1 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES SECRETARY'S ADVISORY COMMITTEE ON HUMAN RESEARCH PROTECTION MEETING FRIDAY NOVEMBER 3, 2006 The Advisory Committee met in the Galaxy Room in the Sheraton National Hotel, 900 South Orme Street, Arlington, Virginia, at 8:30 a.m., Ernest Prentice, Ph.D., Chairman, presiding. PRESENT ERNEST D. PRENTICE, PH.D. Chair BERNARD A. SCHWETZ, DVM, PH.D. Ex. Sec. CATHERINE SLATINSHEK, MA Ex. Sec. JEFFREY BOTKIN, MD, MPH Member MYRON GENEL, MD Member NANCY L. JONES, PH.D. Member DANIEL K. NELSON, MS, CIP Member NEIL R. POWE, MD, MPH, MBA Member JAMES H. POWELL, MD Member FRANCINE C. ROMERO, PH.D., MPH Member SAMUEL TILDEN, MD, JD, LLM Member EX OFFICIO MEMBERS MARGUERITE BARRATT NSF HOWARD BRADLEY SSA KATHRYN LYNN CATES, MD USDVA ROGER CORTESI EPA SALLY FLANZER AHRQ DENISE H. GEOLOT, PH.D.,RN,FAAN HRSA PETER T. KIRCHNER, MD DOE JEFFREY W. RODAMAR Dept. of Ed. DAVID SHORE NIMH LINDA TOLLEFSON FDA 2 ALSO PRESENT KELLEY BOOHER Office of Human Research Protections MICHAEL CAROME OHRP JULIA GOREY OHRP JULIE KANESHIRO OHRP IVOR PRITCHARD OHRP KEVIN PROHASKA OHRP IRENE STITH-COLEMAN OHRP 3 A-G-E-N-D-A Remarks, Ernest Prentice, Ph.D., Chairman, SACHRP. . . . . . . . . . . . . . . . . . . . .4 Report of Subcommittee on Research Involving Individuals with Impaired Decision-Making Capacity, David Strauss, M.D., Co-Chair . . . .6 BREAK Panel on Research Involving Individuals with Impaired Decision-Making Capacity . . . . . . 55 Robin Elliott, M.A., Executive Director, Parkinson's Disease Foundation. . . . . . . . 58 Representative Anne Blanchetai Donahue, J.D., Vermont House of Representatives. . . . . . . 83 Sharon M. Grandinette, M.S., President, California Association of Physical and Health Impairments . . . . . . . . . . . . . . . . .104 Public Comment. . . . . . . . . . . . . . . .170 Wrap-up and Adjourn . . . . . . . . . . . . .191 4 1 P-R-O-C-E-E-D-I-N-G-S 2 8:35 a.m. 3 DR. PRENTICE: Good morning, 4 everybody. Why don't we get started with our 5 agenda. As is customary, I'll provide an 6 overview of the meeting today. We are going 7 to begin at 8:35 with a report on our newest 8 subcommittee on research involving decision- 9 impaired individuals. That would be given by 10 David Strauss and I'll introduce him in a 11 moment. 12 Then we'll have a short break. 13 We'll reconvene for our panel and I will 14 introduce all of those individuals at that 15 particular time. We'll have a comment period 16 from the public between 12:00 and 12:15 and 17 then a wrap-up and try to adjourn by 12:30. 18 If you will recall, we talked 19 about the charge given to the Secretary's 20 Advisory Committee on Human Research 21 Protections yesterday and it involves 22 vulnerable subject populations. 5 1 Over the last three and a half 2 years we have examined additional protections 3 for children, additional protections for 4 prisoners who are involved in research, and 5 our latest endeavor is looking at additional 6 protections for individuals who have some form 7 of cognitive impairment. 8 I'm really kind of excited about 9 this latest subcommittee. I think it's long 10 overdue. It's going to be a very, very 11 important endeavor. I am delighted that the 12 chair of this particular subcommittee is Dr. 13 David Strauss and I would like to introduce 14 him at this time and then have him come up and 15 give us a report on the initial steps in 16 formulating this subcommittee and their 17 charge. 18 Dr. Strauss is an Associate 19 Clinical Professor of Psychiatry, Director of 20 the Office of Human Subject Research and 21 Psychiatry at Columbia. He is also Chairman 22 of the IRB at the New York State Psychiatric 6 1 Institute. 2 He is Co-Director of the Ethics 3 Public Policy and Human Rights Core of an NIH 4 funded HIV Center for Clinical and Behavioral 5 Studies, and recipient of two NIH grants on 6 Research Ethics Training and Enhancement of 7 Human Subjects Oversight for Psychiatric 8 Research. 9 He consults. He teaches on a wide 10 range of activities dealing with research, 11 ethics, and regulatory compliance. He is 12 currently a member of the NIH Research Ethics 13 Study Section and is also on one of our 14 subcommittees, that is the subcommittee 15 dealing with Subpart A. Now he's on two 16 subcommittees. We are really getting our 17 money's worth from you, David. 18 David, it's our pleasure to invite 19 you to come up here and address SACHRP. 20 DR. STRAUSS: Hi. Good morning. 21 Thank you, Ernie. It's really an honor and 22 privilege to be here. I was speaking this 7 1 morning with Anne Donahue who is a Vermont 2 state legislator and I was reminded of my 3 first encounter with this whole business or 4 the whole conflict related to research 5 involving subjects with impaired decision 6 making. 7 I was an eager young attending 8 psychiatrist on our brand new schizophrenia 9 research unit. For reasons unclear to me I 10 was asked to give a tour to a New York state 11 legislator who was visiting and wanted to see 12 what kind of monies we had invested in our 13 research operation. 14 Now, coming from work as a 15 clinician primarily into this new job as a 16 clinician on a research unit, I was very much, 17 let's say, protections oriented and so I 18 proudly announced to the state legislator that 19 we never include subjects with impaired 20 decision making or subjects who lack capacity 21 in any of our research studies. That is how 22 concerned we are about their rights and well 8 1 being. 2 He stopped dead in his tracks and 3 he said, "But isn't that exactly why we funded 4 this operation, for you to help those people 5 who are most in need of help?" It made the 6 point to me that I was focused perhaps too 7 much on one side of the story. 8 I think the challenge that we are 9 talking about here today is how to strike a 10 proper balance between protecting the rights 11 and welfare of people who have impaired 12 decision making formulating what kinds of 13 appropriate protections are in order, while at 14 the same time recognizing the really critical 15 clinical and research needs of those 16 populations. 17 I say those populations because in 18 fact, we really need to be broad in conceiving 19 of those people, those groups of people whose 20 decision-making capacity, whose ability to 21 freely and in an informed way consent to 22 research is impaired or absent. 9 1 This is the charge that we've been 2 given in this new panel. I don't know that it 3 makes sense to read it but let me just say 4 that the goal really is for us to develop 5 recommendations for consideration by you, by 6 SACHRP, about whether guidance or additional 7 regulations are needed for research involving 8 individuals with impaired decision-making 9 capacity. 10 It makes specific reference to 11 relevant provisions in Subpart A and the 12 related FDA regulations and asks that we 13 develop one of a few products. Like I said, 14 recommendations on the interpretation of 15 specific Subpart A provisions in order to 16 enhance protections, and/or recommendations 17 for a new subpart under 45 CFR 46. 18 By way of background, 46.111(b) 19 says when subjects are likely to be vulnerable 20 to coercion or undue influence such as 21 children, prisoners, pregnant women, mentally 22 disabled persons, or economically or 10 1 educationally disadvantaged persons, 2 additional safeguards have been included. 3 Within the criteria for approval 4 under Subpart A, that is really the extent of 5 guidance that we are provided. Additional 6 safeguards have been included. Let me 7 emphasize that fact that how one goes about 8 providing those additional safeguards is 9 really not presented within the body of the 10 regulations or in formal guidance, No. 1. No. 11 2 is we really don't have a working or 12 operational definition of what it means to be 13 mentally disabled. 14 Right there I think the challenge 15 to the field is what kinds of additional 16 safeguards are we really interested in. How 17 would we go about structuring those, No. 1. 18 But perhaps even before that, how do we define 19 those who are in need of protection and what 20 does it mean exactly to be mentally disabled? 21 Also within Subpart A under 22 membership criteria it says, "If an IRB 11 1 regularly reviews research involving a 2 vulnerable category, that consideration shall 3 be given to the inclusion of one or more 4 individuals who are knowledgeable and 5 experienced with these subjects." 6 So when we think about the 7 structure of the IRB working with these 8 populations, we are only told that 9 consideration shall be given. I think one of 10 the other things we need to think about is the 11 structure of review for these populations that 12 we are talking about providing additional 13 protections for. 14 Again, in the approval criteria it 15 says that subject selection is equitable and 16 would be particularly cognizant of special 17 problems with vulnerable populations. 18 I think it's interesting that if 19 we think back actually on the kind or the most 20 notorious stories, the most notorious cases in 21 a fairly notorious history of human 22 experimentation in the United States, many of 12 1 those stories do involve these populations 2 that we are talking about today. 3 We think about Willowbrook, for 4 example, as among those stories, those horror 5 stories, about exploitation of people who 6 couldn't protect themselves. We think about 7 the studies in the Jewish Home for the Aged. 8 We think about more recently the study in 9 Florida that recruited pregnant women during 10 labor into a series of research studies. 11 Each of these notorious cases 12 suggest to us that this is an area where we 13 need perhaps the most thoughtful guidance or 14 the most thoughtful regulatory additions. Yet 15 for many years, and until now, there has 16 really been no guidance, which is not to say 17 there hasn't been efforts added. 18 In the criteria for informed 19 consent, the regulation tells us that we are 20 required to obtain the legally effective 21 informed consent and that we have to seek 22 consent only when we can minimize the 13 1 possibility of coercion or undue influence. 2 There's also reference to legal 3 authorized representative. But beyond this, 4 beyond these considerations, the regulations 5 and guidance is completely silent on the issue 6 of how we involve people who cannot consent 7 for themselves in most kinds of research 8 activities. 9 It is left in many cases to the 10 state and in most cases, the states haven't 11 acted in a constructive way to guide 12 researchers and IRBs into who may be included 13 in research studies and what kind of research 14 may be done with those who actually lack 15 capacity to consent. 16 The guiding principle behind all 17 this, of course, is this notion from the 18 Belmont report which says, of course, that 19 some people are in need of extensive 20 protection to the point of excluding them from 21 activities which may harm them, and other 22 persons require little protection beyond 14 1 making sure they undertake activities freely 2 and with awareness of possible adverse 3 consequences. 4 Again, the principle is quite 5 clear but we have to think about how the field 6 has been operating absent coherent regulatory 7 principles and guidance on how to behave. 8 Actually, what's important and what's 9 interesting is now for the first time there is 10 increasingly systematic research looking at 11 how IRBs apply these regulations. 12 Dr. Gary Chadwick is involved in 13 one project looking at surrogate consent 14 across the country. We have actually very 15 little data in hand about how IRBs are 16 actually applying this principle in practice. 17 From the front line what you often 18 hear frankly is that absent any ideas about 19 how to proceed, IRBs are often conducting no 20 research with subjects who lack capacity. If 21 you take a look at the VA regulations, and the 22 VA does have a policy on surrogate consent, 15 1 even there there is no clear definition of 2 what it means to be decisionally impaired. 3 They use the term mentally disabled but there 4 is no definition there either for what that 5 means. Clearly we don't mean mentally 6 disabled in the way that, for example, the 7 Social Security Administration might conceive 8 of it being unable to work. That is mentally 9 disabled but it's not defined further. Nor 10 are any mechanisms for how one goes about 11 assessing who is and who is not mentally 12 disabled. 13 The point here, of course, is that 14 we need to define the vulnerable group and 15 recognize that there are classes of 16 individuals who may have impaired decision- 17 making abilities but there are separately a 18 class of individuals who have impaired 19 decision-making abilities but who nonetheless 20 may be able to make decisions for themselves. 21 There is interesting research, for 22 example, that shows that even psychiatric 16 1 patients who are involuntarily hospitalized 2 for care and treatment, in other words, who 3 are hospitalized against their will because 4 they are felt to be unable to care for 5 themselves in the community, have been 6 demonstrated from research to have certain 7 capacities including, in some instances, 8 capacity to consent to research studies. 9 Capacity is a very task specific thing so we 10 really need to think about capacity to do a 11 specific thing so we can recognize that there 12 are people who have impaired abilities to make 13 decisions but who may nonetheless retain 14 capacities to do certain things including 15 consent to research. 16 Finally, the smallest group, of 17 course, are individuals who lack the capacity 18 to consent to a research study. We really 19 need to have a coherent framework for thinking 20 about in what circumstances, at what level of 21 risk, for example, is it reasonable to conduct 22 research with people who can't make a decision 17 1 for themselves. 2 I talked about this actually in 3 August when I was here. We have to think 4 about decisional impairment, at least as a 5 starting point, from a very broad perspective. 6 There are many different kinds of ways that 7 people can have impaired decision-making. 8 For example, there's decision- 9 making impairment which can be seen a 10 situational, like I mentioned before, 11 approaching a woman who is in the midst of 12 labor and asking her to consent to a research 13 study is unwise for a number of reasons, but 14 one can certainly say that it is unlikely that 15 she can make a considered and voluntary 16 decision about research. 17 So there are situational 18 impairments. The emergency room is another 19 one where the context doesn't necessarily 20 permit the careful decision that may be 21 required for informed consent. Prisons and 22 other institutions are also situational 18 1 contexts in which subject's voluntariness may 2 be compromised. 3 Part of the original thinking of 4 the National Commission in its original 5 Subpart E recommendations, of course, had to 6 do with the idea that we wanted to protect 7 people who were institutionalized as mentally 8 infirmed both because they were mentally 9 infirmed, whatever that meant, and because 10 they were institutionalized recognizing, of 11 course, that being locked in a prison or being 12 hospitalized are not necessarily environments 13 which engender a sense of self-determination 14 or economy. 15 Those situational impairments are 16 different from disorder-related impairments 17 which are intrinsic impairments, let's say, 18 related to stroke or traumatic brain injury or 19 coma. 20 We also have to think about global 21 versus specific kinds of impairments. As I 22 said earlier, someone who is brought into a 19 1 hospital following an overdose, a sedative 2 overdose, may be globally impaired. A patient 3 with paranoid psychosis may be quite impaired 4 in certain domains but nonetheless, be quite 5 capable in many other domains. 6 We have to think about impairment 7 as also being static or progressive or 8 episodic. For example, severe mental 9 retardation we would see in many instances 10 static impairments, not expected to change 11 significantly over time. 12 Alzheimer's is an illness, of 13 course, in which we see progressive decline in 14 decision-making. And manic depressive 15 disorder is one in which quite typically we 16 see quite dramatic shifts in episodic 17 impairment and return to normal function. 18 I didn't mention this here. Maybe 19 we'll talk about this a little bit more later 20 but there are also, of course, conditions in 21 which what we witness is the regaining of 22 decisional capacity where subjects who, for 20 1 example, experience a traumatic brain injury 2 or other kinds of trauma to the brain and who 3 regain capacity over time. 4 It is important to talk about 5 these things because each of these areas that 6 I mentioned are areas where it is critical 7 that we learn about the nature of the disorder 8 and be able to bring to the field important 9 new research opportunities. If we impair the 10 ability to do any research with these 11 populations, and I would say that sometimes 12 absent guidance that is what has happened, 13 then we are really shortchanging ourselves. 14 Then there is acute versus 15 persistent impairment. Someone who is hypoxic 16 and confused or delirious from a fever may 17 have impaired decision-making ability. That 18 is quite different from someone, for example, 19 with autism. 20 The other points that I think I 21 would like to make today is that we do need to 22 recognize that mental illnesses are diseases 21 1 which affect the brain. There have been real 2 changes really since the National Commission 3 first took on this concept of protecting 4 people with impaired decision-making ability. 5 We need to recognize, and we do 6 recognize now, we do know now, that we are 7 talking about brain illnesses in all these 8 categories that I spoke of before. There has 9 been quite dramatic development of new and 10 more successful treatments for brain disorders 11 with many new treatments on the horizon, the 12 ability to study these things. Sometimes the 13 ability to study these things in the most 14 impaired subjects is increasingly important to 15 consider. 16 We have witnessed the end of the 17 asylum, so maybe the term in the late 1970s of 18 those institutionalized as mentally infirmed 19 had a particular poignancy where patients at 20 that time and previous to that were being 21 warehoused in large mental institutions. 22 That is no longer the case in most 22 1 instances. Hospitals or what they are now 2 called, psychiatric centers at times. The 3 level of care and treatment in most instances 4 is quite different. 5 We have witnessed a real birth of 6 patient rights movements which talk about 7 empowerment and partnership with physicians 8 and with the medical establishment and with 9 the research community. There is a new 10 relationship between science and subjects that 11 didn't exist 30 years ago. We have to be 12 mindful of this. 13 It certainly is the case that the 14 federal government, or under the auspices of 15 the federal government and the OHRP and OPRR 16 before that, there has been a quite dramatic 17 reinvigoration of the IRB system and the 18 system for human subjects protections. 19 One only need to attend the annual 20 PRIM&R meeting, professional meeting of IRB 21 groups, to see the massive increase in 22 interest and membership. It is a field that 23 1 is really thriving now with new levels of 2 professionalism and involvement in protecting 3 the rights and welfare of research subjects. 4 We have mandated investigator training. 5 I think more important is that it 6 might have been said 30 years ago that the 7 need to study the brain was present but we can 8 really see right in front of us some dramatic 9 benefits to research on the brain in every 10 condition that affects the brain. We don't 11 have time to talk about those today but it is 12 an exciting decade where we can expect to 13 learn a lot about how the mind works. 14 Eric Kandel, the Nobel Prize 15 winner, talks all about this new science of 16 mind and how he predicts that we will really 17 understand some basic mental processes as 18 never before including memory and affect in a 19 way that interventions will be possible. 20 It means we need to be able to learn about 21 this. 22 As I mentioned before, 24 1 increasingly now we are seeing real tensions 2 between access to experimental treatments and 3 these mental illnesses and brain disorders and 4 the need for protection. We need to make sure 5 that we are cognizant of the proper balance 6 there. 7 As I said, obviously there have 8 been other attempts, NHRPAC and NBAC before 9 that. We need to really consider what 10 happened in the past in those fields when they 11 have issued guidance and regulatory 12 suggestions. 13 We need to learn from history. It 14 is critical that we consider all perspectives. 15 We need to be careful in defining the 16 vulnerable groups. One of the things that 17 happened with NBAC was that NBAC equated 18 having a mental illness with having impaired 19 decision-making abilities. 20 Having a mental illness is not the 21 same as being mentally disabled or having 22 impaired decision-making abilities and so 25 1 perhaps suffering from a lack of input or 2 perspective on that topic its recommendations 3 were met with a fair degree of hostility from 4 the community of patients and researchers. 5 Like I said, it's important for us 6 to understand impaired decision-making in all 7 its dimensions. I think that we need to be 8 really careful in evaluating the risks and 9 benefits of regulatory change and guidance. 10 By that I mean we need to really be mindful in 11 a pragmatic way of how people in the front 12 line, IRBs, IRB members and research 13 investigators will apply the principles or the 14 regulations or the guidance. 15 We really need to be thinking 16 front line in terms of how these things will 17 be translated. It is not really a time for us 18 to be talking about concepts or principles. 19 It's really a time for us to think about how 20 we can create a meaningful practice of 21 research protections in these groups. 22 The folks at OHRP, Ernie, Bern, 26 1 and others have been thinking about the 2 membership of this new subcommittee. I 3 thought we should be called the Decisionally 4 Impaired Subcommittee but Cathy Slatinshek 5 said that was a bad idea. 6 We really want to make sure that 7 we have real clinical and scientific expertise 8 related to the disorders affecting the central 9 nervous system, critical care medicine, and 10 healthcare literacy. We have been working 11 hard sending out feelers, evaluating a lot of 12 helpful input from many of the members of 13 SACHRP and others around the country. 14 What is really kind of interesting 15 to me is not just that there is a lot of 16 interest and involvement in this subcommittee 17 but so many people who otherwise say no 18 because they are too busy to everything have 19 said, "This is an important enough issue for 20 me that I will make it my priority if asked to 21 serve." 22 There is a lot of interest and I'm 27 1 not talking just within science. I'm talking 2 about really in all communities that we have 3 made contact with. It's not surprising but it 4 is nonetheless important to note. 5 We have decided, of course, that 6 we really need to have strong input from those 7 in the patient and family advocacy field. It 8 is critically important really. These are in 9 many ways the most important stakeholders in 10 this enterprise. 11 Their perspectives are ones that 12 all too often are not taken into consideration 13 in some of the activities that occur. We need 14 to make sure their voices are heard. I say 15 their voices because it is a mistake to think 16 that these communities represent a single 17 perspective. There are many perspectives in 18 this area. 19 There is a really growing field of 20 empirical research ethics. We know a lot now 21 that we didn't know 15 or 20 years ago about 22 informed consent in these populations. It's 28 1 been studied. It's been well-funded in recent 2 years by NIH. There are many seasoned 3 investigators who can speak from data what it 4 means to have impaired decision-making 5 ability. We can learn from them and I think 6 we need to in this process. 7 Legal aspects are critical here. 8 Among other things the committee may come up 9 against this whole notion of legally 10 authorized representatives. It may come up 11 against state laws on surrogate consent. We 12 want to make sure that we have very helpful 13 legal thinking in this process. 14 Then finally, of course, because 15 ultimately the value of our products will 16 depend on our ability to be pragmatic and make 17 these work within current regulatory and IRB 18 systems. We want to make sure we have 19 expertise and research oversight and human 20 subjects protections. 21 In terms of process, we have 22 assembled a long but by no means a complete 29 1 list of contenders and in the next couple of 2 weeks we will be making final decisions and 3 perhaps sending out invitations. So that is 4 by way of background where we're headed, our 5 thinking on this. 6 Ernie, shall we open it up for 7 questions and discussion? 8 DR. PRENTICE: Yes. Thank you 9 very much, David. I'm taking the Chair's 10 prerogative. I often ask the first question. 11 You talked about the requirement for 12 additional protections in the federal 13 regulations, specifically 46.111(b) and 56. 14 111(b). Those regulations have been in effect 15 since 1981. 16 I'm curious to ask you two 17 questions. One is to what extent do you think 18 IRBs who are involved in reviewing research 19 that includes decisionally impaired subjects, 20 have been applying additional appropriate 21 protections. If so, what are the common 22 methods that they have used to provide such 30 1 protections? 2 DR. STRAUSS: Well, I certainly 3 haven't done any systematic investigation of 4 this but let me tell you what I think. I'm 5 sure there are others here, if that would be 6 okay with you, who might want to comment on 7 that who perhaps have other perspectives on 8 that. 9 My sense is that to a large extent 10 research facilities that work with populations 11 of the sort that we are talking about will 12 provide additional protections in the consent 13 process. Originally, or at least until 14 recently, I would say that would primarily be 15 in the form of requiring an independent 16 assessment of capacity. 17 That would be, I think, the most 18 commonly applied additional protection. I'm 19 sure the folks from OHRP and Compliance can 20 speak more to this issue. The requirement is 21 that institutions have policies with regard to 22 what kind of additional protections will be in 31 1 place. 2 The requirement, for example, of 3 an independent assessment of the capacity for 4 subjects who may have impaired decision-making 5 I would guess is the most common kind of 6 additional protection. 7 More recently again, and probably 8 following on some of the empiric literature, 9 many institutions, and I'm talking about 10 outside NIH and outside the major academic 11 centers, have been applying specific tasks, 12 for example, to assess capacity. They may 13 require a mini mental state exam. They may 14 require a kind of questionnaire so they are in 15 that form of consent enhancements. 16 Then I think there is another 17 category that is applied. I can certainly say 18 that at my institution probably what we do is 19 we really have a sliding scale in many ways in 20 terms of risk benefit thresholds and so we 21 adjust our approval threshold. In other 22 words, our view of what is reasonable shifts 32 1 depending on our sense of the vulnerability of 2 the subject. 3 We think about how to approve 4 research based on the subjects who are likely 5 to be enrolled. The more vulnerable the 6 higher our threshold for approval but I would 7 be interested to hear, if you would, Ernie, in 8 what others perhaps who have other 9 perspectives on that might say. 10 DR. PRENTICE: Let me ask one more 11 follow-up question pertaining to vulnerability 12 tied to an acceptable risk benefit 13 relationship. As you know, the proposed 14 additional protections for individuals with 15 impaired decision-making capability, Subpart 16 E, largely reflected the Subpart D categories 17 where if there is an absence of direct subject 18 benefit there is a limitation on risk. 19 In Subpart D, as you know, it is a 20 minor increase over minimal risk and there was 21 a similar type of risk threshold in Subpart E. 22 Could you comment on perhaps what your IRB 33 1 thinks about risk limitations tied to 2 vulnerability? 3 DR. STRAUSS: Again, this is my 4 personal perspective on it. I think it's 5 limiting in many ways. I think in certain 6 instances what winds up happening is that you 7 wind up, let's say, over-protecting groups 8 that don't require protection and under- 9 protecting others that do. 10 I guess my point is that I think a 11 categorical approach in that way is 12 restrictive and ultimately not helpful. In 13 other words, impairments are neither present 14 nor absent. Vulnerability is neither present 15 nor absent. 16 It occurs along a spectrum and so 17 by virtue of having to take those subjects and 18 that research and box them into a particular 19 one of two categories you are limiting 20 essentially, forgive me, wisdom of an IRB who 21 is closer at hand and may be in a position to 22 tailor more appropriate safeguards. 34 1 DR. PRENTICE: Okay. Jeff. 2 DR. BOTKIN: That was a very 3 helpful presentation. Thank you. I have a 4 question about what we should consider the 5 spectrum of decisional impairment. I tend to 6 think about this in the context of 7 vulnerability due to the inability of people 8 to make decisions either because they can't 9 understand the information or can't make a 10 rational decision based on that information. 11 It seems to me that there is a 12 spectrum of vulnerability due to people's 13 perhaps other impairments. Not the inability 14 to make decisions but perhaps the influences 15 that are psychological, psychiatric in nature. 16 I'm thinking specifically here of issues like 17 paranoia or people who may be excessively 18 dependent on caregivers or perhaps enhancing 19 therapeutic misconception. 20 Or perhaps even people that have 21 memory impairment who can make a perfectly 22 rational decision today but you ask them next 35 1 week how the research is going and they have 2 no recollection that they are part of a 3 research enterprise. 4 Is it your sense that the kind of 5 measures we might be talking about or IRBs 6 might be utilizing or encouraging 7 investigators utilized to assess decision- 8 making capacity encompass these types of 9 deficits as well that seem to me to be 10 potential significant source of vulnerability 11 for folks? 12 DR. STRAUSS: I think so. Again, 13 this subcommittee will, of course, take its 14 charge from you and from the parent committee 15 but I think at the start, we need to cast a 16 wide net and to make sure we survey the whole 17 landscape and then think about what we can 18 best accomplish from a pragmatic perspective. 19 Yes, I mean, I certainly think 20 those areas that you mentioned are areas that 21 are critical. If we are only talking about a 22 kind of points to consider or a method of 36 1 enabling IRBs to focus on these kinds of 2 issues, then we'll have accomplished 3 something. 4 What you raise, I think, speaks to 5 the issue also of expertise on the IRB because 6 an IRB can't arrive at those kinds of 7 understandings of complexity of decisional 8 impairment without appropriate expertise. 9 DR. PRENTICE: Other questions? 10 You have obviously looked at the charge and 11 this is a very complex charge, in my opinion. 12 How long do you think it's going to take to 13 actually develop a series of recommendations 14 that would fulfill the charge? Do you have 15 any idea? I mean, years, decades, a lifetime? 16 MR. NELSON: David, before you 17 answer, I'll caution you when I was sitting up 18 there launching the Subpart A subcommittee and 19 Ernie asked me the identical question, I very 20 flippantly and too fast said, "When we have 21 completely revised the subpart or when UNC 22 wins the national basketball championship, 37 1 whichever comes first," and that came within 2 the year and he didn't let me off. Be careful 3 how you answer. 4 DR. STRAUSS: All right. 5 Obviously I have no idea. 6 DR. PRENTICE: Good answer. 7 DR. STRAUSS: I think part of the 8 reason of bringing together this subcommittee 9 will be to gather the necessary expertise in 10 the room. I think once we do and once we 11 refine a reasonable aim in terms of product 12 and process we'll be able to report back or 13 ask this committee how far you would like us 14 to go, where you would like us to focus and so 15 on. 16 But these preliminary ideas, I 17 think, again, are with the aim of casting a 18 fairly wide net. We are unlikely to change 19 the world even in two years of the standard 20 subcommittee process but I think we may 21 recognize several key areas where change on a 22 short time table is critical. I hope that we 38 1 can accomplish at least that within the 2 typical scale. We haven't yet met so it is 3 hard for me to say what we'll learn in that 4 process. 5 DR. PRENTICE: There are obviously 6 two ways your committee could go in terms of 7 a final product. One is recommendations on 8 guidance and the other is recommendations that 9 there be a new subpart. 10 Would you comment on what you see 11 as the advantages and disadvantages, the pros 12 and the cons of either one of those outcomes 13 recognizing the fact, of course, that you 14 haven't had the benefit of any subcommittee 15 deliberations on that but I know you've been 16 thinking about that. 17 DR. STRAUSS: I think that there 18 are problems in terms of interpreting the 19 regulations which cut across the kinds of 20 situations and disorders that investigators 21 and IRBs grapple with. 22 The issue of vulnerability, for 39 1 example, in its broadest form, I think, or 2 remedies regarding vulnerability will overlap 3 significantly with some of the kinds of things 4 the committee will consider. If we look at 5 111, again the reference there is to people 6 who are, for example, economically 7 disadvantaged. 8 We may see in the process of 9 thinking about additional protections for 10 people who have impaired decision making that 11 the kinds of recommendations we will want to 12 make will have importance for some of those 13 other categories of vulnerable subjects as 14 well. 15 We want to be careful not to 16 define a new subpart that is too specifically 17 focused on a certain category of research 18 subject. In terms of whether a subpart versus 19 guidance is necessary, you know, I'm sorry to 20 be dodging these questions, although I guess 21 when in Rome. 22 I think the starting point for 40 1 some of the discussions has to be what has 2 gone wrong before. Lots of really smart 3 people, well-intentioned smart people, have 4 gotten together and tried to tackle this 5 really critical issue and have produced 6 documents and recommendations which have not 7 made it to the field. 8 I think we really need to 9 understand why that has occurred. I think 10 whether the problem is that the Subpart E 11 concept was too restrictive, whether it was 12 too proscriptive, you know, I think that we 13 need to begin by learning what went wrong 14 before. 15 I don't want to prejudge that so 16 I'm not starting out personally with any 17 preconceived notion. I do feel that a Subpart 18 E that would look like Subpart D might be 19 overly restrictive. 20 DR. PRENTICE: Other questions? 21 Yes. 22 DR. SCHWETZ: David, a question 41 1 from Rome. You refer to casting a wide net 2 which means you will capture a lot of 3 different forms of impairment. The extent to 4 which subjects in a given category of 5 impairment might be vulnerable to risk of 6 research is one consideration that might set 7 a priority for the subcommittee. 8 Unfortunately, the areas that are popular for 9 research don't necessarily match up with that 10 so you are trying to pursue questions relative 11 to risks represented by research when, in 12 fact, the area of emphasis of research today 13 is different than it was five years ago, 10 14 years ago, and will be different than what it 15 will be five years from now because things are 16 either popular or have lost popularity 17 unrelated to whether or not these are 18 important to the health of the people who have 19 these impairments. 20 How would you envision the 21 subcommittee making a decision? Do you track 22 where the research is and look at the risk 42 1 there, or do you look at the vulnerable 2 populations and assign priorities among them 3 as you are trying to narrow what you capture 4 in the big net? 5 DR. STRAUSS: I am going to answer 6 that indirectly but get to the point. It 7 surprises me often when I talk with 8 investigators at some institutions, or at my 9 institution, that they think of assessing 10 capacity as the thing you do when people may 11 have problems with decision-making rather than 12 recognizing that there is an affirmative 13 obligation on the part of the investigator to 14 always make sure that the subject has 15 understood the risks and benefits and 16 alternatives and the choice they are making to 17 participate in a research study. 18 The scenario, of course, is that 19 the investigator presents the consent form, 20 maybe even reads it to the subject. The 21 subject looks at it, signs it, and hands it 22 back, end of story, rather than there being a 43 1 real engagement or dialogue, questions and 2 answers and an assessment on the part of the 3 investigator that the subject knows what he or 4 she is agreeing to take part in. 5 Obviously that kind of assessment 6 of capacity is required. I think it is always 7 required during consent. To answer your 8 question, my thought is that it is conceivable 9 to think about guidance in this area of 10 informed consent that applies in all cases but 11 reflects a kind of changing intensity 12 depending upon the nature of the condition and 13 what is learned during the initial assessment. 14 In other words, the protections 15 have to be tailored in many ways. The 16 practice has to be tailored to the individual 17 subject always. I guess I would wonder if 18 guidance or even a subpart would be better not 19 directly related to particular disorders or 20 particular categories of illness, but 21 recognizes that across the board there's a 22 spectrum with which people can make decisions 44 1 for themselves. 2 I think ideally what we do is we 3 create mechanisms whereby investigators and 4 IRBs, and I'm going to use this word but I 5 don't mean it exactly, are sensitized to the 6 issues and have tools for thinking about it 7 and applying the principles. That is vague, 8 I understand, but again -- 9 DR. PRENTICE: Okay. As you know, 10 we have ex officio members represented on all 11 of our subcommittees and we've got Dr. David 12 Shore from NIMH who has obviously been 13 involved in this whole issue for a very long 14 time. David, would you like to make any 15 comments? 16 DR. SHORE: It depends on the 17 meaning of the word "comments." 18 DR. PRENTICE: This is Rome. 19 DR. SHORE: I actually have been 20 listening carefully and I think based on the 21 discussions that we had at the last SACHRP 22 meeting that I feel even more strongly than I 45 1 did then. 2 As David has suggested this 3 morning that adopting a new set of regulations 4 will have potential adverse consequences for 5 the kinds of research that are most needed at 6 this point. I think that Dr. Strauss' summary 7 was outstanding and I wouldn't have said 8 anything differently had I been up there. 9 DR. PRENTICE: Yes. 10 DR. BARRATT: Let me just add, Peg 11 Barratt from NIH, that David is going to be 12 helping us with leadership on an NIH-wide 13 consideration of these issues so we'll have 14 our own process to try and gather from across 15 our large organization some input for this. 16 DR. SHORE: We have a subcommittee 17 that is going to look at a number of issues 18 including the previous points to consider 19 document on issues of questionable decision- 20 making which was designed to be a sliding 21 scale flexible document. 22 Since it was prepared, as you may 46 1 recall, as a result of a panel in which you 2 participated back in 1997/98, we think that it 3 is probably due for something of an update but 4 for the most part it is a pretty good starting 5 point for us. 6 DR. PRENTICE: Okay. Great. 7 Thank you. 8 Jeff. 9 DR. BOTKIN: I've got two 10 questions I want to pose here. One is the 11 scope of the work of the committee, or the 12 subcommittee. I'm wondering whether much 13 consideration to the question of how to 14 potentially enhance decision making capacity 15 by those who may be deemed as having 16 incapacity. 17 Part of the issue is who has 18 capacity and who doesn't and then you treat 19 them in one way or another. It seems to me 20 there is an opportunity to say by having 21 enhanced decision-making support for certain 22 categories of individuals who might otherwise 47 1 be considered incapacitated you might bring 2 them above that threshold in some fashion. 3 That may well be a naive kind of question but 4 it seems to be perhaps part of the scope of 5 the subcommittee to say are there different 6 ways to approach these patients that would 7 enhance their abilities. 8 The second question I had, and 9 this is I guess a theme for me during this 10 meeting, is characterizing the nature of the 11 current problem. I think there is clearly a 12 lack of conceptual clarity about the regs. 13 IRBs want more guidance about how to do this 14 right and that is intrinsically important and 15 makes the whole effort worthwhile, but I'm 16 wondering what your sense is of the community 17 who does this kind of research, perception of 18 the current situation. Are the risks too high 19 for this group of patients because of how IRBs 20 are dealing with this issue? Are IRBs being 21 excessively restrictive in not permitting 22 important research to go forward? Is it both? 48 1 I wonder whether you have a sense of what the 2 attitude in the field is about current 3 oversight. 4 DR. STRAUSS: It depends who you 5 ask. I suspect it's both. I mean, one of the 6 reasons why I point out the historic changes, 7 the changes in quality of care, and really, I 8 think, especially the changes in the quality 9 of research oversight as a result of the 10 field, the human subjects protections field 11 that we are part of. 12 I think things have probably 13 shifted recently. The loudest complaints, of 14 course, come from two groups. I think 15 researchers who feel that important work that 16 they would like to do can't be done. Many 17 institutions, I can speak around New York 18 State, just don't know what to do with 19 subjects who cannot make decisions for 20 themselves at all and so do nothing. IRBs are 21 reluctant to allow them to do anything absent 22 clear guidance. 49 1 We also hear very vocal complaints 2 from research or disease advocacy 3 organizations whose job it is to try to move 4 care and treatment forward but feel some 5 important research was being hampered. 6 I think there is also a community 7 of people who worry about risks to subjects as 8 being too high. Again, I think there are more 9 mainstream and let's say, more fringe groups 10 that voice opposition to research with some 11 quite important and legitimate concerns and 12 others are antagonistic to the enterprise so 13 I think it covers the broad spectrum. 14 But my sense is now that certainly 15 in the academic communities among IRBs and 16 researchers that people feel that there is 17 inadequate guidance and as a result, research 18 is not occurring. I think that is probably 19 the shift that has occurred. I don't think we 20 have Willowbrook anymore. 21 The first question you asked is so 22 not naive I can't even begin to say. I should 50 1 have mentioned it specifically but of course, 2 I think that is critical, the idea of can we 3 enhance capacity. Now, look, I mean, that 4 could take the form of something fancy but it 5 could simply take the form of a better consent 6 form. 7 At my institution, it's silly but 8 we started requiring a consent cover sheet 9 before every 10-page consent form. It's 10 outlined and bulleted. It tells you what you 11 need to know. On the front of it it says, 12 "This is merely a guide to what you are about 13 to experience," so to speak. 14 The details are within and we will 15 go over those with you but this is a kind of 16 quick and dirty preparation. It's not a 17 paragraph, it's bullets because we think that 18 helps. 19 Even little enhancements probably 20 go a long way and I suspect that there is 21 probably, again, looking at multi-center 22 industry sponsored clinical trials in serious 51 1 psychiatric illness, I'll tell you that most 2 of the consent forms that come to us from 3 outside haven't considered enhancements so I 4 think that is critical. On our long list of 5 potential candidates we have a couple of 6 people whose research areas include that. 7 DR. PRENTICE: Mike. 8 MIKE: David, that was a superb 9 presentation. The Subpart A subcommittee is 10 now going to consider IRB membership criteria. 11 I have a suspicion that will overlap a great 12 deal with the functions of your subcommittee 13 because I suspect there is an enormous degree 14 of variability upon the expertise that is 15 available within various IRBs. 16 Your IRB, I presume, is extremely 17 competent because it's comprised totally of 18 researchers who are involved in this, or 19 people who are conversant in this area but 20 that's not true outside of that. I wonder 21 would you comment on particularly how the work 22 of your subcommittee may interact with the 52 1 efforts of the Subpart A subcommittee in terms 2 of committee membership and education of IRB 3 members. 4 As an aside I would ask you is 5 there any data on how many subjects sign 6 consent after reading the executive summary 7 without reading the full form? I have a 8 suspicion what the answer might be. 9 DR. STRAUSS: You know we would be 10 sending the wrong message if we didn't try to 11 harmonize recommendations within SACHRP 12 subcommittees themselves so I think that we 13 will have to work closely with Subpart A on 14 those issues. Right now I sit on Subpart A 15 and will be co-chairing this new subcommittee. 16 Whether it's possible for me to do 17 all those things going forward we'll see. The 18 perks are substantial but you know. No, I 19 think it would be so silly for us not to work 20 closely together on those kinds of 21 recommendations regarding membership. 22 Like I said before, I think we 53 1 have yet to consider whether we are going to 2 have a separate subpart or whether what we are 3 going to present will either be an addition to 4 Subpart A or an elaboration of the form of 5 guidance of Subpart A. That remains to be 6 seen so we will need to work closely. I know 7 the co-chairs of the Subpart A subcommittee 8 and I am fond of them so I think they'll be 9 good. 10 In terms of how often subjects 11 just read the cover sheet and don't read 12 further, I actually don't think that happens. 13 The cover sheet provides really inadequate 14 information to make your decision. It really 15 is a guide. It tells you the kinds of things 16 to look out for with it. 17 The investigators really have to 18 go through the consent form and then sign the 19 capacity assessment. I mean, you can also ask 20 how often do people understand the consent 21 form. That is another issue. 22 MR. NELSON: Just a quick follow- 54 1 up, Ernie, if I may. I am speaking on behalf 2 of the Subpart A subcommittee. We would be 3 delighted to have David find the time to stay 4 on our subcommittee as well as chairing this. 5 I wanted to get that on the record today. 6 Not only for the liaison and the link between 7 these activities but because of his great 8 contributions to our work. 9 On the question of membership, it 10 is an area where you have to be careful what 11 you ask for. At least what you put out there. 12 I would opine that one of the reasons the 13 earlier efforts in this area that David 14 referenced already did not take root in the 15 IRB community is because they were perceived 16 as in some respects overly prescriptive in one 17 area was quite specific recommendations or in 18 fact, requirements for, for example, numbers 19 of members in certain categories. 20 By the time you get all your 21 categories represented you have a board of 50 22 people, etc., etc. We'll look forward to 55 1 certainly David's subcommittee thoughts in 2 that regard. 3 DR. PRENTICE: Okay. Nancy, would 4 you defer your question to later? Thank you. 5 We are five minutes over. We are going to 6 reconvene at 9:50. Thank you very much, 7 David, for a very informative presentation. 8 DR. STRAUSS: Thank you. 9 (Whereupon, at 9:35 p.m. off the 10 record until 9:51 p.m.) 11 DR. PRENTICE: If people would 12 assume their seats, please. Okay, folks. If 13 everyone would assume their seats, please, 14 we'll try to get started. The microphones are 15 not terribly loud today, so I would encourage 16 everyone to speak directly into the microphone 17 to get the volume up. 18 Now we are going to move into our 19 panel discussion on research involving 20 individuals with decisional impairment. And 21 we have three panelists, and let me tell you 22 what the format will be. I will ask each 56 1 panelist in sequence to come up and give a 2 presentation that should be roughly, well, no 3 more than 20 minutes, if possible. Then I 4 would ask that individual to go back down to 5 the audience and sit down. I think you'll be 6 more comfortable doing that. And then, at the 7 end of the presentations of all three 8 panelists, we'll ask all three to assemble up 9 there at the table, along with David Strauss, 10 who will serve as a moderator. I would like 11 to ask you to hold your questions until the 12 end of all three presentations, if you would. 13 The first panelist is Robin 14 Anthony Elliott, who is the Executive Director 15 of the Parkinson's Disease Foundation. I will 16 give you some information from his bio. I 17 won't read all of it. It is rather extensive. 18 He has been the Executive Director 19 of the Parkinson's Disease Foundation since 20 October, 1996. He is often cited as a leader 21 amongst Parkinson's organizations for 22 prompting collaborative efforts, including 57 1 negotiating a merger with the Chicago based 2 United Parkinson's Foundation in 1998. 3 He has played an instrumental role 4 in the creation and organization of the World 5 Parkinson's Congress in 2006. He was very 6 active in development, communications, and 7 not-for-profit management in New York City for 8 more than 30 years prior to his tenure in 9 Chicago. 10 As you'll find out from his 11 accent, he grew up in Southern England, 12 received his formal education at Bradfield, 13 and then Oxford University after that, and 14 Columbia University here in the U.S. 15 So Robin, thank you very much for 16 agreeing to come to SACHRP and speak with us 17 today. 18 MR. ELLIOTT: Again, thank you 19 very much, Dr. Prentice, for this privilege. 20 I should say that my role with the Parkinson's 21 Disease Foundation are much less deeply and 22 extensively qualified as all the people you 58 1 heard from earlier today. 2 I am a generalist, and a person 3 with great interest in healthcare, health 4 policy, and a certain background also in some 5 of the ethical aspects of this kind of thing, 6 but I feel very humble in the face of people 7 who have worked either in social work or 8 allied health professions, psychiatry, and the 9 other very important front line areas of this 10 sort that are central to the problem that has 11 been addressed by this committee and this 12 subcommittee today. 13 Having said that, as a generalist 14 I have the privilege of talking with all sorts 15 of people, and in the couple of weeks I've 16 had, since being notified of this opportunity, 17 I have taken the opportunity to speak with 18 colleagues in medicine, and clinical research, 19 and in some of the social work disciplines to 20 kind of prepare myself for this. 21 It has been a very interesting and 22 enlightening experience, which has actually 59 1 refired my own curiosity about how one can 2 create and refine systems to meet 3 simultaneously the needs of science and the 4 protection of people, especially human 5 subjects and research, which is the central 6 thing before this committee, so it has been a 7 great experience doing this. 8 I should also say, having looked 9 at my printed slides this morning, I have been 10 traveling in Japan, and some of this had to be 11 done long distance. The committee, I hope, 12 will forgive the occasional assaults both upon 13 the English language and on logic and other 14 things as we go through this, a couple of 15 corrections I'll make on these slides, which 16 I can assure Ms. Hill I shall give you full 17 written correction for after this meeting, for 18 the record. 19 We had a preparation for this 20 discussion in a conference call about a week 21 ago. I raised the question with Dr. Prentice 22 and others whether it would be appropriate for 60 1 a person in my position to talk specifically 2 about a particular disease entity, recognizing 3 that the more general subject before you, of 4 course, has to do with research in general 5 across the entire spectrum of disorders that 6 may involve cognitive impairment. 7 And I was assured by the chair 8 that this kind of, maybe more parochial focus 9 would, in fact, be appropriate, so I'm taking 10 advantage of this, and speaking specifically 11 about the issue as it pertains to Parkinson's, 12 but maybe opening the door for the fact that 13 any given disease area properly described and 14 properly examined by people will provide a 15 portal or a window into the way that these 16 issues would also play out in other disease 17 areas. And I assume this is something that, 18 as we proceed with the discussion, that you 19 will see. 20 I would like to start with just a 21 little description here of Parkinson's. For 22 those of you in the audience who are not 61 1 directly familiar with it; for those who are, 2 forgive me if I run through this quickly. 3 Parkinson's is termed a movement disorder, and 4 has been so for 20, 25 years or so. And it is 5 characterized, medically, by criteria of a 6 movement nature. That is to say, resting 7 tremor, slowness of movement, sometimes called 8 bradykinesia, and rigidity. All of those 9 three criteria that are used as the hallmarks, 10 the clinical hallmarks of Parkinson's, are of 11 a motion motoric nature. 12 What is particularly interesting 13 in terms of the subject before you today is 14 that, increasingly, Parkinson's is being 15 viewed, not just by the world and by the 16 patients who live with it, but by the doctors 17 who study it, as more of a full-body disorder, 18 one that really is multi-dimensional, that 19 extends beyond the motion directing areas of 20 the brain such as the substantia nigra and the 21 dopaminergic system, that is faulty in the 22 creation of Parkinson's, but also extends into 62 1 other areas of the human system, which means 2 that there are symptoms associated directly 3 with the Parkinson's itself that go way beyond 4 the motoric, and include the examples I've 5 given here - fatigue, organomic disfunction in 6 the area of gastrointestinal and other areas, 7 depression, psychosis, cognitive decline, and 8 potentially, dementia. 9 Cognitive decline is now 10 considered one of the descriptive features of 11 Parkinson's disease, and not something that 12 simply happens to older people as they get 13 older, and maybe experience co-morbidity with 14 other conditions such as Alzheimers. 15 Parkinson's itself is, in fact, associated 16 with this, and I'll come to you a little more 17 with that later. 18 Parkinson's, just to give you an 19 idea of the whole frame work here, affects 20 some 1 to 2 percent of the people over the age 21 of 60, which is 500,000 to a million within 22 the United States. That is rather a wide 63 1 range. We don't have a registry, which is why 2 it's a wide range, but it is a significant 3 number of people. 4 Back to the point of half a minute 5 ago. More than 80 percent of people with 6 Parkinson's do, in fact, experience some level 7 of cognitive impairment within 15 years of 8 diagnosis. It is one of the most common 9 facets of the condition. 10 And if you then compare this in 11 Parkinson's with people age-matched controls 12 in the general population, the rate of 13 cognitive impairment is indeed significantly 14 higher in people with Parkinson's than in 15 comparable non-Parkinson's populations. 16 One of the senior clinical 17 researchers, who I spent some time with in 18 Japan three days ago in preparation for this, 19 told me that his own studies in Chicago have 20 shown something like eight or nine times 21 difference. I'm told that that is maybe a 22 little high - five to eight to nine times the 64 1 incidence - which clearly is a very, very 2 distinct difference, and one that many, many 3 people with Parkinson's do suffer this. 4 It is also of note on this slide, 5 the last point on this slide, that the kinds 6 of cognitive impairment that are experienced 7 in Parkinson's are not identical with those 8 that are experienced in other neurologic 9 conditions, most particularly, Alzheimers. 10 Clinicians tell me that such areas as loss of 11 executive function and competence in visual 12 spacial distinctions may be impaired more in 13 Parkinson's than memory, for example, which 14 is, as I understand it, the hallmark of 15 impairment in Alzheimers. 16 So, we are dealing here then with 17 a cognitive impairment, but a cognitive 18 impairment that is unique and different from 19 the cognitive impairments experienced in other 20 neurologic conditions. 21 I took some time, prompted by the 22 people who guided me excellently in this 65 1 preliminary conference call we had a week or 2 so ago to reread the Belmont report. It is a 3 masterpiece, I must say, a masterpiece of 4 ethics and erudition, and a concern for all 5 the various elements here. 6 I was thinking about it in terms 7 of application to Parkinson's. The principles 8 there certainly resonate as brilliantly now, 9 in 2006, as they did in 1979 when they were 10 prepared. The three hallmarks, the criteria 11 here for ethical treatment and approaches in 12 this area that we are dealing with. Respect 13 for persons, which they describe as a cardinal 14 principle that plays out in the process 15 through the practice of informed consent. 16 This area No. 2 of beneficence, 17 which is essentially a way of describing the 18 risk benefit analyses that we need to apply 19 always in looking at how we measure one value 20 against another in determining what is the 21 right and the appropriate way of treating and 22 respecting the rights of people with cognitive 66 1 impairment. 2 And, finally, justice through 3 fairness in participant, which plays out in 4 participant selection, that people should not 5 be unduly burdened, that people should not be 6 unduly exploited, that privileges should not 7 be extended to one group at the expense of 8 others, for whatever reason. 9 This is going to be one of my two 10 or three recurring themes in these few 11 minutes, this idea of what constitutes, then, 12 fairness. I think one of the things that 13 clearly influenced the Belmont people, because 14 they were primarily concerned with the issue 15 of human protections, and very properly so, 16 but one of the things that maybe they spent 17 less time on, less concern with, and maybe the 18 context of the times wasn't the same as it is 19 today, is fairness as applied to opportunity. 20 It is quite as important that 21 people have the opportunity to do something in 22 the right circumstances, and with full 67 1 assurance that they are able to express their 2 preferences here; it is quite as important 3 that they have those opportunities, as it is 4 that they be protected from things that would 5 happen to them of an adverse nature. 6 And so there is this sort of 7 double focus of fairness or justice is, I 8 think, a recurring theme throughout this 9 meeting today, and was referred to earlier by 10 the excellent presentation by Dr. Strauss in 11 several of his comments, and I think is going 12 to be very much like motif of the rest of our 13 discussion today. 14 A point here in terms of how, 15 within Parkinson's, then, what the cognitive 16 impairment, how this issue plays out in 17 considerations about clinical trial 18 participation. This first point, terribly 19 important, came through every conversation I 20 had over the last couple of weeks, that mild 21 to moderate cognitive impairment may not 22 interfere with participation in Parkinson's 68 1 clinical trials. It may not at all; it may 2 be something that, with the right kinds of 3 appropriate controls, here, and assurances of 4 informed consent that, in fact, it might be 5 something -- it is certainly something that 6 should not be a barrier to participation. 7 The word "spectrum" was used 8 earlier this morning. There is clearly a 9 spectrum in the area of cognitive impairment, 10 which can stretch from something extremely 11 mild, to something that is very serious in the 12 area, obviously as we move into dementia, but 13 not all cognitive impairment is dementia. 14 This is clearly very obvious to everybody in 15 this room. 16 It is obvious to all of those who, 17 well, in IRBs in other areas who try to 18 implement these practices, but it is something 19 that clinicians I have spoken to feel 20 sometimes the concern about dementia, for one 21 reason or another, being an excluding 22 criterion for involvement can sometimes spill 69 1 over into forms of cognitive impairment that 2 are much less serious, where the person 3 retains much greater control over their 4 autonomy, and ability to decide what or what 5 not to participate in. 6 And this distinction, this 7 recognition of the spectrum and the different 8 points on it is completely crucial. One of 9 our most serious and wonderful advisers in 10 Parkinson's is a man in this area, Washington 11 area, Ph.D., wonderful background in health 12 delivery, is deeply interested in research, as 13 many people who are educated and who 14 understand the purposes of this and see what 15 opportunities there are, this person would be 16 certainly a very good candidate, and presents 17 himself as a candidate for trials, and has on 18 several occasions. I think he has 19 participated in no fewer than three trials. 20 This person probably at this point does, in 21 fact, experience impairment by this own 22 admission, and by those who are much more 70 1 qualified than I to judge who know him. 2 This is something that clearly his 3 executive function is something he's wrestling 4 with. And yet, would one say that he should 5 not be considered for this by virtue of this 6 particular mildly disabling condition? And 7 most of us, and certainly including the 8 subject himself, would say, no, and he is 9 first in line for consideration for a trial in 10 the next couple of months. 11 Obviously, more serious 12 impairments require special safeguards, and 13 the issue of legally designating 14 representatives is one that is being talked 15 about already today. In my own conversations 16 with the experts, the role of the caregiver 17 comes up again and again and again. The 18 person, most typically a spouse, but doesn't 19 have to be, who is living with this person who 20 is sharing in the burdens and the other 21 aspects of daily life; this person does have 22 clearly a role to play, and the people who can 71 1 think through how this could be routinized and 2 made a formal part of the process, clearly 3 that is something that we should all be 4 looking at. 5 I have reference here to something 6 I know really very little about, and it was 7 introduced to me only when I started this 8 modest piece of research for this undertaking, 9 the idea of a prior-signed document indicating 10 willingness to participate in trials. I had 11 been told by at least one lawyer, this is 12 probably not a great idea; I leave it to you 13 to decide whether it has any value at all. 14 If somebody, when they are of 15 sound mind, but already have the symptoms and 16 the diagnosis of a particular medical 17 condition, whether they are in a position at 18 that point to say that they would like to be 19 available for participation subject to 20 whatever constraints and other involvement 21 that would be required at a later stage of 22 their condition, whether that would be 72 1 something that would hold up in court, I don't 2 know, but it was mentioned to me, and I 3 mention it to you, for what it is worth. 4 I mention here - here is one of my 5 assaults on the English language, for which 6 you will forgive me - I see we have an 7 exclusion criteria; it's supposed to, of 8 course, be criterion. And there is another 9 error in this piece, too. 10 What this line should read, at the 11 end of this slide, is that the references here 12 to dementia in Parkinson's trials, 13 interestingly, being something that, of all 14 the 47 open trials that we have listed on a 15 website that we manage called Pdtrials.org, 16 Of all of the 47 trials that are right now 17 open for Parkinson's, every single one of them 18 that involves intervention excludes somebody 19 with a diagnosis of dementia. 20 There are two problems with this, 21 it seems to us. First of all, one 22 understands, of course, why, in most cases, 73 1 dementia would be an excluding criterion. This 2 is not something that I am challenging for a 3 minute. But by saying -- the act of almost 4 reflexively including this as an exclusion 5 criterion means two things. 6 First of all, quite obviously, 7 when the subject to be studied is one that 8 involves potential treatments that could 9 retard the process of increasing dementia, 10 that would be, by itself, almost by definition 11 would be inappropriate. 12 But also, back to the point I was 13 alluding to a few minutes ago, just the 14 reflexive inclusion of dementia reflects 15 often, I am told, a tendency among the 16 clinical scientists, the sponsors of trials, 17 maybe including government, for all I know, a 18 kind of general mindset that is saying, people 19 with impairment, probably, "Let's not worry 20 with that; it's an extra problem we don't need 21 to take on, so let's not do that," which, 22 going back to the ideas of justice in the 74 1 Belmont report, really violates to some degree 2 - if I'm describing it not in a caricature way 3 - it violates the notion that an individual, 4 in fact, should have the opportunity to 5 consider this, and if the individual is under 6 the appropriate safeguards and constraints 7 able to consider this, it certainly should be 8 something that should be built into the 9 system, and not excluded reflexively as a 10 matter of course. 11 Type of trial, this would be 12 observational. Interventional, I apologize 13 for that, too. The same point made a different 14 way; we need to look, of course, at what kind 15 of trials one is looking at in making it a 16 factor in deciding how one then proceeds with 17 making judgment as to whether somebody should 18 be included or not. 19 Two rather important things on 20 this slide, Nos. 2 and 3. First of all, the 21 whole notion of a moving target. One of the 22 people I talked to, a neurologist who works a 75 1 lot with dementia, made sure that I understood 2 that, particularly in long-term trials in 3 Parkinson's disease, we are talking primarily 4 here just about Parkinson's, since cognitive 5 impairment is a progressive condition when it 6 happens, it means that, for long-term trials, 7 you are dealing with, clearly, a situation 8 that will change over time. 9 It is three to five to seven 10 years, if that is the duration of a very long- 11 term trial, during that period, there is 12 reason to believe there would be a significant 13 deterioration or progression of a condition of 14 this sort, and the process of being able to 15 understand that re-consenting may be required 16 at appropriate moments needs to be built into 17 the system itself. 18 The last point, which, 19 interestingly was raised, maybe not 20 surprisingly to you, by patients as well as by 21 one social worker we work with, the idea of 22 the therapeutic value of participation in 76 1 trials. 2 This person, the social worker I 3 was referring to, has had a lot to do with 4 working with clinical trials in Parkinson's, 5 and with the people who participated, said 6 that she has come up again and again and again 7 with the experience of somebody whose life 8 was, maybe not fundamentally changed, but 9 improved, enriched, to the benefit, not only 10 of their general mood and feeling about life, 11 but their competence in functioning in that 12 life and in their family. 13 This notion of being able to 14 contribute to science, of being part of an 15 autonomous contributing agent, as the 16 philosophers call it, in this process, is 17 something that itself has therapeutic value. 18 I find this, I guess intuitively clear, but 19 also really quite exciting, and something that 20 seems to me should be within the mindset and 21 review of this eminent committee. 22 Research needs. There were three 77 1 areas in which I'm advised we need to be able 2 to -- we need to be planning for maybe making 3 more of the data that we have and the things 4 that we should be doing in an area I guess 5 broadly that you define as research. 6 One is defining and measuring the 7 nature and characterization of the many forms 8 of cognitive impairment. In a condition like 9 Parkinson's, what precisely defines this? 10 What is the spectrum here? What are the 11 stages? Both qualitative and quantitative, 12 what are the elements here that need to be 13 defined? I am advised that we don't have 14 thoroughly pinpointed or examined to the 15 detail every aspect of Parkinson's impairment 16 and dementia, and this could be done. 17 And the issue of databases, there 18 are several databases within Parkinson's, one 19 of which I've mentioned, one of the largest 20 ever produced which now goes back, I think, 21 almost 20 years, a group called DATATOP, which 22 was examining the potential neuro-protective 78 1 effect of an MAOB inhibitor decades ago. 2 There is a database here, a population 3 database, that apparently was characterized 4 for a number of things, including cognitive 5 impairment, when it was first created. And 6 the idea of going back into that and seeing 7 what we can learn about the progress of this 8 condition, I should say this aspect of the 9 condition, the cognitive impairment condition, 10 is something that should be encouraged. 11 And of course, the third point has 12 to do with developing treatments. This is 13 something, in Parkinson's, there is no 14 specific treatment for Parkinson's specific 15 cognitive impairment or dementia. Parkinson's 16 - there is an indication that was given to, a 17 drug that is used commonly in Alzheimers, 18 Exelon, an indication that was approved 19 several months ago for Parkinson's, and it 20 apparently is moderately or mildly effective 21 in some people for some of the time. 22 Clearly, we are very, very short 79 1 of therapies in this area, and the simple fact 2 has really nothing to do with the work of this 3 committee, because I think it is somewhat 4 beyond your scope, but we do need, in these 5 areas, new treatments. 6 But, in a sense, it's not beyond 7 the scope because, of course, these treatments 8 will never proceed unless we have 9 opportunities, to use this word again, for 10 people with Parkinson's to participate in 11 trials that can actually enrich and improve 12 their lives. 13 I have taken the liberty of 14 suggesting five areas in which there is value 15 in spending some time and attention having to 16 do with cognitive impairments in Parkinson's. 17 One is better defining the terms in which a 18 cognitively impaired person may be able to 19 participate in a trial based specifically upon 20 our knowledge of how this is in Parkinson's. 21 No. 2, to develop models to manage 22 participation by cognitively impaired people 80 1 with Parkinson's, protecting rights while 2 providing opportunities, and the issue of how 3 the care-giver comes in as a role, and so 4 forth. 5 And finally, developing policies 6 and programs that engage potential trial 7 participants, family members and care-givers, 8 physicians, and other allied health 9 professionals. This is, in more than one 10 sense, a community endeavor, this business of 11 trying to draw this balance between the 12 various interests and ethical claims here. 13 And all of these groups, in one way or 14 another, need to be part of the way in which 15 we engage and define and refine the issues. 16 So I think I had one what they 17 call, I guess, take home message here in 18 addition to the one that is being stated more 19 eloquently than I have been able to do so 20 about the balancing of claims between science 21 and individuals, it is to maybe just probe 22 half a level down into that and say that, in 81 1 looking at the whole question of how one 2 approaches the rights and responsibilities of 3 people in clinical trials, the issue of 4 opportunity to contribute in some way, the way 5 that people can be part of science, people can 6 help in their own therapy, apart from other 7 things; people can be listened to as well as 8 talked to, and interpreted in appropriate ways 9 in finding some way in which this system can 10 be refined. It seems to me it is a 11 refinement. Obviously, all the fundamental 12 pieces are there; they were there in the 13 Belmont report, and they are there clearly in 14 everything I have heard today about the way 15 this committee goes about its very, very 16 important work. 17 But the question of opportunity, 18 the question of people being able to be part 19 of this process to the extent possible, and it 20 will vary case to case, be able to be agents 21 in their own health and in the contributions 22 they make to their community is something that 82 1 we, the Parkinson's Disease Foundation in this 2 particular nexus that we occupy, which is 3 between science, on the one hand, and patients 4 on the other, we feel is the appropriate 5 watchword for the rest of these discussions. 6 I thank you very much for this 7 opportunity; it has been a great treat and a 8 privilege. 9 DR. PRENTICE: Thank you very 10 much, Robin. We really appreciate your 11 presentation - very informative. 12 Our next presenter is Anne 13 Donahue. Let me tell you a little bit about 14 Anne. Anne is a member of the legislature in 15 the state of Vermont. And, actually, she is 16 now running for her third term. Good luck, 17 Anne. 18 She's been a member of the Human 19 Services Committee in the state legislature, 20 which did extensive revisions of the law on 21 advanced directives for healthcare. 22 She has also introduced 83 1 legislation that would establish common 2 standards as the basis for medical 3 guardianship, or court-ordered treatment for 4 those lacking cognitive capacity. And as a 5 graduate of Georgetown University Law Center, 6 and also Boston College. 7 Thank you, Anne, for agreeing to 8 come to SACHRP and speak with us today. 9 MS. DONAHUE: Thank you. This is 10 a phenomenally interesting, challenging, 11 complex, and important topic before us today, 12 and I'm honored to be able to share my 13 thoughts with you. 14 I bring four perspectives to this 15 table. First, I am a person with a serious 16 mental illness, currently in remission. That 17 means I'm a person who has directly 18 experienced the effects of a psychiatric 19 illness on the ability to make informed 20 choices. Because mental illness can move 21 between relapse and remission, it also means 22 that I can reflect on that experience from the 84 1 position of being, for lack of a better term, 2 well. 3 Secondly, I enter this discussion 4 as a person who has been an advocate within 5 the consumer community for some 10 years. One 6 of the most contentious topics for that area, 7 for advocates, is the treatment of an 8 individual who is deemed not competent to make 9 his or her own treatment decisions, but for 10 whom the recommended treatment is against the 11 expressed wishes of the individual. 12 As an advocate, I also initiated 13 state oversight for electroconvulsive therapy 14 in Vermont. My personal medical journey, my 15 uninformed consent to ECT, and its devastating 16 consequences in my life, bring the reminder 17 into today's discussion that all ethical 18 dilemmas are also shaped by the daily 19 experiences of individual human persons. 20 And all politics is local. I'm a 21 state legislator, and in 2005, we grappled 22 with the issues of capacity, informed consent, 85 1 and the breadth of decision making by an agent 2 when we rewrote the state law on advanced 3 directives for healthcare. 4 Finally, for the past eight years 5 I have been the editor of Counterpoint, which 6 is Vermont's quarterly mental health consumer 7 newspaper. A year and a half ago I followed 8 the fallout of an explosive headline on the 9 cover of the local daily newspaper that said 10 that our state hospital patients were being 11 proposed as research subjects. It was an 12 imprecise truth, but it illustrated a still 13 raw nerve. 14 So first, some perspectives as a 15 person with a psychiatric illness. Mental 16 illness often has a course of recurring and 17 subsiding. Modern treatments have brought 18 both success and limitations. An outcome of 19 both of those factors is that impairments that 20 affect decision making are not static. 21 I speak to you today with a 22 certain degree of rational competence that I 86 1 convey and articulate a level of intelligence 2 and sophistication. And as placeholders in 3 time, I can tell you that I graduated from law 4 school with honors 25 years ago, and I 5 received a national award for public service 6 in the halls of the U.S. Supreme Court 15 7 years ago. 8 Yet, interspersed between then and 9 today, this same person that you see has been 10 curled up hiding under a hospital bed in a 11 psychiatric ward, has tried to drown herself 12 in a bathtub in a drunken stupor, has been 13 carried off by an airport medical team, 14 unresponsive, refusing to hear or speak, has 15 raced at high speeds on back roadways, or with 16 eyes closed on interstates, trying to provoke 17 a physical injury that she believed would 18 allow herself to be cared for, cared about, 19 has run away from police and hidden in the 20 woods, has sat sobbing uncontrollably on a 21 public sidewalk. 22 But that is not the person I am. 87 1 I know myself, and I can therefore say, who I 2 am is not who I appeared to be at those other 3 times. When I went through the many cycles of 4 beginning to respond to treatment, relapsing, 5 and then beginning to respond, there were 6 times that I would wonder, "I'm not sure. Am 7 I back? Is this the real me, the well me, who 8 I am?" 9 And I came to learn that there was 10 a way I could tell. If I had to ask, if I 11 wasn't sure, then it wasn't. When I'm the 12 person who is me, I always know it with 13 certainty. And I can look back and say, not 14 only was that person who was another person 15 under the control of an illness of the brain, 16 but that person did not act like me and, more 17 importantly, did not think like me. 18 That person has neither the 19 ability nor the right to speak for me, or make 20 decisions for me. I am a person who loves 21 life. And by definition, a person who wants 22 to die, who would choose death, if she was 88 1 able, in order to escape the unendurable 2 cauldron trapped inside her mind, does not 3 hold the same persona, is not the same being 4 as the one who loves life. 5 During some of those times I was 6 probably legally competent, but at other times 7 not. That is purely a legal standard, and a 8 line in the sand for something that has every 9 possible gradation. So although competency 10 and capacity are terms of art in treatment 11 discussions, the term used in the charge to 12 this panel, decisional impairment, is a 13 descriptive term that makes it much easier and 14 more accurate to discuss the levels of 15 impairment that may be created by a mental 16 illness. 17 So it isn't just about being a 18 spectrum. It is also about being a spectrum 19 in motion. And the level of impairment in the 20 decision making ability is also tightly 21 interweaved with the kind of decision that is 22 being presented, creating a matrix that is in 89 1 constant evolution. 2 Within that matrix, we need to 3 understand psychiatric disabilities, not only 4 from medical or personal perspectives, but 5 also within the political and social context. 6 The consumer movement was birthed by those who 7 emerged from some of our worst institutional 8 abuses and gained angry voices. 9 It started primarily as a civil 10 rights movement, arguing for the right of 11 individuals to make their own choices in the 12 face of a society that was perceived as 13 impinging on those choices, solely for reasons 14 of social control. 15 This context means that judgments 16 about decision making capacities are sometimes 17 tied to internalize beliefs about altruistic 18 versus oppressive motives. From a provider's 19 perspective, a patient's consent to 20 recommended a treatment demonstrates the 21 ability to understand the risks and benefits 22 appropriately, and thereby establishes that 90 1 the patient is competent to make the decision. 2 On the other hand, if a person 3 with a psychiatric diagnosis is refusing 4 treatment that the medical professional has 5 identified as appropriate, then the patient is 6 identified as lacking sufficient insight to be 7 competent to make that decision. 8 Equally committed individuals 9 making their own assessment of risks and 10 benefits of treatments based on their lived 11 experience of psychiatric care lobby on behalf 12 of the rights of others to make their own 13 decision, but only as long as that decision 14 matches the advocate's judgment of the better 15 course of action. 16 During the debate on ECT in 17 Vermont in the late '90s, advocates suggested 18 that the targets of ECT were mostly 19 vulnerable, elderly women unable to defend 20 themselves against the persuasive power of 21 physicians. They believed that these 22 patients, if empowered to make their own 91 1 decisions, would realize that the risks of ECT 2 far outweighed the benefits. Therefore, 3 consent proved lack of competence. 4 If the issue had been reversed, 5 the implication that age and sex were proxy 6 indicators for competence would have been 7 angrily denounced. But the potential for 8 these social assumptions to have an undetected 9 effect on objective assessments create a 10 powerful added risk factor that must be 11 monitored as part of the challenge in 12 assessing the impact of decisional impairment 13 in psychiatric patients. 14 Despite the desire and advocacy 15 for appropriate protections, there is little 16 consistency in legal approaches, at least in 17 Vermont law, the criteria for commitment to 18 involuntary hospitalization as a danger to 19 self or others, in other words to be deprived 20 of liberty, is unrelated to a determination of 21 capacity to consent to treatment. 22 The separate legal process for an 92 1 order for involuntary medication of a person 2 who has been committed to a hospital does 3 include the requirement that a court rule on 4 the competence to make a treatment decision. 5 On the other hand, under 6 guardianship law, there's no statutory 7 guidance on how decisions should be made for 8 the court orders or guardian decisions on 9 medical interventions for a person who has 10 been found unable to protect their own health 11 or safety due to a mental illness. 12 In the law on advanced directives 13 for healthcare, the revision passed in 2005, 14 which includes experimental treatment by 15 reference, defines capacity on two levels 16 connected to the specific decision being made. 17 The individual needs only to have a basic 18 understanding of what it means to appoint an 19 agent. 20 In contrast, making a healthcare 21 decision requires a basic understanding of the 22 diagnosed condition and the benefits, risks, 93 1 and alternatives. If that ability is impaired, 2 the advanced directive and the authority of 3 the agent are triggered. 4 By right, an advanced directive 5 can be revoked at any time, including by a 6 person who lacks capacity. What if a person 7 wants to be locked in to his or her own 8 informed decision, rather than retaining the 9 right to revoke the directive when incompetent 10 and, therefore, potentially being subjected to 11 the decisions of a relative or guardian 12 instead of their own choices. 13 The term Ulysses Clause within an 14 advanced directive comes from the Greek myth 15 of Ulysses, who commanded his ship's crew to 16 leave him tied to the mast regardless of what 17 he said otherwise in order to escape the 18 influence of the song of the sirens that he 19 knew would overcome him, and lead him to 20 direct the ship into the shoals. 21 Vermont created a unique hybrid 22 solution to the controversial issue of 94 1 permitting the use of a Ulysses Clause in an 2 advanced directive. It significantly raised 3 the threshold of protections for the decision 4 to surrender one's right to revoke an advanced 5 directive when incompetent. 6 The option can be activated only 7 through the intervening actions of a named 8 agent. There are added witnessing 9 requirements, and the directive can only be 10 triggered if the loss of capacity 11 determination has been made by two clinicians. 12 Could a person consent in advance 13 to agree to be part of a research opportunity 14 prior to a loss of capacity? Perhaps, if the 15 specific risks and benefits and the proposed 16 treatment were known in advance. But if one's 17 capacity is lost, the person's consent is no 18 longer valid, then the advanced consent is 19 worthless. 20 A Ulysses Clause in an advanced 21 directive, as an example of an alternative in 22 consent to treatment points to the 95 1 opportunities, not necessarily a specific 2 example, but the kind of thinking and 3 opportunities for creative problem solving in 4 approaching research for those with 5 intermittent decisional impairments. 6 We also need to distinguish 7 between past and current reality in the 8 perceived need for special protections carved 9 out for psychiatric treatment. That was a key 10 debate in 1998 when I had my own state 11 representatives at the time introduce 12 legislation to place the practice of 13 electroconvulsive therapy under state 14 oversight in Vermont. 15 The provider outcries had merit. 16 Why was this single area of medical practice 17 being singled out? Wasn't that creating a 18 special category of oversight for a 19 psychiatric treatment a concession to and 20 potential future contributor to the 21 discrimination against psychiatry? 22 My experience in the practices of 96 1 Vermont hospitals at the time demonstrated an 2 inadequate standard of care. I had signed a 3 consent to ECT after being shown an 4 informational videotape that said that 5 lingering allegations about the risk of memory 6 loss were nonsense. 7 I suffered a devastating loss of 8 years of my life memories that were verified 9 by medical evaluation. My own decision 10 process to consent to ECT is reflected in my 11 journal entries. I wrote that I was afraid 12 that accepting ECT treatment was merely a cop 13 out from addressing difficult life issues, but 14 also that I felt relief in the decision just 15 by the mere fact of doing something, anything 16 different to try to get relief. 17 As journalist Larry Tye said in a 18 new book on ECT, "Can consent be truly 19 informed when a person giving it is sick 20 enough to need electroshock?" And might that 21 question apply to more types of psychiatric 22 treatment than we recognize? 97 1 Yet if my mix of uncertainty, or 2 if the intense desire for relief from pain as 3 a basis for consent are considered 4 unacceptable influences or impairments of 5 capacity, then research for many conditions 6 unrelated to mental health would be put into 7 question. 8 In the same way, if we are to be 9 consistent, then it's hard to find the logical 10 support for either special statutory schemes 11 addressing only psychiatric medication, or 12 open-ended guardianship laws that may allow 13 virtually unfettered discretion in making 14 medical decisions for persons with mental 15 illness. 16 There is one other layer to add to 17 the matrix. If a decision is being made by a 18 person on behalf of someone else, the standard 19 for replacement of the individual's decision 20 comes into issue. 21 For court-ordered psychotropic 22 medications in Vermont, if a person has 98 1 previously expressed preferences regarding 2 medications at a time when competent, those 3 wishes must be followed initially. A so- 4 called substituted judgment standard in which 5 a fact-finder bases a decision on what the 6 person would have wanted if competent. 7 But this standard immediately 8 shifts to a decision to be made in the best 9 interests of the patient if evidence 10 demonstrates that following the patient's 11 preferences has not resulted in significant 12 clinical improvement in the past. 13 In Vermont's advanced directive 14 statute in contrary, a best interest 15 consideration is only permitted if the agent 16 has exhausted all means of trying to interpret 17 what the person would have wanted under the 18 circumstances. 19 A guardian is held to a 20 traditional legal standard of care, but 21 without any standards on factors to gauge in 22 making a substitute decision. In considering 99 1 research, any potential use of a substitute 2 decision maker needs to address how the 3 decisions would be made in relationship to the 4 risk benefit analysis. 5 But ethical considerations are 6 also uniquely tied to the history of stigma in 7 psychiatry. I'll give you a quote: "How do we 8 know what makes them screwy until you treat 9 them?" Unfortunately, that's a 2002 remark 10 from a federal judge on the United States 11 Circuit Court of Appeals during oral argument 12 in a case from Vermont involving an advanced 13 directive for healthcare, and the inclusion of 14 psychiatric illness. 15 Public understanding of mental 16 illness is still far from where we would wish. 17 Those with a psychiatric illness have a right 18 to the same quality of care based upon the 19 same quality and priorities for research as 20 other disabling illnesses. 21 Preserving individual rights does 22 not need to be an obstacle to the ability to 100 1 identify new and better treatments. However, 2 resistance emerges anytime it is perceived, 3 rightly or wrongly, that civil rights 4 protections may be reduced. 5 A year ago, a new contract was 6 signed for psychiatric services provided at 7 the Vermont State Hospital by the academic 8 medical center affiliated with the University 9 of Vermont School of Medicine. And it noted 10 an expectation for research in the area of 11 public sector psychiatry, including a 12 reference to experimental investigational 13 treatment. It caught the stakeholder 14 community completely off guard. 15 Letters to the editor of my 16 newspaper Counterpoint made comments such as, 17 "We might all want to ask ourselves why the 18 state and university insist on conducting 19 experiments on patients at VSH." And there 20 was a fierce campaign to have all research 21 language removed. 22 In opposition, the university's 101 1 director of public psychiatry urged that it 2 would be caving in to stigma against research 3 to withdraw the language, and that it was a 4 critical opportunity to develop a new message 5 about the appropriate place and value of 6 research. 7 Ultimately, the wording of 8 experimental and investigational care were 9 removed. The incident was unfortunate in that 10 the opportunity for dialogue about psychiatric 11 research was lost by the failure to have it 12 discussed before the language appeared in a 13 contract. It illustrates the tremendous 14 importance of communications and dialogue with 15 all stakeholders in order to foster trust. 16 I was recently surprised in some 17 conversations just before this meeting, of at 18 least one comment by a practicing inpatient 19 psychiatrist in opposition to almost any 20 research involving patients with decisional 21 impairments beyond demographic data 22 collection. 102 1 He said, "We have been doing 2 without it for this long, so I don't see why 3 we would want to embark on that slippery 4 slope." I disagree. I don't have a solution 5 for that slippery slope, or how to create the 6 balance, but I do not believe the answer is to 7 rob for myself, or for future generations, 8 from moving more quickly to better 9 opportunities for survival, recovery, and 10 quality of life. 11 The President's 2003 New Freedom 12 Commission Report has made consumer directed 13 and recovery oriented care the 14 transformational principles of mental health 15 care across the nation. In the same report, 16 but much less widely publicized, was the 17 recommendation to, "accelerate research to 18 promote recovery and resilience, and 19 ultimately to cure and prevent mental 20 illness." 21 I believe we need to transform the 22 ways we think about the affects of mental 103 1 illness on decisional capacity, so that the 2 multi-dimensional matrix of factors that apply 3 to all human subject research opens the door 4 to creativity instead of fear, and we work 5 together on solutions, rather than letting 6 history or other unique challenges be barriers 7 to moving us forward. 8 DR. PRENTICE: Thank you very 9 much, Anne, for a very compelling 10 presentation. And we applaud your courage for 11 talking about your personal journey. That 12 kind of perspective is extremely important for 13 members of SACHRP who don't work every day 14 with individuals who have such problems. 15 I would like to move to the next 16 presentation, which will be given by Sharon 17 Grandinette. And let me tell you a little bit 18 about Sharon. I'll read a few abbreviated 19 comments from her bio. 20 Sharon is a special education 21 consultant and trainer who owns and operates 22 Exceptionally Educational Services located in 104 1 Rodondo Beach, California. She has worked 2 with children, adolescents, and young adults 3 with special needs for over 26 years. 4 She has worked in the public and 5 county schools, as well as in private special 6 education school settings as a special ed 7 teacher, program specialist, and 8 administrator. For 14 years, she focused her 9 work on children and adolescents with 10 emotional disabilities and mental health 11 needs, but since 1989, her efforts have 12 centered on children and adolescents with 13 acquired brain injury or other neurological 14 disorders. 15 She is also currently president of 16 the California Association of Physical and 17 Health Impairments. Welcome, Sharon. Thank 18 you for taking your time to come and speak 19 with us today. 20 MS. GRANDINETTE: Thank you. It 21 is an honor to be here today, and although my 22 background is education, I've had the unique 105 1 opportunity of following many of the children 2 that I've worked with over the years into 3 their adulthood, and so I hope to bring a 4 perspective from not only the children's 5 perspective, but obviously ongoing. 6 My goal today with you is to help 7 you understand what we call acquired brain 8 injury, and how it affects decision making 9 skills. Some statistics first. With regard to 10 brain injury, brain injury is the leading 11 cause of death and disability, not only in our 12 country, but world-wide. And we need to look 13 at what difficulties of research access that 14 we may have with the brain injury population. 15 As the other presenters before me 16 have done, we need to define the population. 17 Brain injury is a very broad category, and 18 there are varying levels of severity. We have 19 mild, moderate, and severe levels, and with 20 people who have mild injuries, which is 21 approximately 75 percent of the individuals 22 with brain injury, they certainly look like 106 1 walking, talking, functioning individuals. 2 And yet, they can have decision making issues. 3 There are also varying types of 4 deficits and causes of deficits. So what I'd 5 like to do first is give you a very brief 6 overview of brain injury. When you look at 7 brain injury, it's really an umbrella, and 8 what we are trying to focus on are people who 9 are typically developing, and then acquired 10 the injury after a period of typical 11 development. So I'm not going to focus on 12 those individuals who have had congenital and 13 perinatal impairments; I think they are being 14 addressed in other aspects of what you are 15 looking at specifically in the area of 16 children. But with acquired brain injury, we 17 were looking at both traumatic and non- 18 traumatic events, and I want to go into those 19 a little bit more specifically for you. 20 What are traumatic causes of brain 21 injury? The definition of TBI, or traumatic 22 brain injury, is an insult to the brain. It 107 1 is not of a degenerative or congenital nature, 2 but it is caused by an external physical force 3 that does disrupt the normal function of the 4 brain. 5 And we look at two different 6 types. We look at, with regard to external 7 physical force, we have open brain injury 8 where the skull is broken and penetrated, 9 resulting in bleeding and bruising inside the 10 brain. And the thing about open brain 11 injuries, they tend to be focal or 12 concentrated on a specific area of the brain. 13 We also have closed brain 14 injuries. Here we have impact, and the brain, 15 because it is in the skull, and is almost like 16 Jello, it bounces back and forth, so we have 17 acceleration injuries causing nonspecific, but 18 more diffuse types of injuries, so you are 19 going to have a more global injury. And that 20 is again caused from the brain moving inside 21 the skull. 22 With regard to TBI statistics in 108 1 the United States, we know that 1.4 million 2 people sustain a TBI every year, and more than 3 25 percent of these brain injuries are 4 moderate to severe. That is about 350,000 5 individuals a year. 6 We also know that about 5.3 7 million of these people, or over 2 percent of 8 the population, are currently struggling with 9 long-term or life-long need for help to 10 perform activities of daily living that result 11 from their traumatic brain injury, and these 12 are statistics from the Center for Disease 13 Control. 14 There is a lot of press with 15 regard to traumatic brain injury, especially 16 when we look at some of our military personnel 17 who are suffering from blast injuries. And 18 traumatic brain injury tends to get a lot of 19 attention. 20 Motor vehicle accidents, our car 21 manufacturers are working very hard with 22 restraints. We are looking at booster seats 109 1 for children, and increasing the age for that. 2 I know in California we're at 60 pounds or six 3 years of age; we are looking at increasing 4 that. So we are doing a lot to try and 5 prevent trauma. 6 But what about those acquired 7 injuries that come from non-traumatic causes? 8 What are those? Well, strokes or other 9 cerebral vascular accidents. We know that 10 there are about 700,000 individuals that 11 acquire a stroke in the U.S. each year. And 12 while three-quarters of these are in 13 individuals who are 65 years and older, we 14 know that strokes can and do occur at any age. 15 And I work with a number of young adults who 16 have sustained stroke. 17 We also have AVMs. About 250,000 18 of those occur in the United States annually. 19 And we have cerebral aneurysms, 12 million 20 people a year, 40 percent will survive, which 21 is close to 5 million people a year. I think 22 these numbers are starting to become more 110 1 interesting as they increase. 2 Epilepsy also falls under acquired 3 brain injury. Many people think that seizures 4 just occur and then they go away, and maybe 5 are managed with medication, but we have 6 people who have recurring seizures who then 7 have cognitive damage as a result. We know 8 that we have approximately 2.7 million people 9 in the U.S. affected with epilepsy. 10 And then we have people who are 11 dealing with infections of the brain, both 12 encephalitis and meningitis. And the numbers 13 here aren't as high, but the affects are very 14 detrimental and long-lasting to the 15 individuals who sustain them. 16 About 1,500 people per year in the 17 U.S. have encephalitis, which is an 18 inflammation or an irritation and swelling of 19 the brain, while more than 3,000 people a year 20 in the U.S. suffer from meningitis, and while 21 10 to 15 percent of them die, we tend to see 22 significant deficits here. And this is where 111 1 an infection of the tissues, which is the 2 meninges or the coverings of the brain, as 3 well as the cerebral spinal fluid that 4 surround the brain and spinal cord are 5 affected. 6 And then we have brain tumors. 7 190,000 individuals in the U.S. per year are 8 diagnosed with either a primary or a 9 metastatic brain tumor. And to make more 10 interesting, we have over 120 different types 11 of brain tumors that people are dealing with. 12 In the 1960s, we didn't need to 13 worry about this population so much with 14 regard to research, because only about 10 15 percent were surviving. We now have close to 16 67 percent survival rate because of the great 17 increase in the medical care, but how are we 18 now dealing with them and the affects that we 19 want to see with regard to not only their 20 outcomes, but with regard to some research we 21 may want to have with that? 22 One thing to keep in mind with 112 1 individuals with brain tumors is that the 2 treatment, not necessarily the surgery itself, 3 but the treatment may cause more damage than 4 the tumor or the surgery. Late affects of 5 chemotherapy, for example, can have long-term 6 consequences on an individual's cognitive 7 abilities. 8 We also have anoxic and hypoxic 9 injuries, as well as injury from metabolic 10 disorders. Anoxia where there is no oxygen to 11 the brain tissue, and hypoxia where there is 12 limited or reduced oxygen to brain tissue. 13 Those can be cause for many things that people 14 may not take into consideration that cause 15 acquired brain injuries, such as a respiratory 16 or cardiac arrest, airway obstructions, 17 joking, asthma, strangulations, individuals 18 who are near-drowning victims, as well as 19 people who suffer crash injuries to the chest 20 area. And then with metabolic disorders, 21 individuals who go into insulin shock, or may 22 have liver/kidney diseases. 113 1 There are many other causes of 2 non-traumatic acquired brain injury. Exposure 3 to different toxins, or ingestion of these 4 toxic substances. There are many listed here. 5 We also are looking at intracranial surgery, 6 electric shock or lightening strikes. 7 Certain sexually transmitted 8 diseases, such as AIDS, will cause neurologic 9 damage. There has been so much talk about 10 West Nile virus and insect carried diseases 11 that are occurring across our country. 12 Individuals with hypo or hyperglycemia and, as 13 I mentioned earlier, some forms of 14 chemotherapy. 15 So the background for you on the 16 causes of the different types of acquired 17 brain injury now lead me to tell you, well, 18 just exactly what is the impact. And while 19 all of these acquired injuries to the brain 20 have specific issues, for the most part they 21 tend to have very common occurrences with 22 regard to people's individual needs. 114 1 So, impairments often occur in one 2 or more of the following areas: cognition, 3 communication, health and physical abilities, 4 sensory motor skills, and social and 5 behavioral areas. And what's really important 6 to remember, and I thought this slide was very 7 telling, is that many times, cognitive 8 impairments are often hidden. 9 We tend to see many people with 10 acquired brain injury as the walking, talking 11 wounded. And I tell many people that I wish, 12 sometimes, many of the children that I have 13 worked with and the young adults that I have 14 worked with could wear casts on their heads. 15 Then people would understand that something 16 isn't quite right in there, and that they 17 aren't able to make many of their own 18 decisions. And many times, we look in the 19 wrong place. 20 But impairments affect decision 21 making abilities. Following acquired brain 22 injury, specifically we look at the cognitive 115 1 areas. What is affected? Attention and 2 concentration. Short and/or long-term memory 3 abilities. Thought processes. And then there 4 are varying degrees of confusion and 5 disorientation to time, to place, and to 6 person, and that can be functioning pretty 7 typically one day, and not the next. 8 Limited recognition of their 9 deficits. And this is a really important one, 10 because you have a person who was typically 11 developing who was able to do and run their 12 life and live in their family and work at 13 their job, and many people don't understand 14 that these deficits are now there. 15 Some people call it denial of the 16 deficit; I like to call it, they don't 17 understand the deficit that has occurred, but 18 they think they still function like anyone 19 else. And we also tend to have very 20 egocentric thinking. Most importantly, and 21 the one that is often affected, especially 22 when there are frontal lobe issues, is 116 1 executive functioning skills. And this was 2 mentioned earlier in the Parkinson's 3 presentation. What does this actually mean? 4 Well, the frontal lobes and executive 5 functioning skills, that is the CEO, or what 6 I like to call the secretary of your brain. 7 Individuals who have executive functioning 8 skills issues have difficulty formulating 9 goals. 10 They have difficulty planning and 11 anticipating for the future. They have a 12 great deal of problem with self-regulation, or 13 what we call metacognition, being able to talk 14 themselves through things and thinking through 15 process to problem solve. And they have 16 difficulty with flexible problem solving. 17 For example, and think of this in 18 terms of trying to make a decision about 19 participating in a clinical trial, perceiving 20 the exact nature of the problem, considering 21 relevant information, considering a variety of 22 possible solutions or outcomes, and then 117 1 weighing the relative merits of alternative 2 solutions. Very common in this population. 3 The other thing to take into 4 consideration and, as I mentioned earlier, 5 communication skills are often affected. We 6 call this cognitive communicative deficits. 7 Many have expressive or receptive language 8 deficits. Sometimes you will have an 9 individual who may understand everything you 10 are saying but does not have the expressive 11 ability to let you know what they understand. 12 And while many of them will use 13 alternative augmentative communication 14 devices, do we take the time to really sit and 15 allow them to share their thoughts? Many of 16 these individuals also have difficulty with 17 abstract topics. Certainly research and 18 understanding that is one of the most abstract 19 things we can throw at them. 20 If you are asking them to read the 21 documents, reading comprehension is very much 22 affected. And while a lot of individuals with 118 1 brain injuries may maintain their ability to 2 decode when they read, so they will read aloud 3 to you and sound just like anyone else, they 4 really have no ability to comprehend what they 5 are reading, or very limited. 6 Also, processing the intent of 7 others is an area of concern. And then one of 8 my favorites, confabulation. And this is a 9 term that many people don't quite understand. 10 Confabulation usually occurs when there is a 11 person who has memory loss, but they are in 12 denial of their deficit; they don't want to 13 look like they don't know, because they have 14 always been a person who has been able to 15 function in society, and so they fill in the 16 holes by making things up, or agreeing with 17 you in saying they understand, when in 18 essence, they truly do not. So confabulation 19 is a word to put a star next to. 20 We also must take into 21 consideration the social and behavioral 22 aspects of acquired brain injury. I mentioned 119 1 earlier, they have limited acceptance of the 2 deficit. Sometimes they recognize them but 3 will not accept them. Depression, withdrawal 4 are common. Impulsivity; they will jump at 5 the chance, or just make a quick decision. 6 Poor judgment. They may 7 misperceive social situations. They have 8 problems adapting to new situations. Most 9 important, and another one to put a star next 10 to, there is a mismatch between what they 11 think they can do, and what they actually do, 12 creating a conflict in their self-image. 13 They also have problems meeting 14 behavioral expectations. And, most 15 importantly, since they lose control over 16 their lives, they look for other ways to have 17 control. Many times, that might be behavioral 18 in nature. 19 So I also wanted to take a look at 20 examining fluctuating capacity in the world of 21 acquired brain injury. Couple of things that 22 I would like you to be aware of. Be aware of 120 1 the fact that many individuals will present 2 with normal IQ following acquired brain 3 injury. Their IQ may not change, so they will 4 look like, again, a functioning, competent 5 individual. But, they may demonstrate the 6 following: 7 Emotional ability, ups and downs, 8 and periods of depression. They will have 9 rapid changes in their status during recovery. 10 We do know from the research that it is not a 11 static condition in most cases, that people 12 over time will continue to make progress. The 13 research says, up to five years, and when we 14 look at some of the longitudinal studies 15 coming out of Canada, where healthcare and 16 rehabilitation is not kind of stopped at a 17 certain three-month period, or when the money 18 runs out, we are looking at people who are 19 making changes five, 10, 15 years out with 20 appropriate rehabilitation, especially 21 cognitive retraining. So, therefore, we need 22 to consider whether assessment with this 121 1 population needs to be an ongoing process. 2 Also, you must understand that 3 some of these individuals will have the 4 ability to learn, or know, or do something 5 today, may not be able to access it tomorrow. 6 So if you've explained the process to them on 7 Monday, and on Wednesday they meet with you 8 again, it may not be there. 9 Also, I have hit upon this, but it 10 is very important to repeat - the belief that 11 they can engage in tasks that they really are 12 no longer capable of performing. And as I 13 mentioned earlier, the decoding skills are 14 strong, but they don't always understand what 15 they read. 16 If we look back at what you 17 probably reviewed in the past with regard to 18 what is needed for the consent process, it 19 does require the capacity for the following: 20 gathering information, establishing trust, 21 identifying risks, advocating for oneself, 22 making choices, and then sticking to the 122 1 choice that they've made. Do all individuals 2 with acquired brain injury have this capacity? 3 How do we obtain consent with this 4 population? Well, we have to ask the right 5 questions. Does this individual have a memory 6 problem? Does this individual have the 7 ability to problem solve? Is there a clear 8 explanation given to them so that they 9 understand the process and the procedures? Do 10 they understand the purpose? Can they repeat 11 it back to you? 12 One of the things that was 13 mentioned earlier was the cover sheet that I 14 know that Dr. Strauss uses at his facility, 15 which is a wonderful idea. And because I come 16 from the education background, what do I do? 17 I modify and accommodate everything for my 18 individuals with special needs. 19 How do we modify and accommodate 20 the consent process to the level of the 21 functioning of that person? I might just 22 advise you that you have a special educator 123 1 somewhere advising you on how exactly to do 2 that, because those individuals have expertise 3 in that area. 4 A desire to participate, truly 5 participate in this study, or is this person 6 being pushed by a parent or a guardian to 7 participate? Does this person have the 8 ability to schedule and keep appointments? 9 There is nothing worse than going through the 10 whole process and having your group of 11 individuals for the study, and then they don't 12 show up because they don't have the ability to 13 follow through. Do they have a surrogate? 14 Should one be assigned? 15 With regard to obtaining consent, 16 also, we need to ask ourselves the following 17 questions: how many of these individuals with 18 acquired brain injury will participate, 19 because - and it was mentioned earlier by a 20 former panelist - because they will believe it 21 will alleviate their suffering. 22 Or because they have no insurance, 124 1 and they are desperate for any type of service 2 at all. Or, for those who have lost control 3 over their lives, so that they can have some 4 form of control now at least with one thing. 5 Now here is something that people 6 don't think about. When a person has an 7 injury or an illness, we all gather around 8 them. We give them all kinds of support. We 9 are all there, and after a while, it gets old, 10 and people start to drift away. 11 So, do we have some individuals 12 consenting because the attention regarding 13 their injury has diminished, and now they need 14 attention? Or, are they consenting because it 15 is the only way they now can contribute to 16 society? They used to be very active in their 17 community. They were attorneys, and teachers, 18 and mothers, and they can no longer perform 19 those functions. 20 I want to tell you a little bit 21 about one individual that I have had the 22 pleasure of working with over the last several 125 1 years. Her name is Sara, and Sara had a 2 hypothalamic astrocytoma brain tumor in her 3 left temple lobe at the age of six. She had 4 surgery. She had chemotherapy. 5 As a result of the tumor and the 6 treatment she was left legally blind. She had 7 severe articulation deficits. She had a shunt 8 in place, right penny paresis. She had severe 9 behavioral issues, cognitive learning 10 challenges but not to the degree that you 11 might expect. 12 And she also had endocrine issues, 13 growth issues, and needed to take hormone 14 shots on a daily basis. She also presented 15 with depression and suicidal ideation. She 16 was very, very afraid of the future. She 17 always used to worry about how she was going 18 to be cared for. We always used to tell her, 19 "Let's turn your concerns into goals." She 20 truly felt like she had no control over her 21 life. 22 And so just to illustrate the 126 1 example, when she turned 19 which was just 2 about six months ago, unfortunately her tumor 3 grew back and so looking at all the options 4 experimental treatment was offered for her. 5 So who makes the decision for her? Do her 6 parents? They have been making them for many 7 years. Does Sara? Is it a joint decision? 8 Is she allowed into the planning conference? 9 She was always not allowed before 10 as a child. Is she capable of making the 11 decision? Does she give her input? Is it 12 considered? If Sara does not want the 13 surgery, what are her parents going to do? By 14 the way, at 18 -- before 18 she and her family 15 had been told, "You need to consider whether 16 or not to have her placed under guardianship." 17 Many families I find, and 18 especially because I work with the younger 19 population and with regard to the individual 20 education process, or IEPs, we are required by 21 law by the time that child turns 18 to have 22 the parents decide either to have that child 127 1 placed under guardianship or not because once 2 they are 18, even if they are in school, they 3 get to sign their own individual education 4 plans. 5 Are we looking at that piece with 6 this population as they are aging into 7 adulthood? So what are the risks? What are 8 the benefits and does she have the capacity to 9 understand both? 10 So I want to determine risk versus 11 benefit with regard to Sara. Does she have 12 the capacity to understand the ramifications 13 of having the surgery? Is she aware of the 14 possible outcomes, dangers, and side effects? 15 One of the things she very clearly stated was, 16 "If it has anything to do with me losing 17 anymore vision, I don't want any part of it." 18 What about not having the surgery? Is aware 19 of the prognosis without it? Has she been 20 given alternatives? 21 How do we determine the need for 22 surrogacy or conservativeship or guardianship? 128 1 It is called different things in different 2 states. How sound is her judgment? Does she 3 understand the process? Does she understand 4 the consequences of her actions and decisions? 5 Can she really communicate her needs? 6 Who will look out for her if her 7 parents become ill or die? Remember she is 8 still her own individual. She has not been 9 appointed a surrogate. Here is a very big 10 question. Is she easily manipulated by 11 others? The answer is yes. She is. 12 Here are other factors to consider 13 generally with individuals with acquired brain 14 injury. Something to take into consideration. 15 What age did the acquired brain injury occur 16 because that can have significant impact on 17 deficits and outcomes. 18 You can imagine with Sara with the 19 injury occurring at the age of six she is 20 certainly going to have a different outlook 21 and outcome than someone who acquired a brain 22 tumor at 25 who has their general fund of 129 1 knowledge and life experiences in place. 2 A person with an acquired brain 3 injury may still have an average IQ, as I 4 mentioned earlier, but can have significant 5 memory decision making and problem solving 6 deficits. Once a minor with a cognitive 7 disability turns 18 he or she does have full 8 decision making rights unless they have a 9 surrogate. 10 But what I'm finding in my work is 11 that many young adults with these challenges 12 still have a parent making their decisions for 13 them. Or the parent has significant influence 14 in the decision making process. 15 Very important point to consider 16 is what lengths will parents or guardians go 17 to to cure their loved one? If they believe 18 that participation in the study is going to 19 cure them, what will they do? Is the risk 20 versus the benefit the same or different for 21 the individual with the acquired brain injury 22 than it is for the parent or guardian? 130 1 All questions to consider with the 2 population of individuals with acquired brain 3 injury. I thank you for your time. 4 DR. PRENTICE: Thank you very 5 much. Really enjoyed your presentation. 6 Would the panelists and David 7 Strauss please assemble up at the table? 8 Thank you. I will begin with the first 9 question if Dr. Strauss will recognize me. 10 DR. STRAUSS: What do you say? 11 DR. PRENTICE: Thank you. 12 DR. STRAUSS: Ernie, please. 13 DR. PRENTICE: This is really a 14 question for the panelists, not for Dr. 15 Strauss. It's a question for all the 16 panelists. You have been present all morning 17 and you have listened to the charge. You 18 have had the opportunity to listen to David's 19 presentation with regard to the charge. Each 20 of you have presented your own individual 21 perspectives on the area of mental illness, 22 impaired decision making capability, etc. 131 1 I am wondering what your feelings 2 are concerning the need to come up with 3 guidance for IRBs and investigators in 4 determining what are appropriate additional 5 protections for individuals who may have 6 cognitive impairments of the varieties that 7 you have all discussed with us today. Is 8 there a problem out there from your 9 perspective? I would encourage each of you to 10 comment in turn. 11 MS. DONAHUE: Yes. I found it 12 very helpful to see the different other 13 presentations which I think really had a lot 14 of common points. I think there is a very 15 significant problem in terms of psychiatric 16 issues because of the history and this 17 tremendous resistance and opposition and 18 seeing it as the risk of abuse being very high 19 and that interfering strongly with the really 20 critical nature of being able to do research. 21 But on the issue of regulation 22 versus guidance, it is an incredibly complex, 132 1 I would call it kind of a multi-level matrix 2 of all of these moving factors and to try to 3 put that into regulation I think would be a 4 real barrier. On the other hand, I think 5 there is a very significant need for guidance. 6 I think that the issues are 7 complex and a lot of people don't have the 8 expertise. Guiding principles, strong 9 guidance on some of the important aspects I 10 think would be the way to go and very 11 important. 12 MR. ELLIOTT: I guess my feeling 13 is this is the fundamental question, you know, 14 how you then take all this and then how would 15 we reframe or refine or modify or improve the 16 systems. I'm certainly not one who can tell 17 exactly how you would do this, whether it 18 requires new language, whether it requires new 19 regulatory mechanisms. 20 I guess I merge these two very, 21 very interesting ideas thinking that the most 22 important thing the group could do is find 133 1 some way, and I'm not sure what that way is, 2 to send a signal to the research community and 3 to the IRBs and to the people who make 4 decisions case by case in these various areas 5 that there is -- that the community of people 6 who suffer cognitive impairments should not 7 and must not be excluded from the process of 8 research by virtue of that condition alone. 9 I think that if you look at what 10 is going on in this culture and western 11 culture generally over the last few decades, 12 there has been an extraordinary and very 13 benign and extremely praise worthy and 14 democratically important process to respecting 15 the rights of individuals who were hugely 16 abused throughout human history but most 17 obviously recently the mid 20th century and 18 beyond these egregious instances of abuse that 19 had to be corrected. 20 The system has responded in my 21 view as a lay person observing here, 22 magnificently. In the course of this, you 134 1 know, it maybe has resulted in an imbalance, 2 to use the common metaphor, the pendulum has 3 swung a little bit too much in one direction 4 or another. 5 We have a situation now in which 6 it is just too easy for the IRB or for the 7 sponsor or for the research investigator to 8 say, "Why do we take this on? Why do we have 9 to worry about this when it could create for 10 us ethical problems in these very ethical 11 people, or potentially legal problems. 12 Everybody, of course, is concerned about that. 13 In this situation it seems to me 14 that the issue then is in a thing like 15 Parkinson's where, remember the number I used, 16 which no one has questioned, you've got 80 17 percent of people suffering cognitive 18 impairment. On that fact alone by having -- 19 I'm not saying undue concern for the rights of 20 protection. 21 This is something that is very 22 important, but by not sending a signal, by not 135 1 listening to a signal that the door should be 2 open, then a huge portion of the directly 3 affected population will not be able to 4 participate. 5 The Belmont report itself said 6 that you should protect the rights of impaired 7 people but when their own rights and their own 8 needs are involved, as they are clearly when 9 you are investigating treatments for that 10 population, then you consider not adjustments 11 in the principles but making it possible for 12 them to participate. 13 It just seems to me that at the 14 moment the pendulum is a little bit further 15 over than it should be. I think it is partly 16 this wonderful reaction to horrors of the 17 past. The doctors I spoke to, they said, "You 18 know, if we have a choice, it's easier frankly 19 not to have to worry about something where 20 there could be, as I said, the ethical 21 potential or legal problems. 22 I would say I don't know how it's 136 1 to be done. I'm not at all sure it needs to 2 be through new clear regulatory language but 3 some way of sending a signal that the 4 opportunities as well as the rights should be 5 built into the puzzle better than they are 6 today. 7 DR. PRENTICE: Thank you. 8 MS. GRANDINETTE: Given my 9 educational background and not necessarily 10 that of any clinical research, maybe the 11 question I will ask is considered very basic 12 but is there a way to make the level of the 13 research that the individuals are 14 participating in much like the impairments, 15 mild, moderate, or extreme to the point where 16 there are certain research studies that have 17 no risk involved other than the individual's 18 time and whether or not that matrix that Anne 19 spoke about not only includes the types of 20 cognitive impairments but also the types of 21 research. 22 MS. DONAHUE: Just a very brief 137 1 comment on the stigma aspect with mental 2 illness. No offense intended at all but it 3 happens every time I speak. I dream of the 4 day that no one every would say how courageous 5 of you to speak about your illness in the same 6 way they wouldn't say it if I spoke about my 7 bone cancer, which I don't have. 8 DR. PRENTICE: The podium is 9 yours, David. 10 DR. STRAUSS: I wanted to comment 11 on the panelists' presentations which were 12 moving and compelling and thought provoking. 13 A couple of take home messages from me 14 include, No. 1, you don't necessarily 15 recognize an individual with impaired decision 16 making when you see one. 17 That raises questions for how we 18 even would create a meaningful regulatory 19 structure. We have Subparts B, C, and D. We 20 tend to know what a prisoner looks like, the 21 yellow or red jumpsuit or whatever, and the 22 bars. Children, again, are easily recognized 138 1 and defined. 2 Pregnant women and fetuses we tend 3 to be able to see them. How we can 4 characterize a group of people as having 5 impaired decision making remains to be seen. 6 I think we really run the risk of either 7 casting or including too many or too few. 8 The other issue that I just wanted 9 to comment on that I think emerges from these 10 discussions is the pragmatic requirements. I 11 know I am jumping ahead a year or so but the 12 question is how do we ultimately translate 13 these concerns into frontline practice? The 14 question that I would maybe ask the panelists 15 to think about and really SACHRP to think 16 about with us is who ought to be the 17 gatekeepers here? 18 In other words, by setting 19 thresholds in the form of a Subpart E we in 20 certain ways shift responsibilities to the 21 institution and understanding doing so that we 22 may not be precise enough in how those 139 1 regulations are administered in the clinic. 2 If we talk about consent 3 enhancements, if we talk about individual 4 assessments of subjects and so on, we are 5 shifting a lot of the responsibilities here to 6 investigators. I just want to have people 7 ponder what we can reasonably accomplish and 8 expect. 9 MR. NELSON: Just a quick 10 observation, David. Earlier you referenced 11 the perks of being involved in these processes 12 which are admittedly sometimes slim but I have 13 always thought that a real perk was the 14 opportunity and the privilege to hear panels 15 like this and learn from you so thank you for 16 that. 17 My question is prompted by, I 18 guess, Robin's presentation but I would open 19 it up for any of you. Last night on TV 20 downstairs I watched bits and pieces of an 21 hour-long interview with Michael J. Fox who 22 was responding to Rush Limbaugh and others and 140 1 has been very visible on the campaign trail 2 and has become a very public face, obviously, 3 for drawing attention to Parkinson's disease 4 and more broadly embryonic stem cell research. 5 My question, I guess, or the 6 observation is that it often seems 7 unfortunately to require a public face like 8 this, either a celebrity or a parent or a 9 patient who is really going to take the bull 10 by the horns and get out there in the public. 11 Then the result sometimes is quite a focused 12 limited attention drawing more research 13 dollars to that given disease or disorder, not 14 necessarily to a broader set of issues. 15 The questions that come up for me 16 thinking of that and hearing you talk today, 17 what should the role of advocates be maybe 18 most immediately in the subcommittee 19 deliberations but downstream in the IRB 20 process, out there in the real world, who 21 should the advocates be? 22 What should their role in our 141 1 ethical review, regulatory review process be 2 and how do we go about finding representatives 3 or advocates recognizing that we are talking 4 about such a diverse spectrum of disorders and 5 perspectives and how do we get one that is 6 broadly representative without bringing an 7 agenda, etc., etc.? 8 MS. DONAHUE: Love to jump in on 9 that one because it's a huge issue. The whole 10 direction of mental health care now is very 11 focused on recovery principles and consumer 12 directive care and consumer involvement. 13 I think that is a critical aspect 14 is having that involvement, both because that 15 is the only way to build trust that there are 16 positive motivations here as opposed to 17 oppressive ones, but also because it is very 18 much a part of being involved and being 19 empowered in the process. 20 But the other pieces you raise is 21 very important because even, not even getting 22 into the other categories but even within 142 1 mental illness, there is not a consumer 2 advocacy position even that is consistent 3 across the board. Certainly finding a person 4 who speaks broadly is very challenging. 5 I know I'll go back home to 6 Vermont and when my comments are seen there 7 will be friends who are activists who will 8 say, "How could you even suggest that research 9 would be permitted?" I'm not giving you an 10 answer. I'm acknowledging that it is a very 11 significant and important challenge. 12 MS. GRANDINETTE: We all know that 13 most of these different conditions have their 14 associations. While that would be a good 15 place to start, I think your point is well 16 taken that do they have an agenda. I think 17 you would have to weigh very carefully the 18 individuals who were chosen with regard to 19 keeping that in mind, especially when they are 20 working on getting more federal monies to 21 support their cause. 22 MR. ELLIOTT: I think to 143 1 complicate it further, that is a very good 2 question. It is a very important question. 3 To complicate it even slightly further, what 4 groups like my own, which is the Parkinson's 5 Disease Foundation, that are commonly thought 6 of as patient advocates are really not patient 7 advocates in the really strict sense of the 8 phrase. 9 I mentioned it in my own comments 10 that we represent an intersection between a 11 number of interests. I think many of the 12 foundations, including Michael J. Fox's own 13 foundation, do not consider themselves, by the 14 way, patient advocates, which is very 15 interesting that they don't consider 16 themselves that per se. The fact is we 17 represent the science. Often we work with 18 government. We certainly hope we represent 19 patients' interest. It is often a kind of a 20 nexus there where there are several different 21 contingency interests represented. 22 It is not just -- it cannot be 144 1 simply said, even if it could ever be said, 2 that we were representing patients because of 3 the whole issue there is to what empowers you 4 to say that you represent anybody anytime. 5 The fact is we openly actually do incorporate 6 other kinds of interests into the mix there. 7 I'm not sure if that helps or hurts but it 8 does show what a very complicated situation it 9 is. 10 MS. DONAHUE: I would just briefly 11 add that certainly with the consumer movements 12 and so forth there are specific groups that 13 are self-advocates, consumer advocates, but 14 they do tend to carry agendas. In Vermont we 15 have Vermont Psychiatric Survivors is a group. 16 Every state has protection and advocacy that 17 are federally funded. 18 Their entire focus is on civil 19 rights protections. That's not necessarily a 20 bad thing. That might be their good voice and 21 that's a way of having a kind of formal voice 22 that has an agenda that is an important agenda 145 1 to include considerations. 2 DR. STRAUSS: Sam. 3 DR. TILDEN: I have just a couple 4 of scenarios that I would like to get some 5 comments on. For instance, in terms of the 6 subcommittee's deliberations, the situation 7 where you pointed out, Representative Donahue, 8 that maybe you are in a position where you are 9 offered a clinical trial as an alternative to 10 ECT with medication but that it's a phase 1 11 trial and likely there would be no benefit to 12 you. 13 However, you hold out the hope 14 that it may have some benefit so you would 15 want to participate. Would you conclude that 16 you should be allowed to do that even though 17 your reasoning may not be considered 18 rationale? Then I would like to hear Ms. 19 Grandinette because I think that you brought 20 up that sort of issue in your talk as well in 21 terms of judgment. 22 How do you deal with that and 146 1 should this committee on these situational 2 issues, is that something the committee should 3 deal with? I have my own agenda but I want to 4 keep out of it but I would like to get some 5 feedback on that. I have another one with 6 Parkinson's disease. By the way, all of these 7 are grounded in reality, these questions. 8 MS. DONAHUE: Yes. I think the 9 area of treatment decisions is not that far 10 apart. There are huge parallels. I think the 11 thresholds are higher with research, 12 particularly depending on what the individual 13 benefit might be but there are strong 14 parallels. I can look back and say did I even 15 really have the capacity to consent to the 16 treatment I consented to given all of the 17 circumstances that played in. 18 Should I have been allowed? Yes, 19 I should have been allowed. Should there have 20 been some role or some piece that helped me in 21 that process? I think that is a key question. 22 Certainly if it was looking at a clinical 147 1 trial or an alternative, I think that would be 2 critical. 3 Who makes the actual decision as 4 opposed to, you know, an agent plus the 5 individual I think becomes much more difficult 6 and that is when I start thinking in terms of 7 a matrix rather than a rule because it depends 8 on the degree of incapacity, the changing 9 nature of it. 10 Even the changing nature as a 11 person is improving, for instance. Or as a 12 person is -- when you talk about ECT and there 13 is always short-term memory loss immediately 14 after treatment, should that person be 15 reconsenting each time because they have no 16 idea what they consented to. They don't 17 remember the consent by the time the second 18 treatment is there. It's part of all of the 19 complications and it is a good point. 20 MS. GRANDINETTE: And I think we 21 also need to look at how we are determining 22 the capabilities of the individuals. Many 148 1 people following a brain injury will go 2 through fairly extensive neuropsychological 3 evaluations to determine their ability to 4 process information, what their memory 5 capabilities are, etc. 6 If you do that a month after the 7 injury, you are going to get a different 8 person if you do it again five months after 9 the injury because they are changing. You 10 have to first look at what assessments are you 11 using and a mini mental exam is not going to 12 cut it. I can tell you that right now. 13 I believe that, again, we have 14 this changing nature of the condition so we 15 are looking at trying to make a determination, 16 "Yes, it looks like this person is able to 17 make the decision but, again, as Anne stated, 18 with the memory issues, will they remember, 19 and it goes back again to really making sure 20 that you are presenting the information in 21 such a way that it is understood as well as 22 repeating it maybe every time before they show 149 1 up for the next installation of the research. 2 MR. ELLIOTT: Dr. Tilden's point 3 actually brings, I think, an interesting 4 broader point having to do with self-interest 5 and what is in the interest of the patient. 6 Just in case it didn't come up clearly enough 7 in the earlier discussion, I would like to 8 just draw that distinction myself. 9 The issue of what, in fact, 10 constitutes a patient's interest in the 11 clinical trial needs to be understood in the 12 context of the fact that the trials themselves 13 for the most part are not designed to be 14 directly in the self-interest of the patient 15 in the sense that it will make him or her 16 certainly better in a specified period of 17 time. 18 First of all, the treatments by 19 their nature are experimental and may not 20 work. Secondly, there is the issue of a 21 placebo controlled trial. You may be on the 22 placebo for goodness knows how long. There 150 1 are all sorts of reasons and ways in which 2 people coming into trials are, in fact, not at 3 all assured that by doing so they will 4 necessarily serve their self-interest narrowly 5 defined. 6 In fact, in Parkinson's trials I'm 7 sure the same thing is true across the board. 8 It is unethical for an investigator to suggest 9 that by being part of this trial that the 10 prime purpose of this is you, in fact, will do 11 better. 12 Now, we know that there are some 13 people who, in fact, understand that and hear 14 it in theory but still go in wanting to get 15 this because they think it's the best thing. 16 One can't parse this, over parse it, to the 17 ultimate degree. 18 The fact remains the trials are 19 designed to advance science, not to serve the 20 interest of individual patients at that time 21 in the sense narrowly construed of improving 22 health at that time. That distinction needs 151 1 to be understood. 2 The conclusion for that to me is 3 then that one should not then say that just 4 because this is true that, therefore, somebody 5 engaging in this, impaired or not, is making 6 an irrational decision. Altruism is not an 7 irrational decision. 8 Altruism is something which human 9 agents do, think of, aspire to in all sorts of 10 areas of life. It is not irrational for us to 11 do things that aren't necessarily in our self- 12 interest narrowly defined whether we are 13 cognitively impaired or not. 14 MS. DONAHUE: That is an excellent 15 point in follow-up to one of the things I 16 briefly mentioned and that is the difference 17 when you have an agent making the decision, 18 that different standard between best interest 19 versus substituted judgment. 20 If you are an agent who is making 21 a decision based on the best interest of the 22 patient standard, then in a lot of cases you 152 1 are going to say, "No, even if there is 2 minimal risk." 3 But if your role is substituted 4 judgment, which means you are trying to 5 identify what this person I'm the agent for 6 would have wanted and you know their values 7 and the fact that they wanted to be involved 8 because they wanted to help science. You are 9 going to be appropriately much more willing to 10 consent and say this is what they wanted. 11 Very briefly on the mention of 12 understanding, when I kind of looked at 13 Vermont laws, one that I didn't mention in the 14 talk, sort of a little unique carve out of its 15 own that we have is probably a relic of 16 something. 17 For someone who is developmentally 18 disabled, the statute is old so it says 19 mentally retarded, who wants to consent to 20 sterilization, who has adequate capacity, one 21 of the pieces that's required for that 22 determination is that the clinician, the 153 1 physician has to verify for themselves that 2 they truly are making an informed decision. 3 4 Then 10 days later an advance of 5 any actual surgery there is a 10-day 6 requirement that you find out does this person 7 still understand and is able to consent. It's 8 an interesting little way of addressing that. 9 DR. STRAUSS: Sam, I want to 10 respond to the question. You know, IRBs 11 recognize two fundamental protections. One is 12 in the risk benefit assessment, the other is 13 in the informed consent process. 14 I think when working with a 15 vulnerable, or potentially vulnerable subject 16 certainly, the IRB fundamentally makes a 17 decision about how much of the risk benefit 18 analysis is going to lead to the subject and 19 how much will never be presented to the 20 subject because the IRB will be 21 protectionistic. 22 I think that is the way we do 154 1 business. When you introduce the idea of a 2 clinical trial, phase 1 study which will offer 3 no direct benefit to the subject, no 4 therapeutic benefit to the subject. 5 The first thing that an IRB needs 6 to ask is that an acceptable risk? Are those 7 reasonable risks in relation to the benefit? 8 I think the guiding principle tends to be are 9 the proposed subjects the least vulnerable 10 ones consistent with the aims of the project? 11 In other words, do you need to do 12 that phase 1 study in patients with impaired 13 decision making capacity or should that 14 research first be done in people who are less 15 vulnerable? I think the process, the analysis 16 of the process is one that is quite 17 complicated and it would relate to the 18 specifics of the project. 19 So I would say the answer is no, I 20 wouldn't approve that study until proven 21 otherwise, until the details required the 22 conduct of that study in that population. 155 1 MS. DONAHUE: And to narrow it 2 more that you would only do something with a 3 very severely impaired if that was the only 4 way to get that information. If you want to 5 be able to help and provide a treatment for 6 groups who are very severely impaired and the 7 only way to test it and evaluate it is with 8 that group, if that is the only resource, how 9 can we ever help them if we don't find a way 10 to involve them? 11 MR. ELLIOTT: Just a very quick 12 response to David's point. I think his 13 principle is well stated and the way he states 14 it is very compelling. I would ask only that 15 it be done in the context of understanding the 16 spectrum of disability. 17 If it's a spectrum from 1 to 10 18 and there is a person with a disability rate 19 level of whatever it would be, the very least 20 level, it seems to me that judgment should be 21 made by these wise men and women in these IRB 22 situations that would allow for a person who 156 1 is not very disabled to be able to be part of 2 this decision. 3 DR. TILDEN: I understand and I 4 just think still the issue was who decides, 5 okay? That's what my question was trying to 6 get at. And who is allowed to decide and what 7 does informed consent mean or try to get to 8 some of that. The fact is that it may be if 9 it's a psychotropic drug, the population that 10 would require psychotropic drugs might be a 11 better population than even doing phase 1 12 trials in a normal population. 13 For instance, medical students or 14 whatever who may suffer an adverse affect that 15 this drug would have never helped so it is 16 very complicated. I want to say, David, that 17 I can see why this hasn't gone into action 18 because of the complexities but I really think 19 that you are a very good person to make this 20 move forward. 21 MS. DONAHUE: And I just want to 22 say the whole area of advanced directives, I 157 1 think, helps open up that and that is where 2 versus a guardian you really get into the 3 substituted judgment. What would this person 4 have wanted based on it being a person who did 5 have capacity as opposed to someone who 6 didn't, but who is making the decision and 7 what standard is being used is really 8 critical. 9 PARTICIPANT: First of all, I have 10 a request. Representative Donahue, I believe 11 you were speaking from prepared text which I 12 found very eloquent and I wondered if it would 13 be possible to share that with the committee. 14 MS. DONAHUE: I would be happy to. 15 Actually, I went through this huge struggle, 16 the most amount of time. It was much longer 17 and I had to carve it and I would be happy to 18 supply the full version. 19 PARTICIPANT: Either one as you 20 choose. Like the other comments, I am struck 21 by the heterogeneity of the disorders we are 22 talking about, the heterogeneity of the types 158 1 of disabilities, and the time factor that's 2 involved in terms of the changing state of 3 these disabilities. 4 It strikes me it is going to be 5 very difficult to create guidance that is 6 applicable in all these situations so that 7 ultimately this has got to be -- these are 8 decisions that are going to have to be made at 9 the local level. 10 The question is, and perhaps this 11 has been answered and I haven't been paying 12 attention, is there empiric data regarding 13 this in terms of what is being done and what 14 are the decision making processes that IRBs 15 are using? 16 DR. STRAUSS: Gary, I was 17 wondering if you want -- no? Okay. I think 18 the question is an open one. As I said, I 19 think there are a number of projects that are 20 looking at this. There were a couple of 21 surveys I know in New York State looking 22 institution to institution on how decisions 159 1 were made. There was enormous variability and 2 inconsistency. I know there is a national 3 project underway which Gary is not free to 4 talk about. 5 MR. NELSON: David, I will just 6 mention for Mike for reference in whatever tab 7 it is here, tab -- well, the one we're in 8 right now. There is a paper in here by Laura 9 Roberts who many of us have come to know as a 10 thoughtful author in this area that does lay 11 out some conceptual basis and empirical 12 findings in this area from 1998. I am sure it 13 has progressed since then but that is at least 14 a starting point. 15 PARTICIPANT: Thank you. So I 16 haven't been paying attention. 17 DR. JONES: Again, this is the 18 perk that I have enjoyed the most on being on 19 SACHRP is hearing really thought provoking 20 conversations. 21 I guess the one thing that I 22 wanted to react to was, David, your comment 160 1 just now about how we judge whether or not 2 people should be included in clinical trials 3 with no benefit in going for the least 4 vulnerable because in some ways it seems to be 5 a little bit in tension with Robin was asking 6 us about inclusivity, making sure that we just 7 don't exclude like people with dementia from 8 Parkinson's in clinical trials. 9 I understand your rations and 10 reasons and it fits, but it does seem to be a 11 little in tension with this request that we've 12 had about being more inclusive. Then I guess, 13 too, when you talk about what my earlier 14 comment would have been is that your 15 subcommittee is being asked to do something 16 where the field is not quite ready for regs or 17 guidance but your deliberative processes of 18 how you are going about what things need to be 19 considered are really important. 20 To bring what happens in the 21 subcommittee forward about some of the key 22 decisions that you are trying to weigh is 161 1 really going to be helpful, I think, to the 2 field to understand what are the things that 3 are trying to be weighed as you make a model 4 to manage participation. I think that is 5 going to be very helpful. 6 If I was on SACHRP I would ask as 7 the updates come back, textually give some of 8 that contextualization of the issues so that 9 people can understand more of the decisions 10 that you end up putting forward. I did really 11 like then one thing that Robin was saying and 12 that was developing models to manage 13 participation. 14 I participated on something for 15 the Pew Foundation that was examining how do 16 we consider cloned and transgenic animals in 17 the FDA and when it gets into food and drugs. 18 One things that the biotech community was -- 19 well, not complaining but highlighting was 20 that they were getting dinged for some of the 21 processes that were imbedded in 22 industrialization of agriculture. 162 1 In some ways when you are trying 2 to make decisions about how do you manage 3 human subject protections in decisionally 4 compromised populations, it is against the 5 contextual background like Representative Anne 6 said of the mental health community and how we 7 manage it. 8 I do think you are going to have a 9 hard time with regs but then models for 10 participation and also to think about the cost 11 of these different safeguards, to think about 12 the practicability of being inclusive. It 13 probably is going to cost things like it's 14 going to cost to slow the research sometimes. 15 It's going to have cost with personnel. 16 It's going to have cost with maybe 17 an efficacy role in enabling this research to 18 go forward. Not to be afraid of those costs 19 but also to help us educate so that we are 20 willing to pay those costs so that the 21 research can go forward. 22 DR. STRAUSS: I think that is 163 1 really well put. I think that we have talked 2 about a couple of things today, enhancements 3 and creative models of participation that will 4 be costly in some way as will all models that 5 essentially again make the investigators, the 6 gatekeepers here. 7 That is a model that perhaps will 8 allow greatest access, or at least will 9 prevent the problem of denying access, but it 10 also may be the one that is hardest to 11 meaningfully implement. I think there will be 12 tradeoffs along the line. 13 When I talked about the least 14 vulnerable population idea, we were talking 15 about a study where there was no prospect of 16 direct benefit. This tension between 17 protectionism and access, of course, is one 18 that we struggle with. The FDA certainly 19 struggles with it. 20 There are communities of people 21 who would prefer that there be no drug testing 22 and development. We saw it when the HIV 164 1 medications were first introduced that 2 enormous tension from the community. "Don't 3 protect us. Give us access now." 4 You know, I think that the issue 5 of whether we would allow people who have 6 severe impairments in their ability to make 7 decisions for themselves or their surrogates 8 to enroll them in high-risk no benefit 9 research is a very tough call, especially when 10 we think there may be others in whom that 11 research might be done who can provide the 12 information and consent for themselves. I 13 think that is a tough call. 14 MR. ELLIOTT: Can I just -- I'm 15 sorry. It's just I'm directly speaking to 16 this other point. Just give me a second since 17 I also picked up the tension between the 18 inclusiveness and David's earlier point. I 19 think he has explained it well. None of these 20 principles are completely dominating at any 21 given situation. 22 All of them involve balancing as 165 1 David correctly said. I think what you do is 2 you test it by having the hard cases. The 3 issue of a demented patient in a phase 1 trial 4 which the only purpose of which is to explore 5 whether or not the potential treatment is 6 going to hurt somebody, it's going to be 7 unsafe. 8 That is the only purpose of a 9 phase 1 trial, is it going to be unsafe or is 10 it going to be safe. That is clearly the hard 11 case to test any kind of inclusiveness. I 12 completely agree with him that is not the hill 13 in which you want to fight this battle. 14 Having said that, again, you don't 15 want to then say because of that a person with 16 very mild cognitive impairment would be ipso 17 facto excluded from a trial of that kind and 18 that is really what I think you were saying. 19 DR. STRAUSS: David, you may 20 comment on this. In schizophrenia recently it 21 has been quite clear that certain safety and 22 tolerability studies are really not meaningful 166 1 in healthy individuals. In other words, the 2 lessons learned there really don't translate. 3 They are not applicable when they are then 4 administered to folks who have, let's say, 5 prior exposure to medication. 6 We are seeing some earlier studies 7 done in patients with schizophrenia. In those 8 kinds of issues, we would argue, in the 9 circumstances in which we might argue that the 10 scientific benefit or necessity is clear, that 11 would be an opportunity to make sure you would 12 approve that research with maximal consent 13 enhancements and other kinds of protections at 14 the level of consent and surrogacy. 15 MS. DONAHUE: I like that response 16 much better than what I heard you at the end 17 say just before which is what I was kind of 18 jumping to react to because you termed it as 19 a hard case or a tough decision where it was 20 severe impairment and no benefit except for 21 research and might be the only way to -- that 22 is not a hard case. 167 1 That is like no way. If there is 2 another option, then you are going to go for 3 the other option. If there is no other 4 option, even though there is no benefit, I 5 agree with the way you just framed it now if 6 that makes sense. 7 DR. BOTKIN: A question about the 8 charge of the committee and sort of follow-up 9 to Myron's question about evidence-based 10 decisions. I think Myron's question was 11 largely to the evidence base for 12 characterizing the nature of the problem. 13 I am interested in your thoughts 14 about the evidence based for any solutions 15 that might be articulated by the subcommittee. 16 Really the question is is there an opportunity 17 here for the subcommittee to articulate a 18 research agenda for this arena. 19 The problem of course, would be 20 coming up with some good ideas that sound 21 imminently reasonable but subsequently prove 22 not to be very good ideas. I'm thinking 168 1 specifically here as an example of advanced 2 directives. Twenty years ago we thought this 3 was a terrific idea for end of life decision 4 making. Well, it hasn't been a very good idea 5 and it hasn't worked for the most part. 6 I'm getting a negative reaction 7 there but I think the evidence based tends to 8 clearly suggest that at least it hasn't worked 9 nearly as well as people had hoped it would 10 but, that specific example perhaps aside, 11 maybe we would say that there is a real rule 12 here for advanced decision making with 13 research participation in advance of evidence, 14 in fact, that was a useful tool. 15 Perhaps that is a question for 16 Ernie and Bern, too, which is since we are 17 advisory to Health and Human Services, the 18 Secretary has an opportunity as part of this 19 subcommittee to say, "Here is a gap in 20 knowledge. 21 Prior to making any real 22 determinations about what regulations ought to 169 1 look like, somebody ought to have an RFA 2 directed to the National Institute of Mental 3 Health or some such location to say, "Let's do 4 some research on research or research ethics 5 to try to address some of these issues as part 6 of the long-term approach to this problem." 7 DR. STRAUSS: I couldn't agree 8 with you more that some of these issues are 9 purely, or ultimately, let's say, empirical 10 ones, or at least recommendations that might 11 emerge from a committee are ones that may be 12 amenable to empirical testing before 13 widespread implementation. 14 There is, as I mentioned before, 15 and as many of us know, a really growing field 16 of empirical research ethics with some leaders 17 in the field who we plan to rope into 18 involvement in this process. 19 MS. DONAHUE: Just very quickly, I 20 would be happy to talk afterwards with having 21 gone through very intensive work on advanced 22 directives and where they can be and can go, 170 1 for research as well which is part of what we 2 just did in Vermont. 3 DR. BARRATT: Yes, just to say 4 that NIH does have a program announcement on 5 research ethics and you should be encouraging 6 you and your colleagues to take a look at 7 that. Some of the kinds of work that's been 8 cited here today has been funded through that. 9 DR. LUX: In addition to the need 10 for empiric data on research ethics, there is 11 also a need for empiric data on assessment of 12 capacity to consent. That is a huge area as 13 people have pointed out. Capacity to consent 14 is specific to the thing being consented to so 15 that general assessments of cognitive capacity 16 have not proven terribly useful in this area. 17 There are some early, or actually 18 not so early now, better developed attempted 19 to assess capacity to consent in very specific 20 kinds of situations, notably by Applebaum and 21 colleagues, but incorporating that into your 22 processes may be useful as well. 171 1 DR. PRENTICE: It has been a very 2 interesting discussion. I don't want to halt 3 it yet but we are into the public comment 4 section. We have no one from the audience who 5 has indicated a desire to address SACHRP so 6 would you please step up to a microphone, 7 identify yourself and your affiliation. 8 MS. VANDENBOSCH: Terry 9 Vandenbosch from the University of Michigan. 10 Although I must say I don't speak for them at 11 this point, some of this will be my own 12 opinion. I had two comments. One is from 13 yesterday on Subpart A and that is the 14 decision not to follow up on waivers. 15 I wanted to point out the third 16 criteria under waivers in terms of it not 17 being practicable to conduct research and in 18 terms of getting the informed consent. I 19 wanted to point that out as an area where IRBs 20 may over or under regulate and some 21 disciplines are more affected by it than 22 others. 172 1 My guess is that the committee did 2 consider that and it probably interacts with 3 the definition of research and identifiable 4 data which are also topics of importance. I 5 did want to point that out as a consideration. 6 The second is just to exclaim how 7 much this has been valuable to me today in 8 hearing the various discussions that people 9 have in regards to decisionally impaired and 10 I wanted to say that I felt -- and I wanted to 11 say that I think that it is important in the 12 composition of the committee to also consider 13 nursing homes. 14 There aren't FWAs there and as a 15 nurse many of my colleagues work with nursing 16 homes and run into extremely difficult ethical 17 situations there so I wanted to put a plug in 18 for that as well. Thank you. 19 DR. PRENTICE: Okay. Thank you. 20 Let me respond to your first comment. 21 Certainly the criteria for IRBs granting 22 waiver or partial waiver of informed consent 173 1 is high on the list of the agenda in terms of 2 informed consent but it is part of the 3 informed consent section that Subpart A will 4 be looking at sooner or later. 5 It is going to be a rather large 6 task for them to look at all aspects of 7 informed consent including waivers so it's not 8 that it has been eliminated from the agenda. 9 It has simply has not risen to the level of 10 priority for the next few months. 11 Are there any other comments from 12 the public? With the permission of the panel, 13 I would like to continue the dialogue if there 14 is still interest in doing so because we have 15 a little bit more time. I'll begin with a 16 question. 17 Robin, in your presentation you 18 talked about the Belmont report. You talked 19 about the principle of justice. You talked a 20 little bit later on that these principles 21 sometimes can be in conflict with one another. 22 Certainly the issue of justice is extremely 174 1 important, not only in terms of enrollment of 2 any human being in research but clearly the 3 enrollment of individuals who are cognitively 4 impaired. 5 Sharon, in your presentation you 6 have a slide that was titled, "Why do people 7 participate in research?" One of the bullet 8 points was, "Because I don't have any health 9 insurance." As far as I am concerned, the 10 health insurance in this country is a 11 disaster. 12 I think most people would agree 13 with that. The number of Americans that are 14 uninsured is just absolutely phenomenal. The 15 health insurance plans that I am familiar with 16 really don't provide adequate insurance for 17 mental illnesses. Maybe there are some 18 Cadillac plans but the ones that I know about 19 are rather deficient. 20 Here I go to the thrust of my 21 question. If people with cognitive 22 impairment, mental illness, whatever the 175 1 reason is, and they are not covered by their 2 insurance policies, is there not an incentive 3 for them to enroll in research because that is 4 the only opportunity that they have to acquire 5 treatment. 6 Certainly that tends to promote 7 the therapeutic misconception because they are 8 obviously not enrolling in research for 9 altruistic reasons for the most part. They 10 are enrolled in research because they have no 11 alternatives. I think personally that is a 12 big problem. I don't know how you resolve 13 that. 14 It is my impression at my own 15 institution that a lot of the studies that we 16 have conducted by our Department of Psychiatry 17 involve people who just don't have any health 18 insurance. I would be interested in the panel 19 commenting on this particular issue. 20 MS. DONAHUE: I have a solution. 21 No, I mean, that is the fight for parity, for 22 insurance parity. Vermont actually has what 176 1 is considered to be the most expensive, the 2 most comprehensive parity requirement, 3 mandate. Yet, from my perspective it still 4 falls short. It is staggering to me. 5 It just is absolutely staggering 6 to me that in 2006 in the United States of 7 America despite everything we know in science 8 that we actually allow insurance products that 9 say mental health isn't covered because maybe 10 the product is cheaper. 11 Well, I could give you a much 12 cheaper product if it carved out cancer and we 13 would never dream of allowing that. I think 14 that is the fundamental thing that has to do 15 with healthcare as opposed to looking at it 16 from the impact on research. We've got to get 17 at it. It's an unthinkable situation. 18 MS. GRANDINETTE: And it isn't 19 just people who don't have insurance I find 20 because when you look at acquired brain injury 21 it's really a disease so it doesn't go away. 22 Unfortunately, and I'll give you 177 1 an example of a family I'm working with right 2 now whose son suffered from encephalitis and 3 he had his in-patient rehab and he has had 4 some post-acute rehab and he is continuing to 5 make progress with the cognitive 6 rehabilitation which is going to make him a 7 better contributing member to society and be 8 able to make his own decisions at some point 9 but the cap cut them off and that's it. 10 That family was told by the 11 insurance company it is the public school's 12 responsibility to take care of him now. 13 Either we pay for it through medical insurance 14 or we pay for it through our educational 15 system. 16 MR. ELLIOTT: I think you have a 17 very important point there. I was struck 18 recently when I was talking to a clinical 19 scientist who would never, ever say to a 20 patient that, "You will get better because of 21 this research." That same person, in fact, 22 said that, "You will get good medical care and 178 1 you will have it free and it will be the 2 highest possible quality." 3 In my view that actually is a form 4 of undercutting the issue of thoroughly 5 informed consent. I think actually however 6 well intentioned it was in the context of so 7 many people being uninsured, to my mind this 8 is wrong. Having said that, the reference has 9 been made several times in the last few 10 minutes to empirical data. Empirical data are 11 important here, too, in the Parkinson's area. 12 I was struck recently by the 13 meeting I attended down in Washington when the 14 leadership, for want of a better word, of the 15 Parkinson's community, patient community was 16 there. I asked for a show of hands as to how 17 many of the people in the room had, in fact, 18 ever enrolled in a clinical trial. 19 Bear in mind this is a community, 20 and I did not mention this in my presentation, 21 fewer than 1 percent of people with 22 Parkinson's, fewer than 1 percent actually 179 1 participate in trials. In that room it was 2 more than 50 percent. 3 These were the most educated upper 4 or middle income, whatever it would be, people 5 who, for the most part are the largest single 6 group who go into research. In empirical data 7 terms, it seems that most of the people, and 8 there has been no study of this. This is 9 anecdotal stuff, let me just say for the 10 record. 11 There is a disproportionate number 12 of those who do participate in trials tend to 13 be among those who are not only not 14 cognitively impaired for the most part, but 15 also are in a position perhaps of more 16 privilege. I think, again, we need to look 17 and see what the empirical data are even as we 18 look at the principles involved and then work 19 into any kind of solution we may. 20 DR. PRENTICE: David. 21 DR. SHORE: Excellent group of 22 presentations. I want to express my 180 1 appreciation to the speakers and to OHRP and 2 to SACHRP staff for putting this group 3 together. The presentations and the 4 discussion have been fascinating. 5 There is one issue that has been 6 alluded to a couple times but has not, I 7 think, been dealt with directly. One of the 8 concerns about restrictions and excluding 9 people with certain disorders or certain 10 capacity impairments has focused on the 11 application of the child regs to people with 12 questionable capacity. 13 While participation in trials has 14 been referred to, that is really not the kind 15 of research that is most likely to be 16 threatened because research with the prospect 17 of direct benefit would largely be allowed 18 under the child reg model. 19 The kinds of research that would 20 likely be excluded or made considerably more 21 difficult under the child regs would be 22 research without the prospect of direct 181 1 benefit, nontrials type research. 2 That's been mentioned but hasn't 3 been focused on specifically. Certainly for 4 schizophrenia, bipolar disorder, and 5 depression, part of my current job is to try 6 and improve the treatments that we have for 7 those disorders. 8 Certainly for traumatic brain 9 injury and for progressive degenerative 10 changes in the brain that may be related to 11 Parkinson's disease or Alzheimer's or other 12 disorders, I think the prospect that a 13 particular medication, for instance, is likely 14 to reverse the changes of a severe brain 15 injury are pretty remote. 16 It is much more likely that 17 research on the underlying causes or the 18 clinical course of those disorders, for 19 instance, does a certain type of brain injury 20 improve over time or does it worsen or do 21 clinical presentations change? What is the 22 prognosis for a deteriorating brain condition? 182 1 These are questions of is this the result of 2 a genetic vulnerability or is it the result of 3 some environmental interaction with that? 4 For those kinds of disorders it is 5 likely that underlying -- getting at the 6 underlying causes of the disorder is going to 7 be much more essential before we can get to 8 the point of preventive interventions. 9 While you have all spoken about 10 the access to treatment research to trials and 11 the fact that having impaired capacity should 12 not interfere with that, I'm wondering if you 13 would also comment on situations in which it 14 is perhaps unlikely that any treatment in the 15 near future is going to reverse those changes 16 and on the importance of doing research on the 17 underlying causes which may not have the 18 prospect of direct benefit. 19 MS. DONAHUE: I think that's an 20 area that is very important. We touched on it 21 in the discussion about, you know, if this is 22 the only group where that kind of research can 183 1 happen, how critical it is to find ways that 2 it can happen even if there is no benefit and 3 maybe risk involved and who makes that 4 decision. 5 That is where I was trying to give 6 the example, not as a suggestion but as an 7 example, of the kind of newer thinking. If 8 you created, if you will, a pool of people who 9 because they wanted to for altruistic reasons 10 who had the capacity to consent, who did an 11 advanced directive with the Ulysses-type, you 12 know, "Unless I say no down the line but 13 saying I'm directing my agent. This is my 14 desire. When I no longer have capacity and 15 when it would be of critical value to 16 research, I want to make that contribution and 17 I'm authorizing my agent to authorize that." 18 If you had, in effect, an advanced 19 pool of people. That is not the fastest way 20 and, again, I'm not making it as a specific 21 recommendation, but I think it's the kind of 22 thinking where we could create those options. 184 1 DR. STRAUSS: David, I think that 2 those are the kinds of things we are really 3 beginning to be faced with now. I'll give you 4 an example. Investigators at my institution 5 are involved in really quite compelling brain 6 imaging work looking at with PET imaging 7 markers of disease progression in Alzheimer's 8 disease. 9 Right now the study is being done 10 but it is limited to people with mild 11 cognitive impairment who are evidencing early 12 evidence of Alzheimer's disease. They are 13 trying within what is the only allowable 14 framework for them tracking it over time 15 knowing that once the patient loses capacity, 16 it will be hard to get approval for this kind 17 of research. 18 It's more than minimal risk. 19 There is no direct benefit. What is quite 20 compelling is that quite soon if this marker 21 pans out, and it looks like it will, there 22 will really be a need to see whether that 185 1 progression marker can be demonstrated to be 2 valuable in later disease stages. In other 3 words, how effective is it as a marker of 4 disease progression. 5 We need models, as we have said 6 today, to accommodate that kind of research 7 which can only be done in people with impaired 8 decision making to allow consent or to allow 9 that research to occur, again, under the right 10 circumstances. There are a number of models 11 which are in place. 12 As you know, in New York State 13 kind of the silver lining after a cloud of a 14 law suit, TB versus New York State, were that 15 a series of agreements were made between the 16 Department of Health and the Office of Mental 17 Health which created a number of models of 18 consent for research which are applied. 19 One of them was alluded to -- one 20 of them in principle was alluded to called a 21 patient chosen surrogate model and it 22 recognizes the idea that while you don't have 186 1 the capacity to understand, let's say, the 2 risks and benefits of the research in enough 3 detail to make an informed decision, you might 4 have enough capacity to understand that an 5 important decision is before you and to 6 designate a surrogate to make that decision on 7 your behalf. 8 Now, we have a very elaborate 9 process to do that. It involves having two 10 psychiatrists independent of the researcher 11 assess the person's capacity and it actually 12 requires notification by us of the New York 13 State Mental Hygiene Legal Service which is an 14 independent legal advocacy group. Under those 15 circumstances such research can be done and we 16 do on occasion authorize that kind of process. 17 We also recognize under our 18 allowable rules a process which enables 19 patients, let's say in a longitudinal study in 20 Alzheimer's disease, to at the outset appoint 21 what we call a research healthcare proxy. The 22 typical healthcare proxy is really about 187 1 clinical decisions. 2 In the research healthcare proxy 3 what is required is that the subject make a 4 decision about the kinds of research in terms 5 of level of risk that would be allowable for 6 this proxy to assist with down the road. 7 There are models that can be employed. 8 Let me just say that I think the 9 bottom here is that we also do our best to 10 make sure that we raise the bar of benefit 11 even in this so-called no direct benefit 12 research. People who participate in it and 13 their families don't see it as being only 14 altruistic or only in some fashion 15 exploitative. 16 They get a lot back. They don't 17 get treatment back. They get care, they get 18 advice, they get referrals, they get 19 assessment. There is a lot of benefit which 20 can be secured even in nonbeneficial research. 21 MS. GRANDINETTE: I just wanted to 22 add to that there is a research project going 188 1 on right now at a prominent university in 2 Southern California where the families are 3 doing it because they are getting free 4 neuropsychological evaluations that can cost 5 $3,000 to $5,000 and are not being covered in 6 any other form of insurance. To them that is 7 a benefit. They need that information. 8 DR. SHORE: I think when we are at 9 the point where as we renew our driver's 10 licenses we are routinely asked whether we 11 would want to become an organ donor and 12 whether we would want to participate in 13 certain types of research, when we are at that 14 stage then I think we may have an adequate 15 pool of people who will later on become 16 appropriate candidates for research who have 17 that kind of advanced directive. 18 But at a time at which the vast 19 majority of people don't even have any 20 indication about their end-of-life care when 21 they wind up in the emergency room 22 unconscious, I think if we were to restrict 189 1 research to only those people who have the 2 foresight to create such a document, and since 3 I am probably one of the few people in 4 Montgomery County, Maryland, who actually has 5 such an advanced document because I told my 6 lawyer how to do it since he had never done 7 one before, I think in the future that may be 8 very helpful. 9 I would just caution people that a 10 solution that may not be applicable 11 practically for another five or 10 years still 12 creates a big gap. 13 MS. DONAHUE: And I wasn't 14 suggesting it as an only solution but I will 15 say that Vermont statutes does include a 16 driver's license check off. In fact, it will 17 require very extensive public outreach, a 18 statewide database. Every emergency room is 19 required to check the database when a person 20 comes in to see if they have an advanced 21 directive. Actually, I think, it may become 22 a model for how much more aggressive and 190 1 active involvement of the public. There are 2 model forms that people will be able to access 3 and a whole lot of public education about how 4 crucial it is. 5 MS. GRANDINETTE: Don't forget 6 there are a large number of individuals who do 7 not have driver's licenses because they are 8 cognitively impaired. If you have epilepsy 9 and you have seizures that are not controlled, 10 you can't have a driver's license. If you had 11 your brain injury at 10, you may not ever have 12 a driver's license so how do we access that 13 population? 14 DR. STRAUSS: You know, I don't 15 think we have done a lot of research on the 16 use of healthcare advanced directives. I know 17 that every time a generation of people are 18 motivated by the thought, "I don't want to end 19 up like Karen Ann Quinlan," you know, issued 20 some kind of advanced directive basically 21 saying, "I don't want that kind of life 22 support." 191 1 How well informed those kinds of 2 decisions are it is hard to say. I think 3 there would need to be a more carefully 4 constructed framework for a kind of research 5 advanced directive. 6 By in large I think the way these 7 advanced directives and healthcare proxy rules 8 are administered or implemented I think 9 requires some more attention. I don't think 10 a lot of thought go into them sometimes, 11 Montgomery County and Alabama excluded. 12 MR. ELLIOTT: Just a quick one- 13 liner on this. I'm not an expert in this but 14 what about simply requiring that the advanced 15 directive would always be accompanied by some 16 sort of surrogacy arrangement so they would go 17 hand in hand? 18 MS. GRANDINETTE: So I had this 19 thought earlier in the talk and I thought it 20 was too generalistic, I guess. What do we do 21 when people reach the age of 18 and they 22 become adults, or 21 depending on what we are 192 1 looking at? 2 Does the government require a form 3 that needs to be filled out regardless of 4 whether you drive or not that includes both 5 kinds of things? That is a lot of legislation 6 to impose upon the population but it is food 7 for thought. 8 DR. PRENTICE: Okay. We are going 9 to wrap this up now. I would like to thank 10 all the panelists and David for very, very 11 interesting presentations. I am sure we have 12 all enjoyed the discussion and it is very 13 clear we have a lot of work to do so let's 14 give them a round of applause. 15 We are now entering into the wrap- 16 up. First I want to remind everybody of the 17 '07 meetings, March 12th and 13th, July 30th 18 and 31st, October 29th and 30th. Secondly, 19 Bern, would you like to make any parting 20 comments? 21 DR. SCHWETZ: Thank you, Ernie. 22 Yes, I would. Thank you, David, and the rest 193 1 of the panel for very informative set of 2 comments and discussion. I think this is a 3 prediction and some insight into how this 4 whole thing is going to go with a great deal 5 of complexity and a lot of interest and 6 importance so thank you all for helping us 7 with that. 8 Also, assuming that we are close 9 to the end of this meeting, I'll return to 10 where we started and thank you, Nancy, as you 11 have now helped us through the last meeting on 12 your tenure. Thank you very much for the help 13 that you have been. 14 Ernie, the same to you for the 15 leadership and the insight and all the help 16 that you have been to us. I would hope that 17 we would keep in touch with both of you as we 18 can benefit from your insights and your 19 knowledge in the future so thanks. 20 DR. PRENTICE: Okay. Thank you, 21 Bern. I think I actually speak on behalf of 22 both Nancy and myself when I say it's really 194 1 been a privilege to serve on SACHRP. It has 2 been an absolutely fascinating experience. We 3 have learned an awful lot. There are clearly 4 a lot of challenges in the future. 5 I'm going to kind of miss not 6 being part of the pursuit of solutions to 7 those challenges. All things must come to an 8 end. It is good that there is a turnover on 9 committees like this and you bring in fresh 10 ideas and new intellects. Again, I want to 11 thank everybody and encourage you all to do 12 your best in the next two or three years 13 during your tenure on SACHRP and enjoy the 14 experience. 15 Bern, I want to thank you for the 16 partnership that you foster between OHRP and 17 SACHRP. Of course, I want to thank all of the 18 members of your staff who are, I think, really 19 key in the success that we've had. Thanks very 20 much everybody and the meeting is adjourned. 21 (Whereupon, at 12:24 p.m. the 22 meeting was adjourned.)