M.B.A., Pharm.D., and Dan Nelson, M.S., CIP, Co-Chairs. . . . . . .107 Public Comment. . . . . . . . . . . . . . . . . .233 Wrap-up Discussion and Adjourn. . . . . . . . . .235 3 1 P-R-O-C-E-E-D-I-N-G-S 2 8:37 a.m. 3 DR. TILDEN: Good morning. I guess it's 4 time to get started. I want to thank everyone for 5 attending the 13th meeting of SACHRP. It just opened 6 this morning with running down the agenda for today in 7 the opening remarks. 8 As everyone knows, as a reminder, the 9 SACHRP charter states that SACHRP will advise the 10 Secretary on matters concerning the protection of 11 human subjects with particular emphasis on special 12 populations such as neonates, children, prisoners, the 13 decisionally impaired, pregnant women, embryos and 14 fetuses, international studies, identifiable samples, 15 investigator conflict of interest, and OHRP 16 activities. The members of SACHRP are listed here as 17 well as the ex officio members of SACHRP. 18 Today we plan to have the report of issues 19 and remarks by Dr. Schwetz which will be followed by 20 the report of the Subcommittee on the Inclusion of 21 Individuals with Impaired Decision-Making and Research 22 Subcommittee. We'll have a break at 10:30 and then 23 the SIIIDR Subcommittee report will continue. 24 We'll have lunch from 11:30 to 12:30 and 25 then we'll have the report from Subpart A Subcommittee 4 1 co-chaired by Dan Nelson and Felix Gyi. That will 2 take us through a break until 4:00 p.m. and then we'll 3 have public comment from 4:00 to 4:15, wrap up the 4 discussion and adjourn. I'll save tomorrow's agenda 5 for tomorrow. 6 The first order of business would be to 7 have the minutes approved from the previous meeting. 8 The minutes are at Tab J. Is there any motion to have 9 the minutes approved? 10 DR. GENEL: I move. 11 DR. TILDEN: Second? 12 DR. STRAUSS: Second. 13 DR. TILDEN: There's a second. Any 14 discussion or comment? All in favor? Okay. The 15 minutes are unanimously approved. 16 I would like to yield whatever time I have 17 for the moment and move to Dr. Schwetz and ask Bern to 18 give his report on the issues. 19 DR. SCHWETZ: Thank you, Sam, and good 20 morning to everybody. I will be talking about more 21 than issues. 22 DR. TILDEN: Excuse me. And remarks. 23 DR. SCHWETZ: And remarks. I will 24 summarize where we are on most of the recommendations 25 that have been made by SACHRP and talk about some 5 1 other things that are going on within OHRP. 2 First of all, the last sets of 3 recommendations that were submitted by the 4 subcommittee on research involving children and the 5 Subpart A Subcommittee have been approved by the 6 Secretary and are now posted on our website and those 7 recommendations have been folded in with the rest of 8 the recommendations that the office is working on from 9 these two subcommittees. 10 The recommendations regarding training of 11 individuals that you approved not too long ago have 12 been -- this is training of individuals involved in 13 the review oversight and conduct of research. Those 14 have been submitted to the Secretary so we are hoping 15 to get an answer back from that fairly soon. 16 Regarding Subpart C I think I mentioned 17 last time that we were in the process of gathering 18 information from all of the other federal agencies 19 under the common rule. Their take on the 20 recommendations of SACHRP and the IOM report we have 21 now received all of those recommendations regarding 22 Subpart C, research involving prisoners. 23 The work group within OHRP is considering 24 the input from SACHRP, the input from the IOM report, 25 and the information that we got from other federal 6 1 agencies and they are considering what a new Subpart 2 C might look like to see if that is a direction that 3 we, in fact, want to take. 4 Another consideration is whether or not 5 there may be one or more frequently asked questions 6 that come out of that that we would put up on the 7 website so that's another activity relative to the 8 prisoner information that we are looking at. 9 With Subpart D the work simply continues 10 in terms of developing guidance and getting the things 11 done, that was a large set of recommendations, and it 12 will take us some time to come up with products that 13 will go beyond OHRP. We are continuing to work on it. 14 Regarding HIPAA, there are, believe it or 15 not, still some unresolved issues between offices and 16 agencies that continue to be worked on. I won't even 17 speculate on when we'll see something out of that but 18 I am sure it will be coming. 19 OHRP has posted a new site of FAQs on 20 informed consent on our website in June of '07. OHRP 21 continues to engage in conferences with special 22 populations. The next one is a conference that we are 23 co-sponsoring in Denver on August 22nd and 23rd. The 24 focus of this conference in Denver is the American 25 Indians and Alaskan native issues as it relates to 7 1 human subject protection. 2 We've had a number of meetings and 3 conferences in Indian country to deal with these 4 issues. We are happy to be back planning another 5 meeting on these topics. The other sponsors with us, 6 within the Office of Public Health and Science we have 7 regional offices. We have staff members located all 8 over the country in these regional offices and there 9 is one in Denver. 10 We are co-sponsoring and planning this 11 conference with that regional office that is located 12 in Denver and they have brought together some of the 13 other regions to cover a fair amount of what is 14 referred to as Indian country to get speakers in, to 15 get people from IRBs into this conference. In 16 addition to OHRP and the regional offices, the Indian 17 Health Service, and the Office of Minority Health are 18 also engaged in the planning of this two-day 19 conference. 20 We continue to have QA workshops for FWA 21 holding institutions. We have had a number of these 22 at institutions that have internal IRBs. Thanks to 23 Shirley's willingness to continue to try -- Shirley 24 Hicks, the director of our Division of Education -- 25 willingness to try new things to reach out to the 8 1 community that we oversee, Shirley has had two of 2 these QA workshops now in places where they don't have 3 -- in institutions where they do not have a local IRB. 4 It is turning out to be enlightening the nature of the 5 questions, the training that we should be doing at 6 institutions that are doing research involving human 7 subjects but they are dependent on somebody else's IRB 8 because they have none locally. 9 Two personnel items. Dr. Ivor Prichard 10 has been with us for almost two years. You may have 11 assumed that he was an employee of OHRP which wouldn't 12 have been the right conclusion because he's been on a 13 detail from the Department of Education until last 14 week when he officially became an employee of OHRP. 15 Ivor, we are glad to have you not only 16 with us but working as a senior advisor to the 17 director so Ivor will be working directly in the 18 immediate office of the director to help on whatever 19 broad range of issues we need his help with. 20 The second personnel item, word has gotten 21 around that I'm going to be retiring and it's not just 22 a rumor. I do plan on retiring on September 30th. 23 I'm grateful certainly to all of the SACHRP members 24 and subcommittee members for a very high-level of 25 productivity and a very high fidelity to work that is 9 1 important to the field that we are part of. I'm very 2 impressed by what SACHRP has gotten done. Impressed 3 enough that I look back at my own involvement in 4 federal advisory committees over my 30 years, 25 of 5 which have been in HHS. 6 Over those 30 years I realize that I've 7 worked very closely, not just attending once in a 8 while but hands-on working with six different federal 9 advisory committees in NIH, FDA, EPA, and now in OHRP. 10 I was a member of two of them and I have been the 11 executive secretary or the executive director of two 12 of them. 13 While I was in the FDA I was the direct 14 recipient of recommendations from two other federal 15 advisory committees. Over all of that period of time 16 I have never been involved with a federal advisory 17 committee that was as productive and independent as 18 SACHRP has been. 19 Independent in the sense that you are not 20 constantly wondering what you should be doing and 21 looking for signals of what to do. It's a very 22 directed group and has been extremely productive in my 23 mind in terms of the issues that needed help in the 24 community that we all work in. 25 Dr. Prentice isn't here this morning. He 10 1 will be here this afternoon and I'll give him thanks 2 in front of all of you now but I'll thank him again 3 later for having served as the chair of SACHRP for 4 four years and Dr. Tilden for having picked up at that 5 point and having served now as the chair. And thanks 6 to all of the current members of SACHRP. You are 7 continuing the tradition of hard work and insightful 8 thoughts just as SACHRP has been known for in the 9 past. 10 I think all of my OHRP colleagues who have 11 served as the person in OHRP who interfaces with the 12 subcommittees and for the presentations at SACHRP 13 meetings, as you realize an awful lot of work at 14 SACHRP gets done in the subcommittees and that would 15 not have been as productive if my colleagues from 16 within OHRP hadn't been there to help create that 17 partnership. 18 Also to all of the ex officios for having 19 worked closely with SACHRP and with the subcommittees 20 in a manner that I think makes the subcommittee work 21 more effective by having additional input from 22 relevant federal agencies through the ex officios. 23 Special thanks also to Cathy Slatinshek and to Kelley 24 for making these meetings go as smoothly as they do. 25 Thanks to both of you. 11 1 Sam, back to you. 2 DR. TILDEN: Thank you, Bern. A lot of 3 thanks going around here in those remarks. I know 4 they are well appreciated. 5 We have a thank you as well. I harken 6 back to my daughter when she was about eight or 10 7 years old and her favorite rabbit died. As a 8 veterinarian you might relate to that. Anyway, I had 9 to break the news to her. She wasn't home and she 10 started bursting into tears and saying, "Gee, I just 11 didn't have enough time to spend with him." 12 Sort of as chair I feel that about you. 13 I wouldn't say you appointed me as chair and cut and 14 ran but anyway, on behalf of SACHRP we want to present 15 you with a token of our appreciation. I want to give 16 this to you and if you don't mind standing up and have 17 your picture taken. 18 DR. SCHWETZ: I assume I should open it. 19 DR. TILDEN: If you would like. 20 DR. SCHWETZ: This is not the rabbit? 21 DR. TILDEN: It's the rabbit foot. In all 22 honesty, I think we can say that SACHRP has been very 23 productive over the years. To a large degree it had 24 to do a lot with Bern, I think, seeing a mission and 25 a vision for SACHRP, getting individuals together to 12 1 do that and letting it run. I think in that regard 2 you deserve great thanks for the success of SACHRP 3 over the years. 4 DR. SCHWETZ: It's not the picture of the 5 rabbit either but it is engraved. It's a frame. 6 Whose picture should I put in here? Maybe a 7 collective one of SACHRP. 8 DR. TILDEN: We'll all get out here in the 9 front and get a picture in just a minute. Any one you 10 take would be good, too. 11 DR. SCHWETZ: "For exceptional vision, 12 leadership, and service. July 30, 2007." My name on 13 it, Executive Secretary of SACHRP. Thank you, Sam. 14 DR. TILDEN: Can we get the committee to 15 come up and get a picture? 16 Well, from this juncture we are going to 17 move into the report from the SIIIDR Subcommittee. 18 David Strauss and Laurie Flynn, the co-chairs, will 19 present. 20 DR. STRAUSS: Good morning. This is 21 actually the first time that we've presented to SACHRP 22 since the subcommittee has been formally assembled and 23 convened. We talked over the last year on a number of 24 occasions at this meeting in a way to introduce some 25 of the concepts and to formulate some of the areas 13 1 that we intended to focus on with this new 2 subcommittee. 3 We have, I'm glad to say, got rolling. I 4 think we've hit the ground running. What we would 5 like to do today is present to you some of what we 6 have been thinking about and working on and some 7 material for you to digest and deliberate on, we hope, 8 and discuss with us. 9 Laurie Flynn and I are planning to co- 10 present as co-chairs so Laurie is going to start us 11 off. 12 MS. FLYNN: Thank you very much and good 13 morning. Again, my congratulations to Dr. Schwetz and 14 best wishes. I hope there is a good luck rabbit foot 15 in that envelope somewhere. 16 Also I would like to thank Dr. Tilden who 17 has attended our meetings and been wonderful help and 18 support to the substantive work of our group. Very 19 much appreciate David Strauss' leadership. He has put 20 the yeoman's share of energy and expertise and 21 guidance as we have tackled some issues and problems 22 that are central to the charge that we're addressing. 23 This morning we are going to give you a 24 picture, as Dr. Strauss said, of what we have been 25 doing. We are going to present some issues to you for 14 1 your feedback and give you a sense of the direction 2 that we're taking. 3 Here briefly is an overview what it is 4 that we plan to present to you today. As you can see, 5 we are going to give you a sense of how we look at our 6 charge, what has been the focus and the approach that 7 we've taken, what we have been doing, how have we 8 worked as a group, what are the ways that we have 9 addressed the issues in front of us and what are some 10 of the resources and some of the information that 11 we've had brought to us. 12 Where are we going, how do we see 13 ourselves within what we understand could be a fairly 14 short time frame. How do we see ourselves moving 15 forward productively. Then, again, we hope to get 16 some discussion and some feedback. We very much would 17 like to get your sense of how it is that we are moving 18 along. 19 Here are some of the things that we have 20 for consideration to SACHRP that we bring to you today 21 and would appreciate your guidance on. First we are 22 seeking your support for our priorities for our 23 general approach for the way that we are envisioning 24 moving forward to some recommendations. 25 We have had some very lively and 15 1 substantive conversations and we want to share with 2 you the preliminary points of consensus that our 3 subcommittee has reached. We'll go into these in 4 greater detail. You see them there. We have come to 5 the conclusion that as a basic requirement we need to 6 be sure that there is, indeed, a clear assessment of 7 understanding as it's delineated in the informed 8 consent process in all cases of consent. 9 Secondly, we see a need for a consistent 10 national approach to the definition of legally 11 authorized representative which is an important 12 protection for individuals who are most vulnerable due 13 to their inability to consent to research. 14 We recognize that there is some overlap 15 potentially with regard to the work of the 16 subcommittee that has been dealing with Subpart A. We 17 want to be sure that we are clear about how those 18 issues interrelate. 19 Just to remind the group, from the charge 20 that came to the SIIIDR Subcommittee we were asked to 21 consider whether guidance or additional regulations 22 are required for individuals with impaired decision- 23 making capacity. We were really asked to go at the 24 heart of this issue and take yet again a strong look 25 at the regulatory basis for protections to see if more 16 1 additional regulatory response or guidance to the 2 field was necessary. 3 We do have some starting points, as all of 4 you are well aware, as we look at this issue and 5 consider possible action going forward. Legally 6 effective informed consent is delineated at 45 CFR 46 7 and it particularly focuses on several key points that 8 we have grappled with. 9 To quote the regulation it says, 10 "Information shall be understandable to the subject." 11 We have had considerable conversation in trying to 12 determine what is encoded in that word. What is meant 13 by information must be available in language that is 14 understandable. What does this mean and how can we 15 make sure that it, in fact, is done adequately? 16 We know that special protections in the 17 IRB review and approval process look at a couple of 18 key concepts. No. 1, the balance in risks to subjects 19 which must be reasonable in relation to any 20 anticipated benefits and in relation to the importance 21 of the potential results and the knowledge that may 22 result from the research. 23 Here again we have grappled with how do we 24 assess this and how can we make certain that those 25 individuals who may have decisional impairments are 17 1 adequately assured that a reasonable balance has been 2 assessed. 3 We also know that when subjects are likely 4 to be vulnerable to coercion or other undue influence, 5 the regulations require that additional safeguards 6 have been included in the design of the research. 7 These, again, are core protections and we have tried 8 to determine if they are adequately understood and 9 ultimately can be effectively implemented. 10 Finally, for those individuals who are 11 most vulnerable, those who are unable themselves to 12 provide effective consent where surrogate consent 13 would be necessary, we have looked at the structure 14 and underpinnings of the concept of legally authorized 15 representative. This is the protection and safeguard 16 available for those who are by virtue of impairment 17 unable to provide consent. 18 We have been a busy group. David Strauss 19 is a tough taskmaster. We have had several SIIIDR 20 meetings. As you can see, we have also worked in 21 subcommittees in between the meetings on telephone 22 conference calls as well as various e-mail mechanisms 23 to keep the dialogue going to bring in additional 24 expertise and to maintain a steady march towards what 25 we hope will be some effective recommendations. 18 1 Certainly we have had again a review of 2 past efforts. These are not new topics. These are 3 subjects that have been from time to time very much a 4 focus in the research community. We have taken a look 5 at what has been the strength and what have been some 6 of the problems associated with the National 7 Commission, with NBAC on which I was pleased to serve, 8 with NHRPAC and with the NIH points to consider. 9 Further, we've had expert presentations, 10 been very informative. Many of us come with a greater 11 or lesser degree of knowledge about the realities of 12 decisional impairment and cognitive disability. We've 13 heard and learned more about the impact of these 14 conditions on adults with mental retardation, 15 individuals with Alzheimer's disease, a progressive 16 illness as you know. Very interesting discussion 17 about traumatic brain injury as well as psychiatric 18 illness across a range of disorders. 19 We have been fortunate to have 20 considerable assistance in taking a look at the 21 regulatory basis in federal law for our work. We had 22 help from Laura Odwazny and Julia Gorey. We became 23 familiar with the FAQs on informed consent and had 24 quite a good dialogue and support from our staff in 25 understanding what has gone before and where have been 19 1 the opportunities and difficulties that we want to pay 2 attention to. 3 We also took a look at what is going on 4 out across the country, most particularly with state 5 law which is to be applicable particularly in the case 6 of the issue of legally authorized representative. 7 Here we had Anne Donahue of our subcommittee survey 8 the laws across the country and make a presentation 9 for us on what we do or don't have as a statutory 10 basis in this arena. 11 Finally, David Forster assisted us in 12 reviewing institutional policies, IRB policies with 13 regard to those who are unable to consent, again to 14 give us a picture of where we are and where the field 15 is. 16 Returning again to our charge, looking at 17 the issue of whether guidance and/or additional 18 regulations are required for individuals with impaired 19 decision-making capacity, our answer, I think, to 20 SACHRP is quite clear. Our answer is yes. 21 We do see a basis for action as we have 22 reviewed the past history. As I mentioned, we do know 23 that these issues have been grappled with, have been 24 seen consistently over several decades by a variety of 25 national bodies as issues that we need to do more with 20 1 but it has proven difficult to determine how to do 2 that successfully. 3 Indeed, even as we meet today I think 4 there is a certain sense of frustration that much as 5 we've met and talked and many scholars have written 6 and much investigation has been done, we still don't 7 have the field in quite the place we would like. 8 We know that existing federal regulations 9 and regulatory guidance relevant to protection of 10 individuals who may have impaired decision-making 11 ability is not adequate to address some of the key 12 ethical concerns, widely shared concerns regarding the 13 rights and welfare of this population. 14 These issues continue to come up. They 15 continue to be thorny. They continue to take 16 considerable time at local IRBs. Investigators 17 struggle with these issues and there continues to be, 18 I think, a lack of consistency and clarity. We feel 19 it is important to address it. 20 For those prospective participants in 21 research who are unable to consent for themselves, 22 those who are most vulnerable, the absence of any 23 adequate consistent or as we discovered in many cases, 24 any state law at all, creates a significant problem 25 for research protections. As you will see, federal 21 1 law points to state law and state law is often 2 missing. This is a significant gap in our protections 3 and it's an important area for the subcommittee's 4 deliberations. 5 We believe that the solutions need to be 6 appropriate and must provide the protections that are 7 necessary for this group of individuals who are faced 8 with impaired decision-making capacity. Also needs to 9 balance the other side of that picture which is these 10 individuals often suffer from some of the most 11 grievous and difficult conditions and circumstances 12 that can befall humankind. 13 We need to learn more about these 14 conditions. We need to understand better how to treat 15 and support individuals who are struggling with these 16 disorders and situations. We need to balance the 17 protection of this very vulnerable group with our need 18 to be able to advance our science so as ultimately to 19 support greater degree of recovery in the larger 20 population. This is the critical balance we all deal 21 with in the larger field. 22 We have, we think, possibly a fairly short 23 time frame so we have tried to think through an 24 efficient and effective process to serve SACHRP. We 25 do have a game plan. We will be developing and 22 1 refining back and forth iteratively specific 2 recommendations. We do want to get your feedback as 3 we go along and that is a key part of our hope for 4 today's meeting. 5 We also know we need to get input from a 6 variety of stakeholder groups. We anticipate 7 incorporating information from the OHRP FDA request 8 for information. We know that public comment will be 9 very informative to us as the RFI addresses a number 10 of matters that are central to our charge. 11 We also want to get comment and input from 12 a variety of stakeholder groups, academic and 13 professional organizations, IRB members and leaders 14 who struggle with these issues on a regular basis, as 15 well as representatives of patient advocacy groups who 16 articulate concerns for adequate protections as well 17 as issues around the need for effective and ethical 18 research to go forward. 19 That is how we have come to today and now 20 I'll ask our co-chair, David Strauss, to pick up. 21 DR. STRAUSS: Just a comment again on the 22 game plan. That is to say that we as a subcommittee 23 feel that we need to clarify for ourselves what it is 24 we would like to accomplish first and then decide what 25 is the best way to accomplish that. 23 1 That seems obvious in a way but if our 2 task is to decide whether federal guidance or 3 interpretation of existing regulations is necessary 4 versus whether we are proposing that SACHRP consider 5 new regulations or new regulatory subpart is really a 6 part of our decision-making process so we are thinking 7 to the extent that we can broadly and approaching this 8 as best we can from a broad conceptual background. 9 We want to make sure that we consider the 10 lay of the land. We want to make sure that we have 11 engaged all the necessary stakeholder groups. We want 12 to have your input and support as we present to you 13 what we imagine would be increasingly refined set of 14 recommendations. 15 Part of what is motivating our thinking 16 and part of what is driving our process is our efforts 17 to understand where prior efforts have not succeeded. 18 As Laurie referenced, we are not the first group of 19 highly intelligent, extremely good-looking people to 20 get together and consider how to tackle this issue. 21 Why are people smiling? 22 Thinking about what's failed or what has 23 gone wrong before I think is a critical aspect of how 24 we are trying to approach this and we hope that we can 25 all do that together. Also, it's clear to all of us 24 1 that navigating the rocky shoals of regulatory change 2 or federal agency-wide consensus is an enormously 3 difficult task. 4 We would like to be undaunted by the many 5 warnings that come our way. We hope you will, too, be 6 willing to consider changing what needs to be changed. 7 That, I think, is a key aspect of our philosophy here. 8 It's quite striking. We emerged some 30 years ago -- 9 30 years ago from a period of time in which research 10 with captive and vulnerable populations was common 11 practice. 12 The field has gone an enormously long way 13 since then and yet, where research with these most 14 vulnerable populations is at issue, we still have 15 little or no regulatory direction and efforts 10 years 16 ago and it was quite an amount of activity around and 17 back and shortly after but none of those, in our view, 18 have significantly impacted the practice and we are 19 hoping that you actually and this committee can do 20 better going forward. 21 In that vein we worked hard to think about 22 how to pull together a committee with a range of 23 orientations and expertise. We assembled a group of 24 leaders really in their respective fields that I feel 25 can do the job and I think you will, too. Many of 25 1 these people are known to this committee. 2 From the upper left Dr. Paul Appelbaum I 3 think most of us know is really a world expert on 4 empirical research ethics and informed consent. Dr. 5 Botkin, known to this committee, needs no 6 introduction. 7 Anne Donahue presented to this committee 8 before. She is a Vermont state legislator but also a 9 woman who has suffered a life-long and serious mental 10 illness. She's an attorney who also runs a peer 11 advocacy newsletter in her home state and has been 12 instrumental in affecting regulatory change in her 13 home state with regard to informed consent. 14 We know Laurie who also needs no 15 introduction. David Forster next in line is a VP for 16 compliance at the western IRB, a lawyer and an expert 17 in regulatory compliance issues. We are really glad 18 to have the perspective and the input from the 19 independent IRB and certainly one with the reach and 20 grasp of the western IRB. I think his perspective and 21 experience is really a unique one. 22 Edgar Kenton is a neurologist who is at 23 Maharry and has written extensively on issues dealing 24 with stroke with particular focus on the excess burden 25 of stroke on minority populations and the under- 26 1 served. He has served on numerous federal advisory 2 committees and NIH council and we are really pleased 3 that he was eager to join us. Stroke, of course, is 4 an area in which enormous amount of work is ongoing 5 and research is critical in this area and individuals 6 with stroke or effect in the way that is relevant to 7 the deliberations. 8 We are glad that Lisa Leiden will be 9 joining us, again a member of SACHRP. Again, I think 10 it was at Sam's suggestion that some of the SACHRP 11 members sit on the subcommittees and we think that 12 both Jeff and Lisa's involvement I think will also 13 help move our process forward. 14 John Luce is next. Some of you may 15 remember John who presented to this committee in the 16 spring. John is a professor of medicine at the 17 University of California in San Francisco. John runs 18 the intensive care unit there. He's written on the 19 ethics of research in the intensive care unit setting. 20 He brings a perspective of critical care medicine to 21 our committee which shockingly I think represents an 22 area of research and patient care that has been 23 omitted from many prior efforts to think about the 24 decisionally impaired. 25 John Oldham, next in line, is the 27 1 Executive Vice President for Clinical Affairs at the 2 Department of Psychiatry in Menninger at Baylor. John 3 is somebody whose expertise in psychiatry and 4 administrative psychiatry goes back many years. John 5 was a member and involved in a New York State task 6 force which tackled with some of these very same 7 issues about eight years ago. 8 Laura Roberts, who many of you know from 9 her writings as Chair and Professor of Psychiatry at 10 the Medical College of Wisconsin. Laura's expertise 11 in professional ethics and her particular interest in 12 empirical aspects of research ethics helps round out 13 some of our issues and our interest in making sure our 14 deliberations are informed by a strongly clinical 15 practical and empirical approach. 16 Dr. Gustavo Roman is an internationally 17 recognized expert in vascular dementia. He's a 18 neurologist. He's an FDA adviser and he's Professor 19 of Medicine and Neurology at the University of Texas 20 Health Science Center at San Antonio. It is a great 21 pleasure and great honor that he has agreed to serve 22 and I'm sure will add enormously to our charge. And 23 then there's me. 24 In thinking about what's gone wrong before 25 or what hasn't worked well before, it's important that 28 1 we consider the lay of the land, or as I like to think 2 about it, the long road from principles to practice. 3 If our ultimate aim is to influence 4 practice and ultimately practice relates to the 5 relationship between the investigator and a 6 perspective research participant, and more 7 specifically, investigative responsibilities, we need 8 to envision a regulatory and oversight structure which 9 is pragmatic which can be delivered from principle to 10 practice by the various interrelating levels of 11 oversight, the regulations, the regulatory 12 interpretation and guidance, institutional policies 13 and procedures, in this case state law, IRB functions, 14 and IRB requirements. 15 I think this is part of our interest as 16 well because as we look at the big picture we 17 recognize that at times there can be tensions between 18 a sound ethical and conceptual approach to the 19 problems at hand but one which would be very difficult 20 to translate into meaningful practice. 21 By the same token we need to recognize 22 that the investigator is the final common pathway so 23 we need to come up with models related to informed 24 consent, the assessment of capacity, methods of 25 assessing capacity, identifying research subjects at 29 1 risk for decisional impairment that ultimately can be 2 useful in a pragmatic way in the hands of 3 investigators, in the minds of IRB members, and in the 4 policies of institutions. 5 More to the point, and we'll be making a 6 lot of this today, we need to come up with ways that 7 states, and we would say consistently across the 8 states, take on or address our concerns related to 9 research with those who are unable to make consent. 10 I like pictures but I think we've decided 11 to focus on three fundamental ideas. How do we 12 identify those who have limited ability to consent and 13 those who are unable to make consent decisions for 14 themselves. Prior groups have focused exclusively, 15 for example, on those institutionalized as mentally 16 infirm or for example, individuals with mental 17 disorders. 18 We set out thinking that we would cast a 19 wider net but the question is how do we do that, how 20 wide is that net cast, and how do we approach that. 21 When we do identify those who are unable to make 22 decisions for themselves, how do we decide who may 23 provide consent for those people. These are clearly 24 related and importantly linked concepts. Finally, 25 once we define who can make decisions for those who 30 1 are unable, we have to ask how do we define what kinds 2 of decisions those surrogate decision-makers can make 3 and how do we define a reasonable risk benefit balance 4 when ability to consent is limited or absent? 5 We may say that we don't need to define 6 any unique risk benefit analysis or we may head in the 7 direction that others have gone before using a 8 categorical approach and specified levels of risk. 9 This is part of what we are deliberating on and 10 discussing. 11 In any case, we think that these three 12 important points are importantly interrelated with one 13 another and that none really stands alone in our 14 considerations. Identifying the population, 15 understanding how we define who needs additional 16 protections, understanding the kinds of protections 17 that might be afforded through surrogate consent, and 18 then understanding the fundamental role that a careful 19 risk benefit analysis by an IRB can play is critical 20 here. 21 The committee, I think, and I can't -- we 22 haven't reached a particular point of consensus on 23 this, but it's clear, too, that the committee 24 recognizes the enormous value in leaving a good deal 25 of latitude to IRBs in making decisions. This, I 31 1 think, flavors some of our discussions and perhaps 2 some of our recommendations as well. 3 Let's talk about this first point. We 4 have discussed this before, the preconditions for 5 informed consent or as we would say, the ability to 6 consent requires effective disclosure of required 7 information. It requires on the part of the subject 8 a capacity to understand and appreciate and reason 9 about the relevant facts and consequences related to 10 participation. 11 Finally, the ability to consent requires 12 a context which promotes voluntary choice free of 13 undue influence. These are the cornerstones of 14 informed consent, the necessary preconditions. As we 15 begin to think about it, our group is focusing 16 primarily on two and three. 17 We think that two and three emerge most 18 clearly out of the regulatory mandate of additional 19 safeguards and that notion in 116 that a subject must 20 understand, in our view, informed consent. We will 21 need to touch on this notion of effective disclosure 22 of required information and again, there we will need 23 to work with Dan and Felix and coordinate our efforts. 24 Jeff Botkin pointed out that our concerns 25 would ultimately be less about operator defined 32 1 functions. In other words, we are a little bit less 2 concerned about the required elements of disclosure 3 and what the investigator must do. We are thinking in 4 general more about factors as they relate to these 5 research subjects but that is not a complete 6 distinction. 7 Here are some conclusions that we've come 8 to. We have discussed these with you here before. 9 When we think of ability to consent, and this is how 10 we are conceiving of it, at least in a preliminary 11 way, occurs along a continuum. That means that some 12 individuals will be assessed as being able to make a 13 consent decision despite some impairment or limitation 14 in ability. 15 We are struggling with terminology. We 16 are not quite there yet. These are just some ideas 17 and terms we are playing with at the moment. Other 18 individuals who have limitations in their ability to 19 consent to a degree that they will be assessed as 20 unable to consent. 21 In our view, the ability to consent can be 22 enhanced in some circumstances. Rather than thinking 23 about this as a simple black and white categorical 24 approach, there are those who are able and those who 25 are unable to consent, we know that the clinical 33 1 world, practical world, is far more complex than that. 2 We think about consentability as occurring along a 3 spectrum. Let's just say in this case a spectrum of 4 increasing ability. 5 On the one end we can imagine those who 6 were clearly unable to consent. They have severe 7 impairment or limitations in their ability. At the 8 very far end, at the extreme left side, of course, are 9 individuals, let's say, who are unconscious. Not too 10 far off from that are individuals who are in a state 11 of delirium. They are captive in an intensive care 12 unit setting. 13 At the far other end of the spectrum are 14 those who are clearly able to consent. They have all 15 the necessary capacities and abilities and the context 16 is right for them to make a free and informed decision 17 but there is a large gray area, so to speak, in 18 between in which we could imagine that there are 19 people who have impairments or limitations in their 20 ability owing to intrinsic factors or contextual 21 limitations in a way. 22 We imagine to some extent that by 23 enhancing or working to improve the context or the 24 nature of the informed consent process some of those 25 who are unable may become able. In other words, we 34 1 shift the area of able over to the left increasing 2 that white area. Again, this is the concept. We think 3 it maps on to a real world setting. 4 We also recognize that the ability to 5 consent is task specific. The ability required to 6 make a decision about participating in a specific 7 research study depends on the complexity and the 8 novelty and the level of risk and the level of benefit 9 of the proposed research. This is standard clinical 10 practice. We would say that an individual may be 11 assessed as being able to make a consent decision to 12 participate in one research study and unable to 13 consent to others. 14 So with the imagined hypothetical 15 individual and hypothetical individual's ability to 16 tackle a range of consent decisions we come across 17 another continuum or spectrum. If we imagine that 18 this spectrum has the characteristics of a consent 19 decision, a decision which is of decreasing complexity 20 risk and personal benefit, then we could see that 21 there may be an individual who is clearly unable to 22 consent to higher risk, lower personal benefit 23 research. 24 Let's talk about a man or woman with 25 schizophrenia, someone who has impairment in frontal 35 1 lobe or cognitive functions who may be at that time 2 quite impaired in their ability to evidence a choice, 3 whose passivity may preclude them from saying no in 4 the hospital setting in which they are living and 5 whose ability to reason in a rational way about the 6 consent decision may be influenced or impaired by 7 psychosis. 8 It's possible knowing that capacity 9 represents capacity to do specific things. The same 10 individual may, nonetheless, recognize that they are 11 being asked to make a decision that they may not be 12 able to feel comfortable making that decision for 13 themselves but they may be able to appoint a proxy 14 decision-maker or appoint a healthcare proxy, for 15 example. We would say that there is enough capacity 16 or ability retained for them to do that. 17 We could also imagine that the same 18 individual in the right circumstance with the right 19 kinds of enhancements, the necessary time, perhaps 20 presenting information not solely verbally or in 21 writing but using other methods with the addition of 22 other special enhancements might be able to consider 23 a lower complexity, lower risk, or high benefit 24 research. Again, the details here are less relevant 25 than the fact that we have to recognize that ability 36 1 to consent is task specific. 2 We've talked about this before. I'm just 3 going to show this to you. We recognize that 4 impairments in limitations to consent occur again in 5 a range of circumstances and in a range of intrinsic 6 related -- related to a number of intrinsic factors. 7 We talked about these as situational versus disorder 8 related, global versus specific impairment, static 9 versus progressive versus episodic versus time limited 10 impairment, and acute versus persistent impairment. 11 We think it's important to capture all 12 these kinds of circumstances which may limit or impair 13 one's ability to make a consent decision and they 14 reflect a range of circumstances and the range of 15 disorders that are of interest to us. It is part of 16 what drives us to cast this wide net. 17 Previous efforts have focused on disorders 18 frequently characterized by impaired decision-making. 19 We think these previous efforts have failed for a 20 number of reasons. First of all, they have neglected 21 to address central ethical and scientific concerns 22 regarding other kinds of populations. For example, 23 those in the intensive care unit. 24 They also in effect neglected to address 25 the concept that was behind the regulations, those 37 1 vulnerable to coercion or undue influence that may 2 affect those with psychiatric disorders but certainly 3 it's not limited to those. 4 In contrast we imagine a somewhat broader 5 notion and this came actually out of our May meeting. 6 Those who are vulnerable by virtue of being unable to 7 fully protect their interests through an informed 8 competent and voluntary choice regarding 9 participation. So this is the broader net that we're 10 casting. These are some points of consensus. We'll 11 come back to these but this is part of what we want to 12 bring to this committee today. 13 Okay. Laurie. 14 MS. FLYNN: He was on a good roll there, 15 though, right? 16 So wrapping up a little bit of what our 17 emerging consensus is and trying to succinctly state 18 it, as David has illustrated the group has come to the 19 consensus that impairment in the ability to consent 20 occurs in a wide range of populations and in many 21 different circumstances. We feel strongly that there 22 is no ethical, scientific, clinical, or practical 23 justification to limit our recommendations just to 24 individuals with mental impairments or to include any 25 particular -- exclude any particular subject 38 1 population. 2 So we anticipate addressing the range of 3 populations and circumstances in which there is an 4 impairment or a limitation in the ability to consent. 5 We think this distinguishes our work and is an 6 important reality that the field is facing and that 7 creates a lot of thorny dilemmas. 8 Consequently, the recommendations that we 9 propose will cover limitations in capacity and 10 voluntariness. To the extent that ability can be 11 enhanced, and we know that it can in some cases, 12 SIIIDR will also consider aspects of the process of 13 disclosure. 14 In order to meet our regulatory 15 requirement for understanding, that term that is not 16 so well defined, we again, as I indicated earlier, 17 feel that some formal or informal assessment of the 18 subject's ability to understand the consent decision, 19 some real assessment of capacity is required in all 20 cases of research consent. 21 DR. STRAUSS: Let me say a word about this 22 because this was a topic of considerable discussion 23 and I think it's an important point. We are saying 24 that it's never acceptable for someone to be enrolled 25 in a research study unless the investigator has made 39 1 some kind of determination that that individual has 2 understood that choice that they have made. 3 In some instances with some individuals 4 that determination may be a relatively simple or even 5 intuitive one on the part of the person discussing and 6 documenting consent with the research subject. In 7 other circumstances, that assessment of understanding 8 may require a more elaborate or formal mechanism 9 instrument to determine the capacity to consent. But 10 we are saying in all cases there needs to be some 11 determination, some affirmation on the part of the 12 investigator that consent has been understood. 13 MS. FLYNN: Not only do we find it 14 critical that consent be clearly a process that has 15 been in place, that has been understood, and that the 16 subject who may be enrolled has clearly been assessed, 17 but we recognize that that assessment of capacity 18 identifies those who may be in need of additional 19 safeguards or protections. It's critical in terms of 20 delineating the population that may be most 21 vulnerable. 22 Further, where limitations in the ability 23 to provide informed consent are present, we believe 24 that additional consent enhancements, safeguards of 25 various kinds, and supports may be required. Such 40 1 supports and enhancements may indeed be effective and 2 may enable folks who otherwise would not or could not 3 participate may enable their participation. But for 4 those who are unable following an assessment to 5 provide consent, participation would only occur 6 through the legally authorized representative. 7 There is accumulating empirical support 8 for specific methods to assess capacity and to enhance 9 subject capacity. We know that there are many ways 10 that are quite well validated for assessment. We 11 certainly believe that there are many ways in which 12 investigators may make this assessment. 13 We also know that there are a number of 14 investigators and studies that have documented ways in 15 which capacity may be enhanced with supports. The 16 requirements must be tailored to the nature and to the 17 likelihood of impairment in the potential research 18 subject. 19 The decision about participation must be 20 part of the consideration in the IRB review and 21 approval process. We know that IRBs are looking for 22 assistance here. We know that this is an area where 23 clear and increasingly, we hope, consistent 24 application of the knowledge we have will be of 25 considerable help to IRBs and to investigators. 41 1 So looking back at the framework, we've 2 talked a little bit about how we identify those who 3 have limited ability to consent and those who are 4 unable to make consent decisions. Now we want to look 5 at the issue of how do we decide who may provide 6 consent for those who are unable. This is the most 7 vulnerable group and this is a critical part, we 8 think, of our task. 9 Upon investigation we have come to the 10 conclusion that the legally authorized representative 11 provision really exists as part of a regulatory dead 12 end. Federal regulations require the subject's 13 legally effective informed consent as we all know. 14 Lots of focus on how that may be obtained. Lots of 15 discussion about the significance of this particularly 16 with individuals who may be decisionally impaired. 17 The regulations also allow for consent by 18 a legally authorized representative to the procedures 19 that are used in research. However, federal 20 regulations do not define legally authorized 21 representative. Instead, they point to applicable 22 local or state law. 23 As we have seen, the states with rare 24 exceptions have not defined legally authorized 25 representative for research and some don't define it 42 1 at all. This is a huge ethical gap. It is indeed a 2 regulatory dead end and was of considerable concern in 3 our discussions as a subcommittee. 4 There are some states that provide 5 definition of legally authorized representative to 6 consent to medical treatment often in specific 7 emergency or end-of-life situations but very few 8 states reference research applications at all. 9 State and institutional rules do not 10 address or address consistently the scope of covered 11 research activities. They do not provide definition 12 and identification of the populations who are unable 13 to consent. Again, we have taken a much broader look 14 at who those populations are or may be. 15 They do not consistently address who may 16 provide consent for those who are unable. Some make 17 assumptions again based on statutes around medical 18 treatment but they are not clear and they are not 19 consistent about who may be providing consent in the 20 research setting. 21 Reasonable or acceptable risk is not 22 addressed in situations where a proxy or a surrogate 23 consent is permitted. There is almost no mention of 24 these very critical components of the decision-making 25 process. 43 1 DR. STRAUSS: It's really important to 2 step back a second and remind ourselves that research 3 in 2007 is not a local or institution-based affair. 4 Research in 2007 is a multi-center, multi- 5 institutional, and frequently multi-state enterprise. 6 We all know that as we sit on IRBs those of you who 7 report to funding agencies know that very well. 8 It is the nature of research these days. 9 It is important to recognize when we look at the 10 importance of progress side of the coin here that 11 variability and inconsistency from state to state 12 creates a unique set of problems for doing research 13 with the decisionally impaired. 14 The notion and the fact that most states 15 have no law specifically addressing LAR and those that 16 do do it inconsistently means that with federal rules 17 we only address a small part of the concerns and 18 considerations. It's part of the reason why we've 19 said that we think all three corners of that triangle 20 require attention. 21 It's quite striking because we often point 22 to California as an example of a modern law addressing 23 legally authorized representatives. Of course the 24 California law doesn't actually address with any 25 specificity the identification of those unable to 44 1 consent and it doesn't address at all notions of 2 acceptable risk. 3 If you look within California as we've 4 done, there is wide variability from institution to 5 institution in how they address those concerns. 6 Again, that is in large part because absent specific 7 state guidelines they follow the federal requirements 8 for research, review, and approval and the federal 9 requirements for research, review, and approval leave 10 wide latitude in interpreting what is reasonable in 11 terms of risk and benefit for research subjects and 12 they do not define what kinds of additional safeguards 13 are required for individuals who are vulnerable to 14 coercion or undue influence. 15 Just to get back to that triangle for a 16 momentary digression, it's part of why we think that 17 all three corners, identification of individuals, 18 identification of appropriate surrogates, and some 19 notion of reasonable risk and benefit are required 20 elements in this approach that we're taking. 21 MS. FLYNN: Thank you. It is one of our 22 strongest recommendations and something we think has 23 significant ethical and practical impact. 24 Moving to, again, the consensus that we 25 have arrived at at this point, we do believe strongly, 45 1 and we bring to you for your response, that a 2 comprehensive and consistent national approach to the 3 definition and use of the concept and reality of 4 legally authorized representative is necessary to 5 provide protections for this most vulnerable 6 population and to promote research on those conditions 7 and disorders that befall them for those who are 8 unable to consent, a key protection for those unable 9 to consent. 10 We will consider and again, in a dialogue 11 with you and with others, the merits and the 12 practicalities of recommending proposal of a federal 13 regulation that defines legally authorized 14 representative in research. Something that at least 15 on our early investigation looks like a response that 16 would be extremely helpful in additional protections 17 as well as clarity and support for investigations. 18 We also have discussed and might consider 19 an alternative approach if it seems warranted and more 20 feasible that we encourage the Department of Health 21 and Human Services to promote the development and 22 adoption of model state legislation focused on 23 definition of legally authorized representative in 24 research. Those are two possible pathways to 25 providing an important additional support and 46 1 safeguard for individuals with decisional impairments. 2 DR. STRAUSS: Back to the triangle. This 3 time we're just going to mention in some preliminary 4 ways some ideas about reasonable risk and benefit 5 balance when ability to consent is limited. We have 6 done the least amount of work on this. In fact, we've 7 decided to make this third in our priority list in 8 large part because we think it's the most difficult 9 and we are all procrastinators at heart. 10 But when we think about risk of harm, and 11 trust me, by the time you're done listening to me 12 you'll probably understand these diagrams that I do, 13 we understand that in Subpart A we characterize risk 14 as minimal or greater than minimal. It's a 15 categorical approach. We re forced into making that 16 distinction. 17 I think that existing regulations and 18 regulatory guidance probably give rise to some 19 inconsistencies in the way individual IRBs approach 20 that distinction, that categorical distinction. I 21 know that the Subpart A Subcommittee has done a lot to 22 make that point to this committee and I think we are 23 going to see more on this tomorrow. It's a 24 categorical distinction that can be made but not 25 necessarily all that easily. 47 1 Under Subpart D, the children's 2 regulations, we have a more complicated categorical 3 demand placed on IRBs where IRBs need to create three 4 categories essentially, minimal risk, research which 5 is no more than a minor increment above minimal risk, 6 and then research which is greater than that. 7 I'm not aware, and maybe others are, of 8 data on how well IRBs do that or how consistently they 9 do that but I think it's an enormously difficult task 10 at times and I imagine it gives rise to a fair degree 11 of inconsistency across IRBs. 12 What the impact of that inconsistency is 13 I think is an empirical question. What's interesting, 14 though, is that, of course, in reality risk occurs 15 along a continuum. In Subpart A IRBs are forced to 16 grapple with this fact of life that risk does occur 17 along a continuum. IRBs are capable of making 18 decisions, minimizing risk, requiring additional 19 safeguards and protections in a sense that are 20 tailored to this continuum of risk. 21 One of the things that our committee will 22 be thinking about is this notion that risk occurs 23 along a continuum and to ask a question about whether 24 protections can be tailored in a way that is 25 consistent with that rather than using a categorical 48 1 approach. We've drawn no conclusions. We've barely 2 begun to look at it. I'm mentioning it here really to 3 soften the ground for what may come next for you later 4 on. 5 One of the issues, I think, from a 6 scientific perspective that we need to think about is 7 what is the impact of the categorical approach. If we 8 impose strict limits or upper limits on the kinds of 9 risk research that can be done, we may, in fact, 10 prohibit research of a sort that is critical to 11 advancement in science and therapeutics. 12 It's quite striking to look at the number 13 of requests that have come to HHS with regard to 14 research with exceeds the limit of risk allowable in 15 Subpart D and those are quite small the number of 16 requests. 17 I think it's important for the field to 18 think about whether we are in doing so in creating 19 absolute upper limits of risk discouraging researchers 20 from pursuing critical scientific endeavors, whether 21 we are encouraging IRBs in a sense to play with the 22 thresholds, in a sense game the system to permit 23 research at higher than acceptable risk by calling it 24 something else, or whether, in fact, those thresholds 25 are set at exactly the right place. 49 1 In other words, that we get so few 2 requests for higher than acceptable risk research in 3 Subpart D because we don't need to do that kind of 4 research. Again, these are empirical questions as 5 much of what we are talking about today. It's 6 important for us to be thinking about how the rules 7 actually impact practice. 8 The same is true of benefit. 9 Traditionally when we are thinking about categories of 10 benefit we talk about no prospect of direct benefit or 11 the prospect of direct benefit. Although this works 12 well on paper, the reality is far more complex than 13 that. I can think about a research study that I 14 reviewed just several weeks ago. It's a study of a 15 novel compound intending to enhance cognition in 16 adults with schizophrenia. 17 We've gotten quite good over the years in 18 treating the psychotic or what I call the positive 19 symptoms of schizophrenia, much less capable of 20 addressing the most impairing symptoms, the symptoms 21 that impair cognition and volition. This is a drug 22 that's intending to do that. It is a 12-week placebo 23 controlled study. It's an add-on study to medications 24 that are used to treat the positive symptoms. 25 I think what the IRB struggles with in 50 1 such cases, it's a treatment study. The goal of the 2 treatment is to treat the cognitive impairment but it 3 is a 12-week study. The drug is not available after 4 the 12 weeks are over and half the subjects will not 5 get the cognitive enhancer or the putative cognitive 6 enhancer. 7 We can imagine subjects who might have a 8 response. Ideally some would have a good response to 9 the cognitive answer and at the end of the 12 weeks 10 they stop the drug, they return to whatever cognitive 11 state they were in and where they left. Is that a 12 therapeutic study? Is a study that aims to provide 13 some transient or acute benefit but not long-term 14 benefit for a chronic condition a therapeutic study? 15 It's hard for me to know where to 16 categorize that. I think there are many circumstances 17 in which we would think about studies as prospect of 18 direct benefit solely if their intent is treatment but 19 I think that's too simplistic a notion. Benefit 20 occurs along a spectrum. Really, more importantly, I 21 think the balance of risk and benefit need to be 22 considered as occurring along a spectrum. 23 I think Dr. Shore pointed out when he 24 spoke to SACHRP last year that there are many research 25 studies which offer no prospect of direct benefit but 51 1 which are far more important to conduct because they 2 answer some fundamental question about the nature of 3 a disorder than what we like to call me too studies 4 which on the surface are therapeutic but involve risk 5 against benefit which may not be worthwhile. 6 I'm making these points only because I 7 want to lay out what I think is a complexity in this 8 decision to apply categorical versus another 9 dimensional approach to thinking about risk and 10 benefit. 11 We feel that protections must address the 12 nature and extent of subject vulnerability and the 13 magnitude of research risk and benefit. We need to 14 consider, and we will consider, the relative merits of 15 categorical versus other approaches to risk and 16 benefit analysis. 17 But we also have to be pragmatic. 18 Challenges at the state and institutional levels, IRB 19 and investigative practice, pragmatic considerations 20 must guide our recommendations. In the end, as I 21 pointed out earlier, we really have to come up with 22 models and constructs and mechanisms of oversight that 23 work in the hands of investigators, that work in the 24 hands of IRBs, and that are manageable at all other 25 levels of the oversight process. 52 1 MS. FLYNN: Near-term goals. We are a 2 very practically focused group and constantly by 3 virtue of the makeup of the group asking ourselves 4 what's really going on, what's really happening, where 5 is our field now, and what does our field need. 6 We are going to be seeking additional data 7 on current practice and specifically whether subject 8 welfare and safety and/or scientific progress, as Dr. 9 Strauss just described, is being hampered. We get 10 anecdotal reports of a variety of studies that people 11 would like to conduct. We hear things, we read about 12 things, but we really don't have a current finger on 13 the pulse from key elements in the field. 14 We want to consult with and hear from 15 patient advocacy organizations, academic and 16 professional societies, as well as the IRB community. 17 I think, David, are we not making a presentation, 18 participating in something at the IRB conference? 19 DR. STRAUSS: Yes. We've been asked to -- 20 well, I asked and we've been allowed to conduct a 21 townhall on this topic at the upcoming PRIMR meeting 22 in December. We are hoping to have a very large 23 audience of IRB professionals, institutional officials 24 and investigators as one mechanism of entertaining 25 feedback and input in this general area. That's one 53 1 thing that is in the making. 2 John Luce has also drafted a questionnaire 3 on practices of surrogate consent that we are planning 4 to modify and distribute to various -- not necessarily 5 as a committee but as individuals to distribute to a 6 range of professional organizations that have a stake 7 in this and to advocacy groups. 8 As Laurie pointed out, we recognize that 9 there is a huge gap from a regulatory perspective. 10 It's hard for us to know whether the result of that 11 gap is that there are problems in terms of the 12 protection of the rights and welfare of research 13 subjects or whether there are problems in that science 14 is being hampered. We don't have that data, although 15 I think we have a lot of indirect data that might 16 suggest that both are true. 17 MS. FLYNN: And as we've indicated, we are 18 working hard to provide a draft proposal based on our 19 own deliberations, feedback that we received today and 20 following the meeting, as well as the information we 21 hope to gather from consulting with others in the 22 field. We anticipate preparing a draft proposal for 23 consideration at the October SACHRP meeting. 24 DR. STRAUSS: So just to review, we want 25 your feedback and we've allowed intentionally a good 54 1 deal of time for discussion and perhaps deliberation 2 on some of the general points but we want support for 3 our general approach and our priorities. Obviously 4 we'll be able to answer questions. 5 We would like some feedback on preliminary 6 points of consensus. With this feedback we'll go back 7 to the subcommittee and go back to work, but really 8 fundamental to this is this first point that we think 9 there needs to be some basic requirement for some 10 assessment of understanding in all cases of consent. 11 We say that because that is how we can go ahead and 12 make this cut, identify individuals in need of 13 additional safeguards, additional approaches to 14 assessment of capacity and so on. 15 We also feel, and it was the consensus of 16 the committee, that some national approach, and we 17 wrote national rather than federal because we don't 18 want to presuppose that we are talking about federal 19 regulatory change here, but we believe that a national 20 approach to the definition of LAR and related 21 protections is really critical in moving both the 22 human subjects protections field forward and moving 23 science and related activities forward in some 24 meaningful way. 25 A colleague of mine just forwarded to me 55 1 this past week draft legislation, state legislation, 2 in New Jersey which is intending to draft new state 3 laws allowing for surrogate decision-making for 4 research purposes. What is quite striking about it is 5 that the laws are restricted to what they are calling 6 medical research and it's not further defined. 7 One wonders about all the other kinds of 8 categories of research that examine behavioral, social 9 context of diseases and how those are addressed. 10 There are many gaps. When we speak to individual 11 investigators, and actually we've done this at 12 Columbia and perhaps we'll share this data at a future 13 meeting. We do have a long list of studies that were 14 proposed and not done because of lack of clarity about 15 LAR and allowable research. 16 This is the issue here. We as a 17 subcommittee are asking you in this instance what 18 SACHRP, what HHS might consider by way of promoting, 19 supporting, incentivizing implementation of model 20 state legislation. At our last committee some talked 21 about, for example, financial incentives or 22 disincentives for not doing so, financial 23 disincentives for states which don't have reasonable 24 laws which address this. 25 Anyway, that is not necessarily part of 56 1 the expertise or the purview of the subcommittee but 2 we would like the parent committee to consider this 3 approach. We are also looking for more feedback and 4 more input from OHRP and from HHS council on federal 5 regulatory options in this regard. 6 Finally, we are talking about Subpart A. 7 Although one possibility is that we might propose an 8 additional subpart but clearly there is enormous 9 overlap between our concerns and what has been the 10 domain of the Subpart A Subcommittee so we want to 11 seek some clarification on how we approach these 12 issues. Thank you. 13 DR. TILDEN: Thank you very much for a 14 very well organized and on-the-point presentation. 15 I think we have a break scheduled in here 16 some time so I'm wondering if we should pick up one of 17 these points now. I think we have about 30 minutes 18 until break time and then come back and pick up the 19 other or continue on at that time. Or we could take 20 a break now and then come back and discuss everything. 21 Anybody have any thoughts? 22 DR. GENEL: I vote for taking the break 23 now and then coming back so we can have a continuous 24 discussion. 25 DR. TILDEN: Okay. We'll take a 15-minute 57 1 break and we'll come back and start discussing the 2 points and questions David brought forth. 3 (Whereupon, at 10:07 a.m. off 4 the record until 10:27 a.m.) 5 DR. TILDEN: It's hard to get started 6 without the co-chairs being in their place. David, 7 you want to put those points to those questions that 8 the subcommittee had for discussion? 9 David was concerned we have a lot of time 10 for discussion. I told him not to worry about it 11 because with this group it would all be used up. What 12 about the last slide you had? It seemed like you had 13 two points in particular. Feedback on preliminary 14 points for consideration by SACHRP, last slide, 33. 15 There you go. 16 I guess the first question is basic 17 requirement for some assessment of understanding in 18 all cases of consent. You wanted some feedback on 19 that. We'll open it up for the committee. James has 20 a comment. 21 DR. POWELL: Yes. Can I go back a little 22 bit further than that to the general approaches and 23 priorities. Again, I want to congratulate the 24 committee for this progress to date. I wanted to 25 bring up the issue, David, and you know what I'm going 58 1 to bring up. 2 One of the perspectives that I think is 3 important in this whole area is the perspective of 4 those who are involved in the development of products 5 for the treatment of patients who may be decisionally 6 impaired. One of the things that I would like to see 7 and ask you about is how you expect to get that 8 perspective from those who are involved in the 9 development of those products? 10 DR. STRAUSS: We considered and actually 11 explored the possibility of having representatives 12 from industry sit on the committee. We had a tall 13 order in terms of filling our roster but I think short 14 of your coming and joining us, I think that one of the 15 things that we need to do is recognize that industry 16 represents not only a key stakeholder group but really 17 the inside track of new products development and 18 really barriers to new product development. I think 19 probably industry more than other groups has to 20 grapple with what kinds of research they pursue or 21 couldn't consider pursuing. I think that we need to 22 construct some way to reach out to industry in a 23 systematic way and collect information on the extent 24 to which the absence of regulation has created 25 problems for them. 59 1 DR. POWELL: I think that's the important 2 point. The fact is that some products, or even some 3 areas of discovery, have been isolated because 4 industry doesn't know how it's going to test a product 5 or get it approved and that hinders the research and 6 discovery process and everybody loses when there is 7 not a willingness to invest in those areas. 8 DR. TILDEN: I think it would be fair to 9 say that David has reached out to the PRIMR group and 10 so there would be interest. If there are meetings or 11 arenas where such stakeholders are accessible, David 12 or Laurie wouldn't mind reaching out to those groups 13 as well. Is that fair to say? 14 MS. FLYNN: Absolutely. Just to add a 15 tiny bit more, we also did discuss the possibility and 16 would welcome your guidance and some others that there 17 may be individuals within industry some of us have met 18 over the years who might be able to provide us with 19 some of that specific input on a more informal kind of 20 basis and might also be able, as David was describing, 21 exactly what kinds of research in recent memory has 22 not been able to move forward because of these 23 difficulties. 24 Where would they most wish to see some 25 greater clarity. We would be helped, I think, by 60 1 getting a little bit more concrete and specific input 2 from some of your colleagues in industry and we would 3 welcome that. 4 DR. TILDEN: Neil, you had a comment or 5 question? 6 DR. POWE: I just want to congratulate the 7 subcommittee on laying out a very thoughtful 8 framework. I actually agree with the general approach 9 here. Especially the issue of looking at this as the 10 continuum and not just thresholds as you have laid out 11 for a variety of the issues. 12 I wanted to speak to the point about the 13 basic requirement for some assessment as to how you 14 identify individuals that have limited ability or 15 those who are unable to make consent decisions for 16 themselves. 17 Obviously one would think that the vast 18 majority of subjects, human subjects, would be able to 19 have a good understanding of what a study is and the 20 risk and benefit. So you spoke to informal and formal 21 assessments of understanding. Obviously an informal 22 assessment is something that could be done rather 23 quickly but may be, I guess, subject to 24 inconsistencies or being standardized in approaches 25 and could lead to some lapses. 61 1 On the other hand, a more formal 2 assessment that would be akin to, let's say, an SAT 3 exam would be inappropriate in the vast majority of 4 circumstances. I just wanted to open this up a little 5 into thinking, you know, when should we use -- we are 6 now using informal assessments a lot but could that be 7 formalized and do we have any tools that are very 8 short that have some validity to them in terms of the 9 sensitivity and specificity or identifying the 10 subjects who have limited ability or unable to make 11 consent that would be easy to administer and not slow 12 the process of human subjects research. 13 I just wanted to -- that's what I'm 14 thinking about and whether the subcommittee is going 15 to take on looking at what types of instruments or 16 guidance that could be provided to investigators to 17 standardize this a little bit better but not to impede 18 clinical research. 19 DR. STRAUSS: That is the key question 20 really. I think another way that I think about, and 21 I think Laurie and the group has thought about it as 22 well, we wrote basic requirement but in a sense I 23 think we are also talking about some basic expectation 24 that there be some assessment of understanding by the 25 investigator on the part of the subject. 62 1 I think that it's just not clear as I read 2 the regulations on informed consent and regulatory 3 guidance that there is even that expectation that 4 there be an interaction with the perspective subject 5 such that the investigator makes a determination, 6 formal or not, that the consent decision has been 7 effective. 8 We talk about a legally effective informed 9 consent but the thresholds and standards for that 10 aren't delineated. In the most fundamental way what 11 I imagine is a simple clarification, frankly, of the 12 requirements for informed consent in Subpart A that 13 demand the expectation that the investigator has 14 acknowledged, understood, etc., that the subject 15 understood the choice that they were making. 16 Like I said, I think in the most 17 rudimentary way that could simply be with some 18 populations an intuitive assessment. It's like an 19 expectation that there be some kind of interaction 20 between the researcher and the subject. I don't think 21 there is always that interaction. 22 There is a paper that's published in IRB 23 this month, consent in dementia, and I think the 24 investigators note really wide variability in the 25 extent to which those discussing and documenting 63 1 consent assessed understanding at all of the consent 2 process. Really what I'm talking about here is a way 3 of raising the bar of consent in general but it also 4 provides mechanism for identifying those who require 5 more. 6 Now, the subcommittee is familiar with the 7 research on assessment of capacity and I think one of 8 the conclusions that we drew was that a one size fits 9 all tool other than intuition or common sense wouldn't 10 work. I think that in a sense an IRB who -- an 11 investigator is more familiar with the specific 12 populations would need to propose and justify the 13 methods and those proposals would be, of course, 14 specific to the research and specific to the 15 population. 16 Most investigators, for example, who talk 17 about using the mini-mental state exam would also say 18 that it's really not a very good proxy for decision 19 making capacity. It may provide at its limit some 20 routine notion of intact or not but I think the field 21 would probably say that there is no one instrument 22 that would serve as an appropriate screening tool. 23 MS. FLYNN: Just to add, coming from the 24 perspective of someone who has been on the advocacy 25 side of the equation, I think a number of us on the 64 1 subcommittee felt very much as David indicated, that 2 we wanted to raise the visibility of this whole issue 3 to the investigators themselves. 4 We wanted them to see it as critically 5 important for their own eyes, for their own 6 understanding. We wanted them to see as we do that 7 the consent process is really core to any other 8 protections that we may then need for those who have 9 decisional impairments. 10 We know that in the real world and the 11 real setting a lot of times the issue of consenting 12 the subjects is left to someone else and isn't 13 necessarily thought of as part of what the 14 investigator, principal architect of the research, is 15 really focused on. For this population for the issues 16 in our charge we wanted to say to the investigators, 17 "You really need to pay more attention to this." 18 We need to know that you're thinking about 19 this and your study has adequate design to make 20 certain that as the risks would rise, as the issues 21 around decisional impairment become clearer that this 22 is something that the investigator has foremost and 23 has been structured and clear in what their 24 expectation is for those who would work with him or 25 her. 65 1 DR. STRAUSS: One other just follow-up 2 point. I think the tool, the instrument, is thinking 3 about the method more broadly which is one way that I 4 think an IRB would need to approach the matter. For 5 this population and this kind of study how are they 6 determining that the subject is actually consenting 7 meaningfully rather than just signing a name on a 8 piece of paper. That's one issue. 9 The other issue is really who among the 10 members of the research team has appropriate 11 experience, credentials, etc., to make a determination 12 that someone lacks capacity. I had an interesting 13 discussion with Jennifer Manly, who is a researcher at 14 Columbia who does Alzheimers research, the other 15 weekend her whole team. 16 We all agreed that regardless of the level 17 of risk of the research we would be uncomfortable if 18 a research assistant with no more than a college 19 education made the determination that our grandmother 20 could make decisions for herself. 21 In other words, we were willing to allow 22 that if that research assistant was following some 23 specified assessment tool and had supervision and 24 training but we were very clear, and the committee 25 SIIIDR was as well, that who was assessing capacity is 66 1 a critical component along with what method they are 2 using. 3 DR. TILDEN: I've got Mike and then David. 4 DR. GENEL: Let me add my compliments to 5 the framework that the subcommittee has articulated. 6 I want to touch on an issue that you raised towards 7 the end and that Neil has referred to. That is the 8 notion of a continuum of risk and you referred to 9 Subpart D. 10 I'm hearing a lot of push back from my 11 colleagues in pediatric research that this categorical 12 approach and the variability of interpretation by IRBs 13 is impeding what they feel is necessary research in 14 pediatrics. 15 I think it's in part this sort of all or 16 nothing type of phenomena that at least they perceive 17 is being interpreted particularly for multi-site 18 studies so just to support the notion that you have. 19 This is anecdotal. I think it would be 20 good to have empiric research. We've been talking 21 about having a panel here in October that might open 22 up some of these issues. 23 DR. STRAUSS: You know what's interesting 24 is that under Subpart A, we recognize if you look at 25 the criterion for approval it allows a kind of careful 67 1 balancing of risk and benefit and there is a sort of 2 integration there possible. The risks have to be 3 reasonable in relation to the anticipated benefits to 4 the subjects. 5 I think that a good IRB grapples with that 6 in a kind of holistic way that shifts considerably in 7 Subpart D in which you are really forced to categorize 8 things in terms of absolute risk and absolute benefit 9 notions. 10 DR. GENEL: Well, one of the things that 11 I'm hearing is the fact that IRBs are putting much 12 more emphasis on discomfort than actual risk. They 13 are excessively weighing the notion of discomfort in 14 making those decisions. I'm not going to make any 15 judgment on that. I'm only, if you will, reporting 16 from the field but I think it bears on what you're 17 talking about in terms of what SIIIDR is considering. 18 DR. TILDEN: David. 19 DR. SHORE: Yes. I just wanted to comment 20 briefly on this idea of kind of a general evaluation 21 of consent capacity for pretty much everyone who is 22 being considered as a potential participant. At NIH 23 we've seen over the past five or 10 years a number of 24 approaches to dealing with this and I'm wondering 25 which of these you might consider to meet the kind of 68 1 criteria that you're describing. 2 For instance, we've seen situations in 3 which the signature lines contain a statement on 4 behalf of the investigator that they believe that this 5 person does have the capacity to provide informed 6 consent. Of course, there are no specific criteria 7 but in many cases now when we see the investigator 8 sign there is some statement that links to capacity. 9 Another approach is we are seeing 10 situations in which the investigator would ask the 11 potential participant to summarize the study and 12 potentially the risks and benefits in a very informal 13 way but, again, often without any specific criteria. 14 The third issue that seems to be coming up 15 is the use of a small number of questions. The UC San 16 Diego group has been attempting to use shorter 17 versions of consent capacity evaluations. They are 18 down to three questions, the purpose of the study, the 19 risks, and the anticipated benefits. 20 They score them on a zero to two scale. 21 I'm wondering whether these kinds of approaches to 22 fairly informal assessments would fit in with the kind 23 of recommendation you're making, or did you have 24 something different in mind? 25 DR. STRAUSS: Well, first of all, let me 69 1 just say that we haven't gotten much further than you 2 see here today but I think what we've envisioned is a 3 whole range of possibilities. Again, I think with the 4 idea that the IRB would expect a proposal for consent 5 process in the way that they would expect a proposal 6 for other kinds of research procedures, that process 7 would need to be considered and approved by the Board 8 and it would be approved in relation to the kind of 9 research that was involved. 10 The de minimis expectation would be some 11 notion of assessment. I think, for example, at my IRB 12 every consent form includes the statement that, "In my 13 opinion." -- the statement by the investigator, "In my 14 opinion, the subject understood the risk benefits, 15 alternatives, etc., of participation." 16 They have to sign that. It's an 17 attestation. The scenario in which the subject shows 18 up for the appointment, comes in, is given the consent 19 form, reads it, signs it, and participates in the 20 study without any kind of substantive interaction is 21 not a reasonable one in any case it seems to me. 22 Yes, I think all those kinds of things 23 would be important. I think what we might see is that 24 if we created this expectation that we would 25 increasingly see a field in which new and improved 70 1 methods would be studied and developed over time. 2 Again, the trick is not to make something 3 that is too burdensome where it's not necessary but I 4 see this as in a sense raising the bar in general on 5 consent which is why I see it in many ways as Subpart 6 A process to a large extent. All those suggestions I 7 think are the kinds of things that we are imagining. 8 We do that now in my IRB. 9 But, for example, if we're talking about 10 a higher risk, high vulnerability, low personal 11 benefit kind of study, right? I'm not talking about 12 people who can't consent. I'm talking about people 13 who may have limitations -- then we may request some 14 more formal assessment of capacity and an independent 15 assessment of capacity using some formal tool like the 16 McArthur Competency Assessment tool but that would 17 depend. 18 DR. TILDEN: We've got Dan and Jeff. 19 Everybody will have at least one bite at the apple. 20 Then we'll open it up to the ex officios. 21 MR. NELSON: Just to follow up on that, I 22 guess I had until now conceptualized this as two 23 separate notions and maybe where you're taking us is 24 also a continuum like the other things we've been 25 talking about. 71 1 Until now I had distinguished the up front 2 assessment of capacity to engage in the consent 3 process in the first place as the McArthur and the 4 mini-mental status and these kinds of things as 5 opposed to when I see you talk about understanding in 6 all cases of consent -- back to that first. I agree 7 with you in some cases that you think it would be 8 intuitive. If you are to get consent from the SACHRP, 9 you're not going to go through -- well, maybe that's 10 a bad example but you wouldn't have -- 11 DR. STRAUSS: At the end of day two I 12 think we could get anyone to sign anything probably. 13 MR. NELSON: Right. You wouldn't go 14 through the same kind of assessment or wouldn't be 15 required as if you were dealing with stroke patients, 16 let's say. Now when you talk about understanding in 17 all cases of consent, I hear you talking about the 18 kind of things I see IRBs implementing, the post- 19 consent process. 20 "Did you understand what you're getting 21 into? Repeat back to me the purpose of the study," 22 etc. Are you suggesting that this really a continuum 23 or that both of those would fold into what we're 24 talking about or are they two separate kinds of 25 notions? 72 1 DR. STRAUSS: I'm thinking about this pre- 2 imposed. I'm not sure -- I mean, obviously if someone 3 is in a coma or someone is in an intensive care unit 4 or someone's clinician says, "Hey, listen. I've been 5 working with this person for a long time and, trust 6 me, she may be able to agree and go along with you but 7 there is no way she understands what's going on here. 8 Such is the nature of her dementia." 9 I think in those instances you don't need 10 to formally sit down and run through a consent form 11 and see what they can do. Right? I'm really thinking 12 post. It's part of the consent process is what I 13 would say. Part of the consent process is some 14 assessment that consent is occurring. 15 MR. NELSON: Presumably there are still 16 populations or individuals within populations. You 17 wouldn't even get that far into the process. There's 18 no point in taking them to the end to see what they 19 understand because somebody has assessed up front that 20 they are not able to really engage in a meaningful way 21 in that consent process. 22 DR. STRAUSS: Right. That's right. I 23 think that there are different kinds of protections 24 that are in place in those kinds of circumstances. In 25 other words, the IRB should be wary of how subjects 73 1 are identified and recruited into research studies. 2 In other words, you could have a clinician be a 3 gatekeeper in a sense or family member in those kinds 4 of circumstances. 5 DR. TILDEN: Jeff. 6 DR. BOTKIN: A couple points. I do want 7 to thank David and Laurie, too, for their leadership 8 of the subcommittee. It's really been outstanding. 9 I'm always fascinated to hear wide-ranging discussions 10 at these subcommittee meetings and then be presented 11 with sort of the eggs back in the carton here in ways 12 that are comprehensible. 13 DR. TILDEN: But they did ask you to speak 14 at the subcommittee. Didn't they? 15 DR. BOTKIN: Yes. 16 DR. TILDEN: So you knew there was a wise 17 decision. 18 DR. BOTKIN: So couple of points here. 19 The first point here about the basic requirement for 20 assessment is phrased here a little bit different than 21 it was earlier in the slides. I would want to 22 encourage us to keep the formal or informal language 23 in there because this assessment really could easily 24 get quite complicated, quite burdensome, quite festoon 25 with regulations about what it is that needs to be 74 1 assessed on a regular basis. 2 I want to keep that concept that this 3 could be informal or intuitive and still be an 4 acceptable way to approach it. Also, I think this is 5 where we have some interface with the Subpart A group 6 working on informed consent. I think that phrase to 7 a certain extent puts an onus on the investigator to 8 do some assessment, but also puts a significant onus 9 on the participant to have some understanding. What's 10 missing here is an onus on the investigators to 11 present information in a way that is understandable. 12 That is sort of already part of the regs 13 but I think that is obviously a central part of what 14 we've been talking about here is to make sure that is 15 where a lot of the emphasis is placed is on the 16 investigator to do this in the right way and then 17 follow that up with an assurance that folks have 18 received that information in a way that is 19 appropriate. Clearly we have to further define what 20 we mean by understand and that is going to require 21 some additional work, too. 22 Two other points that are a little bit 23 tangential that I would be interested in any quick 24 comments. One of the things we haven't talked about 25 yet is really whether we want to link this with an 75 1 assessment at all of voluntariness. I really like 2 Professor Appelbaum's presentation of these concepts 3 around consent and voluntariness being a piece of it 4 is part of the process to look at whether folks are 5 making voluntary decisions or whether there may be 6 factors that would impair their voluntariness. 7 Lastly, I think the other big issue that 8 we haven't had time to address in much detail as of 9 yet is the concept of assent and the role that plays 10 in this whole process. I really see that as a very 11 significant element of this whole process and one that 12 has a lot of complexities obviously in the peds area 13 but as we would think about translating it in this 14 domain, I think it's an interesting and important 15 element of our future discussions. 16 MS. FLYNN: Just a couple of comments 17 back. I appreciate your focus on the issue of how to 18 make the information understandable to the subject. 19 We have not really talked a great deal yet about that 20 and I think we would be very interested in hearing 21 something about what may be going on in the field, how 22 some investigators may be addressing that with some of 23 these populations. 24 We do know a bit about different ways of 25 presenting information but as we have a larger group 76 1 of individuals that we've been considering in our 2 deliberations I think we would welcome some input. I 3 know we plan to have some work later on about how to 4 enhance the consent process and support decision 5 making. Certainly that is key, making sure that the 6 investigator can present information in ways that are, 7 indeed, understandable. 8 The voluntariness I think is key. We 9 haven't yet spent a lot of time on that. I think I'll 10 leave it to Dr. Strauss to see if he wants to add that 11 as a new focal point. It certainly has been a 12 contentious issue with some populations in the past. 13 It is a critical component. How we want to 14 incorporate it into our product I think we would 15 welcome the comments of the group. 16 DR. STRAUSS: I think I agree with Jeff 17 about the voluntariness being an essential aspect of 18 it. There was a little bit of, I think, productive 19 tension at the subcommittee in whether or not we felt 20 that voluntariness and its limitations should be part 21 of our consideration. 22 In the end I think the consensus was that 23 it ought to be although we haven't quite gotten there 24 yet. This notion, the broad notion of what we are 25 concerned with is ability to consent and the ability 77 1 to consent includes these three components. I had 2 said, and I think we will focus both on this capacity 3 for understanding. 4 The reason that we focus so much on the 5 word understanding is that we thought there was a 6 regulatory point of reference there. The capacity to 7 understand is one component of that ability and the 8 voluntariness or the circumstances, etc., some of 9 those are intrinsic circumstances obviously in my way 10 of thinking about it. 11 I think the committee was agreeing to 12 really tackle both two and three here and, again, to 13 a lesser extent, as I said, one, with an emphasis on 14 effective rather than on the disclosure of any 15 particular kind of element. I think voluntariness is 16 part of any meaningful assessment of ability to 17 consent. 18 Some of that assessment may be done by an 19 investigator. Some of it will be done by an IRB in a 20 sense though the context isn't one which promotes 21 meaningful informed consent like trying to get consent 22 during labor. You know the circumstances in which 23 voluntariness may be impaired. 24 Finally, I think dissent is another thing 25 that was discussed at subcommittee is on our priority 78 1 list. It's sort of level two, not quite icing. It's 2 the second layer. 3 DR. TILDEN: Any ex officios want to make 4 any comments or have any input? 5 DR. CHESLEY: Yes. I also wanted to 6 second the thoroughness of the framework and 7 background. I wanted to pick up on this notion of 8 encouragement to explore a bit more what the group 9 means by understanding. I think it certainly to me 10 possible to not be decisionally impaired and yet lack 11 an understanding of the research and research process 12 delivered in the consent form. 13 There are many examples of where that 14 might be the case whether it be from lack of formal 15 education, research looking at migrant workers, 16 research in prisoners, or folks with limited English 17 proficiency. 18 In particular, as we at AHRQ have looked 19 at implementing health information technology in a 20 research context to improve health effectiveness and 21 quality, we have found sort of what we are calling a 22 lack of information technology savvy or literacy to 23 the extent that it impairs ones ability as a 24 researcher to broadly include all populations in 25 research. 79 1 I see this topic as linked to one that 2 will be on the agenda later for this meeting as we 3 look at diversity in clinical trials because I think 4 that we are facing as a research funder an issue where 5 we are trying to ensure broad inclusion in our 6 research projects but also face a population that is 7 at different levels in terms of visibility to 8 understand. I'm just encouraging that be explored a 9 bit more. 10 Then one last comment that is really just 11 kind of a technical Government comment. You mentioned 12 this notion of looking at regulations and I would just 13 encourage the group to think about options for 14 providing guidance in that area that would include 15 regulations but that would include other more flexible 16 and certainly more timely ways of getting to where the 17 subcommittee was trying to get to. 18 DR. STRAUSS: I'm sorry. Do yo mean in 19 lieu of pursuing regulatory change or do you mean as 20 a place holder? 21 DR. CHESLEY: I would see it as a parallel 22 track recognizing the challenges of regulatory 23 development. There are a number of ways to get 24 guidance while at the same time you are pursuing the 25 regulatory route. 80 1 MS. FLYNN: Just to add, I want to thank 2 you for your first comment about our use of the term 3 understanding and being sure we are broad enough and 4 sensitive enough to the range of individuals for whom 5 this is an issue. That is very important and we do 6 need to spend a little more time with it. 7 Again, I, for one, as one member saw our 8 efforts here very much as promoting whatever tracks 9 will work for us. We see a field and we see a 10 situation, I think, in the science as well where some 11 guidance, some help, some concrete examples, some 12 models, indeed some Government action. All and any of 13 those things I think could be very helpful. 14 DR. STRAUSS: The notion of there are 15 certain universal limitations and impairments that 16 we've studied -- not we but the field has studied 17 clearly. 18 It's really striking if you look at 19 research, Dr. Appelbaum's research, for example, or 20 Dr. Luce on therapeutic misconceptions that even in 21 so-called healthy populations of the sort that Dr. 22 Powe is referring to when he was talking about people 23 who we would assume that you see that sometimes more 24 than half, nonetheless, significantly overestimate the 25 personal therapeutic value of research and 81 1 underestimate or misjudge the extent to which 2 treatment is individualized. 3 There are certain universal factors and I 4 think poor literacy, and poor healthcare literacy in 5 particular, are among those. I would really look to 6 SACHRP to perhaps help us decide where we draw the 7 line. 8 Certainly that isn't traditionally in the 9 same category that we consider when we talk about 10 those who are unable to consent. In our view that was 11 just an important consideration, important as an 12 investigator thinks about how to do consent properly 13 but in our view was, if I'm reading the subcommittee 14 right, somewhat outside of our charge. 15 DR. CHESLEY: I would agree. I certainly 16 read it that way as well but as I was walking through 17 your presentation, especially at slide 14, it kind of 18 opens the window a little bit to think beyond that. 19 I think being explicit as you go forward about that 20 very fact would be fine from AHRQ's perspective. 21 MS. MINER: Hi. I'm Caroline Miner with 22 the DOD and our ex officio isn't here today but if she 23 was here, I think she would want to point out that DOD 24 does have a directive that requires the appointment of 25 an ombudsman in any case where there is greater than 82 1 minimal risk research and voluntariness might be in 2 question. 3 For example, if there were active duty 4 military being recruited within the context of their 5 chain of command or something. We have actually 6 addressed the voluntariness issue and we do have the 7 requirement for an ombudsman. 8 DR. STRAUSS: We had three people from the 9 Department of Defense, if I'm not mistaken, come to 10 our July meeting and present. I was surprised because 11 it's not an area of regulation that I'm at all 12 familiar with but that a lot of specific thought that 13 is relevant to our consideration has gone into 14 specific DOD approaches to research participation so 15 it was very helpful. I think it speaks to the 16 enormous contributions that our ex officio members 17 have made and are thinking about things. 18 DR. TILDEN: Well, that gives me 20 19 minutes to have the podium here, I guess. David, I 20 believe I would give feedback on these points of 21 consensus. I would suggest that the basic requirement 22 for some assessment of understanding in all cases, as 23 others have brought out, that the subcommittee -- 24 that's a tenant that would be overlapped with the 25 Subpart A Subcommittee. 83 1 That is a general tenant. If that is a 2 statement of general applicability, I don't know that 3 it would get a big push back on that. I think it's 4 how the assessment is done is where the issues will 5 come about. 6 Generally, although I wouldn't call myself 7 a very good lawyer, I think under the law, 8 particularly testamentary law, one would consider 9 someone or would presume someone competent unless 10 there was some indicia that they weren't. There is 11 this general presumption of confidence. 12 In many instances if you took the members 13 of this committee and ask them their opinion, I would 14 think generally their demeanor and your interaction 15 would be enough to give you a clue whether they were 16 competent to make a decision. My sense is that I 17 would think SIIIDR would want to look at research in 18 populations where capacity or incapacity is likely to 19 be involved. That would be just my feedback. 20 Probably likely where that issue is going 21 to arise to something larger than the general 22 population. Given that, then one would feed into that 23 the issues of whether there's a capacity to understand 24 and decide. Then also in those situations where No. 25 3 comes in, what are the issues relating to 84 1 voluntariness, the coercion or undue influence that 2 would feed into that group. 3 As I think Mr. Chesley stated, there are 4 a lot of these other issues where the Subpart A 5 Subcommittee as you will go along will have to 6 address, I think, in terms of the decision-making 7 capacity and voluntariness related to individuals who 8 don't necessarily have problems with impaired decision 9 making per se. That's one element of feedback. 10 The second piece which no one commented 11 on, I think, is this whole idea of the LAR. This is 12 a difficult issue as I think Laura Odwazny pointed out 13 for a number o