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 of reasons. One is the fact that you 14 have this sort of state/federal piece where they are 15 overlapping jurisdictions and rights or sovereigns 16 that can develop rights. 17 In the federal system in most situations 18 the federal law would trump state law. The issue of 19 consenting to medical procedures and all these types 20 of procedures is particularly problematic. It could 21 be a situation where defining someone to be able to 22 consent to research and research procedures on the 23 federal level which might be useful particularly in 24 situations where states don't have laws because if you 25 are operating under a federally funded mandate, to 85 1 have a regulation saying if there's no state law, we 2 would acknowledge a certain scheme, a certain 3 hierarchy, a certain process where effective consent 4 for federally conducted research is appropriate and 5 outline what that is. 6 The committee certainly could bring that 7 up because it's not like a national approach the 8 definition of LAR. I think you would have to say what 9 is it. Then most certainly that definition will not 10 comport with state law in all 50 states so then you 11 have an issue of whether state law should change. Is 12 federal law going to really supersede state law for 13 research? 14 Then you have the whole problem for 15 medical procedures even dispensing, etc., where states 16 have regulations and laws regulating these things. 17 You may have to get two consents. It may complicate 18 the process in that regard. I do think as the 19 subcommittee goes along that it might be useful to 20 look at some alternative, a couple of alternatives. 21 If you go with the federal approach what 22 would be recommended as a process to get effective 23 informed consent, federally effective informed 24 consent. That might mimic the majority of the states. 25 It may be completely different. I don't know but it 86 1 would suffice for a consent for the research. On the 2 other hand, it will present problems on the state 3 level, I believe, if you want to do a procedure, 4 medical procedure, surgical procedure. 5 You already get consent for many of those 6 procedures but those procedures would be over and 7 above or in addition to a separate consent process and 8 a separate hierarchy. As the subcommittee goes 9 forward I think that those are situations that need to 10 be considered. 11 I do think, though, that one way to get 12 states to adopt a legally effective, legally 13 authorized representative that's effective at the 14 state level, as I said before, is to have NIH as part 15 of their application process either alter the 16 regulations or just as part of the application process 17 begin to identify populations where impaired decision 18 making or capacity is involved and have the applicant 19 address how they intend to deal with the LAR 20 provision. If the applicants cannot -- if there is no 21 provision for LAR in state law, that could be a bar to 22 funding. I think that -- 23 DR. STRAUSS: Of all research or just 24 research with decisionally impaired subjects? 25 DR. TILDEN: Well, it would be for 87 1 research for that project. You submit by project. I 2 believe that test case would all of a sudden generally 3 promote states and universities which are important 4 political entities in states to get this whole issue 5 of LAR addressed. I believe it could be done rapidly 6 like within a year. I think it would promote a state 7 solution that would address some of the issues. 8 That is me just thinking outside the box 9 but I know we have a test case with Tennessee and I 10 just can't imagine any state university who is having 11 their funding compromised because they don't have an 12 adequate way to gain funding would not be in a 13 situation to marshal the support of legislators or the 14 attorney general or whatever to address this problem 15 and solve it in short order. 16 Those are a couple of points I wanted to 17 feedback to you. I believe if you can have the 18 state/fed role piece aligned in unison, that would be 19 the most efficient and effective way to deal with 20 this. Once you begin to have separation there are 21 just constitutional issues in terms of police powers, 22 etc., what states are generally responsible for 23 health, welfare, blah, blah, blah of their populace. 24 When you start to diverge guardianship, 25 healthcare decision acts, all of those have been 88 1 passed at the state level and it's going to being up 2 a lot of questions about how it's going to affect all 3 these vehicles. My sense is that if you can somehow, 4 I would look at both of them. 5 Of course, if a state doesn't act and 6 there is no way to do it, you could pass a floor or 7 some sort of federal solution. When you have a state 8 that is willing to act, it may not be -- it may be 9 more effective and generally more efficient if you get 10 both of those working together. 11 MS. FLYNN: Can I just ask one question? 12 How would you respond to the notion of suggesting that 13 it might be useful for HHS to assist in the 14 development and promotion of a model state statute 15 which was our other potential recommendation. How 16 does that square with your issues? 17 DR. TILDEN: Well, I think that would also 18 be helpful as well because then when legislators want 19 to look somewhere to say how should we handle this, 20 then generally, I'm blanking on the name, but there is 21 a uniform commission or commission for uniform state 22 laws or whatever. 23 There is a place for them to go and say, 24 "Hey, we have some model to pick," instead of trying 25 to create your own. That would also if the Department 89 1 of HHS would promote that for model legislation and 2 work with legislators to try to promote that, that 3 would also be another assistance, I think, to get that 4 solved. 5 But right now the Department has even said 6 that a interpretation of the law by the attorney 7 general of the state, an official opinion, could serve 8 to satisfy the legally authorized representative piece 9 as well as other laws. It's very flexible, in other 10 words, on that regard. 11 DR. GENEL: Sam, on the point of the model 12 state legislation, I believe there is a commission 13 that is responsible for drafting model state 14 legislations. There is a national commission. I 15 don't know how effective it is but there is a process 16 that could be engaged. 17 DR. TILDEN: Yes. 18 DR. STRAUSS: I would like to, if I might, 19 just comment a bit. You know, I think NBAC and others 20 some ten years ago made a lot of recommendations which 21 might have promoted the development of state 22 legislation. What we are seeing is that there are 23 only a handful of states that have specifically 24 addressed consent in the research conduct by people 25 other than the individual subject. 90 1 What we are also seeing is that the 2 various approaches that have been taken, No. 1, are 3 inconsistent with one another and, No. 2, are poorly 4 understood by institutions and investigators within 5 the state. If you remember at the last meeting here 6 Scott Kim showed us data from California which showed 7 that more than half of IRB chairs in California were 8 unaware that California had state rules that permitted 9 or addressed decision making by proxy. 10 I think maybe we undervalue the way that 11 the federal oversight system for human subjects 12 protections has worked. I think that IRBs and 13 institutions look to the feds, look to us, and not to 14 the states for guidance and regulation with regard to 15 research. 16 I would also say that I think that state 17 governments -- again, we've had the somewhat difficult 18 task of reviewing state legislation that is relevant 19 to this issue. The states, I think, are a lot less 20 well equipped to develop and implement these rules or 21 even construct de novo a system for compliance with 22 state rules. 23 I think in many ways we should be careful 24 to not too quickly shy away from the idea of federal 25 efforts. One of the things that we would hope is that 91 1 perhaps in a formal way SACHRP might ask HHS counsel 2 to prepare a written document on the priorities of 3 state versus federal rules in this regard. 4 Maybe not as a SIIIDR co-chair but as a 5 member of SACHRP I would propose or make a motion that 6 we consider such a request to counsel to actually 7 specifically look into the question of whether the 8 relationship of state and federal law on this LAR 9 issue. That's one thing I wanted to point out. 10 The other thing, Sam, is that you 11 commented on a presumption of competence and I think 12 that presumption of competence only works in a 13 clinical context. I mean, it's clinical lore in the 14 medical hospital that people's competence is presumed 15 unless questioned. When we are talking about 16 decisions that are not necessarily in the interest of 17 the individual in the research context, I don't think 18 that presumption is widely agreed upon or reasonable. 19 Again, I think the data is vast that 20 demonstrate that people don't understand, and I'm 21 using the word loosely that many people, a vast 22 majority of people, find some of the concepts related 23 to research to be difficult to comprehend and so I 24 think I would disagree with the perspective that we 25 should again go back to try to identify populations 92 1 who are likely to be impaired. 2 I think the risk there, as we pointed out 3 in some earlier presentations, is that you put in 4 place protections for those who don't need it and that 5 you fail to address protections for populations that 6 do. 7 MS. FLYNN: Just two, if I may, two small 8 additional comments. I certainly support Dr. Strauss' 9 thoughts in this. In terms of the issues around LAR 10 and looking to state or local fixes as opposed to some 11 more consistent effort, however, we may take a 12 leadership role nationally, among the other things 13 that pushed us in this direction. 14 It has been mentioned before but I would 15 reinforce it that today's science is so often a large 16 multi-site, multi-state endeavor and the difficulty in 17 mounting these kinds of efforts where you have such 18 great inconsistency, or even lack of any kind of 19 guidance, really is a significant problem and could 20 become a more significant problem, especially for some 21 of these conditions and disorders that folks with the 22 potential or reality of decisional impairment are 23 facing. 24 Some of the most critical issues we may 25 want to be mounting research about so the kinds of 93 1 delays and difficulties that are already built into 2 large research enterprises are just exacerbated by 3 this gap in ability to provide adequate protection. 4 Then, secondly, as a person who spent 5 many, many hours with the NBAC process, an additional 6 reason why I would urge us to think beyond a 7 population kind of construct around who it is that we 8 are including in our thoughts about protection for 9 individuals with decisional impairment, is the reality 10 that because that effort, as so many prior efforts, 11 was really more narrowly focused and was really very 12 much focused on individuals with psychiatric illness 13 almost exclusively. 14 We've seen very little result. It was not 15 well received by the community that is most at issue 16 there. It was not viewed as helpful. It was, in 17 fact, viewed by many advocates as unduly stigmatizing 18 and unduly rigid. It would, in fact, throw into one 19 big category what we know to be a broad range and a 20 fluctuating situation with regard to impairment and 21 might indeed create an impossible situation in terms 22 of some of the research we may need the very most for 23 some of the individuals whose circumstances are most 24 dire. 25 While this is a shift in thinking, I think 94 1 it reflects the knowledge we now have about these 2 disorders as well as the realities we all recognize 3 not only in terms of diagnosable diseases but 4 circumstances and situations whether it's individuals 5 coming back from Iraq with head trauma or individuals 6 in our own family circle who may be slowly sinking 7 into dementia. 8 We know this is more difficult to grasp 9 and grapple with in broader population but ultimately 10 we think all of these folks fall into the category on 11 an individual rather than population perspective. 12 DR. TILDEN: Right. I don't think we have 13 a disagreement about that. What I'm saying is that 14 when you look at a protocol if somebody wants to look 15 at cognitive function in individuals with head injury 16 from Iraq, when you submit your protocol and you are 17 identifying this population, this would be a 18 population where one would want to address up front 19 prospectively how you are going to deal with getting 20 informed consent. 21 You are going to see a whole spectrum of 22 individuals from those who are fully recovered, let's 23 say, or have very mild cognitive impairment who care 24 for themselves, are fully independent, make all their 25 own decisions versus individuals who are totally on 95 1 the other end of the spectrum and cannot make 2 decisions. 3 I don't think that's where I'm going with 4 this. Where I'm going to is when we say basic 5 requirement for assessment of understanding. My wife 6 just got a letter inviting her to participate in a 7 bone mineral density study for women 55 years of age 8 and older. I shouldn't be saying her age. 9 Anyway, for an osteoporosis study. Let's 10 say they enroll 500 individuals, none of which would 11 be prospectively identified necessarily to have an 12 impairment. If they did have an impairment, it's 13 likely they would just be dropped from the study. 14 When you use some assessment, okay, that 15 creates some issues because IRBs want some assessment. 16 What are you going to do? That creates maybe an 17 expectation of formality that in general would not be 18 necessary. I guess that is my issue in terms of 19 burden here. 20 Is that not a situation that would be 21 better dealt with, the situation where there are 22 populations where there may be a sporadic individual 23 that comes forward that may appear to have a 24 decisional impairment? Wouldn't that be something 25 better handled over on the Subpart A Subcommittee side 96 1 for that type of situation rather than these other 2 situations where there is definitely an expectation 3 that you have to address this up front? 4 It's not that when an individual presents 5 themselves in a study where that wasn't anticipated. 6 They don't have a formality and assessment. That's 7 why I'm saying it's an axiom that you want individuals 8 to have understanding. It's just the question is when 9 you develop the idea of a positive assessment, when 10 that is out there I think that is where there is going 11 to be some confusion or some additional burden that 12 may not really address it and that will be applied to 13 many studies where it would not be necessary. 14 DR. STRAUSS: I think I know where you're 15 going on this and I agree with you. I think that the 16 fundamental requirement for some form of call it 17 acknowledgment. David Shore mentioned before the idea 18 of some sort of attestation I think does belong with 19 Subpart A. I'm agreeing with you. 20 I don't think we aim to group everybody in 21 this new subpart of the world of people, some of whom 22 may have -- I don't think we need to do that. I think 23 you are absolutely right about that. I would also say 24 that I would hope that an IRB charged with reviewing 25 a study that recruited people older than 55 knows that 97 1 some people older than 55 are older than 95 and some 2 of them may in fact have cognitive impairment related 3 to disease or aging. 4 I would hope that an investigator is 5 mindful in those sorts of circumstances. I'm not 6 saying that you want to have a two-hour long 7 neurocognitive battery done but I think you do want at 8 least the person to be cognizant, the investigator, of 9 the comprehension, the ability to consent. 10 Then if you were doing a study, for 11 example, that was higher risk and only in those groups 12 above age 90, you might want to increase that 13 expectation of assessment but it would be tailored. 14 I don't think we're disagreeing. We clarified that. 15 DR. TILDEN: The Dan and Jeff show. You 16 all decide. 17 MR. NELSON: We'll tag team again. Two 18 separate points on the last two items here, I guess. 19 On the LAR question, I think Laurie serves us well and 20 serves the discussion well to stress and highlight the 21 change in the research environment today. Certainly 22 multi-institutional studies, multi-state studies. 23 Nobody has mentioned multi-national 24 studies but we also deal with those. David noted the 25 observation, and I think it's reality, that IRBs are 98 1 maybe generally unaware of their own statutes and 2 guidelines and framework in this area in LAR. If we 3 accept that, now think of the relative dearth of 4 knowledge of all the other states for which they may 5 be approving that study. In other words, the state 6 specific framework or lack or framework in the LAR 7 area. 8 I think having said all that, that is 9 balance against the reality that it would be a tough 10 row to hoe, I think, to be thinking of a truly 11 national or federalized approach to this area. It's 12 a worthy goal and worthy point for discussion, I 13 think, because the patchwork quilt of state approaches 14 or lack of state approaches in so many areas is a real 15 problem. 16 I would be remiss, I think, if I didn't 17 address the last bullet there from Subpart A 18 perspective. I don't know that I have any direction 19 to give or that I'm the one to give it but just to 20 respond at least on a conceptual level I'm glad to see 21 you put that out on the table for discussion. You 22 will see that we did the same in our Subpart A 23 presentation because we also want to be sure to 24 coordinate our activities with SIIIDR. 25 I really don't see or anticipate any 99 1 problems in this area to the extent that Subpart A 2 Subcommittee spawned SIIIDR. That may have been a bad 3 choice of word, too. It sounds like a grade B drive- 4 in movie, Spawn of SASS or something. 5 Let me say to the extent we recommended 6 that SIIIDR be formed in the first place recognizing 7 our own limitations in addressing in a meaningful way 8 the vulnerable populations in the way that you are 9 going to be able to do very well and made the supreme 10 sacrifice of donating a co-chair to the cause in the 11 form of David Strauss, I see nothing but positive 12 cooperation and collaboration in this area. 13 I think this is really just a matter of 14 keeping open the lines of communication and having 15 enough people at both tables, if you will, in Subpart 16 A and SIIIDR to make sure that one of us doesn't go 17 down a road that is being counter productive with 18 regard to the work going on with the other 19 subcommittee. 20 At least I just wanted to acknowledge that 21 we are interested in harmonizing our efforts as well. 22 We have no turf issues from the Subpart A perspective 23 and I think to the extent that your work can inform 24 ours and vice versa I think we'll be able to do that 25 quite well. 100 1 DR. BOTKIN: I want to make just a quick 2 comment picking up on the distinction that Sam made 3 which I think is part of the background. Somewhat 4 obvious and important perhaps to keep aware of, and 5 that is research that is focused on the condition that 6 is associated with the person's impairment. 7 Those are individuals, of course, who we 8 want to go through a complicated decision-making 9 process trying to figure out how best to get them in, 10 to better understand those conditions to better find 11 treatments for folks in that sort of situation. That 12 becomes a complicated process that we're talking 13 about. When the impairment is not related to the 14 research, as with Sam's example, then the threshold 15 seems to me to be very different. 16 You don't include those folks in research 17 and you may want to set a fairly high threshold to say 18 the folks can't have a basic understanding of what the 19 issues are, then it's an exclusion criteria for the 20 research and we don't need to think about LARs in that 21 particular context. 22 That is clearly a fundamental protective 23 mechanism for making sure that folks aren't being 24 abused, vulnerable folks aren't being abused by being 25 enrolled in research for which they can't adequately 101 1 make decisions. Just keep aware of that distinction 2 I think is helpful for me. 3 DR. TILDEN: Okay. Well, that concludes 4 the morning's discussion. 5 MS. FLYNN: May I just ask one just to 6 wrap it up. I'm sorry to interrupt. I wonder if it 7 is possible or feasible through the remainder of your 8 discussion if we might seek some kind of legal opinion 9 to help our ongoing deliberations around what HHS 10 might best choose to do. 11 We have identified this dead end 12 regulatorily with the LAR issue and we don't really 13 know what is legally effective when the Federal 14 Government points to the state and the state is not 15 there. I think we need to get some kind of clarity 16 about that. 17 Similarly we would love to get a clearer 18 sense of how HHS might view the notion of model state 19 statute, what would be the best way for that idea to 20 move forward and to get some kind of motion to seek 21 for the benefit of the guidance of our subcommittee. 22 DR. TILDEN: Okay. Well, I think David 23 did mention he wanted to make a motion. I'm not sure 24 exactly what the motion is. I would say are you 25 trying to have a motion brought forward just for 102 1 clarification that suggest that we recommend that the 2 Secretary provide or develop or obtain a conflict? 3 You might have to work with Julia on this 4 and come back but it would be either a preemption 5 analysis or a conflict of interest analysis, supremacy 6 clause analysis of federal regulations defining an LAR 7 in relationship to state laws, current state laws, 8 something to that effect. 9 I wish I could frame it a little bit 10 better. You might need to get to legal -- your 11 liaison who happens to have some legal training and 12 see if we can come up with a motion and then we could 13 pick it up maybe at the end of the meeting today and 14 discuss it and wrap up. 15 MR. NELSON: I'm not a lawyer, nor do I 16 play one on TV but I sort of put what you just said 17 into lay speak. I wonder if it would serve the cause 18 just to propose a motion that you seek legal options, 19 a reading on what legal options are available working 20 through HHS without presuming what they are or even 21 trying to name them. Is that really what you're after 22 knowing what the possible options are from a legal 23 standpoint? 24 DR. STRAUSS: Yes, there's two components 25 of it and I think that really the subcommittee feels 103 1 that these are somewhat outside of our expertise. The 2 first is the question of federal preemption of state 3 rules, really how federal rules would -- the impact of 4 federal rules absent state rules. That's one. 5 Then the other issue, and I don't know if 6 it's the same process, but it's options with regard to 7 federal efforts to promote the adoption of state rules 8 in this regard. Those are two aspects. 9 DR. TILDEN: Is that the motion you want 10 to present? 11 DR. STRAUSS: Yes. 12 DR. TILDEN: Okay. Do we have a second? 13 Looks like Dan and Jeff want to second that motion. 14 Any discussion? 15 DR. GENEL: What precisely is the motion? 16 DR. STRAUSS: I was wondering, Julia, 17 could you be able to be somewhat more precise or 18 articulate here? 19 MS. KANESHIRO: I think this is largely a 20 question you are going to want to address with Laura 21 Odwazny who unfortunately is not here at the moment 22 but I think you are really asking for direction 23 regarding perhaps the different and more specific 24 definition of LAR either in the subpart or as part of 25 a common rule amendment. Those are really Laura 104 1 Odwazny questions in terms of what the preemption 2 analysis would entail. 3 DR. STRAUSS: The second of it. In other 4 words, what is possible in the way of federal efforts 5 to promote or, as Sam suggested earlier, incentivize 6 the adoption of state rules. How would we approach 7 that? 8 DR. TILDEN: I don't know that we need any 9 special legal analysis. I mean, I'm not sure if we 10 need any legal analysis at all. I think if we -- I 11 thought maybe in October we would address this but we 12 can address it now. 13 If we feel that we -- if you feel a 14 federal option is the best solution to the issue of 15 clarifying and defining an LAR, I think you just need 16 to bring it to the committee and we'll send it on in 17 the federal option via statute regulation or otherwise 18 would be preferable than the current status. 19 That would be one's preference. All I'm 20 saying is that from an alternative standpoint 21 alternatively one could look at development of a model 22 state statute to promote states. And/or I think 23 personally I just know how universities work in 24 general from Alabama. 25 If we didn't have a solution in Alabama, 105 1 I can tell you how long it would take to get one, 2 about six weeks if the legislature is in session 3 because we -- I mean, there are 50 states in the 4 country and I don't know. Someone here may know but 5 I suspect all of them get NIH funding or federal 6 funding in some way where they have an assurance. 7 If they intend to do work with adults with 8 impaired decision making and they have to define in 9 their application how they are going to handle the LAR 10 problem and report that their state has a solution, I 11 suspect it would get prompt attention. That's all I'm 12 saying. I may be off the wall. I just know where 13 money is, it speaks. 14 DR. GENEL: I can't resist, Sam. That 15 will work in Alabama where it's the state university. 16 It won't work in Connecticut where it's the private 17 university. Certainly not as well. 18 I think what we are hearing is we are 19 asking -- the subcommittee is asking for some 20 direction as to what are the potential legal options 21 and among these options what is the course that one 22 would take and what, if any, are the recommendations 23 in terms of these options. If that is the case, I 24 would make that motion. 25 DR. TILDEN: Okay. Seconded? Okay. You 106 1 got that motion? We have that motion? Can you repeat 2 that motion, Mike? 3 DR. GENEL: I move that we ask legal 4 counsel to provide a summary of potential options to 5 address the dead end of the LAR issue in terms of 6 actions that could be taken by HHS, that could be 7 taken by legislation, by guidance, by directive 8 through HHS or that could be taken through development 9 of model state legislation or individually through 10 states and give us a range of options and a judgment 11 as to which of those options are the preferred options 12 and which are the limitations of each of those 13 options. 14 DR. TILDEN: We'll take that as an 15 amendment to your motion. Is that okay? Okay. We 16 have a second to that. Okay. All in favor? Aye. 17 Okay. So it passes unanimously. With that I'll take 18 a motion to adjourn and we'll come back in one hour. 19 (Whereupon, at 11:49 a.m. off the record 20 for lunch to reconvene at 12:58 p.m.) 21 22 23 24 25 107 1 A-F-T-E-R-N-O-O-N S-E-S-S-I-O-N 2 12:58 p.m. 3 DR. TILDEN: We have the report of the 4 Subpart A Subcommittee with co-chairs Felix Gyi and 5 Dan Nelson. 6 MR. NELSON: Thank you. I see Dr. Schwetz 7 is rolling up his sleeves and he's got his suspenders 8 on so we are ready to go to work. I am reminded that 9 I missed the chance. My presentations to this group 10 have gotten increasingly more boring and text-dense as 11 time has gone on. I missed our chance today to at 12 least insert a few slides of alpacas or something just 13 to burn off to retirement. 14 I know Felix would join me in thanking Dr. 15 Schwetz at both professional and personal levels for 16 his active participation in our subcommittee 17 activities and his leadership. We have certainly both 18 appreciated and benefitted from his involvement and he 19 will be missed, I think, both by us and by the 20 research community at large. Thank you, Bern. 21 Let me orient you to the materials you 22 have, both members and audience, because this will 23 become important as we go through. I was told once to 24 never start a talk by apologizing but I will apologize 25 in advance today for some rather text-dense slides in 108 1 some parts of our presentation. 2 Normally, we would reduce these to 3 bulleted points and conceptual issues but this time we 4 have stuck quite close to the script largely because 5 this time there is a script in the form of written 6 recommendations. So rather than ad lib and reduce to 7 conceptual items, we've extracted directly from some 8 of that text so that there is no question which 9 recommendation we are on at a given point when we get 10 to those. 11 The slides you have in front of you and 12 under tab whatever we're in, L, and then there are 13 text documents that follow and I'll point you towards 14 those as we come to those in the presentation. You 15 are obviously welcome to follow along on the slides 16 but they will also be then right in front of you for 17 written notes. 18 So a quick review, as always, of our 19 subcommittee charge and membership and update on our 20 prior recommendations and then we'll spend most of the 21 time on recommendations for consideration today in the 22 areas of case examples illustrating minimal risk and 23 our recommendations on the subtopic under informed 24 consent, waiver of informed consent. Then close out 25 with telling you where we are at in our thinking with 109 1 next topics for our subcommittee's ongoing 2 deliberations. 3 Charge to the subcommittee as abstracted 4 from the memo from the chair back in 2005, now. We 5 were charged to review and assess all provisions of 6 Subpart A of 45 CFR 46 and related OHRP guidance 7 documents and based on this review and assessment to 8 develop recommendations for consideration by SACHRP in 9 three categories. 10 First, interpretation of specific 11 provisions under Subpart A. Secondly, development of 12 new or modification of existing OHRP guidance. Third, 13 possible revisions to Subpart A and the 14 recommendations brought forward thus far have 15 straddled all three of those categories. 16 The goals of our work are to enhance 17 protection of human subjects, to reduce regulatory 18 burdens that do not contribute meaningfully to the 19 protection of human subjects and to promote 20 scientifically and ethically valid research. 21 Our subcommittee membership has grown. 22 David, that was a nice touch to have pictures of your 23 members up on the screen. We would be reduced to 24 little thumbnail prints, I guess, with as many members 25 as we've grown to now but it's nice to put faces with 110 1 names. 2 We have, it seems like, each time added in 3 orange some new members and this time we have several 4 members all from our parent committee who have 5 affiliated with our subcommittee and we are happy to 6 have them on board and those are the ones indicated in 7 orange on the slide as we go down. 8 Ricky Bluthenthal from Rand; Gary Chadwick 9 in the audience from Rochester; Mike Genel here from 10 Yale; Bruce Gordon from Nebraska; Felix, my trusty co- 11 chair, from Chesapeake Research Review; Isaac Hopkins 12 from New Jersey; Nancy Jones from Wake Forest 13 University at NIH; Moira Keane from Minnesota; Susan 14 Kornetsky from Boston; Patty Marshall from Case 15 Western; Gigi McMillan who you will meet tomorrow on 16 one of the subject advocate panels from the We Can 17 Pediatric Brain Tumor Network. 18 Neil Powe from Hopkins has joined us, as 19 has James Powell from Cincinnati, and Ernie Prentice 20 from Nebraska, Francine Romero from the Southwest 21 Tribal Epidemiology Center, and Ada Sue Selwitz from 22 Kentucky. We've had very active and ongoing input 23 from ex officio members some of which you will see 24 reflected in today's recommendations. 25 Our subcommittee meetings; we've tended to 111 1 alternate group teleconferences with group in-person 2 meetings. Of course, sandwiched in between all of 3 these are numerous working group calls and e-mails to 4 carry the work forward. 5 Our most recent meeting was on this floor 6 in this hotel at the end of May, first of June. We 7 really stepped back and reassessed where we were at a 8 number of fronts and then identified, or actually took 9 your recommendations from the last SACHRP meeting and 10 proceeded in three topic areas that you will hear more 11 about today. That was followed by a group 12 teleconference and, again, a lot of work in between by 13 the working groups that we've formed. 14 Just a single slide to update you on our 15 recommendations to date. The first letter to the 16 Secretary was accepted as Dr. Schwetz noted during his 17 opening comments. These contained a large number of 18 recommendations in the areas of continuing review and 19 expedited review that embodied our work from 2005 and 20 most of 2006. 21 We are pleased to have those acknowledged 22 and accepted at the level of the Secretary and now, of 23 course, the hard work of implementing them and 24 modifying guidance continues with OHRP. 25 The second letter to the Secretary has 112 1 been submitted and is in the pipeline hopefully for 2 their similar acceptance. These were recommendations 3 that were approved in March of 2007. I'll note that 4 is the fastest turnaround that I've seen I guess in my 5 experience with SACHRP getting it into a letter and to 6 the level of the Secretary that fast from premiere 7 action on a given set of recommendations and we 8 appreciate that rapid turnaround. 9 These were in the areas of required 10 training and education for several groups, IRB 11 members, IRB staff, institutional officials and 12 investigators with a fair amount of overlap in the 13 concepts of required training for each of those groups 14 with some individual tailoring to the target audience. 15 So the first thing we wanted to follow up 16 on were action items from the last SACHRP meeting in 17 March as they relate to our analytical framework for 18 understanding and applying minimal risk. These are 19 the three action items lifted directly from the 20 minutes you just approved from our March 29th meeting. 21 I'll deal with them in order. 22 The first; you approved just as a 23 reminder, not for further deliberation today but you 24 approved a one-page summary of a recommended position 25 on minimal risk that was included in the references 113 1 for that meeting. Just for your reference that is 2 included under Tab L-3. Again, no intent to rehash 3 all of that today because that was discussed early and 4 approved in March but on the next two slides we just 5 repeated that text as you approved it for your 6 reminder. 7 These, again, provided some conceptual 8 points and then some fairly specific interpretational 9 issues on points within minimal risk where we see 10 problems and see some resolution from guidance coming 11 out from OHRP. Again, those were approved. 12 The last two items. Not actually. I'm 13 thinking back now if there were two separate motions 14 as reflected in the minutes but we've been true to the 15 minutes and reproduced them here. They are quite 16 similar in nature, items two and three. One, SACHRP 17 approved a motion that illustrative examples be 18 developed by the subcommittee and presented as an 19 appendix. 20 After further discussion also approved a 21 recommendation asking the Subpart A Subcommittee to 22 provide examples to illustrate how the proposed 23 concept of minimal risk be implemented. Examples are 24 to be forwarded to the Secretary with the approved 25 summary. Here I would direct your attention to Tab L- 114 1 4 in your binders and also in the back of the room and 2 remind you that these were mailed out by the chair in 3 advance of this meeting for your consideration. 4 We don't have any slides on these cases. 5 It's our understanding from the discussion as 6 reflected in these minutes here that you were looking 7 for us to prepare these and forward them ahead. We 8 did want to bring them back around for your 9 consideration. We are presenting them as an intact 10 set basically of illustrative cases that would then be 11 forwarded as reflected here as an appendix with the 12 summary that you've already approved. 13 We, at least at the subcommittee level, 14 were not under any misconception that OHRP would be 15 bound to use all of these cases necessarily or perhaps 16 any of them exactly as written, but rather they are 17 examples to illustrate some of the points and to show 18 how our analytical framework would be applied. These 19 were cases that were developed over the course of the 20 year that we worked in the area of minimal risk 21 largely by David Strauss with input from the rest of 22 the subcommittee. 23 There are seven cases in total based on 24 our own discussions and SACHRP feedback because, 25 indeed, you have seen some of these as we went through 115 1 our two or three meetings where we presented these 2 recommendations. They were presented as illustrative 3 cases, at least in slide format, so some of them 4 you've seen before. Some were added to fill in gaps. 5 We wanted to make sure that we had a balanced 6 representation across biomedical and social, 7 behavioral, educational research areas. 8 These are basically intact as we last saw 9 them and used them and we are now bringing them 10 forward and hopefully with your approval of them ask 11 that those be relayed as an appendix as indicated in 12 the minutes. 13 With that, Mr. Chairman, I think we would 14 turn it over to you and open for discussion. 15 DR. TILDEN: Is there a motion to approve 16 the appendix and examples? 17 DR. STRAUSS: So moved. 18 DR. TILDEN: Okay. Is there a second? 19 Seconded. Any discussion? Questions or comments 20 about any examples? 21 DR. GENEL: Let me just pursue something. 22 In a way, it's going over old ground but it reflects 23 something else that I had brought up earlier. I think 24 case No. 3 with the proposal for three bone marrow 25 biopsies -- is the connotation of a higher risk 116 1 related to the risk of harm or the risk of discomfort? 2 What I'm suggesting -- is there is a qualitative 3 difference between the potential risk of injury as 4 opposed to the potential risk of discomfort? 5 DR. STRAUSS: I heard earlier that that is 6 a distinction that's important for you in thinking 7 about some of these things. By discomfort do you mean 8 pain? Is pain a discomfort? 9 DR. GENEL: Well, in this specific case, 10 pain to some extent but I would think these would be 11 done under appropriate anaesthesia and local 12 anaesthesia and so forth. I don't know where I come 13 down on this but I am persuaded that there could very 14 well be a difference between something that is 15 perceived by an IRB as being discomfort and something 16 that is perceived as being at risk of injury. I'm 17 just sort of wanting to explore this a little bit. 18 DR. STRAUSS: I think it's a good question 19 for this case in a way because I think you could argue 20 that certain aspects of discomfort may, in fact, be 21 lessened by repeated experience with a particular 22 procedure. Right? For example, let's say anxiety is 23 related to having a procedure of a certain sort done. 24 You have it once and you are nervous because you don't 25 know what to expect. You have it a second time, and 117 1 there is a lessening of related concerns. 2 DR. BOTKIN: Or heightening. 3 DR. STRAUSS: Sorry? 4 DR. BOTKIN: It can go the other way. Now 5 you know what you're getting into. 6 DR. STRAUSS: But my point is if you look 7 at point two, it can go the other way. The argument 8 here -- well, it doesn't say this but it may or may 9 not cause less pain and it certainly doesn't introduce 10 a lower risk of infection or bleeding because they've 11 had prior experience. This actually is really more 12 focused on harm or it is focused on both harm and 13 discomfort but it certainly includes the notion of 14 harm. 15 DR. GENEL: Basically there is a certain 16 inherent risk that some harm may be done. If you 17 multiply that times three, then you multiply that 18 potential times three. Therefore, it goes over a 19 certain threshold, a certain acceptable threshold. Is 20 that the sort of thinking behind it? 21 DR. STRAUSS: Yes, exactly. 22 DR. GENEL: Okay. 23 DR. STRAUSS: But let me just say when you 24 say discomfort do you mean minor discomfort? 25 DR. GENEL: Well, I don't know how you 118 1 quantitate that and that's part of the problem with 2 using the term discomfort. Discomfort can be pain, 3 can be anxiety, can be any number of things. I know 4 we use this and I'm sorry I didn't raise this in 5 March, but I think it's a very fuzzy term. What I'm 6 hearing is that, in practice, the application of that 7 by IRBs varies considerably. 8 MR. NELSON: The use of the term, first of 9 all, wasn't an invention of IRBs. There is regulatory 10 language that requires us to consider risk and 11 discomforts in particular, to relay those through the 12 consent process to subjects. I suspect one of the 13 ideas behind that was to not discount the fact that 14 there could be untoward -- that there could be a 15 downside to participating in studies that don't have 16 any physical risk, if you will, but yet where the only 17 downside in let's say a social behavioral type of 18 study, and those certainly have real-life risks as 19 well, if you will, but also there may be times when 20 there is no physical risk of harm per se but there is 21 still a discomfort, maybe even just an inconvenience. 22 I think IRBs do look at those in the aggregate. 23 Now, Mike, your point is well taken that 24 there may be a tendency to over-weight, if you will, 25 negative influences down that continuum, down that 119 1 scale. If an IRB is looking at a mere inconvenience 2 or a relatively minor discomfort and weighting that in 3 their analysis to the same extent a more serious risk 4 of harm is, that's not a good thing. 5 I think we are probably obligated to at 6 least still use the language because it's out there 7 and that isn't changing but to the extent we could 8 maybe give a signal that these things should all be 9 placed in context if there is a continuum, I think 10 that is a valid point. 11 DR. GENEL: Maybe I didn't read this as 12 carefully as I should but the first place I see a 13 description of discomfort is under the 46.116 which 14 describes the basic element of consent but the 15 previous language in the regulations does not go into 16 and does not mention discomfort until it comes to a 17 disclosure in the consent process. 18 I mean, I'm raising the question to what 19 extent are we bound by the regulatory language that 20 mentions disclosure of discomfort in a consent process 21 in application to examples such as this. I'm not sure 22 I know where I am on this but I think that is what I'm 23 hearing out there and I think it's something we 24 perhaps need to ventilate more carefully. 25 DR. GYI: Mike, this is one of those 120 1 issues that relate to quantifying pain and suffering, 2 pain and discomfort. It really does fall in that same 3 category as we look at this. I know that when our 4 subcommittee met, one of the things that we wrestled 5 with was how do we blend the two together given what 6 you just reminded us of with respect to where the 7 regulations fall. 8 The recommendations, including case 9 examples, just by way of a reminder, is that it is 10 supposed to provide guidance to folks over at OHRP in 11 helping us have some parameters about how we describe 12 minimal risk. 13 Mike, Dr. Caromd, I wonder if there is 14 anything you want to say with respect to this because 15 this is a chance for us to vet some of these issues 16 and it's going to come back into your shop in a way 17 that will raise more questions. If there is any 18 guidance that this committee can give you or the 19 subcommittee can give in addition to what we're 20 talking about now, it might be a good time for us to 21 discuss this. 22 DR. GENEL: If I may, David has just 23 reminded me that the actual regulatory definition of 24 minimal risk is the probability, magnitude of harm or 25 discomfort. I stand corrected. That's in the little 121 1 box next to the graph right there. 2 MR. NELSON: You may stand corrected in 3 terms of where the regulatory language is coming from, 4 but I think your point remains valid that there may be 5 some over-weighting of discomforts, harm, risk that 6 fall along a continuum. 7 DR. GYI: Do you want to say anything? 8 DR. TILDEN: Any other discussion? We 9 have a motion seconded. Discussion? 10 DR. BOTKIN: I wanted to raise a question 11 about -- well, first of all, I think these 12 illustrations are really very helpful and I think they 13 are going to be a terrific asset. I ask about the 14 diagrams themselves and aspects of those that I think 15 I remember much discussion about. 16 There are a couple of aspects that I think 17 are at least worth a question and that's the error 18 bars. What is the meaning of the error bars? Is that 19 variation between individuals? Is it variation and 20 perception of the risk from different observers? Is 21 it implying a greater degree of specificity or 22 objectivity than in fact exist? Might it be better 23 since you've got a fuzzy line for minimal risk simply 24 to have a fuzzy line for the bars? 25 MR. NELSON: A very fair question. 122 1 Indeed, we've gone around many times how best to 2 portray this. This is, without dragging David back 3 into the fray, David likes pictures as he told us this 4 morning. Some of these were very helpful creations of 5 his as we grappled within the subcommittee. Again, I 6 won't put Mike Caromd on the spot to ask him is he's 7 going to use the figures that we rely on but I guess 8 this also has to be kept in that perspective. It's 9 not a given that OHRP is going to lift these, however 10 we approve them. 11 Having said all that, Jeff, when I look at 12 the error bars, the message that I take from them, 13 which is just me, is that, regardless of how tall we 14 draw one of those bars there is a plus or minus to any 15 of that. I guess I kind of think of it as the fuzzy 16 line. 17 It's a way for us to say that for any 18 given bar A representing a population, etc., we can 19 come up with the mean, if you will, that denotes the 20 solid bar but then within that population there is 21 obviously going to be a spread of reactions or 22 background, etc., so it's kind of a way to denote a 23 fuzzy top to that bar. That is just my perception and 24 the fact that others may suggest that we should just 25 simply take them out. 123 1 David, would you like to comment on the 2 error bars? 3 DR. STRAUSS: No, but do you remember in 4 the original draft cover document we spent a little 5 bit of time talking about how this determination 6 really represents an estimate and we use the word 7 estimate still in the cover document here, in the 8 overview document. It was really meant to describe 9 really that this is not a -- although the picture may 10 suggest otherwise, it is not really a quantitative 11 determination. It is really a concept over notion 12 and, therefore, fuzzy and inexact. 13 MR. NELSON: So having said that, to even 14 part of the audience that looks at these denotes a 15 level of mathematical accuracy that in fact isn't 16 true, then we should find a different way to portray 17 it which I think is where your question is leading us. 18 DR. BOTKIN: Or perhaps just -- I don't 19 think I saw a legend that sort of explained exactly 20 that concept. I think as it is is probably fine as 21 long as maybe there is a little explanation why they 22 are drawn the way they are. 23 I don't want to belabor the pictures too 24 much but I think the other aspect of the picture that 25 I will just comment on briefly is having the minimal 124 1 risk threshold as a band as opposed to having it 2 colored below the threshold level because everything 3 down there is minimal risk. It's when you get above 4 that level that you are extending beyond minimal risk. 5 The band issue, particularly with a fuzzy 6 area on the bottom, suggest that there is something 7 that is minimal risk and then there are things that 8 are below minimal risk but that concept doesn't really 9 flow so it's really all that area that is minimal risk 10 and it fades into above minimal risk. 11 MR. NELSON: Again, your point is well 12 taken. Not to make any excuses but we basically just 13 lifted what had last been drafted last September and 14 reproduced them but I do remember that point being 15 made as well. It's correct there's not a top and a 16 bottom boundary to the minimal risk. It goes all the 17 way down, if you will, and we should just portray it 18 that way. 19 DR. STRAUSS: I want to just comment on 20 the legend again that the bar represents the upper 21 threshold. You are right, it shouldn't be fuzzy on 22 the bottom but there is a limit to my word processing 23 skills. 24 MR. NELSON: We can probably find a way to 25 shade anything under that as encompassed within 125 1 minimal risk. 2 DR. GYI: So just to add to the discussion 3 on the whiskers on the top, it seems as if there 4 should be whiskers on the bottom, too, if you are 5 going to keep the whiskers. There is uncertainty on 6 both sides. 7 DR. TILDEN: Excuse me, gentlemen. I 8 believe we had this discussion before and I believe 9 that we agreed as a committee previously that the 10 little error bars, or whiskers I think is the way you 11 are referring to them, right? Yes, that's the 12 whiskers. 13 Those should be removed so I suspect -- I 14 would just say that we would send this document on and 15 maybe we could have an amendment that the document go 16 forward and that we would like to see that the error 17 bars -- I don't want whiskers to be in the minutes -- 18 error bars be removed and that the minimal risk -- the 19 designation of the minimal risk threshold be a solid 20 box drawn from the horizontal access up to the top of 21 the fuzzy bar if we can agree that would meet the 22 needs. 23 I think what I hear the subcommittee 24 saying is, hey, we are going to send this on and we 25 have this text, etc., and the figures will be sent on 126 1 with this notation of what we intended the figures to 2 look like. 3 This was just lifted from the previous 4 presentation but I think we had agreed on this before. 5 If someone would accept an amendment to this effect 6 and move and we'll second it, amend it, and then we'll 7 vote on the whole piece if that is acceptable to the 8 committee. 9 DR. TILDEN: You want to move for that, 10 Dan? 11 MR. NELSON: I don't know if I get to. 12 James? 13 DR. POWELL: One more question. 14 DR. TILDEN: You want to get one more 15 discussion item in? 16 DR. POWELL: Hopefully it's simple. I 17 wonder if the committee discussed the issue of case 18 No. 2 that talked about the cocaine-dependent subject. 19 We talked about having information and putting into 20 place confidentiality measures to reduce the risk to 21 minimal risk. My question was whether the committee 22 discussed the cocaine-dependent versus the healthy 23 subject would be subject to the same kind of risk 24 associated with potential breach and I don't think 25 they would be. The question is, was that discussed? 127 1 MR. NELSON: I understand your question 2 and I think I agree that somebody without a substance 3 abuse problem there would be less risk obviously. I 4 think the confidentiality measures that would be put 5 in place would be put in at a study level. In other 6 words, it would apply to any participant in the study 7 rather than segregating out populations and protecting 8 some more than others. I'm agreeing with your 9 observation but I'm not clear on the follow-up to that 10 or the outcome. 11 DR. POWELL: Well, my question was whether 12 or not that still represents minimal risk even though 13 you put confidentiality measures in place. 14 MR. NELSON: Now we're talking for the 15 subject population as a whole, both cocaine-dependent 16 and healthy. 17 DR. STRAUSS: You might argue that the 18 study would be minimal risk if it only included the 19 healthy subjects to begin with. The question of the 20 level of risk is introduced because of the special 21 risk associated with breach of confidentiality related 22 to the recruitment and inclusion of people who are 23 engaged in illegal activities. By incorporating 24 special protections, the overall study becomes a 25 minimal risk study because you are now protecting the 128 1 cocaine users from the risk associated with breach. 2 I don't know if that answers your question 3 but that's how I would -- remember there was another 4 point in this discussion in which we talked about the 5 study as a whole. The risk level of the study as a 6 whole is only as low as the highest risk for any 7 particular population. 8 DR. TILDEN: I believe that it addresses 9 it, myself, adequately in the sense that to approve 10 the study you would have to make sure the 11 subpopulation at risk had -- that the risk of a 12 subpopulation was minimal or else they wouldn't be 13 able to approve the study at all because the study has 14 no interest if you are just testing individuals who 15 don't have cocaine dependence. 16 The key is to have a comparison group. If 17 you didn't protect -- if you are able to protect the 18 responses of the group that was at this level of risk 19 to the extent that it was minimal, then the whole 20 study could be approved. 21 DR. STRAUSS: At the risk of an error, I 22 think No. 3 in case No. 2 has a typo in it. I think 23 it's meant to say the fact that risk of legal 24 liability is part of the daily life of substance 25 abusers is not relevant in the analysis of minimal 129 1 risk. 2 DR. TILDEN: Oh, okay. Right. So we want 3 to amend it to say that. Page 3, case No. 2, item No. 4 3. You are making a motion that we amend it and I 5 second that. Everyone agree? No nays? Okay. 6 DR. POWE: There's another typo in figure 7 12 legend. 8 DR. TILDEN: I missed that, Neil. 9 MR. NELSON: Second line of figure 12, 10 there's an extra "this" which will be deleted. 11 DR. POWE: I was curious as to why you 12 didn't have figures for three of the cases, that you 13 didn't follow through with figures for those. Was 14 there a reason for that? 15 MR. NELSON: Facetiously, I might say we 16 couldn't figure out how to draw them correctly. No, 17 I'm sure that's not a good reason. I don't actually 18 remember. If I remember, as this evolved literally 19 over a period of months and months, up toward a year, 20 I think we thought the figures were helpful in 21 understanding some concepts but once that was 22 understood, then it didn't need to be repeated and 23 repeated for each case. Of course, that begs the 24 question if this document isn't used as an index with 25 all seven cases, if they each stand alone in other 130 1 words -- 2 DR. POWE: That's what I was thinking. 3 Someone might insert one of these for a particular 4 reason and then that figure would be lost if you 5 wanted that concept to be there. 6 MR. NELSON: David, I don't know if you 7 have any historical perspectives better than the one 8 I just gave. 9 DR. STRAUSS: No. The illustrations were 10 originally meant to help people work with the concepts 11 and the cases were developed subsequently. I thought 12 I understood, Dan, that you were saying before that 13 what we are trying to deliver ultimately to OHRP is 14 the idea. I have never seen OHRP guidance with color- 15 coded pictures so I'm skeptical that we'll get them 16 now. I just want to be clear because I don't know how 17 much we need to worry about this is, I guess, one of 18 the things I'm raising. 19 MR. NELSON: That's my understanding as 20 well and why I made those prefatory remarks. We would 21 be pleased if OHRP uses these as is but I don't think 22 we are under any misconception that they necessarily 23 will, or use them all exactly as written. I think we 24 are trying to pass along as requested the concepts and 25 certainly endorse the notion that illustrative 131 1 examples, whatever they are, will be helpful for this 2 guidance. 3 In the same way I might add that the 4 preceding text that we've already approved, the 5 bulleted list, we don't consider that the final 6 guidance. OHRP has been at the table during this 7 whole discussion and has assured us that they have a 8 very firm grasp on what we are trying to say with this 9 I think enough to take these and turn it into OHRP- 10 type guidance if you will. We are certainly 11 comfortable and confident in that. 12 The same would apply to these cases. The 13 idea behind them is probably as important as the 14 single words or the colors of the pictures. However, 15 I don't want to speak for OHRP, I should also say how 16 they are going to use these once received. 17 DR. TILDEN: Any other comments or 18 questions? Let's have a vote on the amendment 19 regarding the little whisker bars and the minimal 20 risk. We need a motion to amend the figures. Anyone 21 vote no? Everyone for? Okay. The amendment is 22 passed. 23 Now we need to take a vote on the case 24 examples as an appendix to be sent to the Secretary. 25 Do we have a motion to accept the case examples and 132 1 send them on? We need a vote. I'm sorry. Vote yes? 2 It's unanimous. That takes care of that piece of 3 business. 4 MR. NELSON: Thank you. We now move on to 5 what represents, I think, our major recommendations to 6 come out today, at least, and that is in the area of 7 waiver of informed consent. Here again, although you 8 have all the slides in front of you, this really 9 follows very closely along with the written text that 10 you have under Tab 5 now, a five- or six-page typed 11 document. 12 Just by way of background, we always ask 13 ourselves as we dive into these topics what is the 14 issue here. What is the problem and what are we 15 trying to fix. By way of background, which I'm sure 16 is familiar to all of you, obviously obtaining the 17 informed consent of research subjects prior to their 18 participation is traditionally regarded as a 19 cornerstone for the ethical conduct of research and a 20 fundamental protection for participants rights. 21 HHS regulations outline general 22 requirements for informed consent at Section 46.116, 23 one of which Mike Genel just referred to, that include 24 eight basic and six additional elements to be 25 addressed when obtaining informed consent. 133 1 We haven't itemized them here because the 2 issue, at least for today, is not what those elements 3 require. That may be a topic for future discussion 4 but the topic today is the waiver of those elements 5 either in part or in whole. 6 At the same time it is recognized that 7 there is valuable research that would be difficult or 8 at times impossible to conduct if consent were 9 required and that subjects can still be adequately 10 protected in the absence of full consent. 11 Accordingly, the regulations also allow for waiver 12 alteration of some or all of the elements as noted in 13 46.116(d). 14 The waiver allows the interests of 15 subjects to be balanced with societal interests in 16 research and both will be well served, we feel, if 17 this regulatory provision is understood and applied 18 appropriately. 19 However, in practice IRBs may 20 inappropriately utilize the waiver provision for one 21 of several reasons and we have tried to identify some 22 of them here. I should note that this background is 23 for our -- well, it's for background and we don't 24 perceive these to be necessarily relayed along for 25 OHRP because this is just context. 134 1 The reasons include uncertainty in 2 applying the criteria. In other words, whether or not 3 to grant the waiver; inconsistency in reviewing the 4 research including consideration of the waiver of 5 informed consent owing to variability across IRBs and 6 institutions conducting research. This is especially 7 evident when the favor provisions are applied and 8 research conducted at multiple sites. 9 The uncertainty and variability may lead 10 to under utilization of the waiver when it may be 11 warranted. Conversely, lack of understanding on how 12 or when to apply may lead to inappropriate application 13 of the waiver or over application, if you will, under 14 other circumstances. 15 This slide and this section in the printed 16 document recapitulates the text directly out of the 17 regulations. An IRB may approve a consent procedure 18 which does not include or which alters some or all of 19 the elements of informed consent set forth in this 20 section or waive the requirements to obtain informed 21 consent provided the IRB finds and documents that. 22 Here there are four criteria each of which must be 23 satisfied for an IRB to grant a waiver. 24 The research involves no more than minimal 25 risk to the subjects. The waiver or alteration will 135 1 not adversely affect the rights and welfare of the 2 subjects. The research cannot practically be carried 3 out without the waiver or alteration. And, whenever 4 appropriate, the subjects will be provided with 5 additional pertinent information after our 6 participation. 7 Two notes. The recommendations that will 8 soon follow will deal with these on a point-by-point 9 basis, these four criteria. Also a reminder that we 10 are not talking here about the waiver of consent for 11 emergency research under FDA regulations and also as 12 referenced by OHRP regulations through the Federal 13 Register. That is a very specific set of additional 14 protections that are built in for a very specific 15 circumstance and that is not what we are talking about 16 here. 17 We mention it because we have learned that 18 there may be some confusion out in the field when we 19 are talking about waiver of consent under 116(d). 20 People may have this more complicated process in mind 21 for these special circumstances. 22 We look for guidance on interpretation of 23 the provisions under 116(d). The only guidance we've 24 been able to find is referenced in the 1993 guidebook, 25 IRB guidebook, on the pages as noted. It deals with 136 1 several sections, or has several paragraphs rather. 2 I think they are worth reading through 3 because we have the time and because they provide the 4 background thinking at least up to that point in time 5 and they do represent the only existing guidance that 6 is out there right now. 7 "Federal regulations and informed consent 8 specify the information that must be disclosed to 9 perspective subjects. The regulations do permit 10 modifications in the consent procedure and under 11 certain circumstances informed consent may be waived 12 entirely if the research meets certain conditions and 13 note that such modifications and waivers are not 14 allowed under FDA regs." 15 It goes on to state that, "The IRB may 16 approve a waiver of some or all of the consent 17 requirements provided that..." Then it restates the 18 four criteria that I just read through directly from 19 116(d). 20 "Most commentators suggest that the IRB 21 also determine whether the knowledge being sought is 22 important enough to justify whatever invasion of 23 privacy may be required either to obtain information 24 about unconsenting or unaware subjects or to involve 25 them in research under false pretenses. 137 1 "Under the federal policy, but not FDA 2 regulations, if the research is designed to evaluate 3 or demonstrate possible changes in or alternatives to 4 provision of benefits or services provided for under 5 federal, state, or local programs, an IRB may approve 6 alteration or waiver of the consent requirements." 7 This is 116(c), something we really haven't dealt with 8 under 116(d) and the recommendations of (c) today. 9 "If the research cannot practically be 10 carried out without the waiver alteration and the 11 consent requirements, the IRB may approve such a 12 waiver. Both the national commission, the first 13 presidential commission, and the subsequent 14 President's commission for the study of ethical 15 problems in medicine, biomedical, and behavioral 16 research recommended that such waivers be granted only 17 if subjects will not be denied benefits or services to 18 which they are otherwise legally entitled." 19 The final paragraph of existing guidance 20 deals with the topic of record reviews. "Sometimes, 21 especially in epidemiological studies, scientists need 22 to review thousands of records to identify appropriate 23 subjects for their study. Parenthetically, consent is 24 not an issue for record reviews of deceased 25 individuals because federal regulations apply only to 138 1 research involving living human subjects." 2 I note that HIPAA has changed that at 3 least in terms of -- not the Federal Policy for Human 4 Subjects Protections but in terms of things that 5 investigators and IRBs need to deal with. 6 "It is often difficult, if not impossible, 7 to obtain the permission of everyone whose records are 8 contained in the files. For this preliminary part of 9 the research IRBs will generally waive the consent 10 requirement if they are satisfied that the information 11 contained in the files is not particularly sensitive. 12 The investigator has devised procedures to protect the 13 confidentiality of the information to be collected. 14 Thirdly, the study could not practically 15 be carried out if consent were required. Some 16 university hospitals notify all incoming patients that 17 their records may be reviewed for research purposes. 18 Other provide an opportunity to consent or refuse to 19 consent to such use." 20 Why don't we -- I was just going to 21 observe that this tends to focus in some of the 22 existing guidance on an epidemiologic approach as a 23 precursor, if you will, to studies, a preliminary 24 review that might go on to identify and contact 25 subjects more directly. Of course, many studies that 139 1 we see don't go on to that next step. The study is 2 conducted entirely under the waiver. 3 Why don't we stop at this point and we'll 4 now go on to our specific recommendations and see if 5 there are any questions just with the background 6 context for discussing the waiver. David. 7 DR. STRAUSS: I have a question about the 8 so-called intent of the framers. I'm wondering if you 9 could comment on whether there was any other 10 background information that might explain what was the 11 intent of using a phrase like, "Not adversely affect 12 the rights and welfare of subjects," as opposed to, 13 for example, "Not conflict with -- anyway, let me 14 stick with the first part of that. Is there any 15 documentation about what the intent was? Maybe 16 somebody in the room knows. 17 MR. NELSON: Since I was only five years 18 old in 1979 -- no, that's not quite true but I can't 19 speak to the intent of the framers. I wonder if -- I 20 hesitate to pull anybody out of the audience but would 21 be happy if there was somebody with a historical 22 perspective on what the framers had in mind. 23 I think you've seen, David, some just 24 referenced here in this guidance, in fact. Both of 25 the first two presidential level commissions did 140 1 address waivers and, of course, the first presidential 2 commission produced the Belmont report and the 3 existing regulations sprung or evolved from the 4 Belmont report. Beyond that, Gary, would you care to 5 take a stab at that? 6 Gary Chadwick, a member of our 7 subcommittee. 8 DR. CHADWICK: I don't see any green 9 light. There it is. As was explained to me when I 10 used to work at OPRR by Charlie McCarthy, the framers 11 were trying to say in that sentence that people would 12 not be tricked into participating in research that 13 upon finding they had been a participant would feel 14 violated and that's what that was aimed at but they 15 couldn't figure out a better way to say it so it's not 16 tricked into research. Basically waiving consent is 17 a violation of your rights but they couldn't figure 18 out a way to put that in better words and that's what 19 we got. It's the running around in a chicken suit 20 sort of. 21 DR. STRAUSS: But it's sort of a tricky 22 standard in a sense to say that it means that if 23 people were to find out about the waiver they wouldn't 24 object. 25 DR. CHADWICK: Correct. Correct. This is 141 1 the only place in the whole regulation that it's 2 cloudy. 3 MR. NELSON: It raises an interesting 4 point David because we will come to a point in our 5 recommendations here where that becomes an issue if 6 the reasonable person found out that research had been 7 conducted without their awareness. 8 DR. TILDEN: Excuse me. I think Joan had 9 something -- 10 MR. NELSON: We are going to go to Joan 11 right now, in fact. 12 MS. PORTER: I think Gary's recollection 13 is correct. That's the story I always heard in OPRR 14 as well. The commission was concerned about deception 15 research and the circumstances under which that kind 16 of research could be carried out. As we all know, the 17 waiver has been used for many other types of research, 18 retrospective record review and very large studies 19 where practicability is pointed out. The wording 20 practicability has always been a challenge for us. 21 MR. NELSON: Any other comments on the 22 historical backdrop for this? Just to repeat what's 23 already been said, certainly some aspects, in 24 particular one of those four criteria really seems 25 most aimed at so-called deception research and it 142 1 tends to be set aside merely when we're talking about, 2 for instance, retrospective records reviews where the 3 waiver is often used these days. 4 Any other questions on this part? We'll 5 proceed on to the actual recommendations. Again, I 6 apologize for the text dense slides but we wanted to 7 stay true to what you have in writing right in front 8 of you because this is what we are asking for your 9 approval. 10 So recommendation No. 1 in this area. 11 OHRP should develop guidance on the implementation of 12 the provisions under HHS regulations at 45 CFR 13 46.116(d) for IRB approval of a waiver or alteration 14 of informed consent requirements. The guidance should 15 emphasize the following general points. 16 This part of the regulations is intended 17 to allow IRBs to waive informed consent in its 18 entirety or any of the required elements of informed 19 consent. IRBs should use this provision for 20 considering a waiver of any or all of the elements of 21 informed consent found elsewhere in these same 22 regulations. 23 It is important to remember that IRBs must 24 document that a waiver is being applied and how the 25 criteria for a waiver are being met. FDA does not 143 1 have the same criteria for waiver of informed consent 2 to correspond to Subpart A. Therefore, if research is 3 subject to FDA jurisdiction, these provisions do not 4 apply. We would recommend that the guidance 5 incorporate the next five recommendations to follow. 6 I think, Sam, these go on long enough that 7 our past experience suggest we might be well served to 8 stop and deal with each of these individually as we go 9 through. 10 DR. TILDEN: So is there a motion to 11 approve recommendation No. 1? 12 DR. GENEL: So moved. 13 DR. TILDEN: Second. We have a second on 14 the floor? Okay. Now let's open it for discussion. 15 I wonder is it a given that it's not only one would 16 waive consent or alter or waive any element of consent 17 but that consent might be -- in other words, the 18 requirement to obtain consent may occur after the 19 research has begun. 20 When you talk about a lot of 21 epidemiological studies, outcomes research, one would 22 go to a database, get information so that they can 23 contact individuals to do a research study at which 24 time consent is obtained from the individuals to 25 participate in research, i.e., the osteoporosis study. 144 1 They had to have a waiver of all of these elements 2 temporally for some piece of the research but, indeed, 3 that is implied in this as well that there might be a 4 waiver for a certain period of time but then consent 5 would be obtained. Is that fair to interpret it this 6 way? 7 MR. NELSON: I think it would be fair to - 8 - 9 DR. TILDEN: Or does it need to be spelled 10 out? 11 MR. NELSON: It's a good question. I 12 personally think it would be fair to say that not all 13 IRBs would view the identification of potential 14 subjects who will subsequently be approached for their 15 consent to require being addressed under the waiver. 16 HIPAA has added in the partial waiver of 17 HIPAA authorization in order to identify a potential 18 subject enrolled with full consent or not if they 19 don't give their consent but they have the opportunity 20 to HIPAA at that point. 21 I don't know that it would be fair to say 22 that it's universally practiced that IRBs would 23 invariably grant a waiver to identify subjects who 24 will then be approached, for example, to participate 25 in a clinical trial, let's say, or to be presented 145 1 with an opportunity for active consent. I would be 2 happy to hear others. 3 DR. GYI: Sam, just a point of 4 clarification. Are you suggesting a scenario where 5 the database is reviewed in preparation for research 6 and that subjects are then approached after the review 7 process has taken place to ask permission to review 8 the database? I mean, that part doesn't fit for me. 9 DR. TILDEN: To include those individuals 10 in a research project including the data in the 11 database but it may be more. It may be a survey or 12 additional input besides the information that was in 13 the database because if you're looking at outcomes, 14 you may get information but you may want to look at 15 those individuals and get information from five years 16 previously and you want to look at where they are now 17 or what the outcomes are. 18 DR. POWE: Maybe I can give an example. 19 I know of one such study at my institution. Actually, 20 it's a multi-center study. It's the study of chronic 21 kidney disease. Individuals are identified who have 22 mild degrees of kidney dysfunction through laboratory 23 testing. Ordinarily those individuals might not even 24 know that they have mild abnormalities of kidney 25 function. Their doctors may not have told them but 146 1 the intent of the study is to study the epidemiology 2 of progression of kidney disease. 3 Research to identify subjects would go to 4 a hospital database, laboratory database, and obtain 5 and look at the laboratory samples to identify 6 individuals who had renal dysfunction within certain 7 categories and then approach certain individuals to 8 actually enroll in the study and then get consent. 9 That's an example. There are actually 10 many studies like this where even if you try to enroll 11 from the general population as people would not even 12 know that they had dysfunction or fall into that 13 category. 14 DR. STRAUSS: I think this for me raises 15 some questions that require some clarification - so 16 the distinction between access to information and use 17 of that information for research purposes. It's 18 interesting because in the guidance that you cite 19 there's a reference to invasion of privacy and that 20 the IRB needs to consider when sort of the invasion of 21 privacy is warranted by the importance of the 22 research. 23 But invasion of privacy occurs when the 24 researcher without the knowledge of the subject, let's 25 say, is looking at information that the subject 147 1 thought was private or for which there was a 2 reasonable expectation of privacy. And then whether 3 the researcher uses that data for research purposes is 4 really the circumstance by which we ordinarily conduct 5 IRB review and apply for or consider a waiver but it 6 could be argued that it's the actual looking at the 7 data, the access to the data that itself requires some 8 consideration. 9 Obviously many hospitals and institutions 10 have HIPAA rules but I'm not suggesting that -- well, 11 I'm not suggesting that we solve that problem as much 12 as I wonder if that concern or that distinction be 13 part of what you consider -- in other words that you 14 might define in broader terms where the waiver comes 15 into the picture. 16 MR. NELSON: Mike, I think -- are we going 17 to jump in? Just to respond to really the last points 18 of discussion, you'll see as we go through we have 19 attempted here to embed examples to illustrate certain 20 points and it may be that additional examples like the 21 one just brought up are relevant to insert. 22 Mike, go ahead. 23 DR. GENEL: Well, I can't resist. I mean, 24 I don't think we can go there until we harmonize HIPAA 25 with the common rule. 148 1 DR. TILDEN: I'm not going to pick up on 2 that. I just think like in bullet one that the IRB 3 should use this provision for considering a waiver of 4 any or all of the elements of informed consent. I 5 think that's fine. 6 I just wanted to make sure that -- I don't 7 know what OHRP's current thinking on this is but I 8 think I remember reading something that they actually 9 came out with a guidance saying that activities 10 preparatory to research there was an expectation in 11 some situations where IRBs would look at this and 12 grant a waiver -- ordinarily grant a waiver if it met 13 certain requirements. Does that resonate with anybody 14 in the audience what OHRP said about that? Mike? 15 DR. CAROMD: That is correct. 16 Investigators conducting research access medical 17 records in order to identify subjects for a subsequent 18 clinical trial, that activity involves some 19 investigators obtaining identifiable private 20 information so that makes the individuals whose 21 records are being reviewed human subjects of that 22 initial part of the research and that requires either 23 informed consent, which usually isn't practical -- 24 DR. TILDEN: It's hard to get when you 25 don't know who it is. 149 1 DR. CAROMD: Right. You're stuck in a 2 loop there. We helped draft frequently asked 3 questions in a guidance document on HIPAA that 4 addresses this in the context of the preparatory to 5 research discussion that is relevant to HIPAA and we 6 noted that IRBs would have to approve a waiver of the 7 informed consent requirements in order to do that 8 accessing of the medical records. 9 DR. TILDEN: Thank you. Well, it seems to 10 me I don't know whether -- my point was that this 11 should include those types of activities as long as 12 from my perspective that should include this type of 13 activity in terms of the guidance. It's in a FAQ but 14 if additional guidance has come out because it sounds 15 like it's an area that individuals don't understand. 16 In fact, I think I had to write a letter to Kristina 17 Borror about somebody who didn't understand that or 18 something. 19 DR. STRAUSS: Sam, I think the idea that 20 maybe the recommendation in some form would also 21 suggest the development of examples of the 22 applicability of the waiver as well in that section. 23 Not that the committee has to develop the examples but 24 to suggest that would be a good form for the guidance. 25 DR. TILDEN: Any other discussion? We'll 150 1 have a vote. All in favor? The motion passes 2 unanimously. Recommendation No. 2. 3 MR. NELSON: Now we start to work through 4 those four criteria that we already laid out. 5 "Regarding the first criterion under HHS regulations 6 for IRB approval of a waiver or alteration of informed 7 consent requirements, IRBs should interpret minimal 8 risk in accordance with SACHRP's recommendations 9 regarding the definition of minimal risk as approved 10 March 29, 2007." I'll remind you what we're talking 11 about here is the analytical framework that we just 12 re-reviewed on the way to discussing cases. 13 We simply cross-referenced that work 14 already done rather than restating it all but to the 15 extent we will now with OHRP's help be able to 16 hopefully lend some more clarity to the interpretation 17 and application of minimal risk. Any regulatory 18 section like this one that deals with minimal risk 19 ought to rely on that. 20 DR. TILDEN: So would anyone like to move 21 that we consider recommendation No. 2? Okay, moved. 22 Seconded? Seconded. Okay. It's open for discussion. 23 Is this sort of a test case to see how much discussion 24 you can get from SACHRP on something that is already 25 approved? Does anybody have any discussion about this 151 1 in terms of interpreting minimal risk in accordance to 2 SACHRP's previous recommendations? Okay. So being no 3 discussion, should we vote? All those in favor? Not 4 in favor? Abstain? Okay. Dr. Genel abstains. 5 Okay. No. 3. 6 MR. NELSON: In seriousness actually, Sam, 7 to respond, the reason, of course, we've itemized each 8 of these, even this one, is merely cross-referencing 9 the past work that we feel obligated and would like 10 OHRP clearly in whatever guidance comes out of this 11 ultimately to deal with each of the existing criteria 12 in a step-wise manner. We certainly didn't want to go 13 off in a different direction in interpreting minimal 14 risk in the context of waiver than we already have. 15 Okay. Recommendation 3 is longer and, 16 therefore, straddles the next few slides. "Regarding 17 the criterion under HHS regs, this is the second 18 criterion for IRB approval of a waiver or alteration 19 of informed consent requirements. In order to 20 determine whether a waiver of informed consent would 21 adversely affect the rights and welfare of subjects, 22 IRBs should consider the following points. 23 First, whether there are other federal, 24 state, or local laws that provide rights to potential 25 subjects to require informed consent. IRBs should 152 1 seek advice from their legal counsel when appropriate 2 to help the IRB with these determinations. This would 3 be especially important for state specific 4 regulations. 5 This is meant to address the fact that 6 there may well be state statutes in certain 7 jurisdictions, at least that impact on this and IRBs 8 choosing to apply the waiver can't ignore those. We 9 know this is an area of confusion. Even amongst our 10 subcommittee there were some members that were unaware 11 that this might have an impact and we know in the 12 general population out there there's similar 13 confusion. 14 Secondly, whether the subject population 15 in general would consider that their rights were 16 violated if they knew of the waiver or that the waiver 17 has the potential to cause adverse consequences for 18 their welfare or general well being." 19 This gets back to the point raised 20 earlier. Again, I'm probably on thin ice using a 21 legal reference but I call this the reasonable person 22 standard. We are, in fact, approving research to be 23 done using a person's data generally or perhaps 24 specimens without their knowledge or consent. If they 25 found out about that after the fact, for example, 153 1 would they consider that their rights have been 2 violated. 3 This is obviously difficult to get at but 4 we thought that should be part of the guidance. Given 5 that this recommendation all ties together, let me 6 finish the next one or two slides and then we'll tie 7 it together. 8 So we provided two examples of scenarios 9 where a waiver of consent would adversely affect the 10 rights of subjects as just itemized in those points. 11 The first, and we are grateful to Ivor Pritchard for 12 helping us craft this example, deals with FERPA, 13 Family Educational Rights and Privacy Act. It's a 14 federal law that protects the privacy of personally 15 identifiable information contained within a student's 16 educational record. FERPA applies to all educational 17 agencies or institutions, K through 12 and post 18 secondary that receive funds under various programs 19 from U.S. Department of Education. 20 Generally educational agencies and 21 institutions must have written permission from the 22 student or parent, if the student is a minor, in order 23 to release any personally identifiable information 24 from a student's education record unless it meets one 25 of a list of specified conditions for which release is 154 1 allowed. For example, studies to improve instruction 2 conducted by organizations for or on behalf of the 3 educational agency or institution. 4 Other than under such a condition if an 5 investigator from a local university's college of 6 education requests a waiver of consent to review the 7 educational record, for example, grades and GPA of 8 students at the university for the past 20 years and 9 maintain identifiers for this research project, the 10 rights granted to students under FERPA would be 11 violated and the criteria for waiver of informed 12 consent at 116(d)(2) could not be met. 13 This was meant to address circumstances 14 where there are other -- apart from the 45 CFR 46 for 15 protection of human subjects there may be other either 16 federal or state laws that would intervene. 17 Second example is much shorter, example of 18 a scenario where a waiver of consent would adversely 19 affect the rights of subjects. In some cultures the 20 placenta has special meaning and significance so that 21 waiving consent to use placental samples for research 22 might be interpreted by that community as adversely 23 affecting their rights and welfare. 24 These two were our attempt to identify 25 without being exhaustive by any means of times when 155 1 either at a legal level or at a reasonable person 2 standard, if you will, that second item rights and 3 welfare might be violated. These are the kinds of 4 things that have often caused some confusion around 5 certainty in IRBs and applying the waiver. With that 6 Recommendation No. 3 is on the table for your 7 discussion. 8 DR. STRAUSS: I have a case example for 9 discussion. A subject who is homeless and has no next 10 of kin or lives in a state where there is no such 11 thing as an LAR is in an intensive care unit and the 12 research involves a blood test. The research is 13 minimal risk. The research could not be practicably 14 carried out in this population. 15 Let's just say 50 percent of the subjects 16 are also homeless and without available next of kin. 17 Does doing a blood test on an unconscious or comatose 18 patient in an intensive care unit constitute a 19 violation of their right to not be touched, bodily 20 integrity, without their permission or without the 21 permission of an LAR? Can you apply these rules to 22 people who can't consent? 23 MR. NELSON: To borrow from your field of 24 psychiatry, how does that make you feel, David? 25 DR. STRAUSS: First of all, if we're 156 1 talking about drawing blood for research purposes 2 only, I would think we'd be failing the first 3 criterion of more than minimal risk potentially. Now 4 I'm really just speaking off the cuff but I think most 5 IRBs would consider that off limits for a waiver of 6 consent. 7 If they are in the hospital anyway and 8 having blood drawn, I don't think we would probably be 9 but that is just one institution's quick response open 10 to a waiver of consent for those circumstances. I 11 think it's a good example because I can see others 12 coming to a different conclusion. I don't have a 13 straight answer to that. 14 MR. NELSON: Forget the blood test. Let's 15 say a cheek swab for something. 16 DR. SHORE: I was just going to comment 17 that an issue that might interfere with that prospect 18 would be the distributive justice issue. Why would 19 you select people who are unconscious in a hospital 20 bed if you could get blood from somebody who was less 21 impaired? That's a side issue. 22 MR. NELSON: It's an important point and 23 I think, if memory serves, we'll come to that point 24 later that we should never be considering a waiver 25 just for convenience, for example, and that would fall 157 1 under that. That argument would play there, I think. 2 I would hope that the IRB looking at these four 3 criteria in the aggregate and all the circumstances of 4 the study in the aggregate would be asking itself why 5 are you picking on these people as opposed to people 6 who are walking in the door on their own two feet and 7 could ask for swabs from them. It's an interesting 8 example. 9 Others? Jeff. 10 DR. BOTKIN: This is a good discussion 11 because I've never understood this criterion and so I 12 might be getting a little closer. I think the history 13 actually is helpful here because I think whenever you 14 use rights language you get yourself in trouble, 15 particularly ethical rights. 16 I think the example that speaks to legal 17 rights is pretty straight forward. I think the rights 18 language from my perspective is best considered there 19 because you get under a certain element of 20 circularity, as with David's example, for folks who 21 want to say, "My rights are to provide consent to be 22 involved in research." 23 We say, "No, that's not your right because 24 45 CFR 46 defines what your sort of legal rights are 25 but folks may feel that they have ethical rights to be 158 1 informed in all circumstances. How do you deal with 2 that concept of rights in that context? It seems to 3 me I'm more comfortable with the concept of rights as 4 a legal right as opposed to thinking of it as an 5 ethical right because who defines what those are? How 6 do you make a decision about what a sustainable right 7 is in that respect? 8 I think the second example is a pretty 9 good one but it still begs the question does that mean 10 that people in this community have a right to make 11 decisions about placentas? If they don't have some 12 community language that articulates that right, is it 13 really a right? 14 I'm really stuck with the rights language 15 here. It seems to me the second example might be 16 better addressed, say, through the minimal risk 17 criterion. If this is a highly sensitive issue from 18 the community's standpoint, then it may be more than 19 minimal risk to be doing the research. Not physical 20 risk but larger fear of burdensome interventions 21 rather than the rights language. 22 Again, I would like to go back to the 23 history which I think is helpful. There is something 24 here about sort of shocking the conscience which is 25 what we are trying to get to and if this is research 159 1 that for the community involved would be a violation 2 of their ethical norms or some such thing, that sort 3 of language makes more sense to me than rights 4 language which I think is confusing. 5 MR. NELSON: This is a good discussion and 6 these points are where different IRBs come to 7 different conclusions, of course, and why we think 8 guidance is indicated. Then crafting that guidance 9 becomes the challenge within our subcommittee over 10 the several meetings it took to craft these 11 recommendations. 12 You will appreciate, I think, why this 13 language didn't make it into the recommendations 14 you're looking at for all these reasons. We had 15 discussions about other than legal rights, so-called 16 natural rights. Rights we just have by virtue of 17 being human beings is some of what we're talking about 18 here, but then how to describe that and, as you said, 19 who gets to determine that right. 20 Well, I guess, at one level we each do 21 ourselves as humans. That, of course, is part and 22 parcel of this whole process because of the 23 regulations. Apparently we as a society have said we 24 are comfortable with the IRB serving as our surrogate. 25 We are substituting the judgment of the 160 1 IRB to say, "We're reasonable people and we, at least, 2 our comfortable that doing this research under a 3 waiver of consent is not violating our rights as we 4 perceive them," without going to ask each individual 5 whose records, for example, are being accessed. 6 All of these questions get begged and why 7 this is a good discussion to be having. I think we 8 have to -- I don't think we can entirely sidestep 9 using references for rights and welfare because that's 10 what's in the regulatory language. It's kind of back 11 to Mike and risk and discomforts are in there and we 12 have to deal with it. 13 Your points are very well taken, Jeff, and 14 if there is a suggestion on how to insert the right 15 kind of language and the guidance that helps us 16 interpret that regulatory language even though we are 17 stuck with rights and welfare. That is why, for 18 example, in the second example it's interesting 19 placing that under minimal risk, the placental 20 example. 21 I think we would have to -- I would be 22 interested in more discussion on that as to the right 23 placement. We had some discussion there, too, whether 24 that is a rights question or a welfare question. I 25 personally interpret welfare as more of a physical 161 1 well being sort of notion. 2 Really I think what we viewed this as was 3 a possible violation of rights as perceived by that 4 community. Not legal rights, not physical well being 5 but perceived rights as part of that culture based on 6 their beliefs. That's what makes this interesting and 7 hard. 8 DR. BOTKIN: In follow-up I guess I would 9 say I'm not sure how welfare differs from minimal risk 10 then. Is that redundant? If you are concerned about 11 protecting their welfare, isn't that the same as 12 making sure they're not exposed to risk that are 13 greater than minimal? 14 I guess sort of thinking through some 15 terminology it seems to me here I would like to see 16 this mean essentially legal rights and violations of 17 strongly held community values or something and leave 18 it to something that captures this second example 19 where there are groups of folks who clearly hold 20 particular beliefs that this would be -- that the 21 research would violate and make that different than 22 the right to inform consent per se which then gets 23 into a circularity for the argument. 24 DR. TILDEN: Mike. 25 DR. GENEL: Jeff, are you saying that you 162 1 would not even regard this as minimal risk requiring 2 consent? As I read this, the only reason the example 3 is used is saying that this would be an example where 4 you would not apply a waiver. Am I hearing you saying 5 this might be considered to be more than minimal risk? 6 DR. BOTKIN: Yes. I'm trying to figure 7 out -- I agree that the research in the second example 8 shouldn't go forward but I'm struggling with the 9 reason why and I'm not sure it's a rights and welfare 10 reason. I might categorize that under the minimal 11 risk one. 12 DR. GENEL: I would think that simple 13 prudence irrespective of -- 14 DR. BOTKIN: Would you -- sorry. Go 15 ahead. 16 DR. TILDEN: I have a question. Dan, is 17 your notion of welfare a generally accepted notion in 18 the IRB community that it relates to physical well 19 being? 20 MR. NELSON: Oh, I wouldn't presume to 21 speak for the rest of the IRB community. Probably I'm 22 sure -- 23 DR. TILDEN: Or widely held belief. 24 Cultural norm. 25 MR. NELSON: You know, if you look at the 163 1 second bullet on the screen right now, the welfare, 2 general well being, at least in my mind, those tend to 3 flow together but I would be very open to somebody 4 else saying that welfare is more of a general state of 5 mind, if you will, or a sense that could easily 6 encompass not having my perceived rights violated. 7 DR. TILDEN: I'm not trying to be a 8 stickler here. I notice in the example -- we had this 9 discussion before in terms of rights and how difficult 10 it is. I would agree with Jeff that positive rights, 11 rights that are created, usually through a legal 12 entity, although it could be tribal. 13 There are different types of -- there 14 could be positive rights in different ways, different 15 authorities. When you use the term rights and welfare 16 to interpret it from an IRB perspective or an 17 investigative perspective or participant perspective, 18 it's easier to use the concept of rights in that way 19 as a positive right. 20 But when you get to welfare, I think that 21 is a little bit more flexible. The second example, 22 although not having a formal definition of welfare, 23 that it weights just physical well being, you know, I 24 could see where this would fit under a prong of it's 25 not in the best welfare of the participants to have 164 1 this waived. 2 I noticed in the explanation it ends as 3 adversely affecting the rights and welfare, although 4 in the heading it just talks about adversely affect 5 the rights of subjects so it's a little bit ambiguous 6 there. 7 In addition to that, I wanted to point out 8 -- I don't know why I do this but I went back and read 9 all the letters before the meeting that we sent for 10 recommendations and I noticed that in the letter that 11 we sent in November 2006 to the Secretary, which I 12 think has been approved, the Part D Subcommittee sent 13 forward some recommendations related to this section, 14 116(d)(2), and very close to what's here. 15 But it seems to me that when we send this 16 forward, and it's related to the permission of the 17 LAR, guardian or parent, parent or guardian, it's in 18 our notebooks under Appendix A in that letter on page 19 10, November 2006, it points out the IRB should 20 consider federal, state, and local laws pertaining to 21 parental guardian permission alternative mechanisms to 22 protect the rights and welfare of children 23 participants and, when appropriate, when an 24 investigator has adequately considered the norms of 25 the community from which the subjects will be drawn. 165 1 I think we have that recommendation that 2 has already gone forward and so if we take this 3 recommendation and send it forward and just point out 4 that we would also like to -- that this recommendation 5 be considered along with previous recommendations 6 under this section for guardians and parents that it 7 may give enough information in terms of types of 8 examples and situations for the Department to consider 9 and the agency to craft something. I'm not sure we 10 know exactly what to craft. It's a difficult 11 situation. We may need more information to get it 12 right. 13 MR. NELSON: It's not entirely coincidence 14 that there may be some similarities with some of this 15 and what was previously approved with the Subpart D 16 Subcommittee given that the co-chair of that committee 17 was an active participant in these discussions. 18 DR. TILDEN: Correct. I was glad to see 19 that they all fit together actually just to point out 20 when it goes forward to connect the two so it doesn't 21 get lost. 22 MR. NELSON: Sam, on your observation on 23 the third bullet there, I guess, and I see where 24 you're talking about the examples of scenarios where 25 we just said rights, I think that is something of an 166 1 editorial artifact. In an earlier draft those two 2 examples were spread under two separate bullets, one 3 for rights and one for welfare. 4 We decided for some of the same reasons 5 that are already coming up that we couldn't partition 6 them and assign it to just one or the other so really 7 to the extent that the regulatory language instructs 8 us to satisfy that the rights and welfare would not be 9 adversely affected, probably we should just use that 10 language consistently throughout rights and welfare. 11 We had many of the same discussions. Are 12 we talking about rights or are we talking about 13 welfare? Maybe that's a difficult distinction to make 14 with any clarity, at least. 15 DR. TILDEN: David. 16 DR. STRAUSS: I think this is really 17 interesting stuff and I think that your approach in 18 recommendation No. 3 is really a very good one. I 19 think the language and concept of risk is quite 20 distinct from the language and concept of rights. I 21 think that the regulations in general stay away from 22 the notion of rights. 23 Even when we talk about, for example, 24 privacy the regulations and guidance tend to talk 25 about risk of harm related to breach of 167 1 confidentiality rather than the violation of rights 2 per se. This reference in the OHRP, the OPR 3 guidebook, to invasion of privacy I think is a rare 4 reference to that idea. I think the integrity of the 5 research enterprise rests to a large extent on people 6 knowing that access to their private medical 7 information is limited except for important purposes. 8 I think the standard that you have there 9 in a sense, I think it's tricky and I think it will be 10 difficult to apply but whether the subject population 11 would consider that their rights were violated if they 12 knew of the waiver, and I would add and its intent, or 13 that the waiver had the potential to cause adverse 14 consequences, I think that is an anchor point as we 15 could imagine. 16 I think that people do care about the 17 invasion of their privacy. I remember reading a study 18 recently published in a prominent medical journal in 19 which the researchers obtained a waiver of consent 20 from three major institutions to go back and examine 21 all the medical school records of former physicians, 22 graduates of those medical schools including, you 23 know, you name it, their test scores, their preceptor 24 evaluations, notes from their admissions interviews, 25 a range of information that I think any reasonable 168 1 person would believe was private. 2 The information wasn't published, in other 3 words, with any links to them. There was no harm that 4 could come to them personally except the idea that 5 information that they thought they were giving over 6 for a particular purpose to a particular individual 7 and be kept private was shared with people from 8 outside the institution, researchers and research 9 assistants, who they would argue had no access to that 10 private information about them. 11 I think we have to be careful not to get 12 too far away from this notion of a right to privacy or 13 a reasonable expectation of privacy and waivers which 14 might infringe upon that right. I think the way 15 you've done it may begin to address that. 16 I think the reasonable person would not 17 only think about whether their rights were violated 18 but whether they were violated for a good purpose. In 19 other words, they would do a risk benefit analysis, 20 too. I hope we can be careful not to allow -- not to 21 restrict too much our notion of rights and welfare 22 apart from that. 23 DR. TILDEN: Any other discussion? 24 MR. RODAMAR: Would like to pose a 25 question to whether it might be helpful to have an 169 1 additional bullet between the two final ones there 2 perhaps elsewhere. Coming from the context of survey 3 research where often you have large numbers of 4 nonrespondents. You have real issues of statistical 5 power, bias, etc. A lot of the issues that have been 6 dealt with in this document are finely tuned to that. 7 FERPA was mentioned on the slide that's up 8 at the moment. An amendment to FERPA is called PPRA, 9 Protection of People's Rights Amendment. PPRA says 10 that you can have what is sometimes called passive 11 consent or opted-out consent in studies dealing with 12 sensitive subjects. Sometimes there are good reasons 13 for that, for reasons of practicality as we've been 14 touching on. 15 There's a huge difference between having 16 no effort to contact parents and other appropriate 17 persons who obtain informed consent, and giving them 18 a good faith effort to know about the study and a good 19 faith effort to respond to it, versus simply wavering 20 and the requirement for informed consent moving beyond 21 wondering whether it might be appropriate to say where 22 it's appropriate. 23 There should be good faith efforts on the 24 part of researchers to let the study population know 25 about this study and the opportunity to participate in 170 1 it. Thank you. 2 DR. TILDEN: Jeffrey, does that go more to 3 the waiver or to the practicability of doing the 4 research or both? 5 MR. RODAMAR: I would think that goes to 6 both. 7 DR. TILDEN: I notice that the PPRA and 8 Family Education Rights and Privacy Act were both 9 cited in the Subpart D recommendations. 10 MR. RODAMAR: Yes. 11 DR. TILDEN: That would be appended as 12 well. 13 Jeff, did you have something? 14 DR. BOTKIN: I just want to go back and 15 say that I think the move that recommendation No. 3 16 makes is really the right or a creative way to think 17 about this because the regs themselves just say 18 "adversely affects the rights and the welfare." You 19 could easily make the argument that these folks aren't 20 going to know about this and so how could it possibly 21 impact their welfare. 22 If you then make the explicit move to say 23 the question is if they did know about it would they 24 be shocked or upset and that's the welfare we're 25 concerned about, the regs don't say that's the test 171 1 but I think that is an excellent test to pose in this 2 context. 3 Whether there is enough of a foundation 4 within the regs to make that move but I think it's a 5 very creative way and the right kind of question for 6 the IRB to ask about the waiver of a specific 7 recommendation and it's in the second bullet there. 8 I'm wondering whether we could say whether 9 the subject population in general would consider their 10 values were violated if they knew of the waiver. It 11 gets away from the rights language and gets to the 12 sense of we're shot. Our consciences are shot that 13 you would do such a thing. 14 DR. STRAUSS: Sense of privacy. 15 MR. NELSON: In deception research, for 16 example, which we really haven't gotten to yet because 17 that comes into play in criteria three and four we get 18 more into a study where there may be consent but they 19 haven't been told at all. Granted in many cases it is 20 a sense of privacy. 21 DR. TILDEN: I like that notion myself, 22 Jeff. We batted this around, this particular phrase. 23 Before it was different and we discussed it and then 24 changed it. I like the idea of their values, the 25 community values were violated. It doesn't 172 1 necessarily have to be a right in terms of a legal 2 right. It still may have some ethical dimensions. 3 Particularly it comes up as -- I'm sorry 4 Francine isn't here today but when you begin to report 5 non individual data but the report has certain 6 implications about cultures, it has certain 7 implications about high school students in the 8 intercity related to drug abuse or some other 9 sensitive area, that may have some broad 10 stigmatization or problems where it brings up this 11 question. 12 It's not necessarily that you don't have 13 a right to object. It's just that the consequences, 14 though, could be such that the individuals wouldn't 15 want to be associated with it in terms of broad 16 groups. I think there are some issues there with that 17 second bullet. It's not just a rights thing. It's a 18 little bit broader than that, so I would support the 19 notion. 20 MR. NELSON: Jeff, I had made a note from 21 your earlier comments that we are talking about legal 22 rights and/or a violation of strongly held community 23 values. I guess the hanging question was where to 24 work that in. I think it is into that second bullet 25 whether values as a single word on its own replaces 173 1 rights or not given that we're still stuck with rights 2 as regulatory language as a reference point. I guess 3 I'm still a little uncertain on that point. 4 DR. BOTKIN: Legal rights are covered with 5 the first bullet. 6 MR. NELSON: Right. Right. 7 DR. SHORE: This seems like a slippery 8 slope to me. I'm just concerned that if we don't 9 accept the IRB as in effect speaking for the potential 10 participants who are going to have their consent 11 waived, then you could rule out virtually any study 12 involving a consent waiver. Somebody might be upset. 13 If somebody might be upset is the reason 14 that you are not going to grant a waiver, then you are 15 not going to grant any waivers and part of the common 16 rule, of course, is the provision that you're not 17 supposed to use what might conceivably happen later on 18 to decide not to do a particular study. 19 Again, I thought the reason you had 20 community representatives on the IRB was to present 21 that kind of perspective. If there were going to be 22 a large number of Native Americans, then the issue of 23 tissue would be considered and that would rule out 24 certain kind of study. I'm just concerned that if you 25 kind of allow the idea that somebody might someday 174 1 object, then you wouldn't have consent waivers at all. 2 MR. NELSON: Some of the same thoughts 3 were going through my mind because we can always find 4 one person who might have a problem with it and I 5 don't think that's what we're after here for the 6 reasons you stated. 7 I think we thought with the second 8 example, the placental tissues, that was a viable 9 example that we could all agree to because it was 10 more, as Jeff phrased it, more of a strongly held 11 community value as opposed to one person having an 12 issue with privacy rights. 13 You are absolutely right and I don't think 14 we can forget that this whole thing hinges on the fact 15 that we are accepting that an IRB can look at a 16 scenario and speak for all the subjects who will not 17 be asked. If we can't accept that, then this whole 18 thing falls apart. 19 DR. TILDEN: Okay. Well, I think this 20 recommendation has been thoroughly discussed. Does 21 anyone want to propose any amendments before we take 22 a vote on the recommendation as presented by the 23 subcommittee? 24 MR. NELSON: So far the notes that I've 25 just made are in the second bullet that we would refer 175 1 to would consider that their rights were violated if 2 they knew of the waiver and its intent or to somehow 3 get to why are we doing this in the first place, that 4 there is research to be done or research being done 5 under the waiver. 6 Then we have Jeff's proposal to work 7 values into that second bullet as well. I think we 8 would be open to maybe -- maybe this is a slippery 9 slope to start editing on the fly but if the second 10 bullet read whether the subject population would 11 consider that strongly held community values had been 12 violated if they knew of the waiver and its intent, 13 would that get at your -- 14 DR. TILDEN: All right, say that again? 15 MR. NELSON: I'm writing it down. 16 "Whether the subject population -- we're on the second 17 bullet here, the bottom of this slide on page 12 in 18 your printed materials. Well, wait. I don't know -- 19 oh, sorry. We are going to strike the words "in 20 general." "Whether the subject population would 21 consider that strongly held community values had been 22 violated if they knew of the waiver and its intent." 23 I struck the words "in general." It 24 seemed to clutter up things but I'm happy to leave it 25 in. We haven't agonized over every word, believe it 176 1 or not, in each of these recommendations so if that 2 helps some people understand it, that's fine to leave 3 it. 4 DR. TILDEN: We have a motion to amend the 5 second bullet to read as presented by Dan. Do we have 6 a second and vote for the amendment? Second? Okay. 7 Let's vote. All in favor, aye. We can discuss it. 8 DR. STRAUSS: Strongly held community 9 values is a fairly -- can be a fairly narrow idea. 10 Does that include perceptions of a right to privacy or 11 are we talking about subpopulations or small 12 communities? I mean, I understand the example that 13 you gave. Community values seems a bit more narrow 14 than I think is helpful in this regard. I think 15 inserting values alongside of rights or community 16 values alongside of rights would make some sense as I 17 thought Dan was heading for originally. 18 MR. NELSON: The counter balance to this, 19 as just pointed out by David Shore, is that I think 20 most of us would agree that we should be talking about 21 more than the individual -- the perceived individual 22 rights one out of 1,000 subjects who might be 23 involved. How to phrase that, of course -- 24 DR. STRAUSS: I think the community values 25 has certain -- suggest a sort of rare or even 177 1 subcultural kind of set of values. 2 MR. NELSON: To some extent in the 3 placental examples there might be a population right 4 next door or in the same county who wouldn't have any 5 problems with their placental tissues being involved 6 in research. Widely held, broadly held, but whether 7 that addresses David Strauss' concern I'm not sure. 8 DR. STRAUSS: The community thing is what 9 worries me. Widely held values? Strongly held 10 values? Does that work? It's the community that I 11 think is -- 12 DR. BOTKIN: I think that the first part 13 of the phrase that says whether the subject population 14 in general, I think that gets to Dr. Shore's concern 15 about the fact that we're not worried about two 16 percent of the people that object to everything. It 17 would just be a common concern within the subject 18 population that you are dealing with. 19 That sort of gets to the community issue. 20 I agree that the use of the word community is 21 problematic since research may go across a variety of 22 communities. "Rights and" or "rights or." What was 23 the alternative that just came up? Strongly held 24 values. 25 MR. NELSON: Widely held. Broadly held. 178 1 Here is a friendly amendment if you are open to that. 2 Whether the subject population in general would 3 consider that their widely held values had been 4 violated if they knew of the waiver and its intent. 5 As I said, you can see why we shied -- we 6 tossed around words like natural rights and God given 7 rights and positive rights I think was a phrase Sam 8 used. But then that brought up the question what are 9 negative rights. We went around and around on this. 10 We realized in some of these recommendations that less 11 was more. The more words we put in, the more we were 12 in danger of tripping ourselves up. 13 DR. TILDEN: I wonder should we even just 14 severe that phrase? Does everyone agree that the 15 waiver has the potential to cause adverse consequences 16 for their welfare and general well being? That would 17 be as a stand-alone bullet. 18 MR. NELSON: That would be easy enough to 19 break out as a new third bullet if you will. That is 20 certainly fine. 21 DR. GENEL: I have no problem with values. 22 Why not just say values? Whether the subject 23 population in general would consider that their values 24 were violated. Why are we trying to -- 25 DR. TILDEN: We don't need to make it 179 1 anymore than that. 2 PARTICIPANT: How about the word 3 expectations instead of values? 4 PARTICIPANT: That's a different context. 5 DR. STRAUSS: Technically you don't 6 violate a value or violate someone's values. That's 7 not the right terminology. 8 MR. NELSON: I do remind all of us, I 9 guess, as we look at this no matter what we write in 10 this guidance IRBs are still left with the regulatory 11 language of rights and welfare no matter how we 12 finesse it. I think our finessing ought to help 13 clarify what we mean by rights and welfare. 14 Again, I would go back to the key creative 15 part of this which is to say how would people feel if 16 they knew about it. That's the important thing and 17 now we are just sort of clarifying if -- try to 18 describe how they would feel. That would be the 19 problem violated in some fashion. 20 DR. TILDEN: We are stuck here so we are 21 going to have to come to some resolution and move on. 22 DR. STRAUSS: One of the ways to get to 23 the gist of it, again, assuming that what we are doing 24 here is simply saying that we want OHRP to consider 25 guidance which includes the recommendation that IRBs 180 1 consider whether the subject population in general 2 would be opposed to the waiver if they knew of it or 3 something like that. 4 DR. TILDEN: Right. I was going to say 5 whether the subject population would object to the 6 waiver if they knew of the waiver and its intent or 7 that the waiver, something like that. 8 MR. NELSON: Well, if we're really going 9 to be minimalists, the subject population in general 10 would object if they knew of the waiver and its 11 intent. We'll bypass all together rights, values, 12 everything else. They would have a problem knowing 13 that this was done is what we're saying. 14 DR. TILDEN: Okay. So we have a motion to 15 change the second bullet to that, to whether the 16 subject population -- 17 MR. NELSON: In general. 18 DR. TILDEN: -- in general would object to 19 the waiver. 20 MR. NELSON: Would object if they knew of 21 the waiver. 22 DR. TILDEN: If they knew of the waiver. 23 MR. NELSON: And its intent. 24 DR. TILDEN: And its intent. 25 MR. NELSON: Then we'll have a new third 181 1 bullet, whether the waiver has the potential to cause 2 adverse consequences. 3 DR. TILDEN: Okay. So we'll vote on this 4 amendment. All those in favor? Okay. It's 5 unanimous. Amendment is approved. Now we vote on the 6 recommendation. All those in favor? Okay. 7 Recommendation is approved unanimously. 8 MR. NELSON: We have recommendations four 9 and five which each have some meat to it and six which 10 not much. If you would be so inclined, now might be 11 a time to take a break or we can continue plowing 12 ahead. I'll defer to the chair. 13 DR. TILDEN: Okay. It's 2:50 so 15 14 minutes and we'll be back. 15 (Whereupon, at 2:54 p.m. off 16 the record until 3:11 p.m.) 17 DR. TILDEN: Whenever you are, Dan. 18 MR. NELSON: All right. Thank you. 19 Picking up where we left off, Recommendation No. 4 20 refers to the third criterion. If the first two, 21 minimal risk and rights and welfare, are not 22 problematic enough, we know that IRBs and 23 investigators grapple with this one, what does it mean 24 to be impracticable and what does that refer to in the 25 first place. 182 1 Regarding the criterion under HHS regs at 2 116(d)(3) for IRB approval of a waiver or alteration 3 of informed consent requirements, IRBs should consider 4 the following points when determining whether research 5 could not practicably be carried out without the 6 waiver or alteration. This is, I think, our longest 7 recommendation owing to the difficulty people have in 8 applying this. 9 Some is, frankly, just a dictionary 10 reference to help define practicable. The commonly 11 accepted definitions of the term practicable are 12 feasible, capable of being effected, done, or put into 13 practice, and may be practiced or performed, capable 14 of being done or accomplished with available means or 15 resources. 16 It should be noted that this criterion 17 states that the research, emphasis on research, could 18 not practicably be carried out without the waiver or 19 alteration. Put another way, it would not be 20 practicable to perform the research has it has been 21 defined in the protocol by specific aims and 22 objectives if consent was required, the emphasis being 23 that it's impracticable to perform the research and 24 not just impracticable to obtain consent. 25 We think it's important for OHRP guidance 183 1 to really drive that point home and that's why we 2 spent what looked to be several sentences restating 3 the same concept because in our experience people 4 often read this or jump ahead to it's impracticable to 5 obtain consent and the regulatory language is that 6 it's impracticable to do the research without the 7 waiver. 8 The following concepts may help an IRB 9 determine whether the research could not practicably 10 be carried out without the waiver of consent. We want 11 to give credit where credit is due here and thereby 12 note that some of these elements the criteria that 13 follow are drawn from a document published in 14 September of 2005 by the Canadian Institutes of Health 15 Research entitled Best Practices for Protecting 16 Privacy in Health Research. 17 These were subsequently included in a 18 national white paper published not too long ago by 19 PRIMR looking at tissue banking issues. We found them 20 helpful in applying more broadly to the waiver of 21 informed consent and the practicability question. We 22 borrowed from some of those concepts and want to give 23 credit there. 24 Continuing on, now these are into concepts 25 that help get at this practicability question. One is 184 1 that scientific validity would be compromised if 2 consent was required. Examples of this might include 3 the sample sizes required is so large, for example, 4 population based studies, epidemiology trials 5 including only those samples, records, data for which 6 consent can be obtained would prohibit conclusions to 7 be drawn or bias samples such that conclusions would 8 be skewed. 9 Another example, the subjects for whom 10 records would be reviewed are no longer followed and 11 may be lost to follow-up. For example, the proportion 12 of individuals likely to have relocated or died may be 13 a significant percentage of the subject population and 14 the research results may not be meaningful and lose 15 statistical power. 16 Third example, the disclosure of the study 17 purpose as part of the consent process would bias the 18 research subjects so that the results will not be 19 meaningful. This gets more into so-called deception 20 research as opposed to record reviews. 21 Another area of concern or topic to be 22 considered under practicability, ethical concerns 23 would be raised if consent were required. These may 24 be less commonly encountered, but for example, there 25 is a risk of creating additional threats to privacy by 185 1 having to link otherwise the identified data with 2 nominal identifiers in order to contact individuals to 3 seek consent. 4 I would note this cross references in some 5 ways with the criteria for waiving written 6 documentation of consent in the following regulatory 7 section 117 which we are not dealing with today but 8 this is somewhat similar to one of those criteria for 9 waiving written documentation. Another example, there 10 is a risk of inflicting psychological, social, or 11 other harms by contacting individuals or families in 12 order to obtain their consent. 13 (c)There is a scientifically and ethically 14 justifiable rationale why the research could not be 15 conducted with a population from whom consent can be 16 obtained. That may get at the why don't get swabs 17 from homeless people in the ICU discussion we had 18 earlier. Informed consent should never be waived for 19 convenience, nor waived solely for reasons of cost or 20 speed if doing so dilutes the protection of subject's 21 rights and welfare. 22 That is Recommendation No. 4 in the 23 aggregate so we'll go back to the start of that and 24 invite your comments. 25 DR. TILDEN: So we have a motion to accept 186 1 this recommendation No. 4? Okay. And a second? Then 2 we'll open it for discussion. 3 Dan, this is just a comment in terms of 4 interpreting things. The issue that you can't perform 5 research or you can justify a waiver if it would not 6 be practicable to perform the research. Then number 7 (d), you know, on terms of informed consent should 8 never be waived for convenience nor waived solely for 9 reasons of cost or speed. 10 It seems to me the concept of 11 practicability sort of does include a cost benefit 12 ratio. In other words, in terms of efficiency at some 13 point it could become so costly you don't have -- I 14 mean, is that the litmus test where it's an equation. 15 It's not solely cost but it's weighing that together. 16 MR. NELSON: You've just used there in 17 your last couple words the operative word there and I 18 think that is solely for reasons of cost or speed. I 19 agree with you, Sam. At least personally I view cost 20 and speed as one of many factors that might roll into 21 an assessment of practicability. 22 However, I think what our subcommittee 23 wanted to drive home was that shouldn't be the only 24 reason. If that is the only reason that people can 25 come up with that the questions of scientific validity 187 1 as noted above and other factors are stronger 2 justifications for the practicability criterion. 3 DR. TILDEN: Any other discussion or 4 comments? 5 DR. STRAUSS: I just have a question. 6 This references deception research a lot, but of 7 course, deception of a sort is part of much of the 8 research we do, clinical trials where there is 9 blinding. We tell people in advance that they are 10 being deceived essentially, that the study is double 11 blinded. We don't think of it as deception, but of 12 course, there are elements that would be relevant to 13 their participation that they may know. 14 In other kinds of studies where we think 15 that, for example, let's say a substance use study 16 where we are looking to measure physiological and 17 psychological effects of a substance, particular 18 substance, let's say substance of abuse, we know that 19 anticipatory effects or knowledge in advance of what 20 that drug is would affect the study managers. 21 Those are more than minimal risk studies 22 by and large but how do you then not convey that 23 information or do you not see that element of consent 24 as being a required element. In other words, to not 25 tell them the specific drug they will be receiving or 188 1 even the double blinding. I'm wondering if you see 2 that as waiving an element of consent or do you think 3 that is just simply not a required element of consent? 4 MR. NELSON: Well, since you've introduced 5 this morning the concept of continuum in many 6 different aspects, maybe that is one way to look at 7 this. 8 There is a continuum of degree of 9 deception, if you will, all the way from on one end 10 the subject doesn't even know they are part of a study 11 to they know they are part of a study but they don't 12 know quite all the details because a decision has been 13 made and agreed to by the IRB that if they know all 14 the details up front it will bias their response or 15 participation in the study to the example you just 16 gave. 17 Now we are sliding along this continuum. 18 They know they are in the study. They know they are 19 getting drugs but they don't know which drug they are 20 on. I at least personally, and I don't think most 21 people in the field would view that as an example of 22 so-called deception research. Maybe the way to look 23 at that is there is no information that the 24 investigator knows that is being withheld from the 25 subject. 189 1 In other words, the investigator also 2 doesn't know what drug they are on if they are 3 randomized. He doesn't have any information to 4 withhold. I at least do not see agreeing to be 5 obtaining consent, the subject agrees to be randomized 6 into a clinical trial as having elements of consent 7 that need to be waived. It's part of the study design 8 that nobody will know, neither investigator nor 9 subject which arm -- well, they may know which arm 10 they are on or they may be totally blinded. 11 DR. STRAUSS: I agree with you. I'm 12 asking whether you could imagine that there would be 13 a reason to waive a component of a more than minimal 14 risk study if the component itself was -- well, I'm 15 not sure how to think about it. I'm not even sure I 16 have an example. 17 MR. NELSON: I guess if it's greater than 18 minimal risk we're already failed the first criterion 19 so you wouldn't even get to this point. Right? And 20 if it's FDA regulated, it's off the table altogether 21 so the discussion stopped before it's gotten to this 22 point, or the analysis. Right? 23 DR. STRAUSS: I imagine there might be a 24 component of the study that involved deception. Let 25 me think of an example. 190 1 DR. BOTKIN: I was going to try to be 2 quiet but I can't. Looking at (d) on the last slide, 3 this set of points relates to the practicability 4 issue. I wonder whether that might be rephrased to 5 speak specifically about practicability because it 6 says informed consent should never be waived for 7 convenience. 8 It can't be waived for convenience because 9 you have to fulfill all the criteria anyhow. I think 10 what you mean to say here is that practicability 11 doesn't mean simply inconvenient or costly or the fact 12 that obtaining consent is inconvenient or costly does 13 not fulfill the criterion of practicability or 14 impracticability. Does that make sense? 15 This is sort of speaking about informed 16 consent broadly and the second part of the phrase 17 talks about, sort of dilutes the protection of 18 subject's rights and welfare. Again, that refers to 19 another one of the four criteria already or 20 independently. If you are diluting the protection of 21 rights and welfare, then you can't do a waiver anyhow. 22 I think what you want to speak to here is the cost and 23 convenience issues with respect to that being a 24 definition of practicability or impracticability. 25 MR. NELSON: I think I'm tracking with 191 1 you. Let me deal with two points in reverse. One, I 2 suspect the add-on, the last few words there, if doing 3 so dilutes the protection of rights and welfare was a 4 nod to the point that Sam just raised that, in fact, 5 cost and speed may be one factor to be considered but 6 it shouldn't be the only factor. 7 If we are to consider it we need to be 8 careful that it's not diluting beyond what we are 9 willing to accept the rights and welfare. We are 10 certainly wide open to recasting this, rephrasing this 11 however it best makes sense. I'm not sure, Jeff, I 12 entirely followed your first statement. If I heard 13 you correctly, that informed consent couldn't be 14 waived for convenience. Can you restate that or what 15 did you mean by that? 16 DR. BOTKIN: An investigator wouldn't come 17 forward and say, "Informed consent is inconvenient. 18 Therefore, I would like to apply for a waiver." You 19 would say, "Of course not. You have to fulfill these 20 four criteria in order for the waiver to be 21 acceptable." An IRB wouldn't make a decision to waive 22 informed consent because it was inconvenient for the 23 investigators. 24 They would only waive it if it fulfilled 25 all the criteria, one of which is practicability which 192 1 I think this particular point is speaking to as 2 opposed to waiver more broadly. I'm probably not 3 saying that very well. 4 DR. TILDEN: So what you're proposing is 5 to relate (d), tie it a little bit tighter to 6 practicability or impracticability. 7 DR. BOTKIN: Basically the point is you 8 shouldn't call consent impracticable just because it's 9 inconvenient for the investigator to obtain consent or 10 might add additional cost to the research. 11 DR. GENEL: Well, that might make it 12 impracticable. 13 DR. GYI: Jeff, let me see if I can 14 capture what you're saying. An investigator wants to 15 conduct a study in a school system and says, "I have 16 to go to three different schools. It's inconvenient 17 for me to talk with all the students or the parents. 18 Therefore, I should seek waiver of consent because 19 it's not practicable for me to do so." 20 The IRB then should come back and say, 21 "That's not a good enough reason. You have to go out 22 and obtain consent. You can't waive the consent." 23 Would that be a scenario that you might be thinking 24 of? 25 DR. GENEL: I don't think that's an all or 193 1 none proposition, is it? I mean, at some point going 2 to X number of schools is going to become impractical. 3 DR. GYI: But that would be a point that 4 the IRB would then have to assess in conjunction with 5 the investigator's plan. 6 DR. STRAUSS: I think that's covered in 7 (d). I think what Jeff was really pointing out is 8 that it shouldn't begin by saying, "Informed consent 9 should never be waived". What it should say is that, 10 "The determination of practicability should not be 11 based -- a determination that the consent is 12 impractical should not be based solely on 13 inconvenience." 14 MR. NELSON: In fact, I was wondering if 15 moving the word solely up so it also modified "should 16 never be waived solely for convenience." 17 DR. STRAUSS: Apart from that I just think 18 that Jeff is talking about removing the beginning of 19 the sentence. 20 DR. GYI: So would you read that, please? 21 DR. STRAUSS: Can we leave it to the -- 22 MR. NELSON: Don't leave it to us. That's 23 all we ask. 24 DR. TILDEN: Other discussion on 25 Recommendation No. 4 while we get the rephrased 194 1 wording of (d)? 2 DR. STRAUSS: I think it's really good. 3 Again, I think that with this kind of guidance we are 4 less likely to hear the standard justification for a 5 waiver as it would be too much of a hassle to actually 6 go and do this. Here we have a notion of what counts 7 for impracticability that we didn't have before that 8 I think is really useful. 9 DR. TILDEN: That was the goal because, 10 indeed, we do hear that it's too much of a hassle. 11 Another way of saying it wouldn't be convenient. 12 DR. BOTKIN: How about this? 13 "Practicability should not be determined solely by 14 considerations of convenience, cost, or speed." 15 MR. NELSON: Stop there? 16 DR. BOTKIN: I would stop there since I 17 think the second criterion already deals with the 18 rights and the welfare piece of it. "Practicability 19 should not be determined solely by considerations of 20 convenience, cost, or speed." 21 MR. NELSON: We would be happy to take 22 that as a friendly amendment and consider that now 23 part of the recommendation. 24 DR. BOTKIN: Is that acceptable to the 25 committee? Neil? 195 1 DR. POWE: I want to point out one thing. 2 As I look to the first slide on page 14 we define 3 practicable as capable of being done or accomplished 4 with available means or resources which to me means 5 cost or speed or whatever. I'm just wondering if 6 there is a contradiction there. 7 MR. NELSON: I guess I might put back the 8 question based on Neil's observation. I think the 9 subcommittee in drafting this, and again, this went 10 through many iterations before it came to you. 11 Knowing that IRBs have such difficulty, especially 12 with this third criterion, the practicability, that 13 they thought of even going back to Webster's might be 14 a good starting point. 15 I would put back to you, I guess, is this 16 a helpful element to start out with to give a textbook 17 definition, if you will, of practicability before we 18 get to what does it really mean when we are talking 19 about practicability in the setting up for waiving 20 consent. In other words, I don't know that we're 21 married to have to have that in if that seems out of 22 place at this point. 23 DR. TILDEN: I think, Neil, my sense is 24 that it's not just a cost issue. There is some sort 25 of equation or some sort of balancing that would go on 196 1 between being able to conduct the research and the 2 cost. In other words, if you had funding to 3 accomplish consent, it would be a lot cheaper to get 4 a waiver. In that case it may not be appropriate to 5 waive consent if it could be done legitimately. I 6 guess that's where solely the cost piece in that sort 7 of equation. 8 On the other hand, like your friendly 9 neighborhood federal agency, you may get an award but 10 it's cut 25 percent and all of a sudden you may not be 11 able to accomplish your research goals and you are 12 limited financially. You may have to consider these 13 sorts of things within the means of the resources you 14 have to conduct the research. I hate to pinpoint our 15 friends but anyway, it was convenient. Solely for 16 convenience. 17 I think that's my first question. There 18 should be some balancing where just because I don't 19 want to get consent shouldn't justify getting a 20 waiver. I think that was stated several times. I 21 agree with you that it seems to me it is a more 22 complicated calculus than just, "Hey, let's save money 23 and not do it that way." 24 DR. TILDEN: Okay. Where are we now? We 25 have Jeff's amendment. Do we feel comfortable with 197 1 modifying that bullet the way it has been proposed? 2 We voted that on that already. I guess we should vote 3 on the amendment as proposed by Jeff to the fourth 4 bullet. All in favor? Okay. Motion passes. 5 The amendment passes. Then we should vote 6 on Recommendation No. 4 whether we approve that 7 recommendation. All in favor? Okay. So it looks 8 like Recommendation No. 4 passes and is approved. 9 That moves us on to Recommendation No. 5. 10 MR. NELSON: All right. Now we are to the 11 fourth of four criteria which deals with the provision 12 of information following participation, or so-called 13 debriefing as one example of that. 14 "Regarding the criterion under HHS regs at 15 116(d)(4) for IRB approval of a waiver or alteration 16 of informed consent requirements, IRBs should consider 17 the following points when determining when it would be 18 appropriate for investigators to provide subjects with 19 additional pertinent information after participation 20 when the requirements for informed consent have been 21 waived. 22 "First, it is important to note the phrase 23 `when appropriate' in this criterion means that while 24 the IRB must consider if this applies each time a 25 waiver is reviewed, not all protocols which include an 198 1 informed consent waiver are required to incorporate a 2 debriefing process." I thought that was an important 3 point to make. The IRBs should be considering their 4 criterion but it doesn't mean that every protocol has 5 to come out of that consideration with a debriefing. 6 Indeed, many do not. 7 "This criterion is intended to refer to 8 the need to consider debriefing after research is 9 conducted. In these situations it may be ethically 10 required or determined to be respectful to provide the 11 subject with pertinent information after the research 12 is complete. IRBs may want to consider this 13 requirement if..." 14 Here we have two common scenarios, two 15 different scenarios but common scenarios when a waiver 16 is applied and we think they invoke different outcomes 17 under this fourth criterion in terms of the post-study 18 debriefing, if you will. 19 "A subject is included in research that 20 exposes them to situations or conditions to provoke a 21 response for research purposes and the situation would 22 not have ordinarily occurred at that point in time. 23 For example, a debriefing after so-called deception 24 research in which some aspects of the study are not 25 fully disclosed up front." This is with our 199 1 understanding of the historical context discussed 2 earlier why this element was put in in the first 3 place, deception more under the human behavior 4 studies. 5 "Alternatively, information is obtained 6 during the course of the research that directly 7 impacts on the safety or welfare of the subject. For 8 example, a retrospective review of medical charts that 9 revealed something of relevance to ongoing care of 10 patients whose records were included." 11 Again, medical IRBs, biomedical IRBs that 12 apply the waiver for retrospective studies really 13 don't have these post study debriefings because 14 subjects are never approached but there may be 15 occasions when something is learned of relevance to 16 ongoing clinical care and then it would be appropriate 17 to consider a mechanism to relay that information back 18 to the clinical care context. 19 That is it for Recommendation No. 5. It's 20 now open for your consideration. 21 DR. TILDEN: Okay. So we have a motion to 22 approve Recommendation No. 5? Second? Seconded. Any 23 discussion? 24 DR. POWELL: I do have a question. Since 25 I don't have experience in this particular area, not 200 1 having dealt with this type of research, in the case 2 where a patient has never given informed consent, can 3 they withdraw consent or their data from the process? 4 Most of the times I tell patients in instructions 5 instructing people about research and communities that 6 you have the right to withdraw your data at any time. 7 Can a patient who has never given informed consent 8 withdraw that information? 9 DR. TILDEN: There are gurus here a lot 10 more sophisticated than I am that could and should 11 address that probably. 12 MR. NELSON: I think he was looking at 13 you, Felix. A fair question, James. I think the 14 number of times this happens is certainly small, I 15 think, where somebody learned something. Look at the 16 last 100 hip replacements or the last 1,000 cases of 17 disease X, Y, Z and learn something as part of their 18 research analysis that they feel needs to be feed 19 back. 20 I think it needs to be approached with 21 some care or anticipation up front that the person you 22 are going back to doesn't know their records were 23 included, then I guess, yes, potentially if they said, 24 "I didn't want to be in your research study in the 25 first place and now that I know I am, or was, I would 201 1 like my data taken out." 2 I think that is probably a discussion that 3 the IRB and the investigator and probably local legal 4 counsel might have if it reached that point. I think 5 certainly in our hands if this occurred we would be 6 looking to relaying the information. The researchers 7 would not be the ones taking it back to the patient 8 who didn't know they were subjects in the first place. 9 There would be a mechanism to relay that 10 back through a care provider who could then take that 11 information back. That is not an element of deception 12 there I think as much as respectful for the patient 13 caregiver relationship and wanting that to be folded 14 into that pipeline rather than treating them like they 15 were a research subject with an active enrollment in 16 a study. 17 David. 18 DR. STRAUSS: I can think of another 19 example. We have encountered these kinds of things. 20 The answer is, yes, they can. For example, in a 21 family genetic study in which you are working your way 22 through a pedigree and you may approve a waiver of 23 consent for information about family members, 24 secondary research subjects so to speak, that are 25 recorded by the investigator from the proband. I'm 202 1 asking the proband about Uncle Pete. 2 Then based on the information that I 3 received from the proband about this family person, I 4 realize that it's important to actually conduct a 5 direct interview with Uncle Pete. When I approach 6 Pete he gets angry and he says, "Not only do I not 7 want to talk to you but I don't even want to hear that 8 you've recorded any information about me whatsoever," 9 which seems to me is his right to do. 10 In a sense his learning of the study, and 11 forgive the use of the word, he may exercise his right 12 to basically undo the waiver with reference to him 13 specifically. That's the kind of situation. There 14 are other studies where in sort of second components 15 of the study the researcher actually has contact with 16 subjects for whom consent was waived early on in the 17 study. Then we normally would say they have the right 18 to hear about the fact that we have information on 19 them and the right to withdraw it. 20 MR. NELSON: I think at a practical level 21 in the majority of cases I suspect most IRB 22 institution investigators would agree to remove data 23 without a lot of argument if somebody really raised 24 objections and had issues. 25 Joan. 203 1 MS. PORTER: I wanted to comment that 2 HIPAA has some limitations, however, and I can't quote 3 you the exact phraseology but if the data from the 4 individuals has already been used in an analysis or a 5 publication, one is not required to go back and 6 excerpt that and do the reanalysis or the 7 republication. 8 There are some cutoff points. I think the 9 individual can ask that the data no longer be used or 10 the sample no longer be used. It's hard to go back 11 after the publication is finished and the analysis is 12 done. 13 MR. NELSON: That would be the cue for 14 Mike Genel to talk about harmonizing HIPAA with the 15 common rule. 16 DR. STRAUSS: I have a couple of comments 17 about this because this is the one recommendation that 18 sat least well with me. First of all, in the first 19 bullet you first use this term the debriefing process. 20 I think that relates specifically I think to deception 21 research. I don't know if you intend to be so 22 specific there. I think that it sort of detracts from 23 the overall meaning of that bullet point. 24 I think the second bullet has the same 25 problem. You don't necessarily mean debriefing 204 1 because sometimes it's not a debriefing but just 2 merely providing people with some information of some 3 sort. It could be in writing. It could be by mail. 4 I don't know. 5 The third bullet I guess I just didn't 6 understand it. I didn't understand the example 7 because it's sort of very general. Subject is 8 included in research that exposes them to situations 9 or conditions to provoke a response for research 10 purposes. The situation would not have ordinarily 11 occurred at that time point. I don't know exactly 12 what that means. I think if we want to use this as an 13 example, I think we want to be a little bit more 14 concrete. 15 Then, lastly, the last bullet, 16 "Information is obtained during the course of the 17 research that directly impacts on the safety or 18 welfare." I think this is an important point but to 19 use the phrase used here before, it's a bit of a 20 slippery slope. I think it raises a whole bunch of 21 questions about researchers' obligations with regard 22 to incidental findings which I don't know we are ready 23 for in a sense. 24 Again, I think the concept is correct but 25 I think we want to be careful not to open too many 205 1 doors in creating requirements or expectations where 2 we don't really think they are necessary. I think in 3 this last one we might want to give a more specific 4 example where such feedback would be critically 5 important and would be required. 6 MR. NELSON: Let's start from the top and 7 work down because these are all good points. 8 Certainly some of these, especially the main construct 9 was there but certainly some of the details and some 10 of the phrasing was very much evolving rapidly through 11 the course of phone calls and e-mails and things and 12 so hasn't necessarily had exhaustive vetting so we are 13 very grateful for this feedback. 14 On the first bullet -- let me back up one 15 here so it's on the screen. So I think you're right. 16 The last line there, "Required to incorporate a 17 debriefing process." I think we didn't mean to be as 18 specific as that sounded so I would take your 19 suggestion that we just rephrase that to refer to what 20 the regulations actually require the consideration 21 whether pertinent information should be provided. 22 If we just said, "Not all protocols which 23 include informed consent waiver are required to 24 provide information after participation is complete," 25 or "Provide information to subjects after 206 1 participation is complete." 2 That's what the criterion gets at and 3 debriefing is only one example of that, one mechanism 4 for that. Would that satisfy your concern there? 5 We'll just replace, "Incorporate a debriefing process" 6 with "Provide information to subjects after their 7 participation." 8 Now, moving on down I guess the 9 debriefing, at least to me, wasn't necessarily limited 10 to a face-to-face debriefing. I think we envision 11 this debriefing as being defined as providing 12 information that was known but was withheld up front 13 for the sake of conducting the study. Now, the 14 example, you had two issues in this bullet both well 15 taken. 16 It's a rather awkward way of saying we 17 couldn't tell you everything up front because we would 18 have biased your response. If there is a better way 19 to define deception research or to put it into 20 layman's terms, so to speak, I think this is a little 21 bit awkward. 22 Your second point in that gets into the 23 parenthetical. I don't think we viewed debriefing as 24 limited to just one kind of communication mode but 25 simply providing information that was known to the 207 1 researcher but was withheld up front for the sake of 2 conducting and accomplishing the research. 3 Maybe we need to deal with those points 4 separately. How about if we just call it what it is. 5 "The subject is included in research in which some 6 aspects of the study are not fully disclosed up front 7 where doing so would bias the results." Is that a 8 better description of deception research? 9 DR. STRAUSS: I guess my question is if 10 this requirement, this No. 4, was intended solely or 11 arose solely in the context of concerns about 12 deception research, then maybe the recommendation 13 should talk about that and define that in very 14 specific and concrete terms. 15 If in addition we wanted to apply to this 16 last bullet here, in other words, "Incidentally 17 uncovered important information that occurs in the 18 context of research conducted under a waiver," I think 19 that we should specify that, too. Or if we don't 20 think it applies to that, we should just eliminate 21 that. 22 I guess if we think there are -- I don't 23 know what they are but if there are other conditions, 24 other circumstances in which we require providing 25 additional pertinent information after participation, 208 1 I think we should really enumerate them all. This is 2 an area where I think there is a lot of lack of 3 understanding. 4 MR. NELSON: I think we would be happy to 5 add more, I think, speaking for a third example or a 6 third scenario if you can describe it. Speaking for 7 the subcommittee I think we felt these two are 8 important, the two bullets. The first because that's 9 how this came to be in the first place. 10 The second because for biomedical IRBs 11 that are busy granting waivers on a weekly basis for 12 retrospective chart reviews, they look at it and 13 think, "Well, we're not doing the Milgrim study here. 14 How do I even apply this?" This is giving them a way 15 to apply it. They are not sure how to check that one 16 off so to speak. 17 DR. STRAUSS: How do you provide 18 information? Are you talking about the individuals 19 within populations or are you talking about to the 20 group as a whole? You do a retrospective chart review 21 and as you are looking at the chart you see something 22 important? 23 MR. NELSON: I think it's incidental and 24 patient specific. I don't think there is any 25 anticipation that the whole study have a -- go back to 209 1 every subject whose thousand medical records were 2 reviewed or go back to the thousand subjects whose 3 medical records were reviewed and debrief all of them. 4 I think it's meant to get at the incidental finding of 5 direct clinical relevance. 6 DR. TILDEN: I really interpret it as just 7 the opposite. For instance, you do a study of hip 8 replacements, comparing one hip in the Medicare 9 population versus another, artificial hip. You find 10 that when you do your analysis that one hip tends to 11 be better tolerated, safer, and have longevity or one 12 hip has more of a tendency to failure. 13 You are going to write your paper and 14 present this information. Then the question is is it 15 worthy to notify individuals potentially. Not a 16 single individual which is the incidental finding but 17 if there is something of note or worth. If there may 18 be better management of insulin dependent diabetes in 19 the region that you studied using a certain technique 20 than others. You see? 21 MR. NELSON: I see -- 22 DR. TILDEN: Then you have these findings 23 and it was all done without an individual's consent. 24 Would it have any importance to disseminate that in 25 some way or form? 210 1 MR. NELSON: I see exactly what you're 2 saying and I think that is a very reasonable reading 3 of the last bullet there. In some ways we have moved 4 into a different area and that is sharing the results 5 of research with participants. 6 That is, of course, an open question and 7 a debated question when there is research with consent 8 so I don't think it's limited to the setting of waiver 9 studies. I do think it opens up a whole new layer. 10 Now we have James' scenario times the thousand. Now 11 you go back to them and say, "Here is what we learned 12 without your consent." 13 DR. TILDEN: I see I've stirred the 14 committee. They are awake now. We've got some 15 commenters. 16 David, you were the first one to really 17 look like you wanted to jump up here. Then Mike. Let 18 Mike go? Okay. 19 DR. GENEL: I've been waiting to raise 20 that question so you raised it. I mean, I was going 21 to raise the question are we requiring something for 22 a waiver of consent that we don't require or approve 23 for other research. Just a question without making 24 any judgment as to which I would prefer. 25 DR. TILDEN: I'm not making a judgment 211 1 either. That's just the way I read it. 2 DR. SHORE: I'm not clear how you could do 3 a study randomly assigning people to two different 4 surgical inventions and not tell them. In this 5 scenario that you described, I understand later on 6 people would have an interest in knowing what 7 intervention they got and whether it seemed to have 8 helped them or whether another intervention would have 9 helped them more. The scenario you described I don't 10 see how that could possibly be appropriate for a 11 waiver because it's got to be greater than minimal 12 risk. 13 DR. TILDEN: Not if you do it 14 retrospectively. 15 DR. SHORE: Oh, just the chart review 16 part? 17 DR. TILDEN: Just a retrospective review 18 over five hospitals in five metropolitan areas looking 19 at a comparison between hips and outcomes. 20 DR. SHORE: Right, but you would 21 presumably have to present the issue of debriefing to 22 the IRB when you first got the study approved. Right? 23 DR. TILDEN: Maybe or maybe not. 24 MR. NELSON: You may have put your finger 25 on why my first instinct was to restrict this to the 212 1 incidental finding of relevance to a single individual 2 patient because certainly I at least personally 3 wouldn't advocate going back to everybody whose 4 records were including in the whole aggregate data set 5 and telling them what you learned. 6 Neil, I think you had a question. 7 DR. POWE: I was just going to say that I 8 thought it was a narrow interpretation, kind of 9 something to clinically alert you and you need to 10 inform someone. Another question I had was where does 11 the medical provider if it's not different than the 12 researcher fall in this? It talks about informing the 13 individual subject but what about the provider? 14 This could have issues with the patient 15 provider relationship if you leave the provider out of 16 the equation. I think it's a little different if it 17 were a community-based study where this wasn't found 18 through medical records, for example. I just wonder 19 how that information should be communicated. 20 DR. GYI: Neil, you raise a point that has 21 sort of been mulling in my mind as I hear people talk 22 because right now we started from somewhat of a social 23 behavioral perspective and we are sort of gravitating 24 now into a medical model. Let's stay with that chart 25 review of hips and observations. 213 1 What happens if you were to come across a 2 single chart where you have an incidental finding of 3 a patient complaining of loss of hearing and you find 4 out also that during the course of the surgery the 5 patient was inadvertently given very high dose of 6 aminoglycosides in the face of renal failure or 7 compromised renal function. 8 What is the obligation of the researcher 9 to get back to that one individual subject, if you 10 will, to either talk about some outcomes or some 11 damage that's done? I don't think that is the type of 12 setting that we're talking about here. Right? 13 DR. STRAUSS: No, and we would say that 14 obligation wouldn't differ depending on whether or not 15 there was a waiver. In other words, that is a matter 16 of incidental findings related to research 17 participants. Whether or not there was a waiver of 18 consent or not that is not a pertinent fact. In other 19 words, it doesn't change your obligation to do 20 something or alert a subject either way. 21 I'm not so sure. Again, if you look at 22 No. 4 in the criteria, it says, "Whenever appropriate 23 the subjects will be provided with additional 24 pertinent information after participation." I don't 25 know that I think about the people who are the 214 1 subjects of a retrospective chart review would 2 constitute people who have participated in research. 3 MR. NELSON: Again, I think where this is 4 coming from is a perceived need and I think it's a 5 real need that is out there for people who aren't 6 doing behavioral deception studies to have some way to 7 address -- what does this element mean if we, the 8 regulation, say to them, "You must address all four 9 criteria when you apply a waiver." 10 On a weekly basis they are reviewing 11 retrospective chart review studies and granting 12 waivers. What do they do to satisfy? Do they say it 13 does not apply which is, I guess, another option. 14 Maybe that's on the table. If you're not 15 doing this kind of research, this just doesn't apply. 16 Don't worry about it. This was our attempt to give 17 them kind of a meaningful way to answer that question. 18 Whether it's meaningful or not, I guess a way to 19 answer that question. 20 DR. GENEL: Sam, I think there is wiggle 21 room with the phrase "whenever appropriate." I think 22 one can use that to justify virtually any decision. 23 I think this whole subject of informing subject of 24 research of the results of that research is something 25 we probably ought to take up. 215 1 I don't think it's necessarily that is 2 part of the issues relating to waiver. I think this 3 whole concept of whether or not there is an obligation 4 of researchers or the research community to give 5 information back to subjects is one that I think we 6 ought to probably look at in more depth. There are a 7 lot of aspects to it including the resources that are 8 required to do this and so forth but I think it's 9 something that we ought to look at. 10 DR. TILDEN: Okay. Well, in terms of this 11 bullet does this mean we should eliminate the bullet 12 or should we narrow it down or say something like, 13 "Impacts on the safety or welfare of an individual 14 subject?" Where should we go with regard to this? 15 DR. STRAUSS: Again, not having thought 16 about it for as long as Subpart A, I still think it 17 creates an obligation that is not specific to 18 participants who participated under a waiver. I think 19 if we are going to talk either about the requirement 20 to inform people of the results of the research, if we 21 are going to be talking about a requirement to discuss 22 or disclose incidental findings, neither of those 23 things belong here under waiver. I think it should be 24 -- 25 DR. TILDEN: It should be eliminated is 216 1 what you're saying. 2 DR. STRAUSS: Yes. 3 DR. TILDEN: You want to make a motion and 4 amend it? 5 DR. STRAUSS: Why say something briefly if 6 you can say it longer? 7 DR. TILDEN: Okay. We have a motion to 8 just eliminate the second bullet and keep the 9 Recommendation No. 5 otherwise intact. 10 MR. NELSON: Not to argue against that but 11 because we know it's such a question for biomedical 12 IRBs applying the waiver, I think we might be doing -- 13 I think deleting it is fine but replacing it with, "If 14 you're granting a waiver for retrospective chart 15 review studies, this element doesn't apply." 16 Mike is right that "when appropriate" is 17 the operative phrase in this whole criterion and 18 that's why the first bullet really honed in on that 19 and emphasized that point. Really it's probably not 20 appropriate then. That was just the example we came 21 up with when people are doing nondeception research 22 studies how they apply this. 23 DR. TILDEN: So you're saying that we 24 should make a statement that this should not be 25 applied in the context of biomedical research studies 217 1 where waivers are granted? 2 MR. NELSON: Even that is a pretty -- that 3 might rule out valid reasons for doing it. I think we 4 would be better off replacing it rather than deleting 5 it. If we are going to replace it, replace it with a 6 statement that under ordinary circumstances this would 7 not apply -- this criterion does not apply when you 8 are granting a waiver for retrospective review 9 studies. I think to stay silent on it will not 10 address the uncertainty that is out there that led us 11 to tackle this in the first place. 12 DR. STRAUSS: Your first bullet says, 13 "It's important to note that the phrase blah, blah, 14 blah in this criterion means that while an IRB must 15 consider if it applies, not all protocols include 16 informed consent are required to incorporate such 17 disclosure of information." It says it's not 18 required. 19 MR. NELSON: It does when you and I are 20 sitting here having discussed it for the last hour 21 when the guidance is out there on the OHRP website. 22 I'm not sure if they will have the benefit of that 23 context. I don't want to dig in my heels on this 24 because I would like to see it be approved in one way 25 or another and move ahead. 218 1 DR. TILDEN: Well, the first bullet -- I 2 think on the first slide we made an amendment so we 3 are going to say that, "Not all protocols which 4 include an informed consent waiver are required to 5 provide additional pertinent information." 6 MR. NELSON: "...to subjects after their 7 participation." 8 DR. TILDEN: Okay. So we have that. We 9 have approved that. Is that correct? I'm forgetting 10 now but I think we approved that. Now we are on the 11 second slide. 12 MR. NELSON: I don't know that we actually 13 voted on that. 14 DR. TILDEN: We didn't vote? Okay. We 15 probably should vote on that. Slide No. 1 regarding 16 the criterion under -- it's up there. 17 DR. GENEL: And that language would go 18 where? 19 MR. NELSON: After the last comma it would 20 read, "Not all protocols which include an informed 21 consent waiver are required to provide additional 22 information to subjects after their participation," 23 rather than a reference to debriefing. 24 DR. GENEL: Rather than the debriefing 25 process. Okay. The point I want to make is why don't 219 1 we just stop right there? 2 DR. TILDEN: Well, let's vote on it and 3 approve this and then we'll make that point when we 4 take up the next slide. How's that? Or vote and not 5 approve it but let's just vote on it. 6 Jeff. 7 DR. BOTKIN: Yes. I'm wondering if we are 8 actually moving back to an understanding of this 9 criterion that would make the debriefing word 10 applicable again. It sounds to me like we are talking 11 about research here in which there is some interaction 12 with the individual. They have been given an 13 incomplete or a false picture of the situation and now 14 you need to correct that. 15 I haven't heard a good example yet of an 16 information process that doesn't involve that sort of 17 initial so-called deception research piece. If we are 18 saying that incidental findings or clinically relevant 19 findings from the research that people ought to know 20 about. 21 I guess I'm in agreement that is not a 22 waiver issue. That is a broader issue than waiver so 23 are we really talking about research explicitly in 24 this context that is so-called deception research and 25 it's just not relevant to other kinds of research. 220 1 DR. TILDEN: So you are arguing against 2 the motion to change it and leave it with the wording 3 regarding debriefing. Leaving it as it is, "Not 4 required to incorporate a debriefing process." 5 DR. BOTKIN: Well, it might require more 6 rewriting of the recommendation to say that what this 7 criterion is relevant to is this type of research and 8 that it's rarely relevant to biomedical research if, 9 in fact, we believe that. We almost always don't 10 consider this criterion in biomedical research. I 11 can't remember a circumstance in which it has become 12 relevant. Maybe that is how it should be and this 13 ought to speak directly to that. 14 DR. GYI: Just as a reminder, what Dan had 15 read before was under ordinary circumstances this 16 waiver does not apply when -- this criterion does not 17 apply when applying waivers in biomedical research. 18 I think that does recalibrate it for those biomedical 19 IRBs that are applying this in the course of their 20 regular work. 21 I think one of the things that we see is 22 the fact that the IRBs don't know how to apply this 23 appropriately and so they are struggling with this. 24 Having some guidance that parses it out appropriately 25 would be very helpful. 221 1 DR. TILDEN: Okay. So since the 2 regulation doesn't really mention deception research 3 per se, I suggest that -- well, my thought would be we 4 should keep the language, the amended language, saying 5 that, "Not all protocols which include informed 6 consent waiver are required to provide this additional 7 information to subjects after their participation." 8 Then go on to the next slide. Really 9 basically what we're saying is that in considering 10 this element there are two things. It's appropriate 11 to consider it in deception research and it's not 12 really applicable, or we don't feel it's generally 13 applicable to biomedical research like retrospective 14 reviews, etc." That's what I'm hearing. 15 MR. NELSON: I think so and, indeed, the 16 next slide we immediately start out saying, "Criterion 17 is intended to refer to the need to consider 18 debriefing." Maybe Jeff is right. Maybe that word 19 just -- 20 DR. TILDEN: We leave debriefing in there. 21 Okay. Then you might say the first bullet, just put, 22 "IRBs may want to consider this requirement if the 23 subject is included in deception research." If you 24 want to put, "In which some aspects of the study are 25 not fully disclosed," up front, that's fine. Or the 222 1 second bullet would be not or. 2 MR. NELSON: Not or. 3 DR. TILDEN: Just take the or out and then 4 the second bullet says -- 5 MR. NELSON: -- would read, "Under most 6 circumstances this criterion does not apply," and I 7 don't think we should refer to biomedical research 8 because that is a pretty broad category but "to 9 retrospective studies conducted under a waiver. For 10 example, retrospective review of existing medical 11 records." 12 DR. TILDEN: That's the consensus I'm 13 hearing. Neil. Okay. That's why I asked you about 14 it. 15 MR. NELSON: The current state of affairs 16 out there, maybe there's a couple of approaches. One 17 is people have come to their own conclusion that this 18 criterion, the debriefing requirement when appropriate 19 really doesn't apply to retrospective review studies 20 and just discount it right from the get-go. The other 21 approach is they think it must apply because it's 22 there and needs to be addressed. 23 The way they satisfy it is to say if we 24 learn something. We don't expect to but if we learn 25 something that was of relevance to a single patient's 223 1 ongoing medical care, we would think of a way to feed 2 that back to -- to answer your earlier question, back 3 to the care giver, not to exclude them. 4 Where we are heading as a group, I guess, 5 is coming down on the first of those to empower IRBs 6 looking at these four criteria and to accept that the 7 last one doesn't apply under these circumstances, 8 retrospective review of existing records. The 9 references to debriefing would stand because we are 10 accepting that is why it was there in the first place 11 and that is the one that makes sense. Does that 12 clarify the logic? 13 DR. TILDEN: Yes. I think we ought to 14 take a vote on this motion. 15 DR. STRAUSS: Can we -- I think your 16 suggestion -- your language was what we agreed on. 17 Right? 18 DR. TILDEN: Correct. 19 DR. STRAUSS: Your last quote. If the 20 last bullet -- see, I don't think it should reference 21 biomedical. 22 DR. TILDEN: No, it doesn't. 23 DR. STRAUSS: I would write, for example, 24 "Would not ordinarily apply to many of the most common 25 circumstances in which waiver is granted such as 224 1 retrospective chart review," or something like that. 2 As long as it doesn't say biomedical. 3 MR. NELSON: My point was we shouldn't say 4 biomedical so I had already taken that out. I don't 5 know that we can -- it gets into us knowing what is 6 the most prevalent use of it and I don't know that we 7 can necessarily do that. I agree that we shouldn't 8 refer to just biomedical research. 9 DR. TILDEN: Do you want to come back with 10 this recommendation or do you think we have it solid 11 enough to -- 12 MR. NELSON: I think we are comfortable 13 with it. Whether you all know what you're voting on 14 is a different question. 15 DR. TILDEN: Well, I think we're voting on 16 the second slide. "May want to consider this 17 requirement if the subject is included in deception 18 research..." 19 MR. NELSON: "...in which some aspects of 20 the study are not fully disclosed up front. The 21 parenthetical basically stands. 22 DR. TILDEN: Okay. Then the second piece, 23 the second bullet, is that ordinarily or generally it 24 is not appropriate -- 25 MR. NELSON: Can I read what I have 225 1 written down here as a starting point? 2 DR. TILDEN: Yes. 3 MR. NELSON: "Under most circumstances 4 this criterion does not apply to retrospective studies 5 conducted under a waiver (e.g., retrospective review 6 of existing medical records.)" 7 DR. TILDEN: Okay. 8 MR. NELSON: Without any reference to 9 biomedical or other because we could be talking -- 10 what's that? Oh, existing records. 11 DR. TILDEN: Okay. You got that? So 12 let's take a vote. All those in favor? Unanimous. 13 All right. Man, I'll tell you, this Subpart A 14 Subcommittee can wear you out. 15 MR. NELSON: That's our goal. There will 16 be a debriefing tonight over drinks. The last one I 17 truly hope is a no brainer. The last recommendation. 18 That is that IRBs may find it helpful to use a 19 flowchart that summarizes the criteria we have just 20 been discussing when they consider IRB approval of a 21 waiver or alteration. 22 This originally said OHRP should craft 23 that and then we remembered that they have one and 24 it's shown on the next page right here. This is 25 currently existing decision chart that many people 226 1 find helpful to work through the points in 116(d) for 2 waiver. 3 We simply recommended that OHRP should 4 revise its decision charts, reflect recommendations in 5 this area as needed. To be honest, I don't know that 6 anything we have recommended to date changes the 7 underlying regulation so it may not be anything that's 8 needed but if it is, they will look at that and make 9 appropriate revisions. 10 DR. TILDEN: So we have a motion to accept 11 Recommendation No. 6? 12 DR. SCHWETZ: So moved. 13 DR. TILDEN: Second. All in favor? 14 MR. NELSON: Thank you. 15 DR. TILDEN: Passed. All right. Five 16 minutes and we finish up this presentation? 17 MR. NELSON: We will give you the nickel 18 tour of what we have left which is simply just to let 19 you -- there's nothing left to approve or vote on or 20 discuss really here. It was just to let you know what 21 we are working on. I think we can truncate that. 22 We have formed working groups in the 23 following three areas and formed consent in one of the 24 products you just looked at just now, and other 25 working groups and exemptions, looking at exemptions 227 1 and institutional responsibilities. Informed consent 2 is obviously much more than just the waiver of 3 consent. 4 Many other important parts to this 5 including many aspects of documenting consent 6 including a waiver not of consent that we've just been 7 discussing but waiver of documentation. Delinking 8 Section 116 that deals with what we just talked about, 9 waiver of consent from documentation of consent. 10 Use of the short form. Use of addenda, 11 readability issues, and how that plays into overly 12 lengthy and complex consent documents. Just wanted to 13 note an AAMC initiative in which several of us have 14 been involved and OHRP's involvement as well to 15 simplify and shorten consent documents. I think we 16 may hear more about that tomorrow when Howard Dickler 17 is here on one of our panels. 18 Liability and consent issues, testing for 19 comprehension. We started to get into some of that 20 with the first discussion this morning. What do 21 subjects want to hear and we'll hear more about that 22 tomorrow from one of our panels, consenting in 23 international settings. And again, importantly, as 24 discussed this morning, coordinating our activities 25 with SIIIDR and we look forward to staying in touch 228 1 with them as they and we move ahead on related 2 aspects. 3 Exemptions. It's in front of you. I 4 won't read these to you. This is simply a sample set 5 of questions. By no means all of them but that our 6 working group on exemptions and exempt categories of 7 research are thinking about and discussing. At a 8 later date we will be coming back to you with 9 recommendations in this area. Those two slides are 10 there for your perusal. 11 We have reached out to the common rule 12 agencies and have gotten feedback from these listed 13 here and are open to feedback from others certainly on 14 issues that they see and experience in applying the 15 exemptions. We know there are sometimes agency 16 interpretational differences that confound this area 17 and we are interested in identifying those and doing 18 what we can to harmonize. 19 Institutional responsibilities is the last 20 area and we have broadly construed this area or see 21 this as a broad umbrella over several topics or 22 subtopics, assurances, engagement in research, 23 institutional official responsibilities, and multi- 24 site studies. There is some overlap across these 25 subtopics. 229 1 Assurances. You see the kinds of 2 questions we are considering there in terms of the 3 OHRP filing process, who is covered. Some of the 4 areas for confusion and uncertainty in when is an FWA 5 required, who should be filing it, how often should it 6 be modified, should it be often as modified as is 7 apparently indicated under some circumstances. 8 These are some of the questions we are 9 looking at here, again, in the interest of time, I 10 won't itemize each of these but each of these has in 11 some cases a fairly dramatic impact on the work place 12 in the trenches and we are interested in exploring 13 these more. 14 The very last item there we have already 15 done a fair amount of discussion in our last on-site 16 meeting, why are institutions increasingly unchecking 17 the box, as it's become known, to exclude themselves 18 from voluntary compliance with the subparts and with 19 the common rule except where required by funding and 20 is this good for the research enterprise. 21 Engagement in research is an area where 22 OHRP has already been making and we are pleased with 23 what we have seen thus far and understand is the 24 outcoming revision to the engagement letter that I 25 think has been in place since '99 and many of us refer 230 1 to that. That has been a helpful document and there 2 is an update coming that will help there. 3 Again, related questions when 4 investigators go from one institutions to another, 5 variable understandings across and within funding 6 agencies, requirements for additional assurances that 7 are catching institutions off guard. Again, these are 8 the kinds of things we are considering and will bring 9 back to you at a later date. 10 The definition of engagement does include 11 indirect wordese and invariably is undergoing some 12 revision we learned through Mike Caromd and others and 13 we look forward to both responding to OHRP guidance 14 and providing recommendations that may further that 15 guidance. 16 Institutional official responsibilities, 17 an important audience. I guess here I would just 18 highlight that we strongly endorse the initiatives. 19 Dr. Schwetz has accomplished so much in his tenure 20 here I wouldn't single this out as the highlight but 21 certainly we know that he has made a conscious effort 22 to reach out to institutional officials to engage them 23 in this process -- no pun intended -- but to really 24 stress the importance of their role and to get them at 25 the table. We would like to see that continue and 231 1 would like SACHRP to endorse that process and see that 2 it continues. 3 Many other things that institutional 4 officials are responsible for and in fact, that last 5 item there we are wondering if it might be reasonable 6 to construct a checklist of responsibilities and then 7 periodic reminders from OHRP so they are hearing 8 directly from the top, if you will, rather than from 9 an institutional level that they have a job to do and 10 that it's an important job. 11 Multi-site research. Again, several of 12 the things that we've been talking about. What does 13 it mean to be engaged? What does it mean to cooperate 14 across IRBs? Who files an FWA and when? Many of 15 these things feed into this. There is a conference 16 that was held in November of 2006. 17 A report is enclosed in the binders and I 18 believe we will hear more about that tomorrow so we 19 won't say anything more. Certainly how to remove the 20 barriers to cooperative review liability concerns 21 being among the top of those barriers that prevent 22 institutions from sharing review in multi-center 23 studies. More and more of an issue every day and we 24 are pleased to see federal attention to this area. 25 How to allocate responsibilities across 232 1 sites and across IRBs when they do cooperate. We'll 2 note the local accountability issues here. Lynn Cates 3 and others have shared with us the VA has developed a 4 set of points to consider and Joan as they worked on 5 this within their own context developing a central IRB 6 process. We are interested in studying their process 7 and seeing if we can't extend that. 8 Stay tuned. There is much more to come 9 from our subcommittee. We are meeting next in just a 10 few weeks back in this hotel, I suspect. I haven't 11 looked that far ahead but what you just heard in the 12 last five minutes will be on our table and then we 13 look forward to coming back in October with further 14 recommendations on those areas. 15 DR. TILDEN: Thank you very much. Any 16 questions before we move on? 17 Jeff. 18 DR. BOTKIN: It's really an interesting 19 but ambitious agenda. I think the SIIIDR Subcommittee 20 has had little discussions or kept an eye on the 21 possibility of sunsetting of SACHRP in general so I 22 wonder to what extent you have priority list here 23 should SACHRP not be around for more than another year 24 and a half. Are there pieces of this that you think 25 you can complete in that period of time that would be 233 1 top priorities? 2 MR. NELSON: Well, that's a fair question. 3 I'm taken back to one of my very first presentations 4 and the chair, at that time Ernie Prentice, asked me 5 recognizing how big Subpart A was, the entire common 6 rule, how long we thought this would take. 7 I gave a flippant answer that whichever 8 came first we would either revise the entire common 9 rule or UNC would win the national championship in 10 basketball and that happened the next year so that 11 gave me an opening to step off. We have been focused 12 on in some respects where we consider the biggest 13 problem areas. 14 In other respects what are the low-hanging 15 fruit so to speak. What did we think we could carve 16 out and identify a solution rather than just sit and 17 pontificate forever on. I think those are the reasons 18 that continuing review and expedited review came 19 forth, filtered to the top, if you will. Also now we 20 are moving on to these other areas that you've just 21 seen. 22 These are actually distilled from a much 23 longer list. If you look at just informed consent, 24 there's a lot of issues just within that single bucket 25 and I think waiver of consent. You've seen here we 234 1 are pleased to get through this much today. I think 2 the next meeting within just a couple weeks we'll have 3 to spend some time prioritizing what we have left. 4 In these three areas there are groups 5 moving full speed ahead on each of them. I think it's 6 reasonable. What we have on the table right now I 7 think within a year and a half we will make a good 8 solid effort at knocking these off. Whether every one 9 of those questions are answered is probably 10 unrealistic. Some questions frankly are more 11 important than others, have a bigger impact on the 12 field. 13 I think these are the three topic areas 14 that we'll be focusing on for the foreseeable future 15 and whether we have anything that went beyond that may 16 depend on the future of SACHRP. I think these three 17 we see as realistic things. We've got solid people 18 with interest and expertise in each of these areas and 19 see us moving ahead in parallel on all three of them. 20 DR. GYI: Jeff, to simply echo Dan's 21 point, the subcommittee exists at the pleasure of the 22 parent committee, so if there are priorities that you 23 identify that the subcommittee ought to be addressing, 24 we periodically come back to this group to let you 25 know what we're doing so that if there are gaping 235 1 holes or reprioritization that needs to be done, we 2 are looking to this group to give us that direction as 3 well. Keep that in mind. 4 Just another point of clarification. The 5 subcommittee meetings for those in the audience are 6 not open meetings. Those are closed meetings so just 7 as a point of clarification. In August, or whenever 8 it is that we're meeting, it will be just the 9 subcommittee members that will be present and the ex 10 officio members. 11 DR. TILDEN: Thank you, Felix. 12 Are there any comments from the audience 13 or did we put everybody to sleep today? Please 14 identify yourself and whom you represent. 15 MS. POLLOCK: I am Amy Pollock and I am 16 the Director of Government Relations at the 17 Association for Psychological Science. I just wanted 18 to say how happy I was to see on your future agenda 19 issues of consent and international research. In the 20 psychological science community there is a growing 21 trend to conduct such research. 22 Just to relay some anecdotal evidence to 23 you, a lot of our members are facing very interesting 24 and complex issues when it comes to getting consent in 25 third world countries that the anthropological 236 1 community has dealt with for a long time. It would be 2 really useful just to see the subcommittee deal with 3 some of the issues of verbal versus written consent in 4 a way that addresses more experimental research. 5 For example, I have members who conduct 6 research in Fiji and while it is possible to obtain 7 written consent from the local chiefs who are asked to 8 participate in this research, they become highly 9 dubious when they are asked to do it. It affects 10 their research. 11 It seems that obviously there is a great 12 deal of variability in which IRBs will grant 13 permission to obtain verbal research versus written 14 research and I have a number of graduate student 15 colleagues whose mentors are able to do it but they 16 are not allowed to do it. It would just be nice to 17 see some consensus on this issue and some development 18 on that. Thank you. 19 DR. CHADWICK: Finally, I get to speak out 20 of both sides of my mouth. 21 DR. TILDEN: Excuse me, Gary. Public 22 comment is closed. 23 (Laughter.) 24 DR. CHADWICK: You guys. What can I say? 25 This is just a way to confuse me, I'm sure. 237 1 Gary Chadwick with the University of 2 Rochester. Just a 30-second comment to ask the SIIIDR 3 Subcommittee, and perhaps the Subpart A committee, 4 when they talk about consent, the consent is something 5 an individual gives so I have kind of an allergic 6 reaction to the phrase consenting someone because that 7 really isn't correct. You obtain consent from 8 someone. 9 Also consent is something that an 10 individual gives. You can't give it for someone else. 11 It's really permission to enroll that you're giving 12 for someone else. David and I were talking about 13 that. The regulations essentially confound those two. 14 I think ethically and morally consent is an individual 15 issue, not an issue of surrogate consenting and proxy 16 consenting. In fact, I think the literature 10, 15 17 years ago may have some comments on that specific 18 thing. 19 DR. TILDEN: Thank you both for your 20 comments. 21 We are at the final stage or stretch here 22 for the wrap-up discussion and adjourn. I would like 23 to thank the SIIIDR Subcommittee and Subpart A 24 Subcommittee and SACHRP for their participation today. 25 It was a lot of good presentation and discussion. I'm 238 1 looking forward to more for tomorrow after I get a 2 little rest and a drink or two. 3 I want to remind individuals two things. 4 Each of the SACHRP members have been sent information 5 regarding the meeting schedule for next year. If you 6 wouldn't mind looking at that and responding to the 7 agency, to Cathy, about the availability, or Kelly 8 about your availability for those dates. 9 The second thing is that there is going to 10 be subsequent meetings here tonight so if you would 11 take all your materials with you if you expect to see 12 them back here tomorrow. Have them with you for 13 tomorrow because they would be removed if you don't 14 keep them. 15 Is there anything else? Okay. Then 16 tomorrow morning we'll reconvene here at 8:30 a.m. 17 Thank you everyone for your participation today. 18 (Whereupon, at 4:36 p.m. the meeting was 19 adjourned.) 20 21 22 23 24 25