398 1 2 3 Department of Health and Human Services 4 5 6 NATIONAL HUMAN RESEARCH PROTECTIONS 7 ADVISORY COMMITTEE (NHRPAC) MEETING 8 9 Tuesday, April 10, 2001 10 11 12 13 14 15 16 17 POOKS HILL MARRIOTT 18 5151 Pooks Hill Road 19 Bethesda, Maryland 20 21 22 399 1 A G E N D A 2 Tuesday, April 10, 2001 3 8:30-8:45 Brief Recap of Day One Questions/ 4 Clarifications 5 Mary Faith Marshall, Ph.D. 6 8:45-9:00 The National Institutes of Health and 7 Human Subject Protections 8 Ruth Kirschstein, M.D. 9 Acting Director, National Institutes 10 of Health 11 9:00-12:00 Children 12 9:00-9:45 Discussion of Current Definitions and 13 their Interpretation 14 NHRPAC Committee 15 9:45-10:15 Update: Children's Workgroup 16 Alan Fleischman, M.D. 17 Senior Vice President, NY Academy of 18 Medicine, Clinical Professor of 19 Pediatrics and Clinical Professor of 20 Epidemiology & Social Medicine, Albert 21 Einstein College, New York 22 400 1 10:15-10:30 BREAK 2 10:30-11:45 Committee Discussion 3 11:45-12:00 The National Science Foundation and 4 Human Subject Protections 5 Rita Colwell, Ph.D. 6 Director, National Science Foundation 7 12:00-1:30 LUNCH (On your own) 8 1:30-2:15 Update: Social Science and Discussion 9 Felice Levine, Ph.D. 10 Executive Officer 11 Philip Rubin, Ph.D. 12 Director, Division of Behavioral and 13 Cognitive Sciences 14 National Science Foundation 15 2:15-3:15 Public Comment 16 3:15-3:30 BREAK 17 3:30-4:15 Meeting Recap 18 Review Recommendations: 19 Financial Relationships 20 Declaration of Helsinki 21 Genetics 22 Family Members/Subjects 401 1 Children 2 Social Science 3 Mary Faith Marshall, Ph.D. 4 4:15 THANK YOU - ADJOURN 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 402 1 MARY FAITH MARSHALL, Ph.D., Chairperson, Director of Program 2 in Bioethics, University of Kansas Medical Center 3 4 GREG KOSKI, Executive Secretary, Ph.D., M.D., Director, 5 Office of Human Research Protections, Office of Public 6 Health and Science, OS 7 8 MARK BARNES, J.D., LL.M., Partner, Proskauer Rose LLP 9 10 SANFORD CHODOSH, M.D. 11 12 ELLIOT N. DORFF, Ph.D., Rector, Distinguished Professor of 13 Philosophy 14 15 ALAN R. FLEISCHMAN, M.D., Senior Vice President, The New 16 York Academy of Medicine 17 18 SUSAN Z. KORNETSKY, M.P.H., C.I.P., Director, Clinical 19 Research Compliance, Department of Clinical Investigation 20 21 FELICE J. LEVINE, Phase.D., Executive Officer, American 22 Sociological Association 403 1 ROBERT LEVINE, M.D., Professor of Medicine, Yale University 2 School of Medicine 3 4 ABBEY S. MEYERS, President, National Organization for Rare 5 Disorders 6 7 JONATHAN D. MORENO, Ph.D., Emily Davie and Joseph S. 8 Kornfeld Professor of Biomedical Ethics, Director, Center 9 for Biomedical Ethics, University of Virginia Health System 10 11 MARY Z. PELIAS, Ph.D., J.D., Professor, Department of 12 Genetics, Louisiana State University Health Sciences Center 13 14 ROBERT R. RICH, M.D., Executive Associate Dean of Research, 15 Emory University School of Medicine 16 17 ADIL E. SHAMOO, Ph.D., Professor, Department of Biochemistry 18 and Molecular Biology, University of Maryland School of 19 Medicine 20 21 JUDITH L. SIEGEL, Ph.D., Vice President, Head U.S. Clinical 22 Operations, Hoffman-La Roche, Inc. 404 1 DENYSE THORNLEY-BROWN, M.D., Assistant Professor, Division 2 of Nephrology, University of Alabama at Birmingham 3 4 KATE-LOUISE GOTTFRIED, J.D., M.S.P.H., Executive Director, 5 National Human Research Protections Advisory Committee 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 405 1 P R O C E E D I N G S 2 [Time noted: 8:40 a.m.] 3 CHAIRPERSON MARSHALL: Good morning. 4 Welcome to the second day of our second meeting. 5 I would like to begin by thanking three 6 people who have helped make this meeting possible. 7 And they helped make the last meeting possible. They 8 keep me honest. Tony Goodwin and Carla Brown are 9 standing by the door. Thank you all. 10 [Applause.] 11 CHAIRPERSON MARSHALL: We've had, I think, 12 a spectacular meeting and we wouldn't have had it 13 without you. So thank you so much. We are very 14 grateful. And please convey my thanks and our thanks 15 to Barbara Smith too. 16 Thank you. 17 It's my honor to introduce to you -- I'm 18 sure you don't need an introduction -- Ruth 19 Kirschstein, who is the Acting Director of the 20 National Institutes of Health. And she is going to 21 open our meeting for us this morning. 22 DR. KIRSCHSTEIN: Good morning. I'm 406 1 pleased to be here. I'm glad you invited me to come 2 and talk. I want to be sure that -- while I was here 3 for a few minutes at your last meeting, as I recall, 4 I didn't really say very much. And I wanted to be 5 sure that I would perhaps expand for you a little bit 6 on how NIH views what's going on and also how we are 7 approaching the activities. 8 There is no question that the protection 9 of the colleagues that we use as partners in the work 10 we do in clinical research is of utmost importance 11 and is the commitment that NIH has to these 12 individuals and to society and to the country as a 13 whole. 14 And, of course, it's been the focus, as 15 you know, of a number of policies that we have 16 thought about and worked on and have to some extent 17 are still evolving. 18 The philosophy behind those policies and 19 behind everything we do is that our concern about 20 these people must be as deep and as excellent as is 21 the science that we perform. We will settle for 22 nothing less. 407 1 And the protection of these human 2 participants and the clinical trials are actually at 3 the heart of what we are doing. And we are concerned 4 and have been for a long time that we need to do more 5 clinical research. And we are searching, looking for 6 ways to increase the numbers of individuals that are 7 trained as physicians and other health care 8 professionals to enter the arena of clinical 9 research. 10 We have made enormous strides over the 11 last number of years in some basic discovery. There 12 is not a day that does not pass that in the 13 newspapers there are stories that hold -- if you just 14 listen to them and read them -- enormous promise. 15 But the promise can only be fulfilled if 16 we do clinical research that leads to conclusions 17 that can be verified, validated, and then moved on to 18 the next step. And that is only done if we have 19 highly qualified, highly trained, highly skilled 20 individuals who have the same sense that all of us 21 around this table have that when they are performing 22 clinical studies, they must be cognizant first and 408 1 foremost that you do no harm to any patient. 2 And not only do we feel that way because 3 we ourselves believe it, but it's also because as 4 stewards of the public's money, we must assure that 5 those funds are used properly. And we have worked 6 very hard to do this all our lives. And it is no 7 accident, I think, but yesterday when the new budget 8 that President Bush proposed for NIH, the Secretary 9 of the Department of Health and Human Services, Tommy 10 Thompson, repeated, again and again and again at the 11 press conference, how much confidence he had that NIH 12 could spend this wonderful increase that the 13 president is proposing well with appropriate 14 safeguards in stewardship and would make new 15 discoveries that are going to be of very great 16 importance to people. 17 So we take this very, very seriously, not 18 just because we want him to say good things about us 19 continuously, but because we deeply feel this way and 20 this has been a commitment that I have had for the 45 21 years that I have been at NIH. 22 Now, in order to carry out these policies 409 1 and procedures that we are putting in place, we want 2 them to be transparent to everyone that is concerned 3 so that there can be a smooth and transparent way of 4 carrying things out, yet an assurance that it is 5 being done correctly. 6 And we have to respect and operate within 7 the boundaries that define NIH, that define Dr. 8 Koski's position, that define practice because we are 9 not in the practice of medicine at NIH. 10 Now, in order to do that, we want to be 11 sure that our policies and our procedures are very 12 well understood by everybody and by our 13 investigators. We take great pains to put all the 14 material that we have in place in regard to 15 procedures and policies on the NIH web site. And 16 I've picked out some of the pages that you might like 17 and would suggest we hand them out to the members of 18 the committee. And for everybody else, you can reach 19 them and find them on the NIH web site. 20 In addition, we put out something called, 21 "The NIH Guide to Grants and Contracts" and that is 22 also on the web site. And in the web site on the 410 1 front page, we have what we call a "Newsflash." So 2 anything new we do, you can find without any 3 difficulty at all by simply looking at the first 4 page. 5 We have recently put up new information on 6 human subjects and financial conflicts of interest 7 which lists and provides links to all the rest of 8 them. 9 Much of this is based on experience that 10 we have had recently when with the help of Dr. 11 Belinda Seto, who is here -- and actually she ran a 12 program on bioethics that we set up and we supported 13 a meeting that took place at Tuskegee about a year 14 and a half ago that those of you who are nodding 15 remember I was present at and spoke. And since then 16 we have had a number of a activities that we have 17 done. We have provided training grants for 18 bioethical activities as an example. 19 Now, one of the boundaries that everybody 20 has to understand, however, is that NIH is not a 21 regulatory agency. We do not have the regulatory 22 authority that allows certain things to take place so 411 1 that we can basically take people to court. That is 2 the province of the Food and Drug Administration; it 3 is the province of other regulatory agencies. NIH is 4 primarily a research organization. So that our 5 activity comes from the moral sense of what we must 6 do and is looking at the stewardship of the federal 7 dollar. 8 But we don't and cannot demand that people 9 simply do something. We can persuade, we can use our 10 influence, we can do what we have recently done which 11 is to go out and look at what they're doing. We went 12 up to ten sites on what we call pro-active site 13 visits. That means that we have no notion. We don't 14 presuppose that anybody has done anything wrong. 15 We're simply going to take a look. And we have 16 completed those. We were very pleased with them and 17 the results of what went on are being also published 18 on the web site. 19 From them, of course, we learn. We learn 20 that not everybody does things the same way, and that 21 is the great thing about the NIH research system 22 because we can suggest then to one person, one group 412 1 that perhaps having learned something from another 2 that it might be useful to use. 3 We can put policies in place. We can put 4 certain requirements in place, but we do not and 5 cannot demand. 6 On the other hand, if those policies are 7 not followed and there is no reason why that is not 8 so, and if this is a continuing process, we do have 9 the ability to terminate funds to that organization. 10 I also want to remind you that the funds 11 that we give for research grants are not given 12 directly to investigators. They are given to the 13 institution in which those scientists, those 14 clinicians, those clinical researchers work. And it 15 is the institution that has the ultimate 16 responsibility for that activity. 17 One of the things we have been working on 18 more recently is to make sure that the institutions 19 which clearly know they have the responsibility -- 20 they certainly know it when they complain, when we do 21 something they don't like -- that they also know that 22 they have the responsibility to carry out the -- what 413 1 we have charged them to do. And we are working very 2 hard on that aspect of things particularly in regard 3 to institutional conflicts of interest which is 4 something that we have not really, until maybe a year 5 or so ago, have not spent a lot of time considering. 6 The new realities of how institutions find 7 the funds which they need to do their work has made 8 it necessary for them to look at a broad array of 9 sources for funds and it's very important for them to 10 consider and for us to understand the conflicts of 11 interest that might occur. 12 We have, of course, in regard to clinical 13 trials and our oversight of clinical trials have had 14 a longstanding policy that in particular for Phase 15 III trials demands that there be -- and I use the 16 word "demand," that's probably not right -- asks that 17 there be data in safety monitoring boards. And that 18 policy has been generally acceded to because I think 19 it has -- it is general practice that when you are 20 doing very large trials you must be sure that there 21 is a group that can look at the data in an objective 22 way. 414 1 But we recently have decided we need to do 2 some more monitoring on both Phase I and Phase II 3 clinical trials. And so we now ask applicants to 4 submit to the NIH for review and approval a 5 monitoring plan that includes the mechanisms for 6 recording any adverse events. 7 This is still not regulatory, but it is 8 what we expect. Now, there is one place where 9 clearly these move together. And that is that any 10 NIH-supported investigator who is doing the clinical 11 work in a Phase I or a Phase II or even in a Phase II 12 clinical trial under an investigational new drug 13 application approval from the Food and Drug 14 Administration must follow those regulatory 15 requirements and we will watch for that as well. 16 One of the things that is very important 17 in this process of dialogue is communication is 18 between all concerned. We have scientists who are 19 administrators who monitor/oversee what is going on 20 in the research grants and even more so in research 21 contracts and a number of clinical trials, 22 particularly Phase III would be done under a research 415 1 contract mechanism rather than a research grant 2 mechanism. Not all. We leave that to the discretion 3 of the investigators. 4 But we must have dialogue between these 5 people and watch what they're doing and watch what 6 the institutional review boards do. And so we 7 require them to inform us of anything that they are 8 doing for which the Food and Drug Administration has 9 jurisdictional authority. And we therefore learn 10 from what they are holding. 11 An investigator has received a letter from 12 the Food and Drug Administration on some particular 13 aspect of the trial we ask them to share that with 14 us. I must say that until recently that was not 15 something we did and it turned out to be unfortunate 16 and we are now increasing that and making that 17 happen. This is a mechanism for improving oversight. 18 We are evolving just as everyone else is. 19 We think that the knowledge of ethics and 20 research integrity is fundamental to good clinical 21 practice. We require that the trainees who are on 22 our training grants to do research, basic research 416 1 primarily take some sort of training in research 2 integrity and we are hoping that people also have 3 such when they're doing clinical work and we're 4 devising some new ways to do this and we are going to 5 require that these be done. 6 We have this bioethics training grant 7 support which is called a T-15. We have made a 8 number of awards and we would be delighted to have 9 more individuals, more institutions have that. 10 So let me summarize by saying that I think 11 that our approach is based on our notion of 12 objectivity in research. Financial conflicts of 13 interest, but those aren't the only ones, we require 14 the institutions to have written enforced policies on 15 that. And they are required to report to us to 16 manage, reduce, and possibly eliminate those. But we 17 are evolving and we are working on a number of 18 concerns and therefore we need to go further. And I 19 think I'll stop and answer any questions. 20 CHAIRPERSON MARSHALL: Thank you, Ruth. 21 I just would like to make a comment before 22 we entertain questions. And that is that we have 417 1 four of your colleagues at the NIH who work very 2 closely with us on our committee, Alan Sandler, 3 Belinda Seto, Hillman Grave and Judith Wayland. 4 I had the opportunity recently at an 5 Institute of Medicine meeting -- that's looking at 6 assessing the systems of protecting human subjects of 7 research -- of hearing a presentation by Belinda 8 giving us an overview of the efforts that the NIH is 9 making. And I commend you highly. I think that 10 especially in the area of monitoring and your new 11 requirements for some sort of monitoring, not only 12 for Phase III, but for Phase II and II trials is 13 helping to change the paradigm of how research 14 protections are unfolding in this country and the 15 educational efforts that you are making and that you 16 are requiring are wonderful. The presentation was 17 very impressive. So I thank you. 18 DR. KIRSCHSTEIN: I thank you on Belinda's 19 behalf. 20 CHAIRPERSON MARSHALL: And I just would 21 like to say to you that we are working with your 22 colleagues and we are delighted to have them as very 418 1 important members of this group and also to let you 2 know that we are at your service in any way. So we 3 hope that you will ask us in the future -- 4 DR. KIRSCHSTEIN: Sure. 5 CHAIRPERSON MARSHALL: -- if we can ever 6 do anything for you. 7 And let me just ask committee members, ex 8 officio members, or members of the public if you have 9 questions? Abbey and then Jonathan. 10 MS. MEYERS: Yes. One of the repeated 11 things that we are hearing are complaints by IRBs 12 that they don't have the resources to do everything 13 now that all of this is happening. Is there any way 14 that they could put as an indirect cost some of the 15 costs for the IRBs. 16 DR. KIRSCHSTEIN: We are fully aware of 17 that and we are looking into it. It is not an easily 18 solved problem. One doesn't want to interfere with 19 the institutional responsibilities. The indirect 20 costs are set by OMB and so forth. But we are 21 looking into ways in which this might be done. We 22 are very much aware of the problem and we're trying 419 1 to look into it. There are a number of problems 2 we're aware of and there are a number of things we 3 need better coordination within NIH and some other 4 things. I've been talking to many people about it. 5 I see Bob Wood is sitting -- standing -- 6 excuse me -- in the back and he's been enormously 7 helpful to me on clinical trials. I spend a lot of 8 time thinking about this, so we're working on it. 9 CHAIRPERSON MARSHALL: Jonathan. 10 DR. MORENO: I've also experienced the 11 energy with which the institutes are focusing on the 12 DSMB role. I've gotten a lot more calls about being 13 on DSMBs in the last few months than ever before. 14 And they're about as lucrative as serving on NRPAC, 15 by the way. 16 [Laughter.] 17 DR. MORENO: But we do them because they 18 are important. And I'm wondering if you could say a 19 little bit more -- somebody could day a little bit 20 more about how the institutes decide when to generate 21 DSMB, if there are some criteria besides the size and 22 complexity that are intuitive about a trial. 420 1 DR. KIRSCHSTEIN: I'm not an expert and 2 maybe Bob can tell us that or somebody else. But I 3 can tell you what I think. And actually, when I said 4 to you that NIH is not a regulatory agency, those of 5 you who know NIH used to have as part of its 6 structure a regulatory agency called the Division of 7 Biological Standards which was related to vaccine 8 controls. I worked for that agency for 19 years, so 9 I know a lot of -- and then it was transferred to 10 Food and Drug Administration, so I know a lot about 11 regulatory policy. 12 It is the complexity primarily and the 13 size. It is probably also if it's the first large 14 trial of the sort that's being done, if it is using a 15 drug or a vaccine or an intervention that is unique, 16 has never been tried before, all of those things 17 would go into it. But this is why we have a group of 18 what we call health scientist administrators who are 19 physicians, nurses, other people who are very much 20 aware -- statisticians -- who are very much aware of 21 the needs of clinical trials, the needs of the 22 patients to come together with a leader who has been 421 1 involved in clinical trials for years. 2 Dr. Wittis is a clear example of that, who 3 together decide even before they think about putting 4 out any sort of request for such a trial or before 5 the trial has been more than a gleam in somebody's 6 eye, whether or not among the parameters will be the 7 need for a data safety and monitoring board. When 8 there are very big trials, very often they have a 9 coordinating center which is separate from when it's 10 a multi-institutional trial the one I will bring to 11 mind is the one I know most about which is the 12 women's health initiative which is done in something 13 like 44 institutions throughout the country. There 14 is a coordinating center which is in an institution 15 that is not doing part of the trial, but the data 16 come into that organization and the people are 17 supported under the grant to analyze the data as it 18 comes, look at it, determine whether there are things 19 that would make them want to have a DSMB look at 20 something earlier and that supports the DSMB. So 21 there are a number of factors. 22 Bob, would you want to add anything? 422 1 DR. WOOD: Speaking only for the Cancer 2 Institute, our stipulation for DSMBs as opposed to 3 simply a DSM process which might or might not be a 4 DSMB is really reserved for Phase III. And we don't 5 have any -- we're in the process of drawing up some 6 guidance now for our investigator community about 7 what the essential elements of the DSM plan should be 8 for trials other than Phase III. 9 We have no present plans to mandate the 10 use of boards as such. Though my own view is that 11 for trials of sufficient size and complexity and 12 where there's a real chance or where there is some 13 reasonable chance that one might want to make early 14 stopping decisions that are best made on the basis of 15 blinded data, investigators would be wise to consider 16 a formal separate board. 17 The only other thing that I would remind 18 you of is that the DSM plans are actually peer 19 reviewed now on all grants that come in. So in 20 addition to MCI wishes, peer reviewers have a chance 21 to get in on the act too. 22 CHAIRPERSON MARSHALL: Thank you. Bob 423 1 Levine. And one last question. Sorry. 2 DR. R. LEVINE: I just wanted to say that 3 the DSMBs at NIH are there's a great variety of 4 missions and structures. I'm on, I think, four or 5 five of NIH's now. 6 I find that some of them have 7 responsibility for reviewing all research of a 8 certain type that's done within the Institute. I've 9 seen that in NIMH and in NIAID. While some seem to 10 have one DSMB for each particular trial, I've seen 11 that model in Heart, Lung, and Blood and in the Eye 12 Institute. 13 I think one of the great problems that 14 needs resolution is an official statement on the 15 extent to which the DSMBs can be expected or required 16 to share their findings with the IRBs. There's a 17 remarkable diversity of opinion being expressed. I 18 have my own opinion, but I would like to hear yours. 19 [Laughter.] 20 DR. KIRSCHSTEIN: I think I'll take that 21 under advisement. I'm writing down the note to talk 22 to several institute directors and so forth about 424 1 this. I might say that I think that the difference 2 that you're characterizing between National Institute 3 of Allergy and Infectious Diseases perhaps the Heart 4 Institute is that probably the DSMB that you're 5 thinking about in NIAID is related to a clinical 6 trials network that's working on a particular -- 7 particularly the AIDS network as opposed to the Heart 8 Institute doing -- having this for Phase III trials 9 individually. 10 I'll take one more. 11 CHAIRPERSON MARSHALL: Elliot. Welcome. 12 DR. DORFF: Thank you. Appreciate it. 13 Moral behavior in society is in part a 14 function of regulations, but it's much more a 15 function of education. I was very much interested in 16 your educational efforts and the extent to which 17 those could be modeled and other kinds of protocols. 18 DR. KIRSCHSTEIN: What kinds of protocols? 19 DR. DORFF: Well, what I have in mind is 20 that -- I mean, if you're doing the kind of thing for 21 educating researchers that we might recommend to 22 everybody doing research, then I would like to hear 425 1 about that. In other words, what kind of -- I'm 2 looking for curricula. I'm looking for amount of 3 time you spend and what kinds of topics you do. In 4 other words, the kind of educational analysis that 5 would go on in any program just to find out whether 6 this might be a model for us to recommend to other 7 people doing research. 8 DR. KIRSCHSTEIN: I think you can get 9 those details primarily for the kinds of training 10 we're planning for these activities from Dr. Seto. 11 But, in addition, the Office of Research Integrity 12 has a group of educational activities that it is 13 planning in regard to teaching Ph.D. candidates, 14 particularly, but also any other candidates, under 15 training to do research that might be -- that is 16 supported by NIH in general about what it means to be 17 a good and honest and true scientist. And I think 18 you can get it from them. 19 Chris Pascal would be the person to get 20 that from. 21 CHAIRPERSON MARSHALL: Thank you very 22 much. 426 1 I want to just update the folks who 2 weren't here yesterday and Elliot welcome. We are so 3 glad that you're here. We know that you have been 4 working hard because we heard that from Mark Barnes 5 yesterday. 6 Yesterday for those of you who weren't 7 here, we had three primary things on our agenda. We 8 had a report from the financial relationships group 9 that was chaired by Mark Barnes. And the members of 10 the committee who helped Mark are Judy Siegel, Sandy 11 Chodosh, Adil Shamoo, Elliot Dorff, and Kate 12 Gottfried, as always, was a steadfast member and 13 supporter of their work. 14 And I want to say that I made some remarks 15 at our first meeting at the opening session and I 16 exhorted the Committee to help us raise the roofbeam 17 high. And those lawyers can tend to take things 18 literally and damned if Mark Barnes didn't do it. I 19 think he's put us through the roof. He certainly 20 raised the bar very high for those who are going to 21 follow after him as workgroup chairs. So, thank you, 22 Mark and Committee members. You all just did a 427 1 stellar job. 2 My sense of where we are with the 3 financial relationships draft report on the draft 4 interim guidance is that we will do this: we will 5 post on our web site the draft report from the 6 working group. We will ask for comments from the 7 public, for our ex officio members, from any members 8 of the committee who didn't have time or sufficient 9 opportunity to weigh in on the draft report, the 10 committee will convene again; take all of that 11 feedback into consideration, and give us an 12 penultimate draft which we will then ask -- I am 13 going to ask committee members, you all have a 14 mechanism for reviewing materials and commenting on 15 them via our network, our Internet, capabilities as a 16 committee, so I'm going to ask you to do that prior 17 to the next meeting -- our next meeting in July -- 18 when I hope that Mark can then present the 30th and 19 31st of July when Mark can present something to the 20 committee that we feel that we as a committee are 21 ready to move forward with and to endorse. 22 So I'm putting the onus on you committee 428 1 members, please, to get your feedback to Mark prior 2 -- on both of those occasions -- prior to the 3 revision of the draft and then once afterwards so 4 that we can move forward with that at our next 5 meeting. 6 Thank you, Mark, very much, and the 7 members of your group for a stellar job. 8 And I'm going to ask Mary Kay to just give 9 us a brief recap of -- she is going to chair our 10 genetics workgroup of what we agreed to yesterday and 11 let the committee know how we are going to proceed in 12 that area. 13 DR. PELIAS: We've assembled an impressive 14 group of people who have agreed -- more or less most 15 of them have completely agreed and some are a little 16 bit reserved to work with us on this committee. 17 Margaret Borwhat, Denise Thornley-Brown, Abbey 18 Meyers, Sandy Chodosh, Jonathan Moreno, Terri 19 Sergeant, Felice Levine, and I'm hoping that I will 20 be able to call on a couple of consultants, perhaps 21 Doug Levinson and Jeff Botkin, both of whom were here 22 yesterday offering their ideas about human subjects 429 1 and others as -- I'm new to this, so I don't know how 2 many people I'm supposed to involve and so on, but 3 we'll work on it. 4 Also, we're supposed to include the ex 5 officio members of the committee. At any rate we see 6 the charge for the working group. First of all, 7 there are several topics, but the first and foremost 8 topic will be defining a human subject. We intend to 9 gather definitions that have been incorporated into 10 the common rule and see if we can find any common 11 ground in the common rule for definitions of humans 12 subjects. And we'll try to figure out whether or not 13 we can synthesize a single definition, certainly one 14 that is broader than genetics which is where my own 15 personal interest is. But we'll work outside of 16 genetics for quite a while. 17 The second question in relation to human 18 subjects is to try to determine when a family member 19 becomes a research subject from whom we must obtain 20 consent and if we have to obtain consent, how should 21 we go about doing it. So this is our primary 22 interest for at least the next couple of months. And 430 1 then as we were discussing this last night, I think 2 we agreed that we might continue along with the list 3 that Francis Collins presented to us yesterday in 4 solving issues having to do with genetics, the next 5 one being the need for community consultation if risk 6 of stigma goes beyond the individual. This is 7 something that has been addressed on occasion, but I 8 don't know that it's ever been addressed formally. 9 The next topic might be research with 10 stored tissue samples, and the next one, the question 11 of blanket consent for future use, both of which go 12 to one of my favorite words, and that is to 13 "anonymize." 14 And the last topic that we might get to 15 one of these days has to do with disclosure of 16 research results, results that are generated in 17 research laboratories, whether or not we should do 18 something with intermediate results that have not 19 been confirmed and are not clearly approved. Whether 20 they have significant implications for a subject's 21 health or a family's health. Whether we are going to 22 get involved in questions of law and malpractice, and 431 1 whether we have a duty to provide care and 2 counseling. 3 But, first of all, we could spend the rest 4 of our lives doing all of these topics, I think. But 5 first we will try to define a human subject, and that 6 will take a great deal of energy and cooperation. 7 That's is. 8 CHAIRPERSON MARSHALL: Thank you very 9 much, Mary Kay. Those fundamental definitions and 10 assumptions are really important and they are truly 11 the hardest work. So thank you for taking on that 12 challenge. 13 Our agenda today involves and update, a 14 report from the Children's workgroup. Alan 15 Fleischman has, as you all know, reported to our 16 group. He actually got us going at our first 17 material and helped us define the issues that we 18 should be pursuing and then like any wise committee 19 we decided that we would invite him to help us do 20 that. So we are delighted that he is now a member of 21 our committee and chairing the workgroup. And I am 22 going to turn the floor over to Alan. And, yes, we 432 1 will switch places, Alan. So, thank you. 2 DR. FLEISCHMAN: Thank you. I want to 3 start by saying that we had a stellar children's 4 workgroup. Although we've only had one moment in 5 time when we were either in a room or on a telephone 6 together and this is clearly a work in progress. 7 Even the children's workgroup have not had adequate 8 time to comment on the draft that is before you 9 today. 10 What I would like to do today is to first 11 tell you about the group; second tell you a little 12 bit about children's regulations and Subpart D so 13 that we're all at the same place, and walk through 14 the workgroup report which has 21 areas of interest, 15 but only talk about four of those which I think are 16 the most important issues to raise for conversation. 17 And I would like to raise each of those individually 18 for conversation. 19 The workgroup included several members of 20 the committee. Susan Kornetsky, Felice Levine, Mary 21 Faith Marshall, and Kate Louis Gottfried was both a 22 participant and staff support. I want to say that we 433 1 are indebted to Ms. Gottfried who has really been 2 more than a stalwart, but a tremendous contributor to 3 this process. And I would like to say publicly that 4 as an ethics group, 22 hours a day, seven days a week 5 seems like more than even we could expect from an 6 employee of either a public or private institution. 7 But we are receiving that kind of support. 8 There were outside members as well of this 9 group; John Abramson, Myron Genel, Christine Gleason, 10 and Skip Nelson from the Pediatric Research Community 11 and Academic IRBs within the Children's World. 12 Gilman Grave represented by Judith Whalen from the 13 NIH; Suzanne Roberts from the FDA; Don Rosenstein 14 from the NIMH who chairs their IRB and has mental 15 health interests; Susan Winer who is an advocate as 16 the parent of a child who has had a serious illness 17 and died; and I think that covers it. 18 Now, some of these folks were only at the 19 meeting by telephone. But I want to give credit to 20 them for that hard work. We will also add to the 21 group Jonathan Moreno from the committee and James 22 Lechman and Robert Murray as we go forward with this 434 1 work. 2 The charge to the committee was not to 3 look at everything about children's research, but to 4 primarily look at both Subpart D and some specific 5 questions that were asked of the Secretary of Health 6 and Human Services to respond through the October 7 2000 Public Health Service Act. And there were ten 8 questions and we did try to at least address in some 9 level all of those ten questions at the request of 10 Dr. Koski and others in Health and Human Services. 11 Now, let me remind you that Subpart D -- 12 CHAIRPERSON MARSHALL: He's a true medical 13 humanist, he's not using slides. 14 DR. FLEISCHMAN: We're going to go low 15 tech today because I want to walk through some of 16 these things and I think we will be better able to 17 have a dialogue. 18 Subpart D reminds us that there are four 19 levels of permissible research in these regulations. 20 The first has to do with minimal risk research which 21 is permissible in children. And we've heard that 22 definition many times reminding you that in the 435 1 definitions "minimal risk" means that the probability 2 and magnitude of harm or discomfort anticipated in 3 the research are not greater in and of themselves 4 than those ordinarily encountered in daily life or 5 during the performance of routine physical or 6 psychological examinations or tests. The workgroup 7 has some comments about that that we'll get to in a 8 moment. 9 The second permissible risk is those -- 10 and permissible research is research that has the 11 prospect of direct benefit to the individual child. 12 The third -- 13 DR. R. LEVINE: Alan, I want to comment on 14 that. What you've done is you've read the subtitle. 15 The subtitle is not related to the text of the 16 regulation. The text of the regulation never says 17 that research holds out a prospect of direct benefit. 18 It says that research -- or it is concerned with, and 19 I quote, "Interventions or procedures that hold out 20 the prospect of direct benefit." And it's only those 21 interventions or procedures that the level of risk as 22 a threshold standard is related to. 436 1 Thank you. 2 DR. FLEISCHMAN: The third permissible 3 research has to do with research involving greater 4 than minimal risk, no prospect of direct benefit to 5 individual subjects, but likely to yield 6 generalizable knowledge about the subject's disorder 7 or condition. And the committee has some thoughts 8 about that level as well. 9 And then, finally, the 407 section tells 10 us that research not otherwise approvable which 11 presents an opportunity to understand, prevent, or 12 alleviate a serious problem affecting the health or 13 welfare of children can be approved through a federal 14 process at the level of the Secretary. And we'll 15 comment on that. 16 Section 408 of Subpart D speaks to the 17 requirements for permission and assent of children 18 and the ability to waive those in certain 19 circumstances. 20 The workgroup -- and I'm going to turn to 21 its draft 4501 document. The workgroup took it's 22 charge seriously and attempted in its single meeting 437 1 to at least address each of the areas of concern. 2 There were four general impressions that the 3 workgroup had about regulation of research in 4 children. 5 The first was that to this group of 6 investigators, ethicists, and advocates, the existing 7 regulation seemed to be sound, have worked, and are 8 in need of clarification in order to enhance the 9 uniform use of the regulations. 10 Second, that the workgroup believes that 11 the investigators who do research in children and the 12 IRBs that review and monitor research in children 13 must be adequate to the task. 14 And that I think is an important question 15 that needs to be raised about what constitutes an IRB 16 able and competent to do review of children's 17 research. And as part of that, there was concern 18 that there be adequate representation among the 19 community members of people who actually, 20 unaffiliated with the research, have the community 21 standard and understanding of children's issues and 22 advocacy for children's interests. 438 1 Fourth, the workgroup believes that the 2 regulations are applicable to social science 3 research, but require further clarification in that 4 regard and we're going to leave that primarily to our 5 social science research working group which we'll 6 hear about more later in the day. 7 There is some concern about clarification 8 in this area, understanding by IRBs of exempt and 9 expedited work as well as the importance of 10 confidentiality and privacy in social science 11 research. 12 Now, let me focus on four major issues. 13 As I say, the workgroup commented on 21 areas, but 14 four of which we want to focus your attention on for 15 conversation. And I think, Madam Chairperson, that I 16 would take one at a time and then ask for comment if 17 that's okay. 18 CHAIRPERSON MARSHALL: That's fine. The 19 floor is yours and this is your session. 20 DR. FLEISCHMAN: The first question asked 21 was the appropriateness of the regulations for 22 children of differing ages and maturity levels 439 1 including legal status. Which raises one of, I 2 think, the important questions that need 3 clarification concerning adolescent assent and 4 concent. 5 We know that legally emancipated minors 6 may be treated as adults in terms of research, but 7 that's a small group of adolescents. There are, 8 however, a group of adolescents who are felt to be 9 what has been called "mature minors." That is, 10 adolescents who have at capacity to assess risks and 11 benefits and understand their interests and have the 12 ability to think longitudinally about consequences. 13 There are also adolescents who in 14 virtually every state are allowed to concent for 15 clinical care around certain specific diseases. 16 Primarily sexually transmitted diseases, pregnancy 17 care, things of that sort. And although the National 18 Commission had recommended originally that those 19 children who are allowed to legally consent to 20 clinical care ought to be allowed to consent for 21 research in those areas. 22 That did not transpose word-for-word into 440 1 the present regulations. So there is still some 2 concern and confusion among the IRBs as well as the 3 investigators concerning what may we allow 4 adolescents to consent to without involving parents? 5 What level of assent is involved in such work when 6 parents are giving permission? And the workgroup 7 does believe that there are times when it might not 8 be in the interests of the adolescent to inform the 9 parent about an illness or behavior which is under 10 study. 11 That the IRB presently, through Section 12 408, has the authority to waive parental permission 13 in such cases when the IRB creates an adequate 14 process for the protection of the adolescent. Which 15 generally will include processes which will have 16 separate independent advisors or counselors for the 17 adolescent as well as monitoring of the consent 18 process. 19 The question as to how much work needs to 20 be done in determining that the adolescent has the 21 capacity to make these judgments and whether in every 22 case an adolescent would need to have such an 441 1 assessment or whether the capacity determination 2 ought to be tied to the level of risk; and if it were 3 minimal risk there would be an assumption of capacity 4 versus higher levels of risk would require more 5 involvement of independent assessments of capacity. 6 These are things that need some 7 clarification and we believe ought to -- let me just 8 finish the presentation and we'll then open it for 9 conversation -- we believe ought to be within the 10 purview of the IRB as presently allowed in Section 11 408, but requires clarification so that the IRBs will 12 be using this in a uniform manner with examples and 13 clarity of suggestion. 14 So let me pause here and take some 15 comments or questions about just this issue now, the 16 adolescent assent/consent issue. Abbey? 17 MS. MEYERS: Excuse me, but I have to step 18 backwards a bit because there are some assumptions 19 that you're asking us to accept before. First of 20 all, I want to raise the question about the 21 composition of this committee because it seems that 22 there are very few members of this committee on your 442 1 workgroup and most of the members are not from the 2 committee. And I don't think we've really determined 3 what the composition of workgroups should be. 4 Because, you know, if I was going to try to pass a 5 recommendation on the oil business, I'm not sure 6 whether, you know, a gas station owner should be the 7 members of the committee. I think we really need to 8 examine that. 9 Secondly, you're asking us to accept your 10 basic theory that the current system is just fine, it 11 needs a little bit of clarification. And I can't 12 accept that. I don't think that the current system 13 is adequate in today's world, especially when we have 14 commercial companies out there soliciting children 15 with Toys-R-Us coupons to come in and participate. 16 So that's just a basic thing I wanted to say before 17 we focus in on the adolescent thing. 18 DR. FLEISCHMAN: If I can just comment on 19 the workgroup composition. There are six members of 20 this committee and there are only 17 -- well, five 21 members of the committee and the staff executive on 22 this workgroup. We did ask, as was suggested in the 443 1 actual Public Health Act, we asked experts in 2 children's issues -- 3 MS. MEYERS: There are 11 outsiders from 4 what I counted and there's five members of the 5 committee. So I think that the ratio there is not 6 quite right. 7 DR. FLEISCHMAN: Well, we actually do have 8 the FDA and the NIH representatives who are liaison 9 to the committee. I guess we could call those 10 outsiders. But I didn't consider them that way. We 11 also asked people who have different knowledge bases 12 in children's issues, realizing that children go from 13 the one-pound premature to the 300-pound line backer, 14 it is a very broad research base with different kinds 15 of expertise both in the biomedical as well as in the 16 psychosocial areas. 17 I will say, though, that none of the 18 committee members were shy or reticent and to my 19 knowledge none -- and they can speak for themselves 20 -- non dramatically disagreed with this report yet. 21 It may well be that in their second or third reading 22 they have things to tell us about it. 444 1 To comment about the general issue that 2 you raise, we do actually talk about incentives in 3 this report. We make some specific recommendations 4 about the incentives and I would very much, Abbey, 5 ask you to focus on the regulations when you ask if 6 something needs reassessing or rewriting. 7 It may well be that we need to rewrite 8 these regulations. But in my opinion we need not to 9 rewrite the regulations in order to take care of the 10 problem you address which is a very serious question 11 about recruitment and incentives which the workgroup 12 is interested in and comments on. 13 So the question that we need to think 14 about is whether the structure of the definitions as 15 well as the permissible levels of research are flawed 16 or need such overwork or such redoing that we need to 17 rewrite the regulations and we may well need to do 18 that. I don't believe we do. But we may have to do 19 that. 20 We started the workgroup by asking that 21 question and there were no members of the workgroup; 22 and correct me if I'm wrong, there were no members of 445 1 the workgroup present or on the phone who believed 2 that the regulations required rewriting. 3 Susan. 4 MS. KORNETSKY: Abbey, I would just like 5 to add that I fully agree with what's been said, and 6 I also see your concern. I think before we sort of 7 jump to rewriting the regulations, I agree, there 8 probably have been some misuses of interpretation of 9 the regulations and I think that's what we are trying 10 to sort out. Whether it's that there's guidance 11 needed and how they are intended to be applied, or 12 whether the regulations per se, are just -- you know, 13 are not workable. And I think we are starting with 14 the context that the regulations may be workable. We 15 have a lot of work to do to educate and then people 16 and guidance in working within the regulations. 17 DR. FLEISCHMAN: Kate. 18 DR. GOTTFRIED: I just also wanted to 19 mention that the financial relationships workgroup 20 was composed of five members of the committee and 21 this is a similar situation. And what was felt was 22 that in order to get information to provide to the 446 1 NHRPAC as a whole, we needed some greater expertise 2 in the area. 3 Mary Faith herself is an expert in 4 children in prisoners, but we needed people who 5 really work in the area of children's research to get 6 better informed in order to make an assessment with 7 respect to the regulation and whether it might 8 require revision. 9 MS. MEYERS: Shouldn't there be some kind 10 of ratio? I mean, was the four or five members on 11 the financial relationship thing, was it 11 non- 12 members. 13 MS. GOTTFRIED: The workgroup process has 14 evolved to recognize that we need as broad input as 15 possible. With respect to the financial 16 relationships instance, we had already had a document 17 that they were specifically reacting to. In this 18 particular instance, we knew that there were also 19 specific areas to focus on and that we needed a 20 certain amount of expertise. We asked for volunteers 21 from all over the committee, the NHRPAC committee and 22 as you know everyone is spread very thinly. So there 447 1 is only a certain amount of workgroups that each 2 committee member can sit on. 3 DR. FLEISCHMAN: I have a list of people 4 in order of recognition, Felice, Adil, Bob and Mark. 5 And we will continue to use this methodology. 6 Jonathan is on the list. Felice? 7 DR. F. LEVINE: I also wanted to 8 underscore, I think, what Susan said and as the co- 9 chair of the social and behavioral science working 10 group, I can see this as a bit of a theme which is 11 the issue I addressed in December and that is that 12 the rules often are not, per se, the problem. But 13 it's that gap between the language and the 14 implementation. 15 Now, it may be that the recurrent 16 identification of gaps become such a preponderant 17 fault that the language itself needs to be clarified. 18 But I have felt from the outset, both in this group 19 and on that conference call, and on my conversations 20 with Mary Faith that ultimately addressing the common 21 rules and where they may need clarification, 22 expansion, or transformation, as we discussed 448 1 yesterday is well within the scope of what we might 2 do. But nothing jumped up so powerfully that we 3 thought that needed to be addressed before we really 4 analytically understood the applications and the 5 problems. And I think that's what Alan is trying to 6 speak to. 7 DR. FLEISCHMAN: Adil? 8 DR. SHAMOO: This question is really to 9 Kate and Mary Faith and that is in concordance with 10 Abbey's remarks we as a committee -- I personally, 11 for one, I don't know how the workgroups were 12 formulated, why members were there. They never 13 brought the membership back to this committee to sort 14 of give them the nod; usually we will say yes. I'm 15 just -- in the process that's one. 16 Second is that the workgroups are weeding 17 out -- and I said to Mark, "I won't bring it up." 18 But I'm glad Abbey brought it and induced me to say 19 that -- and that is, these workgroups are really 20 functioning as subcommittees. They are bringing 21 well-written drafts with recommendations with 22 specifics and the process is not transparent. I 449 1 would like to see -- one of my frustrations was, one 2 reason I had my own statement on financial 3 relationships is what was said during the working 4 group despite the fact that I think Mark did a 5 brilliant job and a stellar, but nevertheless was a 6 summary of what went on. 7 The public at large doesn't know those 8 deliberations and I want people to be on record what 9 they are saying rather than only confidentially they 10 are talking about it. And I think we need to clarify 11 the process by the chair before we proceed. 12 CHAIRPERSON MARSHALL: Thank you, Adil. 13 You are raising some housekeeping issues, you and 14 Abbey both. And I will attend to those now. 15 My promise and goal is that everything 16 that we do will be transparent. We are finding our 17 way. I am delighted that Terri Seargent who was here 18 yesterday has, at my request, joined the workgroup on 19 genetics and Doug Levinson as well. And I made an 20 appeal yesterday to any member, public member, ex 21 officio member, or member of the committee who would 22 like to serve on the workgroup to let us know. So, 450 1 my plan is for there to be an open invitation for 2 participation on the workgroups. 3 And, again, Adil, we are finding our way. 4 So I think that the process that we set up, for 5 example, with the financial relationships workgroup, 6 we cannot sort of craft documents as a committee. 7 That's not an efficient use of our time. So there 8 has to be a mechanism for something to be brought 9 back to the committee as a whole. So I hope that the 10 workgroups are not functioning as subcommittees. 11 They can't. 12 So the process of having this document put 13 up on the web as a draft for input from any and 14 everyone, I think is our mechanism for involvement. 15 And I truly do mean that. So I am encouraging the 16 members of the committee who are on our list serve, 17 even though they may not and can't sit on every 18 workgroup, they have an opportunity to participate in 19 the creation and the drafting of these documents as 20 the process moves along. 21 So what was presented yesterday was by no 22 means a fait accompli, nor was it intended to be. So 451 1 now it will be on the web site. It is open for 2 comment and input from anyone. And I truly mean 3 that. 4 So if you have other suggestions in terms 5 of how workgroups should proceed, I would welcome 6 them. Let me just finish. Because I very much do 7 want us to be transparent. We have to be by our 8 charge, and morally in terms of what we're about. 9 So let me know if you have thoughts in 10 terms of the mechanisms. 11 Now, I hear what Abbey is saying is a 12 concern that I second. Abbey, the participation, 13 meaningful participation, of the public or of persons 14 who are advocates for research subjects is near and 15 dear to my heart. So, again, there is an open 16 invitation from the Committee, perhaps we need to be 17 more thoughtful in terms of appointing people. So 18 your concern is about ratio and numbers. And I hear 19 you. So as a committee, then let us be committed to 20 that, in forming workgroups as we move along. 21 MS. MEYERS: My concern is that, we 22 shouldn't put together a group of people who are 452 1 regulated by the regulations and then say to them, do 2 you want to be more regulated? Do you think these 3 regulations are sufficient? I think it should be 4 people who don't make their living in research who 5 are the majority of that committee. 6 DR. FLEISCHMAN: I've got a hold to the 7 list and hope that we can continue on this. Bob, are 8 we talking about the topic that Mary Faith has just 9 spoken to, or are we moving back toward adolescence? 10 Let's stay with Mary Faith's conversation for a few 11 moments. 12 DR. R. LEVINE: I want to speak to Mary 13 Faith's statement, but I don't want to lose my place 14 in the queue -- 15 [Laughter.] 16 DR. R. LEVINE: -- that caused me to raise 17 my hand in the first place. 18 CHAIRPERSON MARSHALL: Let me just also 19 say that I think that we have got some room in our 20 schedule today where we might carve out some time to 21 talk about these housekeeping details because they 22 are very important. So let's go back to the children 453 1 and then at the end of the day, let's do talk about 2 these. 3 DR. R. LEVINE: Meanwhile, back at the 4 children. 5 DR. FLEISCHMAN: Okay. Robert. 6 We're going to go back to the children and 7 on my list at the moment are Bob, Mark, and Jonathan 8 and we're talking specifically about the adolescent 9 consent/assent issue. 10 DR. R. LEVINE: I want to begin by saying 11 that it's very important that everyone who 12 participates in this discussion recognize that the 13 language of the regulations is very important. There 14 is no such thing as beneficial research. The 15 subtitles -- well, when the National Commission 16 issued its report and recommendations on research 17 involving children, it said flatly, there is no such 18 thing as beneficial research and that you must 19 instead be looking at each component of the research 20 to see whether or not it holds out the prospect of 21 direct benefit. 22 The danger of talking about beneficial 454 1 research is that you get into what I call the fallacy 2 of the package deal. If one thing looks a little 3 beneficial, then everything is approved according to 4 standards designed to be more permissive for 5 beneficial procedures, not research. 6 When the regulation writers then issued 7 proposed regulations that referred to beneficial 8 research, the National Commission intervened and 9 said, no, you just didn't get it so that the 10 regulation writers then wrote what we now have on the 11 table in front of us, that procedures or intervention 12 either do or do not hold out the prospect of direct 13 benefit. At that point the National Commission went 14 out of business and the regulation writers wrote 15 subtitles that had nothing to do with the texts and 16 these have polluted commentary on these regulations 17 ever since; that people keep talking about 405 18 research involving greater than minimal risk by 19 presenting the prospect of direct benefit. 20 And I think it's very important. It took 21 20 years to get the concept of beneficial research 22 out of the regulations. The final step was to 455 1 rewrite the Subpart B for research involving the 2 fetus and pregnant women and in vitro fertilization. 3 And the reason that came out containing the concept 4 of beneficial research is that the Commission's 5 report on the fetus was issued before it had the 6 opportunity to engage in clarification of its 7 concepts which resulted in the Belmont Report. 8 Thank you. 9 DR. FLEISCHMAN: Mark. 10 MR. BARNES: I pass because I was standing 11 in queue for the procedural points. 12 DR. FLEISCHMAN: Jonathan. 13 DR. MORENO: It's not clear to me, Alan, 14 in the final analysis where we're going to stop, at 15 Subpart D when we're talking about pediatric research 16 or we're going to look at other regulations beyond 17 those that govern DHHS. Because, for example, the 18 Department of Education also has rules governing 19 research involving minors. So I guess I want to get 20 on the table that whatever we do with that -- well, 21 wait, my understanding is that NHRPAC and OHRP have 22 responsibilities beyond the concern about how 456 1 compliance with the common rule with the DHHS. 2 DR. FLEISCHMAN: Greg. 3 DR. KOSKI: I would just say, Jonathan, 4 that in this specific case there has been a specific 5 request made to NHRPAC on behalf of the Secretary and 6 the Department of Health and Human Services through 7 our office which has been charged with responsibility 8 for responding to Congress on a series of specific 9 questions that have been asked relative to Subpart D. 10 Given the time frame in which we have to 11 accomplish this goal, I would urge that while we not 12 preclude broader discussion in the future, that we do 13 all that we can to focus on the specific task at hand 14 which is to address those specific questions issued 15 by the Congress. Thank you. 16 DR. MORENO: I'm fine with that, but I 17 wanted to make it clear why we're doing D and we 18 definitely need to worry about education and others 19 to make sure that there is coherence with whatever we 20 come up with. 21 DR. KOSKI: The Department of Education 22 does subscribe fully to the common rule. And, you 457 1 know, certainly the provisions that -- as does 2 National Science Foundation and others, so that we 3 want to be sure as we think about research involving 4 children in the broadest context that we, you know, 5 understand the specific venues in which research is 6 conducted outside of the clinical trial. 7 DR. MORENO: Right. They subscribe to the 8 common rule, but not to D. They have their own 9 version of what we call D for DHHS. That needs to be 10 clear to everybody in the room who is concerned about 11 adolescence and kids in research. So that's why I'm 12 so concerned that we not -- after we do what Congress 13 wants us to do, we not stop there, but we go on to 14 look at other areas of pediatric research as we can. 15 My second comment has to do with -- is 16 somewhat related actually to what Abbey brought, 17 namely, we need to have somebody -- especially when 18 we're talking about adolescence, I think, and in 19 light of some of the controversies about pediatric 20 research, we need to have somebody who knows about 21 diversity research with kids who is at least a 22 liaison to the group. And Alan and I both, I think, 458 1 know people -- in New York -- for example who -- 2 DR. FLEISCHMAN: Well, we've asked Dr. 3 Robert Murray from Howard to join us. He's agreed. 4 I certainly have some interest in that area. He has 5 more than interest. He's been a world leader in 6 discussion of both adolescent and sickle cell 7 research in children. So I think you're right. We 8 would be happy. I can speak as the -- is it chair in 9 the workgroup? Yeah. I guess it's chair of the 10 workgroup. The workgroup, I think, would be happy to 11 have other members with specific expertise and 12 advocates. We also, I think, would be happy to go 13 through a systematic review of the different standing 14 regulations or other authorities. 15 I tried to explain what the charge was to 16 this one six-hour meeting -- 17 DR. MORENO: You did a beautiful job. 18 DR. FLEISCHMAN: -- in which we tried to 19 address a specific request of Dr. Koski and the 20 Secretary. And I don't think we've done a terrific 21 job. I think we've done an adequate job for the time 22 that we've -- 459 1 DR. MORENO: Well, for six hours. 2 DR. FLEISCHMAN: -- we didn't do it. 3 DR. MORENO: I saw Dr. Murray's name 4 there. I guess what I had in mind was more survey- 5 oriented research which is the area that has tended 6 to be problematic with the diverse population. And 7 there are a couple of people who we can talk to about 8 getting involved and helping us with that. 9 I'm going to reserve my comment about 10 process until we do the housekeeping. 11 One comment I did have on research 12 involving adolescents in particular, since that's 13 what we're supposed to be talking about, is -- this 14 is what happens to you when you hang around a medical 15 school long enough -- I feel like I lack data about 16 how much -- what's the universe of experience that we 17 have with respect to research involving adolescents? 18 What do we know about what's actually been done? How 19 assent or consent has been accomplished. 20 I mean, I really feel a profound lack of a 21 database when we talk about this topic. And I wonder 22 how -- I'm assuming it's going to be very hard for us 460 1 to get that kind of information. But I think that 2 this is not the last time that we're going to have 3 this problem of lack of information about what the 4 experience has been with the regulatories. 5 DR. FLEISCHMAN: Actually, this is an area 6 where we know a great deal. There are many other 7 areas where we don't know a lot. The side of 8 adolescent medicine has been concerned about this 9 issue since its inception in the '80s. And in 1995, 10 they did publish some guidelines which are in your 11 packet. The society could give us the information 12 which assisted them in this regard. There are some 13 models of best practice out there. There are 14 guidelines. There are data about adolescent in 15 research. There had been a lot of discussion in that 16 area. 17 So we could amass that information for you 18 and I think it is available in this particular area. 19 Susan is agreeing with me. Because the field of 20 adolescent medicine, although it is fairly new, it is 21 as old as the regs, having been created in the '70s. 22 DR. MORENO: Right. I guess what would be 461 1 very helpful for those of us who don't know that 2 stuff is to have a presentation at another meeting, 3 maybe 15 minutes or so, laying out what the 4 experience has been. 5 MS. KORNETSKY: Yeah, I would just like to 6 add that I think in talking about that, we might want 7 to consider involving someone from the society of 8 adolescent medicine. I think they also have share 9 frustration that certain types of research 10 specifically in drug and alcohol abuse have not been 11 able to go forward. So I think that that would be 12 very, very helpful. 13 DR. FLEISCHMAN: Kate and then Felice. 14 MS. GOTTFRIED: I just wanted to say with 15 respect to adolescent medicine that I had contacted 16 on several occasions Renee Jenkins also from Howard 17 who is an expert in adolescence and unfortunately she 18 just had not ever returned any of my calls. So we 19 are still pursuing that with permission ultimately of 20 the committee. 21 DR. FLEISCHMAN: Felice. 22 DR. F. LEVINE: I took seriously the 462 1 charge of the working group and the construction of 2 it to be children or children and youth. I saw the 3 specific request that we focused on as directed to 4 Subpart D as currently implemented because there 5 needed to be a response, but that working group would 6 go well beyond that and that indeed I don't -- I 7 think that that would need to embrace all aspects of 8 social and behavioral research on children and youth 9 and that those would not be just restricted to the 10 social and behavioral science working group. 11 In that regard, I thank, in addition, the 12 Society for Research of Child Development, ARA, and 13 we've talked about having more of the texture of the 14 social and behavioral science perspective in each 15 individual working group so that there's much more 16 attention to that work done in other agencies beyond 17 HHS. 18 We tend to keep using the language of 19 health or adolescent health or surveys and we should 20 link to the work in adolescent medicine and when 21 indeed it's because of the centrality of health- 22 related concerns, appropriately so, for human subject 463 1 participation as well as in this group. But as we 2 are embracing all aspects of the combinant rule, this 3 workgroup will clearly have to be a lot broader. 4 DR. FLEISCHMAN: Mark. 5 MR. BARNES: I just wonder the extent to 6 which the issues of adolescent assent either in the 7 working group's deliberations or elsewhere has been 8 considered in light of local community conditions and 9 mores. Because I can imagine that -- well, we know 10 that in different States in Rhode Island versus -- 11 heavily catholic Rhode Island versus heavily 12 protestant Alabama versus heavily agnostic California 13 that there are different rules -- 14 [Laughter.] 15 MR. BARNES: That there are different -- 16 will all due respect to Elliot. 17 [Laughter.] 18 MR. BARNES: That there are different 19 rules about what areas of health care in which 20 adolescents can consent for themselves according to 21 the different State rules and I wonder the extent to 22 which any kind of approach to these issues in 464 1 defining a particular assent process or kind of 2 laying out guidelines or considerations for IRBs to 3 make would take account of these local conditions or 4 local state -- which are really State statutes 5 because they're not local statutes. 6 And then just as a kind of an aside to 7 that, you know, in the HIPPA regulations that came 8 out, in regard to privacy of adolescents' -- of 9 medical records, including adolescents, the Clinton 10 administration actually punted on the issue and 11 basically said that nothing in HIPPA would violate 12 any particular state law regarding adolescents' right 13 to either consent to health care or to consent to 14 release of their medical records. 15 So, in fact, even the HIPPA regulations 16 which are really quite comprehensive in their draft 17 form really allowed -- they really stood aside and 18 let the States make all the decisions about 19 adolescent consent to disclosure of personal 20 information. So it's a long question, but that's the 21 question. 22 DR. FLEISCHMAN: Well, I think local 465 1 standards will be very important for IRBs to think 2 about and I know that in this area, like in many 3 others in research ethics, the HIV and AIDS world has 4 dramatically impacted on the adolescent world in 5 terms of the importance of developing approaches to 6 measure capacity in young people and allow them to be 7 in clinical trials when that was the really only way 8 that they could get the kind of cutting-edge 9 treatment that they appropriately deserved. So there 10 were areas like San Francisco and New York and Miami 11 where IRBs were -- and Newark -- where IRBs actually 12 were in the forefront of thinking about these issues. 13 And much of the work that came out of the 14 Society for Adolescent Medicine Guidelines in 1995 15 was actually generated by a good deal of interest 16 because of these young people and their needs. So I 17 think the local, both the laws and the culture and 18 the communities and the IRBs will reflect some of 19 this. What the workgroup has said though is that 408 20 allows for IRBs to make these judgments. To waive 21 permission of parents, but to set up a protective 22 process so that the young people can be protected, 466 1 determined to have capacity by whatever methodologies 2 that are appropriate and then counseled by people 3 independent of the research. And that IRBs can set 4 up these methodologies and allow adolescents then in 5 certain specific instances or certain specific 6 protocols to go forward without parental permission. 7 So those would all take into account the local mores 8 and standards. 9 Bob, and then I am going to open up after 10 Abbey to comments from our liaison and public members 11 on the issue of adolescents particularly and I would 12 like us to focus on adolescents so that we can get, 13 hopefully, this morning to the three other issues 14 that we also need to at least have some comments on. 15 DR. R. LEVINE: I was part of the Society 16 of Adolescent Medicine's group that worked on those 17 guidelines. And I wrote a paper that was published 18 in the same issue of the Journal of Adolescent 19 Medicine which went beyond the guidelines developed 20 by the group to attempt to see what would be 21 permissible under existing regulations. I did 22 acknowledge at the end of the paper that some of the 467 1 things that I read as permissible were highly 2 unfamiliar and that they shouldn't go ahead and do 3 them until they had the endorsement of some credible 4 national deliberative body. 5 I want to say that one big problem area 6 that's been presented particularly to those who want 7 to study adolescents' risk behavior is the standoff 8 between the requirements of the regulations and 9 practicality. If you want to -- I've been involved 10 with one group of anthropologists whose problem is 11 that they want to track very young adolescents, what 12 I call middle-aged adolescents, 13, 14. They have a 13 way of identifying risks of which ones are more 14 likely than average to enter the hard drug abusing 15 culture. They want to do some, you know, work 16 attracting them as they go into this culture. 17 Frankly, my fear is more for the anthropologists than 18 anyone else. 19 [Laughter.] 20 DR. R. LEVINE: But they had this problem 21 that when you're dealing with a 13- or a 14-year- 22 old, it's very hard even in those States who say that 468 1 young people or old adolescents can get counseling 2 for drug abuse without their parents' awareness or 3 permission. When you're getting down at those age 4 levels, it's very hard, especially since these people 5 are not seeking counseling and don't yet have the 6 problem. But if they say, we have to get your 7 parent's permissions, there is not going to be any 8 research. So I think that's something that I would 9 like to see addressed by the group. Thank you. 10 DR. FLEISCHMAN: Abbey? 11 MS. MEYERS: In terms of the controversy 12 that led to this whole examination of what's 13 happening with children, it's because of a 1997 law, 14 the FDA modernization act which has a little 15 amendment in it that calls for pediatric exclusivity 16 which is, if you study a drug for use in children 17 which leads to the relabeling of the drug for 18 pediatric uses, you get six more months of exclusive 19 marketing rights. And since most drugs are labeled 20 for children over eight or children over 12, it led 21 to a huge upsurge in pediatric research on drugs that 22 are primarily used for adults. And it's not the 469 1 drugs that children really need, it's more or less 2 the drugs that are the biggest selling drugs. So the 3 focus is on getting arthritis drugs approved for 4 children. And some children are going to need 5 arthritis drugs. 6 So that raises questions of whether some 7 of these drugs are being used improperly on children 8 just for the sake of getting them through the testing 9 process, et cetera. And whether there's truly an 10 informed consent in many of these cases. I mean, I'm 11 waiting for the studies to -- pediatric studies on 12 Viagra and then maybe people will say something is 13 wrong here. 14 So the question here is not really 15 adolescence in effect. What is the political 16 question now. The question is, children about ten 17 years old and younger is where the focus is. 18 DR. FLEISCHMAN: Actually, the workgroup 19 at its first conversations was concerned precisely 20 about the opposite issue that you raised. And that 21 is, the pediatric community, the clinical pediatric 22 community is terribly concerned that the vast 470 1 majority of medications being used in children today 2 have never been tested in children. And that the 3 pediatric community applauded the approach both that 4 the NIH and the FDA have taken to try to increase 5 clinical trials in children. 6 At the same time, both of those agencies 7 made it clear to the pediatric community that there 8 would be no decrease in the standards of regulatory 9 approach nor decrease in the research ethics 10 requirements which would be monitored and supported 11 through IRBs and through the regulatory structure. 12 The pediatric community, at least as both 13 reflected in this workgroup and in many other 14 conversations I've had, was quite pleased that there 15 are now most pharmaceutical companies willing to 16 embark on what are more difficult trials, more 17 expensive trials, for all of the reasons that we 18 understand and that is the consent processes are more 19 complicated, the monitoring needs to be more careful. 20 It requires more staff to do these studies. But the 21 pediatric community was comfortable both with the 22 increasing numbers of research studies because of the 471 1 need and with the maintaining of tight scrutiny of 2 the standards of research ethics. The committee 3 actually began with one of its outside members quite 4 upset. A national leader in pediatric infectious 5 diseases quite upset at most of the antibiotics that 6 he uses, most of the medications that he uses have 7 never had adequate study in the pediatric community; 8 harming, in his opinion, far more children than have 9 ever been harmed in randomized clinical trials that 10 are carefully done. 11 So I think it is important that we realize 12 there was some change in the FDA. There was some 13 change in the NIH in terms of its desire to 14 rationalize research in terms of women and children. 15 But that there were no changes in the standards that 16 we're obligated to maintain. And I don't think there 17 are data to support that the standards have been 18 generally overridden or not maintained. 19 There is also no requirement that a drug 20 that has no usage in children be tested in children. 21 And, you know, I think the comment about drugs that 22 don't have appropriate uses in children just -- you 472 1 know, I don't think that that's a fair assessment of 2 what either the pharmaceutical industry nor the 3 pediatric community would allow in terms of children. 4 5 MS. MEYERS: The drugs that need most to 6 be tested in children, Ritalin has never been because 7 the patent is gone. 8 Antibiotics where they're patents are 9 gone, nobody is doing the pediatric studies because 10 there's no exclusivity for an unpatented drug. And 11 so the focus has really been on the drugs that are 12 most lucrative. The asthma drugs are still not being 13 tested on children. 14 DR. FLEISCHMAN: We did hear at the last 15 meeting the commitment of the National Institutes of 16 Child Health, and Dr. Alexander is here, to try to 17 help to get some of that research accomplished. And 18 I would have to say that many of the drugs that you 19 have mentioned have had studies done and that there 20 are randomized clinical trials of various 21 methodologies. Is it perfect, has it been completed, 22 is the last word in? No. But that's the reason why 473 1 we need to look at these regulations so that those 2 who wish to do such work could do it in a safe and 3 effective way. 4 Mark? 5 MR. BARNES: Can I ask a quick question. 6 I had thought that -- and maybe I don't really 7 understand the law and the regs here, but I had 8 thought that before any of these trials could 9 proceed, or these adult approved drugs could proceed 10 with children, that there was a very careful FDA 11 screening process; am I wrong about that? 12 DR. FLEISCHMAN: Well, perhaps we could 13 as, our representative on the workgroup from the FDA. 14 If you would introduce yourself and tell us your 15 thoughts about that. 16 DR. ROBERTS: I'm Rosemary Roberts and I 17 work for the Center for Drugs on the Pediatrics team. 18 You are correct, Mark. The statute indicates that 19 the FDA is to request the studies to be done at the 20 sponsors. So although we have asked sponsors to send 21 in proposals of pediatric studies so we know who is 22 interested in doing trials, once those proposals come 474 1 in, they are looked at by the appropriate regulatory 2 division and we determine if there is indeed a public 3 health benefit that would be gained by studying these 4 products in children so that we can get them 5 appropriately labeled. 6 And once that is done, then it's 7 determined what kind of studies are necessary in 8 order to be able to get that information. So the FDA 9 is very much in the driver's seat as to what studies 10 are being requested of industry. 11 Now, we certainly have heard the criticism 12 that indeed it's the lucrative products that have 13 been getting to the gates first. And, indeed, many 14 of the products that have been granted exclusivity 15 have been some of the blockbuster drugs. There are 16 also some drugs that are not blockbusters that are 17 being studied too. And we are concerned about the 18 antibiotics and we are concerned about the drugs that 19 are off patent because they have fallen in the crack. 20 There is nothing for them to gain. 21 And as we are working now and as there are 22 many people interested in the renewal, one of the 475 1 areas of greatest interest is, what can be done about 2 those products that have not benefitted from this? 3 But we are requesting the studies and we 4 look very carefully at the information we have and 5 what's necessary and we put that request out. And 6 industry then has to meet the terms of that request 7 in order to qualify. 8 DR. FLEISCHMAN: Thank you. And Dr. 9 Roberts is on our workgroup and has been helpful 10 thee. I would comment that in the workgroup report 11 we did not accurately depict what Dr. Roberts just 12 described and on page 2 she's given us some new 13 language to put into the report and that will be 14 done. 15 Adil and then Rabbi Dorff. 16 DR. SHAMOO: I just want to state that 17 what she said is true, if it's FDA busters in IND 18 applications. All the NIH-funded research in 19 children does not follow the same process. As a 20 matter of fact, NIMH just funded research in two to 21 four years old, two to six or two to four on Ritalin, 22 Abbey, as a matter of fact. A large number of -- as 476 1 a preventive measure, as a matter of fact, which is a 2 very disturbing type of -- protocol. 3 So, FDA is not in the drivers' seat for 4 all the proposed research in children and we should 5 keep that in mind. And also we should keep in mind 6 that the pharmaceutical industry, if it is not IND 7 type of research, they will do that research. They 8 do that research by privately funding some hospitals, 9 some academic centers to conduct research and there 10 is one of them at Yale University. 11 Dr. Levine I am sure can correct me if I'm 12 wrong, he will jump immediately -- and that is -- 13 [Laughter.] 14 DR. SHAMOO: -- and that is that it's a 15 privately funded, at least the Wall Street Journal 16 Report indicates 1,400 children to prevent 17 schizophrenia from occurring. Even though the 18 chances of schizophrenia occurring in those children 19 is no more than 10 percent. 20 DR. FLEISCHMAN: Elliot. 21 DR. DORFF: I just wanted to respond 22 directly to the question that you asked at the end of 477 1 your presentation just so that you know that it was 2 at least heard. 3 I do think that the degree of risk is an 4 important thing in terms of figuring out what drugs 5 should be or what -- not just drugs, but other kinds 6 of protocols of research should be used with children 7 -- with adolescents, in particular, and I think one 8 of the real issues that you get in this in regard to 9 adolescents is the same that you had with adults, but 10 more so. Namely that you have to figure out who is 11 judging. Whether the adolescent understands the 12 degree of risk. 13 And I think that, you know, the greater 14 the risk, definitely the greater precautions that you 15 have to -- that we have to take and we have to build 16 into the regulations. And among those precautions 17 are people from outside the whole protocol who are 18 willing and able to make sure that the adolescent 19 understands what's going on. 20 DR. FLEISCHMAN: Yes. And in the guidance 21 of the Society for Adolescent Medicine, that's 22 precisely the approach that they recommend. Within 478 1 what they believe to be the regulations as they stand 2 now IRBs have the capacity and the authority to make 3 such determinations to moderate risk versus the need 4 to determine capacity, the need to have counselors 5 available outside of the research, and the need to 6 monitor the whole consent process and ongoing 7 research. And that's what has been recommended and 8 IRBs actually in several parts of the country are 9 actually doing that based in 408 in the regulations. 10 I think it's Felice and then Bob. 11 DR. F. LEVINE: Maybe a complimentary 12 point because I was going to bounce off of Bob's 13 point. While we talked about addressing this with 14 respect to DHHS, I would like to commend in the 15 spirit of the language of this document that when we 16 talk about assent and consent and the capacity to age 17 and staged appropriate for the child to invoke assent 18 without necessarily consent that we recognize and use 19 examples that are not just grounded in clinical 20 trials, that much of the work supported by NIH 21 includes non-clinical, social/behavioral research and 22 that we want to be and are included under this and we 479 1 have often used that provision to permit very 2 important work on runaway kids on youth networking, 3 at-risk youth and the evolution of gang formation and 4 other kinds of work where parental consent or 5 parental written consent is not known or even 6 possible. 7 So I think working in some examples 8 irrespective of the common rule in what goes on in 9 other agencies just within the family of terrific 10 work supported by NIMH, NICHD, NIADA and others we 11 should include in this. 12 DR. FLEISCHMAN: Bob?. 13 DR. R. LEVINE: I'm sorry Abbey isn't in 14 the room right now, but I wanted to point out that 15 Abbey is very concerned that Ritalin is not being 16 studied and Adil is very concerned that it is. 17 The fact that something is not reviewed -- 18 not being done under an IND does not mean that there 19 will not be rigorous review. 20 In fact, I believe that the review that 21 one gets at NIH when you're applying for a grant or a 22 contract is at least on a par with that provided by 480 1 FDA where you have a goodly number of experts and 2 people who are concerned about the well-being of 3 children evaluate applications for grants and 4 contracts. 5 The statement that there are private 6 interests that are funding research that is not 7 regulated by anybody is counterintuitive. Why on 8 earth would anybody want to study a drug without 9 getting an IND when if they don't get an IND they are 10 not eligible to apply for a change in the package 11 label. 12 Any time that there is a commercial 13 interest there has to be an IND or else it's an 14 exercise in futility. 15 Thank you. 16 DR. FLEISCHMAN: I'm going to ask for our 17 liaison and public members if they have comments 18 about the issue of adolescent consent to please come 19 to the microphone. 20 And if you would identify yourself. 21 DR. RUBIN: These are a little general, 22 but they do -- I'm going to just try to restrict it 481 1 to the portion on adolescent assent; consent is a 2 little difficult. 3 Phil Rubin from the National Science 4 Foundation, ex officio. Sorry I stepped out of the 5 room for a moment before, but it was pointed out that 6 the National Science Foundation hasn't adopted 7 Subpart D and because we think in certain cases it's 8 too restrictive. For example, in this case, 9 regarding the appropriateness of regulations of 10 children of differing age, we feel the regulations 11 are overly restrictive for normal behavior and social 12 science research and are not appropriate for the kind 13 of no-risk and minimal risk research that we normally 14 support. 15 Related to that is, basic research does 16 not promise direct benefits to participants and the 17 regular provisions and the common rule supply 18 adequate protection. We've been over and over this 19 and I just want to make kind of a little note on that 20 and we've provided detailed comments. And so we have 21 specifically written that regarding Subpart D, if 22 there's going to be a recommendation from this group 482 1 that there's a federal-wide adoption of Subpart D 2 that once again we understand the constraints that 3 the group is under and the need to respond, and we 4 would like to actively work with you. 5 But if there is going to be a 6 recommendation of this group, please alert us so that 7 we can get our General Counsel involved because, once 8 again, we're trying to work and that's not something 9 that we feel needs to be done. But it's just kind of 10 particular. If something like that is going to be a 11 recommendation, we would like to be even more 12 actively involved as part of the process. At the 13 moment we are happy with what is going on. 14 DR. FLEISCHMAN: Other public comments? 15 Liaison comments? 16 [No response.] 17 DR. FLEISCHMAN: We are going to take a 18 ten-minute break. We will come back to continue 19 working through the workgroup's recommendations. Ten 20 minutes. 21 [Brief recess taken at 10:23 a.m.] 22 DR. FLEISCHMAN: We are going the move on 483 1 with the next major issue. And it speaks to the 2 second question asked of the Secretary by Congress 3 and that has to do with the issues around minimal 4 risk, definitions, and applicability. 5 Reminding you that "minimal risk" was 6 defined in 46.102 as meaning, "the probability and 7 magnitude of harm or discomfort anticipated in the 8 research are not greater in and of themselves than 9 those ordinarily encountered in daily life or during 10 the performance of routine physical or psychological 11 examinations or tests." 12 The workgroup concluded that that 13 definition was essentially acceptable and should be 14 considered an absolute standard. Realizing that 15 these were the socially acceptable risks to which the 16 society places children in the normal daily average 17 routine, visiting the doctor, going to the dentist, 18 receiving routine care, playing at home or with 19 friends as well as the routine kinds of psychological 20 testing that children generally have. 21 Now, here the committee felt -- or, excuse 22 me, the workgroup felt that minimal risk considered 484 1 as an absolute standard -- 2 [Laughter.] 3 DR. FLEISCHMAN: -- I'm sorry -- 4 [Discussion off the record.] 5 DR. FLEISCHMAN: No, actually, just to 6 comment. I didn't say this yesterday to Mark, and 7 I'll wait until he gets back, but his workgroup 8 report used NHRPAC in its language. Our workgroup 9 report uses "workgroup" in its language. And I think 10 that's an important distinction, so I'm holding to 11 that. 12 The issue then was socially acceptable 13 risks for average and normal healthy children. These 14 are issues that have been debated and have been 15 controversial over the years. The feeling of the 16 workgroup was that this needed clarification and we 17 have all had distributed to us a draft report from 18 what has been called the "407 Committee". 19 Now, you'll be reminded that Section 407 20 of the regulations speaks to those research proposals 21 who are not otherwise permitted through the 22 regulations, but could be permitted through a process 485 1 which would include the Secretary's approval after 2 public comment and review at the federal level. 3 In fact, there has been a small group that 4 has been convened in order to review some proposals 5 through that approach, and they gave us the benefit 6 of their wisdom in looking at the process of 407 7 review as well as setting certain approaches or 8 standards. The workgroup read that report. It 9 didn't endorse it in its entirety, but believes it's 10 a very important helpful document to help us in our 11 analysis. 12 And in that report the committee suggested 13 daily life is interpreted to mean the daily life of 14 healthy children in the general population. It 15 wasn't the general life or daily life of a child in a 16 socially deprived environment or a child perhaps 17 internationally in an environment where there might 18 be guns firing over their heads, it was felt to be 19 the daily life interpreted of healthy children in the 20 general average population. 21 This becomes important when we consider in 22 the next grouping the concept of minor increment over 486 1 minimal risk and the definitions of disorder or 2 condition. 3 To remind you, in 46.406 which basically 4 speaks to research involving greater than minimal 5 risk and no prospect of direct benefit to individual 6 subjects, but likely to yield generalizable knowledge 7 about the subject's disorder or condition. This is a 8 group of research projects that are permissible 9 through IRB review, but there are certain specific 10 codicils that go with that review. 11 First, the magnitude of the research risk 12 must be small, above minimal. A small increment. 13 That's why the word "minor." 14 And, second, that experience has an 15 experiential qualifier. The experience of the 16 intervention is reasonably commensurate with those 17 inherent in the research participant's actual or 18 expected medical, dental, psychological, social, or 19 educational situations. 20 Now, those, I think, are important parts 21 of that subsection which the workgroup believed were 22 appropriate needed clarification with examples, but 487 1 were an appropriate method for IRBS to determine 2 which types of research might be allowed or 3 permissible in children who had a disorder, disease, 4 or condition. 5 Now, the concept of condition has had some 6 conversation as well. The workgroup attempted a 7 first look at this problem. And it felt -- on the 8 top of page 6 -- a relevant condition addresses those 9 aspects of the environment that impact on the child 10 such as the biologic, environmental, social, 11 emotional and behavioral determinants of the child's 12 well-being. 13 Thus, on the one hand poverty might be 14 considered a relevant condition, social condition 15 worthy of careful scrutiny. And on the other hand, a 16 genetic or familial predisposition to a disease or 17 disorder might be a relevant biologic or social 18 condition which places a specific child outside the 19 purview of normal, average, healthy children. 20 This is the way the workgroup is 21 recommending that we deal with the concept of minor 22 increment over minimal risk and the concept of 488 1 disorder and condition. 2 I will pause here to take comments from 3 the group. I'll start with Jonathan and then Abbey. 4 DR. MORENO: Let's start with the notion 5 of minimal risk as absolute. And this actually 6 applies, of course, not only to D, but to the common 7 rule generally. I have heard Greg's predecessor say 8 publicly that this is the understanding of the 9 predecessor agency of the meaning of minimal risk. 10 And I think it's important to get on the record that 11 your interpretation is not the first interpretation 12 that goes to this point that it's an absolute 13 standard. 14 Though -- and maybe somebody from OHRP can 15 help me with this -- when I go to the OHRP web site, 16 I look for a guidance or a "Dear Investigator" letter 17 to put this on the record. Now, maybe there is 18 something on the record in some guidance in the 19 earlier -- a decade ago or when I was too young to 20 read, but -- 21 DR. FLEISCHMAN: That was more than a 22 decade ago. 489 1 [Laughter.] 2 DR. MORENO: It would be worth whatever 3 the document that's finally produced, it would be 4 worth, it seems to me, referencing any official 5 statement to this effect. Because I have 6 encountered, even now, IRB educators who interpret 7 this as a relative standard. 8 DR. FLEISCHMAN: May I use this 9 opportunity to remind the committee and our other 10 members that it is the recommendation of this 11 workgroup that a series of memoranda, we can call 12 them whatever the appropriate language will become, 13 clarifying several areas, including this one. The 14 workgroup is recommending that we develop such 15 memoranda or guidance -- or whatever the appropriate 16 language of art will be -- as we move forward, which 17 will interpret the regulations. That is the 18 workgroup's hope. And those, of course, would have 19 hopefully a background or historical context, some 20 information about what the bases would be for such 21 and then the specifics as well as some specific 22 examples which we think will be helpful to IRBs that 490 1 aren't chiseled in stone, but would then be able to 2 be evolving as new problems come up over time. 3 You know, there were no MRIs ten years 4 ago. There were words to read, but there weren't 5 MRIs ten years ago. There were no -- so, you know, 6 we would need to have a fluid document that would be 7 able to get some examples. I have Abbey and then I 8 have Susan and then Sandy. 9 MS. MEYERS: Well, I want to know how this 10 section that you just went over would affect healthy 11 children in a placebo group? Children who don't have 12 the illness, and, for example, I think I've been 13 hearing about a study for an antibiotic because on 14 otitis media and they're going to be studying 15 children who don't have otitis media, perfectly 16 healthy kids, because the likelihood is they will 17 have otitis media sometime during their childhood. 18 And the second thing is, and maybe Greg 19 can answer this, there was a study by NIH which I 20 believe your office closed down on studying healthy 21 children of obese parents who were put through a 22 series of extraordinary tests. You know, tests high 491 1 blood sugar, low blood sugar, and so forth, just to 2 monitor them to see if they would come down with 3 diabetes eventually. Again, these were healthy 4 children. 5 DR. FLEISCHMAN: I'm going to ask us to 6 hold off on the placebo discussion until we actually 7 have a full discussion of placebo-controlled trials 8 which is coming soon to this table in the next few 9 minutes. So let's hold off on that one, but I will 10 ask if Greg wants to comment on the issue relevant to 11 children in a family having been subjected to -- been 12 subjects of research to look at a predisposition 13 toward future illness? 14 DR. KOSKI: I'm not going to go into 15 details about the specific study in question except 16 for the fact that there are some elements of that 17 that have already been discussed. It was a study in 18 children of obese parents who had a strong 19 predisposition of developing obesity, studies 20 directed toward understanding the metabolism in 21 children and so it's a study that is, you know, 22 currently still in process and I won't comment about 492 1 that further. But, again, I think it's very 2 important of we again have this discussion, the 3 dialogue about, you know, how we consider risks and 4 have the disorder really is. 5 DR. FLEISCHMAN: I think that the 6 workgroup -- I'll give you a moment if I can just 7 comment on this. Thank you. 8 The workgroup did not review that specific 9 protocol. But did speak about the concept of 10 condition. And I don't know that protocol. So I'm 11 not going to comment on it specifically. But the 12 workgroup did argue that a predisposition, whether 13 genetic or social, toward future illness would allow 14 IRBs to place such research into this category that 15 obviously have to review it. 16 They would obviously have to consider it, 17 they would obviously have to consider what a minor 18 increment over minimal risk was, but that this 19 workgroup, just so we're clear on this, would argue 20 that there are certain conditions that would allow 21 children who were asymptomatic from specific disease 22 or diagnosis at this time to have minor increment 493 1 over minimal risk research because of either genetic 2 or social factors, biologic, or others that would 3 predispose them. And this was what the workgroup is 4 trying to talk about at the top of page 6. And now I 5 have Susan, Sand, Bob, and Adil on the docket here. 6 MS. KORNETSKY: Just quickly going back to 7 Jonathan's comment about the absolute or relative and 8 was part of the working group and I support -- 9 DR. FLEISCHMAN: Excuse me, please. 10 MS. KORNETSKY: -- I support the position. 11 I do want to point out and I think it was pointed out 12 yesterday that one of the books that IRBs often use 13 and they are to train and for themselves something 14 that the OHRP put out a while ago, the IRB guidebook, 15 and there is some conflicting information about -- 16 specifically about how to interpret the standard. 17 And I know yesterday there was discussion about 18 genetics. And although I realize there are guidance 19 letters and there's no guidance specifically on this, 20 but if there are portions of that guide book that do 21 not pertain anymore are being evaluated, it would be 22 helpful for the community to know that. 494 1 DR. FLEISCHMAN: Sandy. 2 DR. CHODOSH: I want to get back to this 3 business of the minimal risk, because, you know, 4 despite the fact that I've been involved with this, I 5 can't tell you how many decades, there is still a lot 6 of confusion about how an IRB looks at minimal risk 7 and how a subject looks at minimal risk. And I think 8 that it's an argument that I had with Charlie 9 McCarthy many years ago that to me minimal risk, 10 something above minimal risk depends on what the 11 person has. And that if you don't take that into 12 consideration, you are not being realistic about what 13 patients expect or what subjects expect. 14 Subjects who are already suffering from 15 shortness of breath say, with my kind of diseases, 16 chronic bronchitis and emphysema, don't consider have 17 a pulmonary function test at any risk whatsoever. 18 Don't consider having a chest X-ray any risk 19 whatsoever. This is within their normal framework of 20 how they look at things and one should -- I know that 21 there are IRBs which will view that and take that in 22 consideration as opposed to this business of just 495 1 above minimal risk for a healthy person. 2 This concept of the healthy person doesn't 3 really relate to patients. And if we're protecting 4 subjects, we should look at it from both sides. We 5 are not really protecting them if we sometimes keep 6 them from having adequate research because we think 7 that maybe the risks are too great, even though 8 they're the same risks that they have from having 9 their disease. 10 DR. FLEISCHMAN: Sandy, just to respond, I 11 think one of the great pieces of wisdom that the 12 National Commission did here was to precisely 13 separate out those children who had a disease, 14 disorder, or condition which would then allow for 15 such similar kinds of work as the work you're 16 describing in those adults with chronic obstructive 17 pulmonary disease. And that allowed then for this 18 concept of minimal or even minor increment over 19 minimal to be a permissible level of risk for those 20 children who had that experience as you described for 21 adults. 22 DR. CHODOSH: I think what I'm saying is I 496 1 have seen such confusion among IRBs as to how you 2 look at this, that it needs to be clarified more than 3 on paper. I think we need to have an educational 4 process that really is devoted toward the point of 5 you, what does the subject expect, and I think that 6 IRBs act differently in this regard and it goes back 7 to a lot of problems that we have with IRBs and how 8 they view things, but we'll get to that later at some 9 other point. 10 DR. FLEISCHMAN: Thank you. Bob. 11 DR. R. LEVINE: Thanks. I agree with both 12 Sandy and Alan. The Commission -- National 13 Commission necessarily left the definition of "minor 14 increase" vague. I think the idea that Sandy is 15 trying to get across is what you find in the criteria 16 for justification of minor increases. This 17 particular one is that the procedure must be 18 commensurate with what would be expected in the 19 child's actual life experience given the condition or 20 disease the child has. So children in Sandy's 21 practice would find pulmonary function tests and 22 chest X-rays highly familiar. 497 1 I want to emphasize that the purpose of 2 putting in the commensurability standard was not to 3 say, well, here's a kid with leukemia who is going to 4 have ten bone marrows anyway, another one won't hurt, 5 was really meant to make it possible for the child 6 prospective subject to understand what was being 7 proposed to say, we're proposing to do a bone marrow 8 examination, but this is one you don't have to have. 9 And the kid can say, "Oh, I know what you're talking 10 about, I don't want that." 11 The other point I want to make is that in 12 the 20-some odd years since the Commission made its 13 recommendations on this topic we have had multiple 14 case reports, analytic case reports of actual 15 experiences of IRBs, many of these are published in 16 the IRB journal. And what they do is tell us the 17 reasoning that went into a decision by a particular 18 IRB to call something either a minor increase above 19 minimal risk or no increase, and I think we can 20 profit from those. Even though it's not specified in 21 any regulation, you get the general sense that a 22 minor increase would include such things as lumbar 498 1 punctures, bone marrow aspirations, things of this 2 sort, but they would not include left heart 3 catheterization and some other things like that. 4 Thanks. 5 DR. FLEISCHMAN: Adil. 6 DR. SHAMOO: I don't know if you looked at 7 the NBAC's recommendations on this issue of minimal 8 risk and they discuss it very much indeed here and 9 they weigh in, in that that should be an absolute 10 standard. They took the probability of harm and the 11 magnitude of severity and potential of harm that they 12 can very specific -- they made specific 13 recommendations that said, "should not be left to the 14 discretion of one local IRB, but rather should be 15 reviewed by a national review panel with public input 16 into the review process." And that would be the 17 method I would take. 18 That if you leave it to the local IRB, you 19 will see the confusion Sandy is talking about and 20 others have been talking about and you will see the 21 slippery slope, one IRB doing something and another 22 IRB doing another and then 10, 15, 20 years from now 499 1 we'll be back on square one. 2 Having said that, let me go back to what I 3 really wanted to ask and that is the condition. We 4 really need to discuss -- because condition I bet you 5 in this entire room we all have some genetic 6 predisposition to something. So we have all 7 conditions. The question is, is the risk to the 8 children for the future, are we talking about we're 9 going to consider the condition and therefore make 10 allowable research on them if the risk is .1 percent, 11 1 percent, 5 percent, 10 percent, 20 percent, 50 -- I 12 could understand it if you tell me it's 90 percent. 13 I could understand if you tell me even 60 percent. I 14 may even consider 50 percent. But now we have 15 research that's being proposed for this quote/unquote 16 condition that's in the 5 to 10 percent. 17 I wouldn't want my child to go into 18 research as a subject because he has a risk 5 to 10 19 percent to contracting disease A or B or C. And this 20 is the exact example I just brought up a few minutes 21 ago about schizophrenia research. Siblings of 22 schizophrenic children have a somewhere between 5 to 500 1 10 percent risk. That's considered a condition and 2 that was a justification used for using preventive, 3 modified risk experiment, a very powerful drug. 4 You're talking about Haldol, Clozapine, Respiradol 5 type of drugs. 6 And we really need to wrestle with that 7 issue and come one way or the other. What is the 8 percent risk we consider a condition. If you just 9 say the word "condition" forget it. It's meaningless 10 because we all have conditions. 11 DR. FLEISCHMAN: Abbey. 12 MS. MEYERS: I just wanted to say after 13 you had introduced this whole section that it seems 14 to cancel out the other section on placebos. Because 15 here we're talking about protecting healthy children 16 who don't have symptoms and yet in the other area 17 we're talking about giving healthy, asymptomatic 18 children some kind of tests, whether it's a blood 19 test, or X-ray, or whatever, there's some risk in it. 20 DR. FLEISCHMAN: Elliot. 21 DR. DORFF: I just wanted to at least make 22 it clear for myself if for nobody else, that if we 501 1 take Sandy's point seriously, then the language that 2 you have here on page 5, "The workgroup concluded 3 that minimal risks should be considered an absolute 4 standard" would be incorrect because then "minimal 5 risk" would be -- if I understand you correctly, 6 right, then "minimal risk" would be defined according 7 to the particular condition, I'm sorry, that the 8 child has; right? So that in other words minimal 9 risk for an asthmatic child would be different in 10 terms of tests about, you know, lung function and the 11 like, than for a child without asthma. 12 So, I mean, I don't know where we want to 13 go with this, but I think we should be at least 14 clear. 15 DR. FLEISCHMAN: Let me clarify the 16 workgroup's thought on this. That minimal risk would 17 not be different, but that children with asthma have 18 a disorder or condition or disease in that case which 19 would allow for research to include a minor increment 20 over minimal risk even if there was no intended 21 therapeutic or beneficial arm. 22 So that if we had children with asthma and 502 1 we were looking at various interventions, education 2 interventions, other kinds of things, we could, as an 3 IRB, look at a different level or risk than minimal. 4 Minimal being the average normal healthy child and 5 through this 406 section children with asthma having 6 a condition could then have those kinds of studies 7 that Sandy is talking about. 8 The workgroup would like to keep the 9 definition of minimal risk absolute and that is 10 compared to the average daily life of a healthy 11 normal child, but reminds us that there is another 12 category which is why Adil's point about what 13 constitutes a condition is an important one because 14 the workgroup is arguing that the IRB is going to 15 have to consider that. The workgroup has not done 16 the work that Adil has suggested. I don't know if it 17 would wish to, and that is try to put a percent on 18 different things. I mean, 5 percent risk of very 19 serious illness, to me as a clinician, sounds quite 20 significant actually. But, you know, I don't -- a 60 21 percent risk of a significant illness to me as a 22 clinician is overwhelming. I mean, it requires very 503 1 different review, having nothing to do with research, 2 having to do with clinical care. 3 So, for me, as an IRB member, if I were 4 sitting with an illness that had a 5 percent 5 incidence serious illness or disorder, I would be 6 very comfortable -- and I tell you this very 7 personally and having nothing to do with this 8 document, I would be very comfortable with reviewing 9 research that would look at predisposition for that 10 problem, try to help us as clinicians to understand 11 which children need more interventions, preventive 12 interventions, or whatever. 13 So I think the workgroup is trying to 14 argue that IRBs need to learn that there are such 15 conditions, some of them are biologic, some of them 16 are social, but that are important to child health 17 which would then allow for the IRB to consider the 18 minor increment over minimal risk category. 19 When we looked -- "we" meaning when I 20 looked at the NBAC report, particularly the NBAC 21 report on adults with mental disorders, who had 22 questionable capacity in order to determine whether 504 1 they could participate in research, I have to tell 2 you that I disagreed with their categorization of 3 minimal risk and everything else. 4 What I believe they were asking of us as a 5 community of researchers is to go down a slippery 6 slope and to add into the minimal risk category 7 things that would not be in the minimal risk category 8 in the present definition in my opinion. But they 9 asked us to do that because they eliminated the minor 10 increment over minimal risk category. And that, I 11 think, for the sake of children, is a better approach 12 for IRBs than to try to shoehorn into the minimal 13 risk category things that are not in the experiences 14 of average healthy children. 15 So that was my personal response to the 16 NBAC report when they wrote that one. Their most 17 recent report does lean heavily on that approach in 18 terms of their consistent view of this. Now, if 19 there are people who are from NBAC or have other 20 views of that, I'm happy to have them come to the 21 microphone and talk about it. But from the 22 perspective of the children's regs, it would be 505 1 different than the NBAC recommendations and from this 2 observer, it gives the IRBs a much better, more 3 carefully constructed and thought out way to protect 4 children. 5 Adil. 6 DR. SHAMOO: What you missed from there, 7 you didn't mention that the proposed intervention -- 8 if the proposed intervention has no value, there are 9 no data indicating it's preventive to that disease in 10 the future, why do it. It's a fishing expedition. 11 And most of the research, some of that is being 12 proposed. They have no clue that the drugs used to 13 relieve symptoms necessarily will prevent the 14 occurrence of the disease, and that is the one we 15 should worry about. I personally don't think you 16 would approve, even if 5 percent where the 17 intervention is high risk like Clozapine or 18 Respiradol, and there are no data whatsoever that 19 would prevent the occurrence of the disease ten years 20 later. 21 And the scientist -- are horrible. 22 DR. FLEISCHMAN: Well, I'm not going to 506 1 get into the specifics of that research project, but 2 it is certainly in my opinion the responsibility of 3 the IRB to begin with a careful assessment of the 4 scientific rigor and validity of the hypothesis and 5 the questions being asked. 6 DR. SHAMOO: -- are being accrued by IRBs 7 and that's why I don't want to depend on local IRBs 8 all over the country each having their own standard 9 rather than a national or regional IRB where these 10 things are discussed at public hearings and deciding 11 those terms -- not each local IRB. 12 DR. FLEISCHMAN: The workgroup in its 13 conclusions will request that we carefully think 14 about IRB accountability and monitoring of IRBs 15 whether or not it results in having national IRBs. 16 The workgroup will recommend, as you will see at the 17 end, that we need to develop measures of 18 accountability for IRBs both prospective 19 credentialing as well as post hoc evaluation and 20 accountability of IRB practices which I think is 21 going to be a great challenge for the field of 22 research ethics. 507 1 But the workgroup is certainly cognizant 2 of the importance, Adil, of what you're arguing, and 3 that is that there needs to be some accountability of 4 local review at some kind of structure or regional or 5 national level. 6 I have Mark and then Jonathan and Greg. 7 Bob before Greg. 8 MR. BARNES: This is related to a point 9 that Adil made earlier. I think that there really is 10 some need for conceptual clarity about what these 11 regulations regard as a child having a condition or 12 subject to -- subject's disorder or condition and 13 there are some concepts in the law of employment 14 discrimination related to disability and particularly 15 genetic discrimination that are actually very 16 applicable here. And let me just briefly, you know, 17 kind of give you three different cuts on what it 18 might mean. Okay. Just briefly. 19 Maybe subject to a disorder means that the 20 individual child has a proven higher probability of 21 developing a particular condition over time. Or it 22 may mean that the individual child has an 508 1 individualized risk of developing a particular 2 condition at any point in time, or it may mean that 3 the individual child is a member of a group defined, 4 however you wish to define it, by race, ethnicity, 5 poverty status, income level, geographical residence, 6 environmental exposures, et cetera, where the group 7 has an epidemiologically sound probability or 8 epidemiologically proven probability of its members 9 developing a condition at a particular point in time 10 over whatever time period you want to define it. 11 And then in any of these or in more, 12 because you could spin out, you know, many more 13 permutations of what it means to have either 14 individualized risks or being an individual that's a 15 member of a group that has a heightened risk, then 16 you also have to reach the point of what is the 17 probability breakpoint on the condition. And then 18 even within that, you have another set of 19 circumstances to evaluate which is what is the 20 morbidity or immortality of the condition? What's 21 the severity of the condition if it does happen? 22 So I just want to point out that embedded 509 1 in Adil's point there are multiple points, you know, 2 none of which I think has been fleshed out in the 3 literature particularly, and I don't think that you 4 can really -- I mean, it seems to me that the 5 workgroup -- either the workgroup has to do it or 6 somebody has to do it, but if this research on 7 children is going to continue, somebody has to 8 grapple with those issues. 9 DR. MORENO: Alan, you'll be happy to know 10 that my comment actually follows Mark's. 11 I was going to suggest that if -- not 12 knowing whether this is the case or not, if the 13 advisory committee has the resources that we 14 commission a legal and a philosophical paper on the 15 question of the meaning of the concept of condition 16 and it's applicability. We are desperately in need 17 of some conceptual clarity on this and it could be so 18 critical to what you are doing and we are doing with 19 respect to kids that I actually think this is a very 20 high priority. 21 You asked the question whether there was 22 anybody around who had experience with the NBAC and 510 1 you didn't look at me which was very nice of you. In 2 fairness, I do want to say that the report that I 3 helped to draft on the role of persons with 4 diminished decisionmaking capacity in research was 5 not about children. It was specifically not about 6 children in research. And I did, and I think I can 7 prove it because I think it's still on my hard drive, 8 have a draft that included a minimal risk category 9 that was -- I'm sorry, a minor increment over a 10 minimal risk category and that was pegged to 11 examples, interestingly enough, examples that I 12 gleaned from various reports, the Alzheimer's group, 13 for example, had a task force that identified 14 specific examples of minor increment over minimal 15 risk procedures, the Tri-Council the Canadian Tri- 16 Council had examples that were almost identical -- a 17 lumbar puncture for example -- to those represented 18 in the Alzheimer's task force. 19 The Commission decided that as a manual 20 concept we are prisoners of our examples. And 21 therefore, that -- and this is something that we need 22 to worry about too, I think, even though we may 511 1 reject it ultimately, that IRBs will, feeling legally 2 driven in some cases, stick only to those examples 3 and not use them as guidance, but as hooks and be 4 constrained by them. 5 DR. FLEISCHMAN: Bob. 6 DR. R. LEVINE: Most of what I wanted to 7 say would have been in response to Elliot's question 8 that the way things are particularized to specific 9 diseases or conditions is not through changing the 10 standard of minimal risk, but rather to say that 11 there are additional justifications when there's a 12 minor increase and that is the knowledge you are 13 pursuing has to be of importance to understanding the 14 disease or condition that the child subjects have, 15 and also that the experiences must be commensurate 16 with those that they would expect in their actual, in 17 this case, medically defined situation. 18 This is why it's so important now to do 19 what Jonathan says about getting a definition of 20 condition because in people who are just predisposed 21 to have something, there is not yet anything that's 22 commensurate with their actual life experience. I 512 1 look forward to the paper that gets commissioned, if 2 it does, in clarifying this sort of thing. 3 I also want to agree most vigorously with 4 Alan's concern about the NBAC report. I think it was 5 a very serious error to omit the minor increase 6 category in the report on people with decisional 7 incapacity. I didn't know before that Jonathan had 8 proposed it be included, but I want to congratulate 9 you for that. 10 DR. MORENO: Thank you. 11 DR. FLEISCHMAN: Greg will be next. But 12 actually the report, I think, was on adults with 13 mental disorders. 14 No, I think that was an even better reason 15 to be opposed to that report; right. 16 DR. KOSKI: Well, actually, Bob already 17 made the point that I was going to make. But in the 18 sense of a more general comment, it seems to me that 19 it's as egregious to omit or exclude children from 20 research that would help us to understand 21 particularly those diseases and conditions that 22 affect them. It's just as egregious to exclude 513 1 pregnant women from research just because they happen 2 to be pregnant women, recognizing that there are 3 special situations that arise there. But there 4 clearly is a need to know about these disorders, you 5 know, how they develop and so on. 6 So I mean, we've already heard about the 7 problems of using drugs to treat children where we 8 don't really know how the drugs work in the children 9 and all that. Perhaps, you know, the notion of 10 actually treating diseases with those drugs that we 11 don't even understand either is a serious concern to 12 me. 13 So, you know, I say that not only as an 14 investigator, an IRB member, but as a parent and 15 everything else, we want to make sure that we 16 recognize in doing this that research has enormous 17 value and we just have to be certain as we're trying 18 to do that it's going to be done appropriately. 19 DR. FLEISCHMAN: I'm going to call on 20 Elliot and then I'm going to ask our liaison and 21 public members for comment specifically around these 22 issues about minimal risk, minor increment over 514 1 minimal risk, disorder and condition. 2 Elliot. 3 DR. DORFF: Just a note about defining 4 things, if we're interested in defining a condition. 5 Everybody would love to have what philosophers call a 6 "necessary and sufficient condition" to define 7 something. But there are very few -- once you get 8 out of the world of constructed worlds like 9 mathematics and logic, there are very few necessary 10 and sufficient conditions that exist. I mean, I can 11 give you one. A bachelor isn't a married man. Okay. 12 But that's about it. 13 And so then the question is, in the real 14 world, what do you mean by a definition. And the 15 entomology of the term coming from the Latin means 16 that you're drawing a boundary around something. So 17 part of the way that you come to a definition is that 18 you try to describe what's inside the things that 19 you're talking about and what's outside the things 20 that you're talking about. 21 Now, sometimes you can do that pretty 22 well. Even if you can't get to a necessary and 515 1 sufficient condition, you can try -- you can more or 2 less describe what a table is even though any given 3 definition that you give me I can show you something 4 that's not that, that's probably a table or something 5 that fits it that isn't a table, because that's just 6 the nature of things. 7 And you gave me functional definition or a 8 definition of native, you know, it's made up of 9 certain things or a formal definition has a certain 10 form or something on that order. And there will be 11 some very funny things that end up being called 12 tables by your definition and some things that you 13 think are tables that are not. 14 But, nevertheless, that kind of thing is 15 something that we more or less can define. When you 16 get to things much more complicated like an illness 17 or a condition, you may be able to give at least some 18 stabs at what it is. But maybe in the end the best 19 that you are going to be able to do is to give some 20 examples. Some examples of things that are indeed 21 the kinds of things you're talking about and some 22 things that are not the kinds of things you're 516 1 talking about. 2 The only reason why I'm making this point 3 is because if indeed we are going to be looking for a 4 definition of condition or disease, I think we 5 shouldn't deceive ourselves into thinking that that's 6 going to be very neat and clean in the end. That 7 somebody is going to come up with the definition. 8 They're going to say -- you know, and everything is 9 going to be wonderful in the world. 10 One of the things that you learn when you 11 go from philosophy 1A to philosophy 1B is that the 12 world doesn't live by philosophy. 13 DR. FLEISCHMAN: Thank you. Comments from 14 our liaison and public members about this area of the 15 discussion. 16 If you would come to the microphone and 17 identify yourself, Doctor. 18 DR. WILL: Ben Will from the NIH, although 19 I'm speaking just as myself, not representing anybody 20 in particular. 21 Actually, my comment really actually goes 22 back to the last comment by Elliot Dorff. I often 517 1 struggle with regulations and how to interpret them 2 and in the end what I often find myself doing, having 3 sat on IRBs for many hears is asking myself the 4 question of whether or not this research is ethically 5 acceptable and what was my intuition about whether 6 this is a sound research project or not. And we can 7 then attempt to figure out how the regulations work. 8 And I think there is some value to doing that 9 approach rather than just first trying to define each 10 of these terms, and I'll try to give you a couple of 11 examples of how this comes up. 12 I think that -- and I think the point I 13 want to make is I might be more willing to be more 14 relaxed on the definitions of minimal risks because 15 I'm concerned about the implications of putting too 16 much weight on the subjects of condition requirement 17 or on the prospect of direct benefit requirement. 18 I think the problems with the subject 19 condition requirement and putting a lot of weight on 20 that is that it then asks children to participate in 21 non-beneficial interventions precisely because they 22 have a disease. And I think that puts additional 518 1 burden on children with a disease. I think the 2 problem with the putting too much weight on the 3 prospect of direct benefit is that it only 4 contributes to the therapeutic misconception. 5 Now, just give me a moment to back up and 6 try to explain examples I'm talking about. I think 7 Phase I oncology research we all believe is 8 acceptable research to be done. That's research that 9 we couldn't even conceive of occurring in people who 10 did not have untreatable cancer. It would be 11 inconceivable to do that on children without that. I 12 think that's the example of where we want to think 13 about subject's condition and think about the risk of 14 that as being more than minimal risk, but because I 15 have this disease and it's a balanced situation, we 16 might accept that. 17 I wonder whether for other experiences 18 that involve non-beneficial research in children such 19 as conscious sedation which is an incredibly widely 20 used circumstance that while there are risks of that, 21 thinking of that as a minimal risk even though I 22 realize that may sound provocative, thinking of that 519 1 as a minimal risk intervention would allow us to 2 avoid only doing procedures involved in conscious 3 sedation on children with a disease or trying to 4 expand the notion of disease or condition very 5 broadly. 6 DR. FLEISCHMAN: Thank you. 7 Other comments from the committee or the 8 liaison and public members? 9 [No response.] 10 DR. FLEISCHMAN: Okay. then we're going 11 to move on to continuing our discussion through this 12 document. I'm going to skip to page 7 of this 13 document. Question 4, under the question from the 14 Congress, the definitions of direct benefit to the 15 individual subjects and generalizable knowledge about 16 the subject's disordering condition we have had some 17 of this conversation about condition and we want to, 18 in this area, talk about -- I'm sorry. 19 Oh, maybe they don't. 20 It's question No. 4 on page 7 is where I 21 am. 22 [Simultaneous conversation.] 520 1 DR. FLEISCHMAN: All right. I'm sorry. I 2 think we're reading from the same words. Are we 3 reading from the same words? 4 CHAIRPERSON MARSHALL: Yes. 5 CHAIRPERSON MARSHALL: But different 6 pages. 7 Okay. Since I've scribbled on this, I 8 will now not use the pages, but I will try to focus 9 us to where we are. 10 Okay. Does everybody have where we are? 11 We are under question 4, "The definitions of:" 12 Okay. What I'd like to do is take this 13 time to begin to talk about the -- there's a serious 14 question and problem with placebo controlled trials 15 which the workgroup gave a first look at. Because I 16 think this is one that's going to take more 17 conversation. And in that second paragraph the 18 workgroup said, in general, the use of a placebo 19 controlled trial is acceptable when it is not known 20 if a new therapy is beneficial and there is no 21 existing standard efficacious treatment. Such trials 22 examine both efficacy and toxicity of the active 521 1 treatment. 2 Even in the instance where there is a 3 standard treatment, the use of placebo controlled 4 trials can be ethical depending on the seriousness of 5 the disorder under study, the risks of the standard 6 treatment and the natural history of the disease. 7 The prospect of direct benefit to 8 individual subjects may be possible because a subject 9 might be randomized into the active arm or the 10 treatment. And that the treatment if proven 11 effective may be available in a crossover design or 12 at the end of the initial study. 13 Individual IRBs will need to review 14 placebo controlled protocols carefully, but may be 15 determine that some level of risk above minimal is 16 acceptable for the potential benefit of participating 17 in such a trial. 18 And there is a second part to this 19 conversation about placebos, and that is the part 20 about what constitutes a placebo. There has been a 21 lot of conversation in the child research ethics area 22 as to, for instance, the injection of a non-active 522 1 substance as a placebo as opposed to the injection of 2 an active substance and whether that's a level of 3 discomfort that is acceptable in a placebo controlled 4 trial for a child not receiving an active substance. 5 So there is consideration about this whole 6 issue. The workgroup does feel that placebo 7 controlled trials are ethically defensible in certain 8 specific circumstances and that controlled trials 9 might allow for certain types of placebo like even 10 injection in certain specific instances and that IRBs 11 would have some availability to determine this. But 12 these are, I think, very complex and difficult 13 decisions and this conversation, I think, needs to 14 open to the committee for some thoughtful comments. 15 Adil. 16 DR. SHAMOO: I have a simple one and then 17 later on after the other people talk I will ask 18 again. 19 The simple one is this, in the animal regs 20 they use the word "discomfort" and "pain" and I think 21 in the children's regs, whatever we are going to 22 write or draft, we should start talking about 523 1 discomfort and pain to children. Because I presume 2 we all agree, children are as valuable as animals and 3 animals has been in existence for 30 years, 40 years. 4 DR. FLEISCHMAN: Actually, the workgroup 5 has chosen to add an additional indignity so that in 6 the concept of risk would be both pain, discomfort, 7 and indignity. So that would, I think, even go 8 beyond what you're suggesting. That's the language 9 that the workgroup has chosen in the document. 10 Comments about placebo controlled trials. 11 Abbey. 12 MS. MEYERS: Well, this goes back to what 13 we were just talking about. Because if we're talking 14 about healthy children who aren't supposed to have 15 any risk or we're talking about, you know, absolute 16 minimal risk and we say that placebo controlled 17 trials are okay with healthy children in the placebo 18 group, then we're canceling out what we just said. 19 In other words, a child in a placebo group should 20 have the condition, it seems to me. Because then the 21 minor risks would be worth it. 22 But if you're going to study healthy 524 1 children and expose them to any of this, which is at 2 the very least emotionally upsetting, I don't think 3 they should be in a placebo group. 4 DR. FLEISCHMAN: Can you help me just to 5 understand your concern. You don't believe they 6 should be in the treatment group either. 7 MS. MEYERS: Healthy children? 8 DR. FLEISCHMAN: Well, that's right -- 9 MS. MEYERS: Why would they be in this 10 study. 11 DR. FLEISCHMAN: -- but what I don't 12 understand is your -- generally, as I understand 13 placebo controlled trials, there's an active 14 substance and a non-active substance. 15 MS. MEYERS: Right. 16 DR. FLEISCHMAN: So if children were 17 healthy, they shouldn't be in either arm; right? 18 MS. MEYERS: Right. 19 DR. FLEISCHMAN: Okay. So I'm not sure 20 what the concern is. 21 MS. MEYERS: The concern is -- 22 DR. FLEISCHMAN: A trial of an active 525 1 substance for children who don't have a problem 2 wouldn't be approved. So I'm not exactly sure what 3 the specific concern is. 4 MS. MEYERS: Well, what about that 5 diabetes trial and those children here at NIH which 6 the IRB approved. 7 DR. FLEISCHMAN: Exactly. 8 MS. MEYERS: They were healthy children. 9 Their only sin was that their parents were fat. 10 DR. FLEISCHMAN: Okay. Coming back to 11 that trial so just we're clear so we can focus the 12 conversation. My understanding was, that wasn't a 13 placebo controlled trial. That was a group of 14 children who had some studies done to look at a 15 predisposition to a problem and we may disagree about 16 whether that should have been done or not done. But 17 it wasn't a placebo controlled trial. It was a group 18 of children who were thought to have a predisposition 19 toward a problem and were studied in ways that you 20 may not think were appropriate. 21 MS. MEYERS: Any day of the week you could 22 pick up a newspaper, get on the subway and look at 526 1 the advertisements, call this telephone number to 2 volunteer to go into this clinical trial. They are 3 soliciting healthy people, adults and children all 4 the time, especially children now because the 5 pediatric exclusivity thing. And they're looking for 6 healthy people. Even if they're going to study cold 7 medicines, or flu medicines, or whatever, healthy 8 children are being studied and given placebo and 9 active substance. 10 DR. FLEISCHMAN: Bob. 11 DR. R. LEVINE: Abbey, I wanted to respond 12 earlier when you brought up the example of using 13 healthy children as controls for a placebo controlled 14 trial of antibiotics. I can't imagine that any 15 scientist would propose to do that, and I can't 16 imagine that any funding agency would agree to fund 17 it, and I can't imagine that any IRB would approve 18 it. When you do a placebo controlled trial of a new 19 treatment, it doesn't make sense unless all the 20 subjects have the disease or condition you're trying 21 to treat. 22 The fact that we see posters in subways is 527 1 a little distressing. But they're not inviting 2 healthy people to come in for placebo controlled 3 trials. They may be inviting them to come in for 4 studies in basic physiology, but usually they don't 5 go to the expense of posting those in subways because 6 they can find a lot of them around the university. 7 I want to address what's in the paragraph 8 of the working group's report. I think the standard 9 for justification of placebo control, what you have 10 done is you've eliminated one category as being 11 ethically problematic and that's put in terms of 12 depending on the seriousness of the disorder. 13 What you then leave is how do you justify 14 the other placebo controls. And what you've done is 15 tried to squeeze placebo under the rubric of 16 therapeutic because there's a chance to get 17 randomized to get something else. 18 If you take seriously the clinical 19 equipoise justification of a clinical trial, if you 20 can say convincingly that the active agent that 21 you're evaluating is at the outset not known to be 22 better or worse than placebo, then you have basically 528 1 what you're arguing at the outset is that as far as 2 you know, this will be the equivalent of an inert 3 substance. They may both be non-therapeutic. But I 4 think what you're hoping for is that the active 5 substance will be effective. 6 I think a way to articulate the standard, 7 coming out with nearly the same results is that the 8 primary justification of placebo is that withholding 9 of known effective therapy for that condition will 10 not, in and of itself, result in any serious risk of 11 an adverse consequence. 12 What this permits then is let's say, if 13 you want to look at a new treatment for allergic 14 rhinitis, you can say, there are 100 treatments out 15 there, but we want to see whether or not this one has 16 efficacy. If you withhold one of those hundreds of 17 treatments for allergic rhinitis, the worst you 18 expose the patient to is transient runny nose. 19 If you say to the parent and the child, at 20 any time the child can say, "I want out of this"; you 21 say, "why do you want out of it?" Because I want 22 treatment. I want relief of my runny nose. Now, 529 1 you've got an outcome measure of the trial. This is 2 a way it's commonly done. 3 The standard though, I think, has to be 4 you can't withhold any effective therapy when such 5 withholding plausibly presents a risk of a serious 6 adverse consequence. The serious adverse consequence 7 could be prolonged discomfort. I mean, you don't 8 have to die to call it serious. 9 And that's the way I would like to see the 10 standard written. Thank you. 11 DR. FLEISCHMAN: Sandy. 12 DR. CHODOSH: Actually, I want to get back 13 to something that is being misinterpreted, I think as 14 a placebo. There are instances where an antibiotic 15 indeed may be given to a healthy child. If you were 16 trying to figure out the pharmacokinetics and the 17 toxicity in the early stages and what the dose should 18 be, that is the way that it's normally done. I had 19 to say that I would oppose that. I've always opposed 20 it. My feeling is that those Phase I trials should 21 be done to people who have the illness on which that 22 drug is going to be used. 530 1 The FDA has taken a different point of 2 view. That until you know the normal, quote 3 "pharmacokinetics in normal people" then you can 4 evaluate whether it's different in sick people. 5 That's not the way it's developed over the 6 years. By and large Phase I studies in adults have 7 gone on to show that they're fine in healthy people, 8 but then they really repeat them in the sick people 9 that really need the drug. So you don't always know 10 that difference. But don't confuse the two. There 11 is a place at some point probably for doing or giving 12 a healthy child a drug that it will need. Because 13 you need, at some point, to figure out what is the 14 proper dose. Then you go on. It's not a placebo. 15 No placebo in there. 16 DR. FLEISCHMAN: And, Sandy, I'm going to 17 ask to hold that because that's precisely what we are 18 going to talk about in about eight minutes, and that 19 is the Phase I trials both in oncologic studies with 20 seriously ill children and then pharmacokinetic 21 studies with children not as seriously ill. 22 DR. CHODOSH: The only reason I brought it 531 1 up now is that Abbey mentioned use of antibiotics -- 2 DR. FLEISCHMAN: No, no, that's very 3 helpful. But what I don't want is to move us now 4 into that -- to maintain your help -- no, to maintain 5 your help of not confusing us, we are going to stay 6 with placebo controlled trials and Bob's definitional 7 and justification comments was very helpful. 8 Any other comments from the committee 9 about placebo controlled trials? 10 [No response.] 11 DR. FLEISCHMAN: Any comments from our 12 liaison or public members about placebo controlled 13 trials? 14 Sandy. 15 DR. CHODOSH: I'll pipe in on placebo 16 controlled trials in that that is that something 17 again has happened by and large in drug development 18 which is a little bit disturbing. And that is the 19 fact that placebo are not always used in mild 20 disease, like in allergic rhinitis say, in which we 21 are showing quotes, "equivalence to drugs that are on 22 the market." You go down the road and after about 15 532 1 such pairings, and new drugs, that you really don't 2 know that that drug that was developed for the 15th 3 time is really any good at all. Because the others 4 really have never been exposed to the true situation 5 of no therapy at all. It happens in antibiotics. 6 There are a lot of situation in which this is 7 occurring. And the FDA allowance of equivalence or 8 accepting equivalent type studies, there are places 9 where placebo really would make a difference, 10 although not in the antibiotics studies, I don't 11 think. 12 DR. FLEISCHMAN: Actually, that's a very, 13 very important comment because one of the members of 14 the workgroup who is a national expert in otitis 15 media antibiotic trials argued that he has been told 16 it's unethical to develop a placebo controlled trial 17 around the treatment of otitis media in children 18 because there is, quote, "known efficacious treatment 19 for otitis media in children." When one unpacks that 20 argument there is very little that was ever done that 21 created the thought that there was no efficacious 22 treatment for otitis media, but is certainly the 533 1 standard of care. 2 Now, when people are beginning to question 3 that and look carefully at that question and want to 4 do placebo controlled trials it becomes very 5 difficult. So, he for one was really quite vocal 6 about the critical importance of placebo controlled 7 trials early on in studies and the problem of 8 efficacy trials as you've pointed them out. 9 Greg. 10 DR. KOSKI: Well, it probably doesn't need 11 to be said, but I will anyway, that in many 12 instances, placebo responses can be so dramatic that 13 in fact they outreached the actual therapeutic 14 responses to medications that are being given. And 15 we see this particularly in trials that may often 16 affect the children population because of the use of 17 pharmacologic agents for treating behavioral, and 18 tensional disorders and so on. 19 So, again, I think we need to be very 20 careful as we pointed out in the discussion of the 21 declaration of Helsinki yesterday, not to simply have 22 a blanket prescription against placebo, but to 534 1 recognize that placebo is a very critical part of the 2 scientific approach to determining whether or not 3 drugs are truly safe and effective and we need to 4 recognize their appropriate use as well as their 5 inappropriate use. 6 DR. FLEISCHMAN: Judith and then Bob. 7 DR. SIEGEL: I was just going to actually 8 bring that up. I mean, when you're looking at risk 9 assessments and you look at the number of patients, 10 for instance, you have to include in the trial that's 11 an equivalency trial versus the number of patients 12 you actually may have to treat in the placebo 13 controlled trial, you will find that the population 14 that you put at risk in the first place is much less 15 in a placebo controlled trial. 16 And, again, speaking to the opposite, if 17 you go with those kinds of definitions that talk 18 about increases of diseases that there will be no 19 increase in, for instance, morbidity and mortality 20 and look at those as the kind of trials that you 21 might want to go in with less patients at first than 22 going right into an equivalency trial, then you start 535 1 to get a much better, I think, look at the relative 2 risks of doing this type of research using placebos 3 particularly. 4 DR. FLEISCHMAN: Bob. 5 DR. R. LEVINE: Now that it appears that 6 we've turned it all around and everybody's speaking 7 in favor of placebos, I want to take a little bit of 8 it back. There were stories in the media a month or 9 so ago about a proposal to conduct a placebo 10 controlled trial of a human surfactant in newborn 11 infants. And the justification for this was that the 12 non-human surfactant preparations had been evaluated 13 in pediatric or neonatal intensive care units ten 14 years ago or more and that the state-of-the-art in 15 running an intensive care unit for neonates had 16 changed dramatically. And so at this point it would 17 be unclear if there was an equivalency or a non- 18 inferiority trial. 19 It would be unclear as to how much of the 20 good effect would be due to the changed condition in 21 the intensive care unit and how much of it would 22 actually be due to the new human peptide C surfactant 536 1 preparation. 2 I think that before our comments could be 3 taken to mean that we would ratify that sort of 4 trial, I would have to say that before we could do 5 that, there would have to be considerable discussion 6 within this group. As to whether or not the change 7 in the state-of-the-art intensive care units would 8 invalidate equivalents or non-inferiority trials, 9 particularly when there is evidence that the old 10 surfactant does seem to prevent very serious adverse 11 consequences in at least some of the children. Thank 12 you. 13 DR. FLEISCHMAN: Adil. 14 DR. SHAMOO: I have a question. When are 15 we going to discuss putting real serious drugs for 16 the first time on healthy children. That's really 17 the issue I want. When is it going to come out. Is 18 it going to come out in Phase I studies, or are you 19 saying your working group have eliminated and we will 20 never do a drug for the first time in healthy 21 children? Isn't that Phase I that's going to come 22 up? 537 1 DR. FLEISCHMAN: I think so. 2 DR. SHAMOO: Okay. I'll wait. 3 DR. FLEISCHMAN: And if it doesn't then 4 we'll have to take it up in addition. 5 DR. SHAMOO: I will wait and the placebo 6 is something that there's a consensus -- no, there is 7 no consensus. At least I for one will say I do not 8 agree with all the type of placebo unless they are 9 under unique or compelling circumstances rather than 10 blanket statement, "no placebo"; that's ludicrous to 11 have any blanket statement, absolute statement. 12 But the way we are using it now, we have 13 opened the door such that I think you could do almost 14 a lot of experiment which were not done -- they were 15 not supposed to have been done with the previous even 16 ranks. They pushed a lot of category four, I call 17 them "category four"; you call them, I think category 18 407. They pushed them to mean 406. IRB pushed them 19 to mean 406 even though they are 407. 20 The fenfluramine experiment, for example, 21 which you are very aware of since you lived in New 22 York City, that was 406 by the way, it was not a 407. 538 1 That was not the category where you have to go all 2 the way to the Secretary in public hearing. They 3 basically camouflaged the direct medical benefit, 4 they camouflaged the risks, and to me personally I 5 don't believe fenfluramine is a low-risk drug to be 6 taken. And that was known 15 years before the 7 experiment. 8 DR. FLEISCHMAN: Abbey. 9 MS. MEYERS: I just want to say that 10 whatever your committee does on this section about 11 placebos, it has to be in concert with the last 12 section that we talked about because there it says 13 that healthy children cannot be experimented -- 14 participate in clinical trials. Here it says that 15 they can and the two sections are very confusing. 16 And, you know, placebos, nobody -- I don't 17 think there's anybody who knows anything about 18 science who is going to say placebos are bad and 19 should be outlawed. Everybody understands the 20 importance of placebos. But I don't think in many 21 cases that some of these trials have been approved 22 with truly ethical standards. And, in fact, in many 539 1 cases if there was another standard therapy, it 2 should have been compared against that. 3 In the case of the surfactant, they should 4 have compared some of the babies with the old 5 surfactant to some of the babies with the new 6 surfactant instead of saying, "let's put some of them 7 on placebo" which means death. 8 So I think a lot of these decisions are 9 being made now even in the context of all the new 10 awareness about bioethics. They're being approved in 11 ways that are unethical. 12 DR. KOSKI: I don't think it would be fair 13 to leave the impression that the surfactant trial in 14 question was ever done. It was not done. 15 DR. FLEISCHMAN: And I think, Abbey, Bob 16 was agreeing with you to say that that surfactant 17 trial, as he described it, ought not have been done 18 and it wasn't. Uh-oh. 19 DR. R. LEVINE: No, I'm sorry. That would 20 presume more knowledge of the trial than I have. 21 What I said is I would not want what we're talking 22 about to be extended to cover something of that sort 540 1 without a lot more further discussion. 2 DR. FLEISCHMAN: Okay. And I don't think 3 the working group had any intention of this paragraph 4 covering that sort of trial. And if we need to be 5 more clear on that, we can be. 6 Susan. 7 MS. KORNETSKY: As a person who sits on an 8 IRB that reviews a lot of randomized placebo trials 9 with children, one of the things that I think IRBs 10 practically struggle with is, which is alluded to in 11 here, and I'm interested in people's opinions not 12 necessarily from the working group is the discussion 13 here that in the placebo arm might receive the 14 potential for direct benefits. I think a lot of IRBs 15 struggle with that and whether there is a potential 16 for direct benefit. 17 What's written here which is frequently 18 used as justification is that they might be able to 19 -- they might be randomized into the ARM, or they 20 might be able to receive it as a crossover at the end 21 of the trial which isn't necessarily always true. 22 And we've come up against that because many times 541 1 that is used as a justification. 2 So, I guess, you know, I have my own views 3 about this which I'll -- you know, but I guess that's 4 where I feel IRBs sometimes really struggle is in a 5 placebo arm, can you make the justification that 6 there might be a potential for direct benefit. 7 DR. FLEISCHMAN: I think it will be very 8 helpful for the committee as well as others to give 9 comments to the working group very specifically about 10 this issue and as Susan is describing it, and as Bob 11 has described it, the justification for what most 12 people think in some circumstances is appropriate and 13 permissible research. 14 Did I have Mark's hand up or not? No. 15 Sandy? And then we're going to on to our 16 fourth -- after Elliot we're going to go on to our 17 fourth item. 18 DR. CHODOSH: What I heard from Adil sort 19 of bothered me. And that is that he has now presumed 20 that this group has come out saying that placebo 21 studies are fine everywhere and that is not the case. 22 That nothing that I said should presume that and I 542 1 would hesitate to have that be passed on as if that 2 were what the committee -- 3 DR. SHAMOO: I did not -- 4 DR. CHODOSH: You did say that. 5 DR. SHAMOO: No, I said, Bob. 6 [Laughter.] 7 DR. FLEISCHMAN: I think what I took as 8 Adil's comment was that we have some work to do in 9 justifying, clarifying in this area and I think that 10 the workgroup is quite comfortable in receiving that 11 input. 12 Elliot. 13 DR. DORFF: Susan, what would happen if 14 the rationale that you just described for placebo 15 studies were actually written into the conditions of 16 the study? In other words, that it wasn't just that 17 people approved such studies on the hope that other 18 could be crossover use of it or something on that 19 order, but that that it would actually be written 20 into it. I don't know enough about this stuff to 21 know what would happen. 22 DR. FLEISCHMAN: Susan. 543 1 MS. KORNETSKY: Well, I think, I mean, in 2 a very practical sense we really sort of struggle 3 with this issue of potential for benefit in the 4 placebo arm where, you know, in adult studies you 5 don't -- obviously you need to review the protocol, 6 but you're not -- you don't have to categorize 7 different things. So, I mean, I really think that's 8 the crux of the matter here and we've done some 9 talking around it, but that's the thing. 10 I mean, we try and write those things in. 11 You know, we've often asked for availability of drug 12 at the end of the trial. We've asked for questions, 13 can this be done as a crossover, and sometimes its 14 just not possible. And so you're really stuck with a 15 group of children with a condition or disorder, I'm 16 not talking about normal children, who you know are 17 not -- you know, have a 50 or, you know, however it's 18 stratified, you know, percent and is that 19 appropriate. 20 DR. FLEISCHMAN: Elliot, I have sat on two 21 IRBs that have demanded it be written into trials or 22 not allowed such studies to go forward. So IRBs have 544 1 the authority to do what you're suggesting. 2 Sometimes it's complex because they're hopeful and 3 the pharmaceutical company will not agree and yet the 4 investigators and the families even want such a 5 trial. So it becomes a difficult issue for the IRB, 6 but it is possible to reject such a study unless it 7 is designed in ways that are ethically acceptable. 8 MS. KORNETSKY: We have rejected them and 9 we've required changes and I think we've, you know, 10 done different things. And you have to take a lot of 11 other things -- I don't think you can sort of say 12 standardly what you should or shouldn't do. You have 13 to take everything into context. 14 DR. DORFF: Right. But it seems clear to 15 me from this conversation that if you could indeed 16 insist on that, then people would feel much better 17 about placebo studies, ethically, because then you 18 would be able to say that if the drug does indeed 19 prove to be effective that the people who were not 20 given the drug would then get it retroactively, or at 21 least to the extent that it could be. 22 Now, if I've got this completely wrong, 545 1 which I think I have -- the faces that I'm seeing -- 2 then fine, then tell me. But the point is that if 3 that is true, then even if we couldn't demand it as a 4 standard, then we could say that IRBs ought to aim 5 toward that. 6 DR. FLEISCHMAN: Greg. 7 DR. KOSKI: Well, it's important to 8 recognize that when you're developing a new drug, 9 there's potential benefits and there's potential 10 risks. So requiring that a child be given the 11 opportunity to be exposed to the potential risk is 12 something that you might want to think twice about 13 because it's a double-edged sword. 14 The likelihood that any given drug is 15 going to be shown to be safe and effective in one 16 trial is essentially zero. Now, it happens, perhaps, 17 in some rare occasions that a drug will be that 18 dramatic. But, in fact, we need to be very careful 19 about it. So the -- you know, the thoughtful 20 exercise of reasoned judgment in each of these cases 21 is something that you really have to strive for and 22 it's very hard to achieve that through a blanket 546 1 statement that you have to require the active drug 2 afterwards. It's complicated. 3 DR. FLEISCHMAN: I have on the list, Bob, 4 Judith, Adil and Susan. 5 DR. R. LEVINE: I think the most recent 6 discussion underscores the reasons for my 7 recommendation that justification of placebo be 8 evaluated in terms of whether withholding known 9 partially affected therapy could result in a serious 10 adverse consequence. If it could, then a crossover 11 design doesn't help you. It just means that you're 12 exposed to the possibility of a serious adverse 13 consequences for half of your time in the trial. But 14 everybody then gets exposed to that possibility. 15 And giving the drug after the trial is 16 over is a good idea, but it still doesn't mitigate 17 the problem of placebo controls. If there's going to 18 be an exposure to a possibility of a serious adverse 19 consequence, then you've got a big problem with 20 ethical justification. Depending on how serious the 21 consequence is, it might rise way above the threshold 22 of a minor increase above minimal risk. 547 1 DR. FLEISCHMAN: Judith. 2 DR. SIEGEL: I wanted to comment on the 3 question of, is there any benefit or potential 4 benefit in a placebo controlled trial. There is 5 quite a large literature on placebo controls and the 6 whole issue of placebo effects. 7 And I think the question is, can you say 8 that the effect you get on drug X for instance, and 9 if you get the same percent response, let's say, on 10 placebo as you get on drug X, does that qualify as a 11 therapeutic response. And, again, in many trials the 12 way you evaluate it, placebo and your drug look 13 exactly the same. 14 Now, can say that there is no effect of 15 the drug. Or, is a 30 percent or a 40 percent, or a 16 50 percent placebo response which is also not 17 uncommon in certain areas, equal to the effect -- 18 some effect. 19 Now, clearly if you have a 50 percent 20 placebo response rate, you are looking for a drug 21 that can actually do much better, but can you say in 22 those trials that there has been no benefit. And I 548 1 would suggest that possibly during the deliberations 2 of this a review of placebo response that you can 3 find in the literature might be helpful. 4 DR. FLEISCHMAN: Thank you. Adil. 5 DR. SHAMOO: [Off mic.] I think there is 6 a great deal of placebo design that is done because 7 it's cheap and fast. And we are all not talking 8 about that. But that's really the reason because you 9 can get statistical data faster and cheaper in a 10 smaller number of patients, et cetera, et cetera. I 11 don't want to go there. 12 Let's go over this following scenario. 13 You have children who have an illness and you put 100 14 of them on placebo for one year and 100 on the new 15 drug. But it is a slow progressive disease, but you 16 don't know that, and let me give you the outcome, for 17 example. That after the one year, and I will even 18 take Elliot Dorff's example, you are so kind that you 19 gave the medicine to those children whom they were on 20 placebo after one year. You find out that after you 21 give them the drug they never reach at all the same 22 therapeutic outcome as those who were on drug 549 1 therapy. 2 My question to you is, how would you 3 handle a scenario like that in your placebo? And 4 that's not farfetched. 5 DR. FLEISCHMAN: No, no, this is 6 absolutely critically important to children what 7 you're saying. If you'll drop your microphone for a 8 moment. 9 We have to suggest that those 200 children 10 have a disease for which there is no known 11 efficacious treatment. A placebo controlled trial 12 has now determined, over the course of a year, that 13 there is efficacious treatment to slow down this 14 progressive disorder. The 100 children who have been 15 randomized into the non-active substance group now 16 given the substance have not had the benefit of the 17 earlier treatment, but we didn't know that it was 18 effective. 19 So we now know it's effective, so all 20 future children, theoretically, could now be given 21 such a treatment and these children who were in the 22 placebo arm have benefitted all of the children with 550 1 this disorder now and forever and they've also maybe 2 slowed down their process, but not as dramatically as 3 it would have been if they got into the active arm. 4 But the key here from the ethical analysis 5 of whether a placebo controlled trial was appropriate 6 is that we had no knowledge of what we now have 7 knowledge about a year later. 8 DR. SHAMOO: But you are assuming that 9 there was zero current existing efficacious medicine. 10 Let's assume the slowing down of the illness, there 11 was medicine which is not as good, 20 percent or 30 12 percent. 13 DR. FLEISCHMAN: Well, that then changes 14 the IRB assessment as to whether a placebo controlled 15 trial is appropriate. 16 Bob I think helped us -- 17 DR. SHAMOO: No placebo control is that 18 what you're telling me? There will be no placebo 19 control. 20 DR. FLEISCHMAN: Well, you know, the devil 21 is in the details, Adil. Bob explained, I think, 22 very nicely that justification has to do with the 551 1 ability to withhold or withdraw a treatment without a 2 serious negative consequence. That allows then, 3 based on knowing the natural history of the disorder, 4 knowing the disease, it allows an IRB to assess in 5 what circumstances a placebo controlled trial might 6 be appropriate and conversely in what circumstances 7 it would not be appropriate. But that's often going 8 to be a judgment call based in assessing those facts. 9 Now, that's why you and I both agree we 10 need review of IRBs and accountability so we can look 11 at how they're making those judgment calls over time. 12 And we need methods for assessing that, not in a 13 punitive manner, but in an important prospective 14 educational manner. But that's separate from the 15 issue of what is an ethically defensible placebo 16 controlled trial. 17 Greg. 18 DR. KOSKI: There's an article that was 19 written by Bob Temple and Susan Ellenberg that is, I 20 believe in JAMA. I don't know the exact reference. 21 Where is it? Oh, that's right. In the Anals of 22 Journal Medicine. That is well worth reading for 552 1 people who want to learn everything about placebo 2 controlled trials. 3 But, Elliot, you mentioned that placebo 4 controlled trials are, you know, faster and cheaper. 5 There may often be some truth to that. That's not 6 necessarily bad. In fact, the demonstrating quickly 7 that a drug is, you know, clearly scientifically 8 better than an existing therapy or that actually is 9 safe and effective is part of the strategy for 10 effectively minimizing risks to the numbers of 11 participants. And we could, perhaps, leave ourselves 12 in a position of subjecting individuals to, you know, 13 years of no treatment through the lack of development 14 of an effective drug. 15 And, again, I'm saying this not to 16 abdicate, you know, for, you know, doing unethical 17 research in any population, but to again point out 18 that we need to be very careful about how we consider 19 the role of placebo and not jump to conclusions that 20 would take us down a path that we wouldn't want to 21 get to. Because clearly we want to make sure that we 22 can reap the benefits of research appropriately. 553 1 And, as I keep saying, do it in such a way that we'll 2 be proud of the result that we get in the end. So 3 it's a difficult problem. 4 DR. FLEISCHMAN: Okay. Let me just tell 5 you where we're at in terms of the time and the 6 process. For those of you who came as guests this 7 morning, the children's discussion is going to 8 continue for a short time after lunch. And I 9 apologize if that's a problem for you. Because we 10 didn't want you to have that problem, but it has had, 11 I think, a very fruitful discussion. We have a part 12 that our chairperson has allowed us to put over until 13 after lunch. 14 So what I'm going to ask is, Elliot and 15 Sandy to make their comments and then we're going to 16 adjourn for lunch and return at an appropriate time 17 that Mary Faith is going to tell us about. 18 Let's have the two comments and then we'll 19 give the microphone to Mary Faith. 20 DR. DORFF: It just strikes me that this 21 particular piece of your report, Alan, is it seems to 22 me applicable to adults as well. I mean, except for 554 1 the issue of, you know, talking about assent and 2 concent and that kind of stuff which is a separate 3 issue. The issue of placebo studies and the kind of 4 criterion that Bob is suggesting, I think would be 5 true for adults as well. 6 DR. FLEISCHMAN: I think the 7 justifications of placebo controlled trials, the same 8 justifications hold. And I agree with you. But 9 because of the surrogate decisionmaking process, we 10 tend to allow adults to consider these issues more 11 carefully or themselves and make autonomous choices. 12 So it's an even more complex issue in the child area. 13 If we can get through it in the child area, then the 14 adult people, as is usually the case, will benefit 15 greatly from the children learning about these 16 things. 17 Sandy. 18 DR. CHODOSH: I have to go back to the 19 example that Adil mentioned and that is where there 20 is no other therapy that's been known, and therefore, 21 they go in a placebo. And you did not consider the 22 other possibility, that is, that the drug causes 555 1 harm. And that you would find this out very quickly 2 and that you would not expose additional people to 3 this drug and it would stop that research. And 4 believe me, there are many drugs like that out there 5 that you never hear about that you need to find that 6 out. And if you don't find that out, you could go on 7 forever giving toxic drugs to people. 8 DR. SHAMOO: Quick answer to Sandy. And 9 that is, we haven't talked, Alan, at all at what 10 stage of drug development are we going to use 11 children. We haven't talked about whether there is 12 -- what extent of animal study, what extent of adult 13 study, before we start injecting them into children. 14 We haven't talked about that. 15 DR. FLEISCHMAN: Actually, the workgroup 16 in its preliminary comments does make the comment, 17 and I agree with you, I haven't said that here. The 18 workgroup makes the comment of the obligation to look 19 at medications and other interventions in animals and 20 adults when appropriate before children. 21 Of course, there are children-specific 22 diseases like prematurity that requires interventions 556 1 with drugs without adult trials like the surfactant 2 trials. But, indeed, the workgroup agrees with that. 3 It has been the practice, it is the general approach 4 and we should make that clear. 5 I'm going to now ask Mary Faith to direct 6 us. 7 CHAIRPERSON MARSHALL: What we would like 8 to do is adjourn for lunch now and ask that we 9 readjourn early, at 1:00 -- reconvene, thank you. 10 Rita Colwell has had a delay because of 11 her flight this morning. But she is going to join us 12 after we reconvene at 1:00. So I realize we've taken 13 some of your lunchtime, but we've had a fruitful 14 discussion and we want to continue to do that. 15 I would just like to make the observation 16 that this particular discussion about placebo and 17 assessing risk and benefit really does beg the 18 question of ongoing monitoring as a procedural 19 safeguard during the trial which is something that we 20 have spoken to as well. And I think that this really 21 does show the need for that. 22 So we will see you back here at 1:00. 557 1 [Whereupon, at 12:05 p.m., the meeting was 2 recessed to be reconvened this same day at 1:00 p.m.] 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 558 1 A F T E R N O O N S E S S I O N 2 [Time noted: 1:15 p.m.] 3 CHAIRPERSON MARSHALL: Shall we begin? 4 I know that we will have folks wandering 5 in and we have been on a tight schedule, but I want 6 to make sure that we have all the time that we need 7 for our ongoing discussion of children, and our 8 discussion this afternoon about social and behavioral 9 sciences, and also to take care of some housekeeping 10 issues, and to recap what we've done over the course 11 of the past two days, and to get you all home on 12 time. 13 Dr. Rita Colwell, who is the director of 14 the National Science Foundation is with us this 15 afternoon. We are delighted and honored to have you 16 to speak to us about the National Science Foundation 17 and research ethics. And perhaps she may have a 18 moment or two to have a conversation with us, if 19 there are people who have questions. 20 DR. COLWELL: Thank you very much, Mary 21 Faith and also Greg. I appreciate the opportunity to 22 be here and apologize for being late. But flying out 559 1 of Boston is not always easy. 2 [Laughter.] 3 DR. COLWELL: I thought I would get some 4 good response on that. I must say it was a lot 5 easier than the flight back for LaGuardia two weeks 6 ago when we emergency landed in Newark. I don't 7 recommend that. Newark is not exactly a tourist 8 place, especially in an emergency. 9 I am delighted to be here today to talk to 10 you about a really very important subject that you've 11 been focused on, and that is, human research 12 protections. 13 Let me begin by saying how much we value 14 our work at NSF with you in NHRPAC. Because 15 providing safe and ethical and equitable treatment to 16 human participants in research is -- well, it's an 17 undertaking of the very highest of importance. At 18 the National Science Foundation we put it at the very 19 top of our priority list. 20 Now, there is no question that the work of 21 this Committee is vital. I don't have to tell you 22 that, you know that. And it's also evidenced by the 560 1 very good public interest as well. 2 Those who participate in our research 3 deserve our highest respect. They are the unsung 4 heroes of the nation's research enterprise. We 5 simply couldn't do our work without them and when we 6 think back 50 or 75 years ago, the situations that 7 involved human subjects, we realize we've come a long 8 way, but we still have a way to go. 9 Taking the human subjects seriously as 10 partners, exercising vigilance over their treatment 11 are absolutely necessary if we are going to sustain 12 the public's trust in this enterprise. 13 I would like to add that Greg Koski's 14 office has been extremely helpful in this process of 15 clinical assessment and we appreciate that, Greg. 16 We've been able to share our perspectives 17 of these issues with Greg and his staff and I know 18 that we'll continue to do that in future. I think it 19 will be useful to talk to you today about the 20 National Science Foundation and the ways in which 21 people involved in our research enter into our 22 activities. 561 1 First let me begin with a few words about 2 my own research experience. I'm a microbiologist by 3 training. I evolved into becoming a molecular 4 biologist. For many years my research has focused on 5 cholera. It's largely controlled in the United 6 States, but it's a devastating presence in the rest 7 of the world. It's endemic in Bangladesh, for 8 example, where I've done most of my research over the 9 last 25 years. As my colleagues and I have 10 researched this disease, cholera, over the years, we 11 have had occasion to involve people in our research, 12 and in fact, we have a study underway right now with 13 about 52,000 people in 50 villages. 14 We've worked with human volunteers in our 15 study carried out at the University of Maryland 16 Medical School with the Center for Vaccine 17 Development. And that's an example of the kind of 18 clinical research, field research and clinical 19 research involving human subjects. But it's the 20 clinical research that usually comes to mind when we 21 consider safeguards for those involved in our 22 research. 562 1 It's usually the focus of our discussions 2 about human research protection and many of the 3 mechanisms that are in place to protect humans in 4 research take their cue for this particular model, 5 the clinical model. 6 Now, our cholera research has involved a 7 number of epidemiological studies which is another 8 quite different instance of research involving human 9 beings. In this case, we ask people to share 10 information about their health, their personnel 11 characteristics to help us understand the 12 distribution of disease in order to prevent and 13 control it. 14 Now, we have outreach workers who are part 15 of sort of an extension team working in the villages. 16 Our concerns in this kind of study focus on keeping 17 that information confidential and protecting the 18 individual's privacy. And making sure the 19 individuals are participating voluntarily and 20 understand what the experiments are about. 21 Now, my third and final example requires a 22 bit of background, if you will bear with me. 563 1 Filtration and chlorination of drinking 2 water is the best method for controlling cholera; no 3 question about it. We had cholera in Washington, 4 D.C., New York, Philadelphia, and Boston at the turn 5 of the century. In fact, not only cholera, but 6 yellow fever and a few other things. Washington was 7 called a miasmic swamp in those days. We might still 8 call it a miasmic swamp. 9 [Laughter.] 10 DR. COLWELL: For different reasons. 11 Filtration and chlorination of drinking 12 water is just not yet possible on a massive scale for 13 the Bangladeshi population. If any of you have 14 visited there, you will understand exactly what I'm 15 saying. And so we chose to test whether a simple 16 filtration, through inexpensive surrey cloth folded 17 four to eight times would alleviate the problem. We 18 found that it removed 99 percent of the cholera 19 vibrios from the water because they are associated 20 with zooplankton and they attach to the surfaces that 21 are in the gut, zooplankton, and they also attach in 22 a particular manner particularly to the remnants of 564 1 ecdyses as the zooplankton metamorphose. 2 That led to a sociological study to see if 3 this would be culturally acceptable. Indeed, it is. 4 We were told that the men would not drink water that 5 had been passed through the unclean cloth worn by 6 women. Well, it turned out to be nonsense. We had 7 been using it to strain yogurt anyway before they 8 drank it. So it was culturally acceptable. But it 9 involved a proper study with sociologists, 10 professionals, and our private team. 11 So now we are in the process of 12 determining whether with this very simple technology 13 we can reduce the incidence of cholera. And so we 14 ask people in these villages to provide us with 15 information about their social, their cultural lives, 16 or to let us observe them as they go about their 17 daily activities collecting the water, bringing it to 18 the household, feeding the children, washing 19 vegetables and so forth. That's another way in which 20 we engage humans in our research. 21 Well, I've taken you on this brief journey 22 and I don't think it's unfamiliar to you. But it 565 1 illustrates an important and sometimes neglected 2 truth. Scientific research involves and engages 3 human participants in many different ways and on many 4 different levels. 5 The studies differ substantially in the 6 risks they pose to individuals. Some may pose very 7 little risk in the case of surrey cloth there's very 8 little risk in using it; we hope to prove that there 9 will be a lot of risk in not using it. But it 10 requires extra vigilance to ensure confidentiality 11 and privacy because the kind of records we keep in 12 Matlab if any of you are familiar with that, studied 13 the village that has been in operation for, I think, 14 40 years and the data are extraordinary; everything 15 from illnesses, onset of puberty, onset of menses, 16 numbers of children, illnesses and the degree of 17 illness and so forth. 18 These kinds of -- this kind of information 19 may have consequences for the social and cultural 20 lives of communities and they raise broader concerns 21 about the source of consent or whether our research 22 may alter what we've set out to understand. Just as 566 1 an example, we have to be very careful to have a 2 buffer between villages because there is exchange of 3 information and obviously if the filter works very 4 dramatically others will use it and the experimental 5 results get confounded. 6 But there's also the very difficult 7 decision that if it becomes dramatically successful, 8 when do you stop the study and begin to implement it 9 for everybody? 10 So it's not news that human arrangements 11 are complex. It isn't surprising that accommodating 12 them in our research, while maintaining our 13 responsibility to those who participate, is a huge 14 task. It's going to require all the creativity and 15 subtly that we can muster and I'm absolutely 16 certainly that this forum is up to the task. 17 There are some other considerations that 18 make our work on these issues timely. The research 19 enterprise itself is changing. We have to be 20 flexible and agile so that we can adapt to these 21 changes. Let me explain what I mean by this. 22 Today advances in science and technology 567 1 are occurring at an unprecedented pace. We find it 2 natural to talk about revolutions in genetics, 3 information technology, nanoscale science, 4 engineering, the knowledge base has simply exploded. 5 In a matter of a year, we now know more about us 6 genetically in terms of our sequence than we've ever 7 known in history. The pace of science and technology 8 has accelerated. Although I find it astonishing, 9 it's true, 50 percent of all scientists that have 10 ever lived are living today. Kind of hard to think 11 that as being true, but it is. 12 There is simply more research underway 13 today than ever before in history. The sheer volume 14 of our activities as scientists is putting a strain 15 on our current systems for ensuring adequate human 16 research protection. There are other changes that 17 are increasing the strain. Research is becoming more 18 collaborative, multidisciplinary, in fact it's almost 19 mandatory that you involve many disciplines, 20 especially in health research. 21 And we bring together researchers from 22 many institutions and discipline. There are cross 568 1 sectors. For example, in Bangladesh we have cultural 2 differences that we have to respect. 3 We now have virtual research teams and 4 partnerships that span academia, industry, local 5 governments, state governments, provincial 6 governments. And research is increasingly 7 international in scope with different modes and 8 attitudes on different continents towards the kind of 9 research that we do. 10 We have the ability to call in the best 11 talent worldwide and more and more of the phenomena 12 we study are global in character. For example, in 13 our studies in Bangladesh we have been able to 14 correlate the epidemics rather neatly with sea 15 surface temperature and sea surface height. And this 16 gives us a prediction. So we are involved in 17 satellites in several countries, India, Bangladesh, 18 China. 19 It's not surprising then that we face a 20 host of new challenges in protecting the people 21 engaged with us in our research and we've come a long 22 way from the lone principal investigator like Dr. 569 1 Hansen in Norway working on a disease that he studied 2 so carefully. You know, the single investigator with 3 straightforward protocol, homogenous group of 4 subjects. We are more likely now to encounter 5 cultural, linguistic, legal, policy considerations, 6 cultural considerations when we just begin to draft 7 up plan of action for a research program in almost 8 any field of study. 9 At the National Science Foundation this 10 changing research scene is fast becoming the norm 11 rather than the exception. Our mission is to 12 maintain the health and vitality of fundamental 13 research across all the disciplines in science and 14 engineering and in education at all levels. 15 And in that process we support the 16 disciplines in their constant struggle to reach the 17 -- frontier while maintaining their fundamental 18 capability. Although we support much of the 19 fundamental research that underpins advances in 20 medicine, the NSF does not support medical research. 21 We fund everything else except clinical and medical 22 research. 570 1 And that means much of the research we 2 support does not fit the traditional clinical model. 3 In fact, much of the research that we support doesn't 4 involve humans in any way. That's true, for example, 5 of research on sunspots, and formation of black 6 holes, or fundamental mathematics. But to end my 7 description on that note would leave you with a very 8 incomplete perspective on NSF because we do support a 9 wide range of fundamental research that does involve 10 human participants. 11 Now, before I describe that research, let 12 me just put the NSF activities in a larger context. 13 NSF accounts for about 4 percent of federal research 14 and the development that goes with it. But that 4 15 percent supports about 50 percent of the non-medical 16 fundamental research at colleges and universities. 17 So it is very significant. 18 And there are very important areas of 19 fundamental research directed toward understanding 20 human beings in all their complexity. That 21 percentage is even higher because the education, 22 social, behavioral, psychology, sociology studies, 571 1 anthropology, archeology. Every year NSF supports 2 almost 200, 000 people, individuals. That doesn't 3 count the people who see the IMAX films or the kids 4 who watch the Magic School Bus. We are talking about 5 individuals. And these are scientists, engineers, 6 teachers, students. And you can see, we have a very 7 large stake in maintaining high standards and finding 8 effective ways to ensure adequate safeguards as we 9 move our research agenda forward. 10 There is no question but that a top 11 priority for the research community, for society, and 12 above all for the individuals who are involved in our 13 research are these issues you're discussing. 14 Okay. Now, let me give you a sampling of 15 some of the SNF-supported research that does involve 16 human participation. We have a very large portfolio 17 in the economic, social, psychological, behavioral, 18 and cognitive sciences. The ways we go about 19 studying humans range framework MIIs -- to careful 20 observation of infants to simple anonymous surveys, 21 full range. Many of the questions these 22 investigations address are fundamental to our future 572 1 prosperity and quality of life in this nation. Among 2 them are studies of how infants and children learn, 3 how individuals like us make decisions, how we assess 4 risks. 5 Other research is unravelling the 6 processes that support innovation, creativity, our 7 capacity to adapt to change. In fact, we'll be 8 launching a major study on change and its effect 9 socially, behaviorally. 10 In brief, these studies aim to understand 11 humans, us, in all of our complexity and diversity. 12 Now, so too does the research in groups, communities 13 and populations. Understanding how we organize 14 ourselves, how we behave in groups, how we misbehave 15 in groups, too, I might add. 16 [Laughter.] 17 DR. COLWELL: How we build institutions 18 and how we respond to those institutions and how 19 cultures and societies come into being and how they 20 evolve. These questions cover an entire spectrum of 21 very, very important human activity from industry to 22 politics to culture to law. 573 1 There is such rich territory to be 2 explored here that it brings to mind one of my 3 favorite quotes. It's from the 18th Century poet, 4 Alexander Pope. "The proper study of mankind is 5 man." Except today I'd say, "humankind." 6 Well, I could go on. There are many, many 7 examples, but I wanted to end my comments with two 8 examples that might be less familiar to you. And 9 each in its own illustrates how people entering into 10 our research in new ways and how seriously NSF takes 11 the issue of protecting their interests. 12 Now, the first is from information 13 technology and the networking that's associated with 14 IT. Few of us welcome have predicted the speed with 15 which these technologies have become pervasive 16 influences in our lives. Just think about it, bar 17 codes in the supermarkets which we all take for 18 granted, nearly a decade ago we were fighting about 19 whether we really wanted that infringement on our 20 privacy. Well, here it is. 21 There's no doubt that we need to 22 understand the human and social dimensions of these 574 1 changes. And so NSF is sponsoring research on the 2 effects of IT in the Internet on human learning and 3 other aspects of human psychology. And we're 4 supporting research on the human computer interface 5 with these wide-ranging potentials to provide 6 universal access, including the development of new 7 communication resource for people with disabilities. 8 If some of the things that we have underway come to 9 fruition, we will quite possibly see Christopher 10 Reeve walk. It's not out of the question. So the 11 shunts for the brain to pass the lesion in the spinal 12 cord. 13 These studies involve a reciprocal 14 relationship between humans and technology. Computer 15 scientists learn from the cognitive sciences, 16 linguistics, neurobiology and vice versa. They learn 17 from the IT as well. These technologies are rooted 18 in math, physics, engineering, computer science. But 19 the research agenda is increasingly turning toward 20 humans. 21 In the future as the pace of technological 22 change accelerates, we're going to see these studies 575 1 integrated into research programs from the very 2 beginning. We will need innovative and very flexible 3 models that allow us to address the new developments 4 in the context of human research protections. 5 Now, the common rule, familiar touchstone, 6 has always provided us with the flexibility to allow 7 us to accommodate the dramatic changes that have 8 swept through science and engineering. But it has 9 also kept us attentive to the interests of research 10 participants. So it's important as we consider the 11 need for change and the approach that we take to very 12 high-risk studies, that we maintain the flexibility 13 for research that is not high-risk. Flexibility for 14 research that is not high-risk. 15 Now, I suspect that in your discussions 16 yesterday with Francis Collins when you talked with 17 him, that we're a step in this direction. In a 18 similar vein at NSF we're beginning to anticipate the 19 impacts of nanotechnology and the ethics of its use. 20 It's really astounding some of the things that will 21 be happening with motors that are the size of maybe 22 two or three or four red blood cells stacked one on 576 1 top of another. It's really, really amazing. We 2 recently held a workshop to discuss these issues. 3 So let me conclude with another example 4 that takes us even further away from the traditional 5 models of work with human participants. In some 6 cases we need to map new terrain, not only in 7 designing our research, but also in establishing 8 nurturing relationships and collaborations with those 9 with whom we wish to study. Now, what's the example? 10 All of the NSF-supported research in the 11 Arctic adheres to broad guidelines. It's agreed 12 through interagency process, in fact, I go from here 13 to the Arctic Commission on which I serve. Now these 14 guidelines establish the ethical responsibilities of 15 researchers toward the people of the north, their 16 cultures, their environment. The guidelines are 17 called the principals for the conduct of research in 18 the Arctic. They're intended to promote neutral 19 respect and communication between the scientists and 20 the northern residents. In one of the NSF's arctic 21 projects, a team of UPIC elders traveled to a museum 22 in Berlin to work with the astonishing, undocumented 577 1 collection of UPIC cultural artifacts. They were 2 brought from Alaska to German in the late 1880s. 3 Three of the elders spoke only UPIC. Two 4 were in their 80s and the other others were in their 5 70s. They worked with over 6,000 objects describing 6 their significance, their use, their providence. And 7 we captured their research in photographs and on 8 videotape. 9 Now, Ann Feenin Reedin [ph], the cultural 10 anthropologist, who worked with the elders called 11 this field work turned on its head. Because the NSF 12 grant didn't fund her work but went directly to the 13 Association of Village Council Presidents in Alaska. 14 And the group of UPIC leaders identified their own 15 research objectives and they chose their own 16 researchers, their elders to conduct the study. 17 The elders were at once, at the same time, 18 the researchers and the subject of research. In this 19 case they weren't even interested in the return of 20 the artifacts which you might suspect would be the 21 end of a story. Instead, they just wanted to 22 document and preserve the aspects of their culture to 578 1 enlighten and empower their descendants. A perfectly 2 human desire. And the research was immeasurably 3 enriched by their participation at every stage of 4 this research project. 5 I know we can learn from these examples. 6 They teach us that embracing our unsung heros and 7 respecting their interests is the only way to 8 approach our research. And so with these thoughts 9 that I've shared with you, I'm grateful to have had a 10 chance to talk with you. Thank you. 11 [Applause.] 12 CHAIRPERSON MARSHALL: Rita, thank you 13 very much -- Dr. Colwell. You've enriched our 14 thinking. I was looking at the faces of the 15 committee members and our liaisons and the public 16 members as you were speaking and I think they were 17 just rapt with attention to the stories that you were 18 telling. 19 Let me ask whether anyone has questions of 20 Dr. Colwell. I would like to say to you, Dr. 21 Colwell, that we, as a committee, enjoy the fruitful 22 interaction with Phil Rubin and with Jack Mitchell 579 1 who are ad hoc -- or liaisons with the NIH. We 2 certainly had some -- in the last two days, I think, 3 some good conversations back and forth. And we also 4 want you to know that we as a committee are here to 5 serve you in any way that we can and certainly as new 6 research paradigms evolve, we would like to be a part 7 of that and to help inform the research ethics of 8 those new paradigms. So we are at your service, we 9 would like for you to know that. 10 Let me open the floor and ask whether any 11 of our committee members and our ex officio members 12 or our public members would have questions of Dr. 13 Colwell. Adil. 14 DR. SHAMOO: [Off mic.] Dr. Colwell -- 15 colleague of your at the University of Maryland, 16 School of Medicine. We have met a few times. 17 DR. COLWELL: Yes. 18 DR. SHAMOO: My question to you is, as you 19 know, the human -- protection of responsible conduct 20 research and by the time we train scientists in other 21 requirements for responsible conduct in human 22 research it's really too late. they get that -- they 580 1 should get that training in high school, even middle 2 school, and certainly in college. NSF plays a major 3 role in educating especially in college campuses all 4 across the country. How can NSF help us by preparing 5 some of that preliminary training in responsible -- 6 research inculcated in those -- 7 DR. COLWELL: Again, there are many ways. 8 We do have a group at NSF, Phil Rubin's group -- by 9 the way, I brag about NSF. It's an extraordinary 10 agency with extraordinary people and you've met a 11 couple of them. 12 Rachelle Hollander is someone who is 13 highly respected, one of our NSF people and her group 14 is involved in funding research. And we have an 15 education and human resources directorate with 16 educating K-12. In fact, the president has in the 17 current budget designated the NSF as the lead agency 18 for science and math education which we take very 19 seriously and very responsibly and welcome. 20 A president of the Sigma Xi some years 21 ago, we produced a booklet, ethical conduct in 22 research and we distributed that very, very widely. 581 1 That has been very useful because it has been 2 included in curricula. The Academy -- the National 3 Academy of Sciences has also produced documents, and 4 I'm sure you know all of this. But I think it's very 5 important to make these documents available to 6 provide them to schools and to include them in 7 science teaching. So I think you have a very valid 8 point. 9 In fact, we really ought to include them 10 in some ways in the first four years, because we have 11 discovered that that's when kids are really 12 scientists and then that valley of death between 13 grades 4 and 8 which we've got to work on to keep 14 them as scientists. So a very early education is 15 important. 16 CHAIRPERSON MARSHALL: Others who might 17 have questions or comments that they would like to 18 make? Yes, Elliot. 19 DR. DORFF: In our December meeting Felice 20 actually made a report about -- based upon the study 21 of the American or the documented American 22 Association of University Professors about how the 582 1 common rule did and did not apply well to non- 2 scientific research using human subject. I mean, 3 that is non-medical research. Right. 4 [Laughter.] 5 DR. DORFF: Yes, that's right. That's 6 right. I'm sorry. That's a very bad error. Right. 7 8 [Laughter.] 9 DR. DORFF: I'm sorry. I'm a philosopher, 10 what do you want? 11 [Laughter.] 12 DR. DORFF: But I was wondering, to what 13 extent does NSF have varying rules about human 14 subjects, you know, protection of human subjects 15 given the various -- I mean, because you're talking 16 about things from -- medical things like cholera to 17 anthropological research in Alaska, to -- I mean, 18 clearly, as you said, you're from one end of the 19 spectrum to the other, from a questionnaire to an 20 MRI. 21 DR. COLWELL: Right. We don't really have 22 varying rules. In fact, I'd turn to Phil because 583 1 it's my understanding that it's pretty much across 2 the board. 3 DR. RUBIN: [Off mic.] It's pretty much 4 across the board the policy usually the guidelines 5 that they set down -- not signatories -- Subpart D -- 6 there are a couple of -- that I could go over in 7 detail, but in general we follow the guidelines here, 8 while we're here and while we're working with this 9 group -- in my IRB chair -- 10 The point of the enterprise is to work 11 with this group on one other thing and follow up on 12 an earlier question in training and in new programs 13 -- [Off mic.] built into -- 14 AUDIENCE PARTICIPANT: Use the microphone 15 so we can record you. 16 DR. RUBIN: We basically go by the 17 standard guidelines that we would do under NIH grants 18 with the exception that we try to emphasize that for 19 many of our enterprises, not all, where things are 20 low risk. And in some of the research, like usually 21 human computer interface, interface psychology 22 experiment, you're seeing words on the screen and 584 1 hitting a button. We want to make sure that the 2 valuable resources that are needed to protect 3 subjects are put on the high risk enterprises. 4 CHAIRPERSON MARSHALL: I think I've got 5 Bob and then Abbey. 6 DR. COLWELL: And then I have to bolt. 7 DR. R. LEVINE: I enjoyed your 8 presentation very much. I'm a member of one of your 9 working groups, the one that's directed by Stuart 10 Platner, and he's trying to find out or having us 11 explore together how particularly social and 12 behavioral scientists can find their way in the 13 current complicated regulatory ecology. I think also 14 that there are some guidelines out there that if 15 interpreted strictly and applied to your work could 16 -- I think during your very interesting story of your 17 work with Cholera I was reflecting on the fact that 18 it's a violation of the Declaration of Helsinki and 19 maybe you would want -- well, I mean, the Declaration 20 of Helsinki is something that we've discussed here. 21 It rules out research in a lot of important and 22 interesting areas and one of them just happens to be 585 1 yours. 2 DR. COLWELL: Well, you mean cholera or 3 Bangladesh? 4 DR. R. LEVINE: No, I'm talking about the 5 use of simple preventions that one can afford in 6 Bangladesh without using what might be called the 7 best proven therapeutic method as it exists in other 8 parts of the world. 9 DR. COLWELL: This area is a clinical 10 research area. So, we, the villagers are monitored 11 by physicians on almost a daily basis. And this is 12 under NIH guidelines and it's NIH supported. So it's 13 not a rogue study. 14 [Laughter.] 15 DR. R. LEVINE: The point I'm really 16 trying to make indirectly is that yours is not a 17 rogue study like many, many research projects it's 18 funded by the National Institutes of Health. 19 DR. COLWELL: And I should have the 20 National Institutes of Nursing because they are the 21 ones -- 22 DR. R. LEVINE: Well, they're one of the 586 1 "i"s at NIH. 2 DR. COLWELL: That's okay, they don't 3 always get the credit they really deserve. Right? 4 DR. R. LEVINE: But like so many ethical 5 and scientifically valuable studies funded by all of 6 the "i"s at NIH, they are in violation of the 7 Declaration of Helsinki and it's not because they're 8 doing anything unethical, it's because the 9 Declaration of Helsinki is wrong. 10 [Laughter.] 11 DR. COLWELL: I've been asked to do a lot 12 of things, but to change the Declaration of Helsinki 13 single-handedly -- 14 PARTICIPANT: We're doing that. 15 CHAIRPERSON MARSHALL: Abbey, you have 16 question? 17 MS. MEYERS: Well, I want to ask you about 18 the third-world countries. We have this intricate 19 set up of IRBs and all these safeguards here, but one 20 of the incidents that triggered this whole 21 investigation of ethics is the HIV study with 22 pregnant women in Africa. Now, what are we to do 587 1 about third-world countries that don't have patient 2 protection systems? 3 DR. COLWELL: Well, fortunately, I've done 4 my work in Bangladesh where we in fact have 5 superimposed the systems employed here. They do have 6 the subject review committee at the International 7 Center for Diuril Diseases Research Bangladesh where 8 I have worked for the last 25 years. They have the 9 same kind of committees. In fact, the director, 10 David Sach is a Johns Hopkins physician detailed to 11 ICDRB. 12 I've done some work in Africa and all I 13 can say is an off-the-top-of-the-head response which 14 is that you follow the rules wherever you are and you 15 simply impose them as you do your work. 16 MS. MEYERS: You followed the rules in -- 17 DR. COLWELL: In whatever I must do for my 18 students and my subjects and my research here in the 19 United States is what I feel I must do when I'm in 20 Africa or in Bangladesh or in Pakistan. 21 MS. MEYERS: So you're following American 22 rules? 588 1 DR. COLWELL: Yes. 2 DR. R. LEVINE: Abbey, I'm afraid you 3 believe too much of what you're reading in the 4 papers. The places where the short duration AZT 5 trials were done in developing countries had what 6 they called "Research Ethics Committees" which are we 7 called institution review boards. 8 CHAIRPERSON MARSHALL: Thank you so much, 9 Dr. Colwell. 10 [Applause.] 11 CHAIRPERSON MARSHALL: We are going to 12 proceed with the children's discussion for the next 13 half an hour. So, Alan Fleischman, Dr. Fleischman is 14 going to retake whatever control one can have over 15 this motley group here and in the room. 16 [Laughter.] 17 CHAIRPERSON MARSHALL: The out-of-control 18 group. 19 DR. FLEISCHMAN: I actually was enjoying 20 this. 21 [Laughter.] 22 DR. FLEISCHMAN: I was quite taken by the 589 1 Arctic adventure. 2 I would like to talk about the fourth 3 issue that the working group thought was the most 4 perhaps controversial and then do some summation all 5 in this 30 minutes. And the fourth issue speaks to 6 part of the answer to question six, the expectations 7 of child research participants and their parent or 8 guardian for the direct benefits of the child's 9 research involvement. 10 And here the working group focused 11 primarily on the issues of Phase I trials and the 12 concerns about therapeutic misconceptions, issues 13 that have been well written about and of concern. 14 The group started with an acceptance of 15 the critical importance of Phase I trials for 16 children. That is to say, if you could not do 17 research in Phase I trials for children, then you 18 could never discover new therapeutic interventions 19 for children. And that, in and of itself was felt to 20 be problematic. 21 So the question was, how have we done 22 Phase I trials, and how ought we to do Phase I trials 590 1 in terms of justifications? 2 The working group was also aware that some 3 groups have attempted to do what are called Phase I 4 and II trials. That is to say looking at both 5 toxicity and efficacy at the same time in creatively 6 designed trials, or at attempts at creatively 7 designing trials. 8 In an attempt then to generate some 9 potential of therapeutic benefit in the trial. So 10 here again, I ll explain to you the workgroup's 11 conclusions or recommendations, but we are in need of 12 some conversation and some assistance in thinking 13 this issue through. The workgroup believes that the 14 issue of therapeutic misconception research is very 15 troubling and most troubling perhaps in Phase I 16 trials, yet an important area for children s 17 research. 18 Phase I trials generally have a very low 19 likelihood of or no potential for benefit and that is 20 even controversial. If we speak to some of our 21 families, particularly advocates in the area of 22 cancer treatments, the families have told us that 591 1 there is the hope that the next new drug will be the 2 right drug. That even being in the Phase I trial 3 might show miraculously, and I use their language, 4 that there is some biologic or perhaps therapeutic 5 benefit and then that drug could be used for their 6 child in that therapy. 7 Even though they are aware and 8 knowledgeable about what the purposes of the research 9 is and that is for toxicity measurement, they argue 10 that these are far more symbolic for them than what 11 they are in terms of the classic pharmacological 12 approaches. And I think that I've personally and I 13 think the workgroup as well is concerned about 14 understanding that perspective and giving it some 15 value in this whole conversation. The perspective of 16 the families of children with life-threatening 17 diseases. 18 Therefore, the workgroup concluded that 19 such trials ought to be allowed, that it was 20 extremely important for new therapies to be 21 introduced, but the potential subjects for such 22 research need to be sick children, need to be 592 1 children for whom standard treatments have failed to 2 offer the hope of cure, and I personally dislike and 3 won't use the language of "the children have failed." 4 It's the rest of us that have failed. 5 And the alternative options include 6 palliative care, noninterventions which need to be 7 both offered and perhaps integrated into these 8 trials. But that IRBs ought to be allowed to approve 9 such studies and we need to consider whether they 10 ought to be approved through the mechanisms of 406 or 11 407. And these I think to justify these studies will 12 take some hard thinking and in it's important that we 13 consider this. 14 From the parents' perspective they see 15 this as potentially benefiting their children. From 16 the academic's perspective they see that as hopefully 17 a minor increment over minimal risk research with 18 safeguards to assure the children's safety. 19 And then finally we talked a little bit 20 about Pharmacokinetic Phase I trials or the first 21 steps of understanding the treatments for children. 22 Those I think are different kinds of trials because 593 1 they actually have already had a substantial amount 2 of work done in adults and others for whom we really 3 do know something about toxicity and have some 4 ability to think about that and can do efficacy 5 studies at a much earlier phase. So that wasn't as 6 troubling in this regard. 7 So let me open up this conversation, I 8 don't know if I have articulated this well. But let 9 me open up this conversation and turn to Bob for his 10 wisdom. 11 DR. R. LEVINE: Alan, that s a very good 12 presentation. I want to bring up a point that didn t 13 become clear until toward the end. That, if I hear 14 you correctly almost everything you said until the 15 last minute was addressed to Phase I trials in the 16 field of oncology, cancer chemotherapy. 17 DR. FLEISCHMAN: And other life- 18 threatening kinds of diseases. 19 DR. R. LEVINE: Well, in general Phase I 20 studies on other types of life-threatening diseases 21 with the exception of most infections are done in 22 normal controls and that presents us with a very 594 1 important problem but a different problem. 2 The problem with Phase I oncology, I don't 3 know if everyone here appreciates what Phase I 4 oncology looks like. Do you all know about a dose 5 escalation design? 6 DR. FLEISCHMAN: Why don't you go ahead 7 and unpack that. 8 DR. R. LEVINE: All right. What you do is 9 you start the subjects and they're usually as, Alan 10 pointed out, people who have cancer and where all 11 known therapies have failed to produce any good 12 effect or they may have produced a good effect and 13 now the tumor has become resistant. You start people 14 out then on a cancer chemotherapeutic agent that has 15 never been tried before in humans, or if it has been 16 in the case of children, sometimes -- most of the 17 time they've been tried first in adults. 18 There is a dose escalation design. You 19 begin with a low does that you do not expect to have 20 much bad effect and you do not expect it to have any 21 good effect. And then you keep elevating this dose 22 until you get to a level where two out of three 595 1 subjects have life threatening complications. Then 2 you drop back one dose and say that is the maximum 3 tolerated dose and it is the maximum tolerated dose, 4 the MTD that is then used in your Phase II studies 5 where you're beginning to look for therapeutic 6 effect. 7 These studies are highly problematic with 8 adults. We tell -- well some data. In 1,200 and 9 some odd consecutive Phase I oncology studies carried 10 out at National Cancer Institute, only 2 percent of 11 the patients had even a partial remission and .16 12 percent had a complete remission. 13 The first time I presented those data in 14 public I got a letter from the woman who claimed to 15 be the .16 percent. She had far advanced breast 16 cancer, volunteered to get in the study and had a 17 complete remission and years later there were still 18 no evidence of disease. And she had changed her 19 career form teaching anatomy to teaching medical 20 ethics. Possibly an adverse effect. 21 [Laughter.] 22 DR. R. LEVINE: The problem we have is 596 1 that we will present these data to adults who are 2 candidates for a Phase I oncology studies. We say 3 there is very nearly no possibility of benefit and 4 depending upon where you are in the dose escalation 5 there could be very grave adverse effects. They 6 agreed to participate and the next day you walk onto 7 the oncology unit and say why are you in the study 8 and they say it's the only chance I have. 9 Now, with children the benefit side of 10 the equation is somewhat better. In Phase I they 11 have had a higher percentage of partial and complete 12 remissions. But it is still not a very good balance 13 and the problem of getting consent to this or 14 permission plus assent I think is probably even more 15 vexatious than the problem with adults. Thanks. 16 DR. FLEISCHMAN: Yes, Denyse. 17 DR. THORNLEY-BROWN: I'm a little hung up 18 by the term "cure" in here, because there are a lot 19 of treatments that may not cure people but can 20 improve their quality of life and to offer parents 21 something -- a Phase I trial that probably won't cure 22 or may not even palliate, as opposed to something 597 1 that may be beneficial to the child. That word just 2 kind of bothers me. I think that something needs to 3 be added. So if standard treatments have failed to 4 offer the hope of cure or improvement of quality of 5 life, or something like that. Because I think that 6 one word is bothersome. 7 DR. FLEISCHMAN: Thank you. Adil. 8 DR. SHAMOO: Thanks. I have a couple of 9 quick questions for clarification from you. Is the 10 Phase I trials you are discussing, is that 407? 11 Under 407 or not? 12 DR. FLEISCHMAN: The working group thinks 13 that they would not be under 407. 14 DR. SHAMOO: So they would be under 406? 15 DR. FLEISCHMAN: Well, that s where we re 16 looking for conversation of whether they re under 406 17 or 405. 18 DR. SHAMOO: Well, because that s a -- 19 yeah, that s a very crucial what we do about it. 20 The next question is, the way you said 21 that orally versus what s written. Orally you said 22 basically, it s, my understanding it s prohibited on 598 1 healthy children, Phase I clinical trials on healthy 2 children. They have to be sick. Is that what you 3 said? 4 DR. FLEISCHMAN: What I m specifically 5 talking about are Phase I trails in this paragraph on 6 oncology drugs with seriously ill children who s 7 future looks grim and for whom the treatments have 8 not resulted in enhancing the quantity or quality of 9 their lives. Or as Bob pointed out, they were better 10 and have now gone into remission. 11 DR. SHAMOO: My question is then the same 12 one a few hours ago and that is, when are we going to 13 talk about introducing new drugs on healthy children 14 that are not sick? This is what Abbey s question is, 15 this is what my question is. Are we going to talk 16 about it or are you just saying that will never 17 happen? That according to 407, that is prohibited 18 only the Secretary after public hearing can approve 19 it. Are we still stuck with that? 20 DR. KOSKI: I can think of very few, if 21 any, examples where the first use of any new 22 pharmacological agent is in children, certainly in 599 1 healthy children. Every new pharmaceutical agent 2 that I m aware of apart from, maybe we can come up 3 with some kind of an unusual example that is a 4 disease that s unique to a child, that s the only we 5 that you could ever introduce it and there are 6 probable some examples that we could search out, I 7 would bet. 8 To my knowledge just about every new 9 pharmacological agent is first introduced for Phase I 10 testing in adults and generally the oncology drugs, 11 those which have severe toxicity are generally in the 12 people who are ill, whereas other drugs would be 13 tested in normal healthy volunteers. 14 DR. SHAMOO: But my concern is that we 15 define for the purpose of allowance of research on 16 healthy children, we define the benefit in such broad 17 terms that was the 407 FDA advisory, to include 18 futuristic disease. 19 So somewhere there is the thinking and I 20 just want to confirm it then. Somewhere there s the 21 thinking that we are going to use those new drugs on 22 healthy children. If that is the consensus that we 600 1 will not use healthy children to introduce new drugs, 2 we want to have it on the table and we all agree, 3 that that practice which you said are extremely rare 4 is not as rare as you re saying, but if that is the 5 consensus then it s wonderful. But that s not my 6 understanding from written documents that I have 7 read. 8 DR. FLEISCHMAN: The working group would 9 be happy to review any specific examples that could 10 clarify your concern for us. Because like Dr. Koski, 11 we don t -- we can t think of a circumstance. If 12 there were new drugs for child-specific diseases then 13 they would be studied in the children with those 14 diseases and they might well be studied in such 15 children. 16 DR. SHAMOO: Fenfluramine study was not 17 sick children. They were healthy children and was 18 approved under not for 407, but for 406. 19 DR. R. LEVINE: I must say that 20 fenfluramine was a single dose and it was not a Phase 21 I study. It was a dose that was designed to study 22 the basic biology and to this day no one has ever 601 1 attributed any toxicity to a single dose of 2 fenfluramine. 3 DR. SHAMOO: But it was on healthy 4 children that are not sick. 5 DR. R. LEVINE: No one is disputing that. 6 It's just that does not happen to be the topic we re 7 discussing right now. 8 DR. FLEISCHMAN: Dr. Koski and then I d 9 like to weigh in on this. 10 DR. KOSKI: You know, if we put on the 11 futuristic hat that you're suggesting, Adil, one 12 could for instance in the advances of medicine 13 identify a possibility where there is a genetic 14 modification factor that might be utilized to 15 actually correct a developmental abnormality that 16 could result in a deformity or some other kind of 17 thing at birth that could actually be delivered 18 perhaps in to a fetus or something. I m really going 19 off the wall here. 20 But where the only way that one could test 21 it, the only applicable scenario would be in a child 22 for the Phase I study. There s no way that you could 602 1 really tell, I mean you could squirt it in I suppose 2 an adult I suppose to see whether or not it would 3 make them sick. Even there it s hard to come up 4 where we would actually end up in a situation of 5 doing the first testing in healthy children -- 6 DR. SHAMOO: Then why don t we have 7 language which is very clear such that the 8 fenfluramine type of experiment, even though it s one 9 dosage, fenfluramine is a high-risk drug, was used on 10 healthy children, that that will not happen again. 11 Otherwise, what we are doing, we are 12 having again not clear language for IRB s to make 407 13 type of protocols, speak up Abbey with me -- 407 14 protocols as 406 and they are then allowed. Why 15 aren t we so clear then? 16 I m agreeing with Greg and I m agreeing -- 17 I love you both for saying that, but lets but it in 18 the language, in English, black and white. Not in 19 Arabic in my native language. 20 21 DR. FLEISCHMAN: Let me keep us on track 22 here though. Because we began this conversation 603 1 discussing Phase I trials. Whether you and I agree 2 that the fenfluramine study ought not have been 3 approved, has nothing to do with the conversation 4 about Phase I trials. 5 DR. SHAMOO: [Off mic.] 6 DR. FLEISCHMAN: Well, no it doesn t. We 7 could in fact talk about that study as an example of 8 whether we, if we were the IRB reviewing it, would 9 have allowed it to happen. And we could discuss that 10 case example and we might come to agreement or we 11 might not. But it was not -- 12 DR. SHAMOO: But you said 407 versus 406. 13 You said this is part of our discussion. The Phase I 14 clinical trial, you said, and we want to decide 15 whether it falls under 407 or 405, even you said, not 16 406. 17 DR. FLEISCHMAN: Let me see if I can 18 recap for a moment so that we re clear. Okay. 19 Because I don't mind the direction you're going. I 20 just want to be sure that when we get there we know 21 where we've been and where we're going. 22 The issue around whether normal volunteer 604 1 children, if we can use that term -- in normal 2 healthy children who assent and are given permission 3 by their parents to be part of a study that has 4 something to do with the medication placed into them 5 in order to study some physiologic phenomenon, that 6 is not a Phase I trial. That is a research study. 7 It's got a hypothesis, it's got a question. It needs 8 to be assessed as to what is the level of risk of 9 putting a chemical into a youngster. 10 We have to decide, as an IRB, if we were 11 looking at it, is there any potential that that 12 intervention can give benefit? We have to decide, 13 does that child fit into a child with a disorder or 14 condition that's relevant for the study, and then we 15 figure out whether it fits in 405 or 406 and if it 16 doesn't, but we as an IRB think it's an absolutely 17 important study that we as an IRB think ought to 18 happen, but we can't approve it, then we kick it up 19 to a 407 review as per the recommendations of the 407 20 committee. 21 DR. SHAMOO: You are saying we will not 22 weigh in, in such kind of an issue. We as a 605 1 committee, as NHRPAC, we will not make a statement on 2 healthy children having new drug, high-risk drug 3 introduced into them? 4 Because what I understood you and Abbey 5 understood you, and I asked that specific question to 6 you, Alan, you are really doing a good job on both of 7 us it looks like and maybe not intentionally. When I 8 asked about when is the time that we're going to talk 9 about introducing new chemical entities or new drugs, 10 need not be a drug, new chemical entity and new drug 11 into healthy children is that we have to wait for 12 Phase I trial or I could bring it up when we were 13 discussing 407. And you said, no, let's wait for 14 Phase I. 15 Now, that I bring it here, this is not a 16 topic of conversation. My thinking is that we need 17 to weigh in, make it very clear through our 18 conversation and whatever we agreed on, what we are 19 going to do when we introduce, and I give you, you 20 said there is no example. I brought you an example, 21 then that's not the right example. 22 Fenfluramine, a high-risk chemical entity, 606 1 is not even a drug, was tested on healthy normal 2 children, all blacks and Hispanics, in New York City 3 for over 100 children. They were paid 25 buck to go 4 to Toys-R-Us -- a $125 to the parents plus other 5 amenities. Now I want to know if that kind of 6 research will continue under our own workgroup 7 recommendation? Is that clear. 8 DR. FLEISCHMAN: I think that we could 9 analyze that specific case here. I don't think we 10 would need to either write new regulations nor even 11 interpret present regulations to come to conclusions 12 concerning that specific protocol. 13 DR. SHAMOO: I will then ask the committee 14 and ask Mary Faith Marshall that we discuss that kind 15 of an issue either as a committee as a whole. It's 16 your committee, you are the chair, you are refusing 17 to even consider its deliberation. We should 18 continue on that and we will drop the discussion. 19 Because my understanding and Abbey's understanding, 20 and she doesn't have a foreign accent, was that we 21 will discuss it. 22 DR. FLEISCHMAN: Don't get me wrong, Adil, 607 1 and you don't -- and you and I actually don't agree 2 on -- don't disagree on this issue. The workgroup 3 would be happy to discuss that issue. The workgroup 4 would be happy to come out with a comment for you on 5 that issue. I don't think that's a problem. I'm 6 just trying to help us to understand that in the 7 frame of reference of where we are the workgroup felt 8 no need to make a comment about that. 9 DR. SHAMOO: There is a great need. 10 DR. FLEISCHMAN: Right. So the workgroup 11 would be happy to take that under consideration and 12 evaluate it and come back to the committee with some 13 comments about it. I don't think that's a problem 14 for either me or the workgroup. 15 DR. KOSKI: I think the important point 16 here, Adil -- I mean, your point is a good one, but 17 in the context of the discussion that we're having, 18 what you're talking about is not a Phase I trial. 19 And that's the difference. 20 DR. SHAMOO: [Off mic.] I asked that 21 question three hours ago. 22 DR. KOSKI: I understand. 608 1 DR. SHAMOO: [Off mic.] 2 DR. FLEISCHMAN: I will take 3 responsibility for having misunderstood the substance 4 of what you were asking then, which I thought -- 5 DR. SHAMOO: [Off mic.] 6 DR. FLEISCHMAN: -- was part of the Phase 7 I trial because of the language you used at the time. 8 Now, again, there's a conflation here. We are not 9 talking about a Phase I trial, so we need to have a 10 conversation about it in a separate conversation. 11 CHAIRPERSON MARSHALL: We've talked about 12 the use of particular cases or example to help us and 13 to help others interpret what we're trying to say and 14 we have a list at the end of our draft comments. 15 So, Adil, I understand and I hear what 16 you're saying, that you have a need to have this 17 particular issue of new drug high-risk in healthy 18 children explicated with the use of an example. We 19 will do that. 20 DR. SHAMOO: Thank you. 21 CHAIRPERSON MARSHALL: And we will also 22 ask for your involvement in terms of that specific 609 1 example and how it's explicated, both you and Abbey. 2 DR. FLEISCHMAN: Let me be even more clear 3 though, Mary Faith. We are not talking about a new 4 drug being introduced into children, Adil. What we 5 are talking about is a provocative agent to study 6 some kind of physiologic response. And we may agree 7 that we shouldn't do that in some circumstances; 8 maybe all circumstances. But in some circumstances, 9 certainly. But it's not the same thing as taking a 10 drug, meaning something that we hope has some 11 therapeutic value and studying it to see if it has 12 therapeutic value. 13 What that specific research study was 14 about was a physiologic provocation by a chemical in 15 order to understand something about physiology and 16 prediction. 17 Now, you and I may agree that we shouldn't 18 do that. I'm only trying to get us to understand the 19 distinction between taking a chemical agent that we 20 think has therapeutic intervention potential versus 21 understanding physiology. 22 DR. SHAMOO: No, I think -- Abbey, go 610 1 ahead. 2 DR. FLEISCHMAN: Abbey? 3 MS. MEYERS: Okay. You know, a lot of the 4 research that is going on is privately funded. So a 5 lot of the information doesn't come out to the public 6 unless the New York Times or the Enquirer gets ahold 7 of it. 8 Now, let's look at a drug that was 9 specifically developed for children, the lung 10 surfactant. I think there's three or four of them on 11 the market. I think Galaxo makes one of them. They 12 were all studied on children. They all had to start 13 in the Phase I trial. Was it studied just on 14 children with respiratory distress syndrome, or was 15 it given to healthy infants along with the -- 16 DR. FLEISCHMAN: Abbey, I was there. 17 That's what I did for a living in my prior life as 18 the director of neonatology for a very large program. 19 There were no normal children given surfactant down 20 their airways. 21 The studies were done after very 22 significant research in animals, some of the first of 611 1 it done actually when I was a fellow at the NIH in 2 1971 in which we used both monkeys and sheep. It was 3 then escalated to humans after a tremendous amount of 4 work in animals and animal models. And it was never 5 given to healthy children. I don't think it has ever 6 been given to healthy children. But it was given to 7 very critically ill, sick, premature infants with 8 full and informed consent and it became a very 9 successful therapeutic intervention which has 10 dramatically impacted on the survival of premature 11 infants. 12 But, there was never a request for it to 13 be given to healthy children. There was never, to my 14 knowledge, from any drug company or anybody else. 15 There was never, to my knowledge, again, physicians 16 who were interested in doing that, in healthy 17 children. 18 MS. MEYERS: Were you involved in the 19 development of lung surfactant, the four or five 20 brands that are out there so that you could 21 definitely say it was only given to sick children? 22 Do you know? 612 1 DR. FLEISCHMAN: Well, no, I don't. But I 2 was, for years, at every meeting at which surfactant 3 was talked about. I mean, these were commercial as 4 well as academic ventures. I just -- it would be -- 5 I could not believe that that happened. I honestly 6 can't. I can't conceive it. And I can conceive a 7 very cynically bad things. 8 [Laughter.] 9 DR. FLEISCHMAN: But I just can't -- this 10 is my friend. 11 MS. MEYERS: What we're saying is that 12 somewhere the federal government should prohibit a 13 drug like that being developed for sick children from 14 being given to healthy people. That's all we're 15 asking. 16 DR. FLEISCHMAN: What I'm saying is, I 17 think it does. You see, that's why I don't have a 18 problem with this. I don't think there's anybody in 19 the pharmaceutical industry or in the academic 20 pediatric or non-academic pediatric community that 21 believes it's not illegal to do that. 22 DR. SHAMOO: Why don't we then make such a 613 1 statement, Alan? If we suspect that's happening -- 2 it has happened. You see, you are teasing out my 3 chemical entity as a provocative agent versus drug. 4 I don't like that. My chemical entity includes drugs 5 in it. I wanted that prohibition in healthy children 6 whether it is a chemical entity fenfluramine or a new 7 drug. Otherwise you are leaving the door open that 8 drugs can be used for the first time on healthy 9 normal children. Because you say it and I don't want 10 your oral words, just what we are recording here as 11 the gospel and as a regulation. 12 DR. FLEISCHMAN: Judy and then Susan. 13 DR. SIEGEL: I actually think, Adil, there 14 are two discussions here. One is drug development of 15 potential therapeutics. When you use the word "Phase 16 I" you are talking about a phased development of a 17 drug. 18 DR. SHAMOO: [Off mic.] 19 DR. SIEGEL: Versus what you're talking 20 about with fenfluramine, which, I mean, you get it in 21 adults, you get it where you use drugs as challenges, 22 where you use drugs to study disease, but you're not 614 1 studying the drug itself for its potential 2 therapeutics. 3 I think if you look in adult drug 4 development you will also find there are instances in 5 adult drug development that aren't oncology studies 6 where you would never give the drug for the first 7 time to a healthy volunteer because probably that 8 healthy volunteer adult could not tolerate it. 9 Drugs for schizophrenia, healthy 10 volunteers do not tolerate those drugs particularly 11 well, especially in drug doses that could be 12 therapeutic. 13 Why would you give that drug to a person 14 who couldn't tolerate it? I would go the same route. 15 If you're saying that do the regulations prohibit 16 giving a drug with potential major toxicity, to 17 anyone, a child or an adult, who could not or should 18 not tolerate that drug, my sense is that the 19 regulations do cover that versus using a drug as a 20 challenge or a provocative agent for something that's 21 totally out of the drug development, a drug 22 development scenario. And I'm wondering whether 615 1 there aren't maybe differences in those two types of 2 research that we really need to deal with. 3 DR. FLEISCHMAN: I've got on the list, 4 Susan, Margaret and Bob, and then Adil and Elliot. 5 MS. KORNETSKY: The only thing I want to 6 add is I understand what Adil's comments are and sort 7 of what he wants to ask the working group to do. I 8 have problems thinking about this committee making a 9 statement that a certain type of research may or may 10 not be permitted. 11 I think what would be more reasonable, and 12 I can't believe I'm saying this not as -- I'm not a 13 regulator -- is more to take those examples and try 14 to work them through what we have existing in our 15 regulations and to do several examples of that. But 16 to come across with a statement. I hear there was 17 discussion here about a drug, is it an 18 investigational drug, is it an approved drug, is it 19 for therapy, is it for provocative? It's very 20 difficult to come out and just make general broad 21 statements. And I think each sample or each example, 22 and perhaps we can use your example, but to come out 616 1 of that and work through the regulations to see 2 whether it's permissible or not and not to make just 3 broad general statements about it. 4 DR. FLEISCHMAN: Margaret. 5 DR. BORWHAT: Well, I appreciate the 6 distinction you made and the clarification, 7 especially about the study Adil was talking about. 8 But for clarification what is the controlling legal 9 authority for research studies like that? We're 10 talking about very specific regulations here. If 11 these regulations don't cover the type of study he's 12 mentioning, what regulations do? 13 DR. FLEISCHMAN: I think they do cover. 14 You see, that's the point. I mean, the working group 15 didn't see this as a specific problem. We now 16 understand that we need to at least address it. I 17 think these regulations do protect those children, 18 and I think this comes under my concern about 19 accountability and review of IRBs and having ways for 20 us to think about what good outcomes would be in this 21 process of review of human subjects research. But we 22 are willing to go through the examples and to see 617 1 where this would fit in these regulations. And if it 2 doesn't, then I'm in full and complete agreement that 3 we need to be as explicit as we can be to prevent 4 children from being hurt. 5 I mean, I don't want to be taken wrongly 6 to support hurting children. I mean, that has never 7 been anything that in my life I can remember having 8 advocated. So, I mean, I just want to be clear that 9 the working group didn't see this as a problem 10 because the working group, I would bet, I haven't 11 asked them each individually, would have believed 12 that this was covered in the regulations, not 13 uncovered and in need of specificity. But it doesn't 14 seem to be explicitly adequate addressed, so we need 15 to at least think about it and see where it might 16 fit. 17 Bob. 18 DR. R. LEVINE: I raised my hand a while 19 back while Judith was speaking. And I want to 20 partially disagree on technical grounds with one 21 thing she said. There's nothing in the regulations 22 for research involving adults that would preclude 618 1 taking a drug for research purposes that present risk 2 with no compensating benefit. 3 In the children's regulations there is 4 very clear explicit language that rules it out. I 5 think the way we could make Adil happy, if I 6 understand his unhappiness, is to say that as a group 7 we endorse, in general terms, section 406 of the 8 Subpart D. That's what rules it out. 9 DR. FLEISCHMAN: Adil. 10 DR. SHAMOO: I couldn't agree more with 11 Bob. 12 [Laughter.] 13 DR. R. LEVINE: [Off mic.] 14 DR. SHAMOO: He must be wrong, he said. 15 [Laughter.] 16 DR. SHAMOO: But that's exactly the point. 17 Thank you. 18 DR. R. LEVINE: Do you want us to endorse 19 Section 406? 20 DR. SHAMOO: With compliance. With 21 compliance and oversight. There's a big difference. 22 DR. FLEISCHMAN: Elliot. 619 1 DR. DORFF: I actually want to talk about 2 something else. Is that okay. 3 DR. FLEISCHMAN: It's okay with me. 4 [Laughter.] 5 DR. DORFF: First of all, he won't say it, 6 so I will. His name is Adil. 7 What I wanted to talk about was the last 8 line of Section 6 that you read. And when you read 9 it, you put in a -- of that draft is what we would 10 call it, in other words an interpretation. That 11 wasn't in the language and I don't know what you 12 mean. Okay. 13 And the alternative options including 14 palliative care are offered. What does that mean? 15 Does that mean they are offered instead of this Phase 16 I drug, or they're offered in addition to, along with 17 the Phase I drug? See, I would be much happier if 18 they were offered along with the Phase I drug. 19 DR. FLEISCHMAN: It depends on the 20 specific protocol. I would be much happier if they 21 were both offered along with and as an alternative 22 option so that families understand and accept the 620 1 reality of their dying child because almost every one 2 of these children will die shortly after they're part 3 of these trials. But that they really understand 4 then that palliative care without this altruistic 5 volunteering of their children is available. And 6 that palliative care within the trial is a mandatory 7 part of the IRB approval process. 8 The problem, of course, is that in some of 9 these trials the toxicities are so great that it's 10 very hard to alleviate any of the symptoms, even in 11 the hands of good palliative care people. So what I 12 meant in my commentary was that both really ought to 13 be available to families. They ought to honestly be 14 told in the consent form that this is purely 15 voluntary. Palliative care is available for their 16 children and the very best of humane care and caring. 17 But if they do get into the trial, then the 18 obligation of the investigator is to assure that as 19 best as possible the symptoms can be handled. 20 DR. DORFF: That's wonderful. I just 21 would ask you to make that a little bit more 22 explicit. 621 1 DR. FLEISCHMAN: Felice. 2 DR. F. LEVINE: Well, I can say I've 3 learned a lot. And I think my response is -- or the 4 issue I want to raise is really that irrespective of 5 what I was taking almost as a facetious proposal -- I 6 mean, to try to see if we could reach closure, 7 meaning that we really should take it up. 8 When I said I learned a lot, I mean, 9 really as obviously I come to this area as a somewhat 10 lay citizen with an interest in ethics, but not deep 11 knowledge of the nature of this kind of 12 experimentation. And as a member of the working 13 group I really saw nothing as off the table. I 14 really saw our first meeting as having, in a way, a 15 very specialized focus because we had a really -- a 16 mandate before us and indeed, at least the part that 17 I could participate in, up until about 12:30, we 18 couldn't do a lot of the brainstorming that we might 19 have otherwise done with some of these issues and I 20 think here and in the last issue that was just 21 raised, it's not just the consent forms, but these 22 are really threshold about the whole consent process 622 1 because these are not only vulnerable children, but 2 these are very vulnerable parents as we were talking 3 about yesterday. So how that consent process 4 unfolds, I think is a really key issue for this 5 working group because of the challenge that we face 6 with children at such medical risk. 7 DR. FLEISCHMAN: And I'm going to in a 8 moment to ask the public people, the ex officio 9 members and anyone else in the audience who would 10 like to make a comment to come to the microphone. 11 There will be some data about this consent 12 process that's being generated by an NCI-funded 13 project in the children's oncology group that's being 14 run out of Cleveland in which we are -- not we, but 15 they, are looking at the whole question of informed 16 consent and both the involvement of the investigators 17 as well as the families in this process. So we will 18 benefit, I think, from understanding more about that. 19 Greg and then if people will come to the 20 microphone to speak specifically about the issues 21 that you've heard us comment around. 22 DR. KOSKI: Just very quickly to add to 623 1 what Alan just said. There is actually a host of 2 research studies being done currently on the consent 3 process, much of that being funded by NIH through the 4 LC project which deals not only with children, but 5 with the elderly, with a whole host of different sort 6 of characters who might be asked to give consent and 7 the issue of informed consent is one that Secretary 8 Shalala announced back in June as being one of the 9 highest priorities that we need to take under 10 consideration and it's our full intent to put that on 11 the upcoming agenda for this committee. So you'll 12 have an opportunity to attack that head on. 13 Thank you. 14 DR. F. LEVINE: Could we get a list of the 15 abstracts of those studies just so that we can see 16 what's underway? Assuming that they've been funded. 17 DR. KOSKI: Right. These studies I only 18 know about them because I served on the advisory 19 committee as a consultant that recently reviewed some 20 of the progress reports on those. I don't know the 21 status of publication, but I would be happy to check 22 into that and report back to the committee. My guess 624 1 is that these investigators would be more than happy 2 to share the results with anybody who is willing to 3 listen. 4 DR. FLEISCHMAN: I see no commentators, 5 but I'm looking. Please. Introduce yourself and 6 give us your comment. 7 MS. OLSTER: My name is Deborah Olster, 8 I'm a AAAS fellow working at the NSF. But my comment 9 is coming from my other life which is as a 10 physiologist. And what I've heard in this discussion 11 is that depending on how you use a particular 12 chemical, you may be calling -- it may be a drug or 13 it may not. And if whatever document you produce 14 comes down to that issue, you may want to consider 15 just using some language to define what you mean by a 16 drug and it might clarify things for people. 17 DR. FLEISCHMAN: Thank you. 18 Let me see if I can conclude -- oh, I'm 19 sorry. Go ahead. Introduce yourself, please. 20 MR. GRAVE: Gilman Grave from the National 21 Institute of Child Health and Human Development. I 22 think that people use Phase I studies to mean many 625 1 different things, and I think we ought to get a nice 2 definition that the whole committee can agree on. 3 I've heard Phase I studies being called safety 4 studies or toxicity studies. I've heard them called 5 PK studies. I've heard Phase II studies called dose 6 ranging studies with efficacy in the small group. 7 And then I've heard Phase III, of course, called 8 efficacy. So I really think that Judith might be 9 very helpful here and Dr. Roberts, because I think we 10 really need a very precise definition of what we're 11 talking about as Phase I. 12 It's such a flexible yardstick in our 13 current discussion. 14 DR. FLEISCHMAN: Thank you. 15 Introduce yourself, please. 16 MS. SHEROV: I'm Vera Sherov and I'm 17 president of CRCR Care, many of you know about it. 18 Citizens for Responsible Care in Research. And I 19 would like to not comment on what you were talking 20 about now, but rather to make a statement which is a 21 bit of a distillation of comments that we submitted 22 to the Office of Human Research Protections. And it 626 1 deals a great deal with normal children, healthy 2 children and what's to be done with them. And also 3 it deals with why this very panel was called in the 4 first place -- was convened. 5 The basic question, and I know that you've 6 heard it from Adil quite a bit, is now in a broader 7 sense, not Phase I, not oncology. Who has the moral 8 authority to volunteer children for drug trials that 9 are likely to be against their best interests? 10 That's the question the public wants to know. 11 Now, we think that federal policy, until 12 now, has been to protect children from non- 13 essential, invasive, painful, medical experiments. 14 Regulatory restrictions were adopted to prevent the 15 inclusion of children in experiments that involve 16 greater than minimal risks and no prospect of direct 17 benefit to the individual subject. 18 We are alarmed by recent policy changes, 19 both by the FDA and NIH which essentially opened the 20 gates to the exploitation of children in medical 21 experiments that are likely to cause them pain, 22 discomfort, and put them at risks of harm without 627 1 medical justification. 2 In 1997 when Congress extended patent 3 rights for pharmaceutical companies to test drugs on 4 children, they were not informed that the system of 5 protections was broken. 6 As Dr. Marshall stated -- wrote, actually, 7 since 1990, the research climate has worsened 8 dramatically. Federal investigations since 1998 made 9 clear that non-compliance with ethical standards and 10 federal regulations was widespread. Research at six 11 institutions was shut down. All federally funded 12 research was suspended at another three institutions. 13 From January 1st, '99 to June 2000, approximately 60 14 institutions, including some of our most prestigious 15 universities were found non-compliant. 16 Since July 2000, OHRP has suspended 17 federally funded clinical trials at seven additional 18 research centers. 19 In her waning months in office Donna 20 Shalala wrote, "I did not expect or want to complete 21 my tenure as Secretary of Health and Human Services 22 by raising questions about the safety of patients in 628 1 clinical research. However, recent developments 2 leave me little choice." 3 Dr. Koski acknowledged the system may have 4 gotten entirely out of control and might have to be 5 reorganized. We must take steps to reestablish the 6 public's trust in the goodness of our endeavor. 7 Given this unsettling climate, we are 8 dismayed, the children are being aggressively 9 targeted. 10 The questions posed by OHRP reveal to us 11 ignorance about the full-blown crisis. These 12 questions presuppose an existing functional system of 13 protections for adults which one is led to assume 14 needs only slight modification for children. But 15 that presumption is totally insupportable by the 16 weight of the evidence demonstrating systemic 17 failure. At this time the system cannot even assure 18 that autonomous adults are safe, thus we believe that 19 it is irresponsible to broaden the recruitment of 20 children. 21 According to the New York Times between 22 1991 and '96 there were 11 pediatric studies; 16,000 629 1 children were subjects in 1996. Now children are 2 being catapulted into clinical trials, becoming means 3 to increase profits. 4 The Boston Globe reports that the drug 5 industry is spending $1 billion a year on pediatric 6 testing. Forty-five thousand children are 7 participating in medical experiments this year. 8 Researchers are getting bountiful 9 financial incentives, 5,000 is not unusual to recruit 10 children. 11 Thousands of healthy children are being 12 sought to serve as drug testing subjects with 13 monetary bribes to their parent, kickbacks to 14 doctors, and patent extensions to drug manufacturers. 15 Without adequate safeguards children are 16 fast becoming casualties of the broken system. The 17 disastrous FDA-approved propulsa [ph] trial is a case 18 in point. Infants were recruited to test a drug that 19 had already killed adults and children. Experimental 20 eye surgeries at the University of South Carolina 21 caused more than the usual complications including 22 transplants that slipped and wounds that broke open. 630 1 The Globe reports that a toddler was 2 subjected to a self-contained experiment in which 3 traditional surgery was performed on one eye and a 4 new technique on the other resulting in unusual 5 bleeding into the eye. 6 Another case involves a pacemaker 7 experiment at NIH that killed an 11-year-old and 8 caused the condition of a 12-year-old to deteriorate 9 badly. 10 This government agencies refuses to 11 provide public information about the outcome of that 12 pacemaker experiment including the number of children 13 helped and harmed 14 Government lawyers at NIH shield doctors 15 from accountability. Now, if answers are not 16 forthcoming the public's outrage will be directed far 17 and wide, not just at the wrongdoers. Will this 18 committee follow up and try to get answers? 19 Unethical research practices are not 20 anomalies. They are a consequence of the 21 inextricable conflicts of interest that have lead 22 researchers to subordinate the health and welfare of 631 1 human subjects for financial interests and helpless 2 children are becoming the sacrificial lambs. 3 No one keeps track of adverse events in 4 pediatric or adult research. Even industry 5 consultants acknowledge, and I quote, there are some 6 time bombs out there and we don't have the 7 infrastructure to monitor research from end-to-end. 8 CIRCare strongly urges mandatory reporting 9 of adverse events to a federal database for keeping 10 track of above-minimal risk research involving human 11 subjects. 12 Some clinicians who had pushed Congress to 13 widen the inclusion of children not anticipating the 14 unintended consequences are now concerned about the 15 lack of professional restraint. 16 Robert Ward of the American Academic of 17 Pediatrics is quoted as saying, "We've heard of drug 18 studies being conducted in motels, in which they rent 19 a block of rooms, they're not provided with equipment 20 to deal with complications and allergic reactions. 21 Are there no mandatory requirements to ensure ready 22 access for emergency medical interventions wherever 632 1 human research is being conducted? Is there such a 2 regulation? Who is responsible when things go wrong? 3 We agree with one statement in the 4 subcommittee's report, and I quote: "Research 5 funder, industry, institutions, investigators, and 6 the public share the responsibility for assuring 7 research is performed in an ethical manner." 8 However, we believe that without mandatory safeguards 9 and independent checks and balances to enforce them 10 vulnerable people, most especially children, are not 11 safe. 12 Dr. Koski acknowledged on CBS 60 Minutes 13 that the federal protection system depends on 14 whistleblowers after the fact. Uninformed consent, 15 the copiously documented series in the Seattle Times 16 demonstrated the same thing as it reported systemic 17 failure to protect research subjects. 18 Clearly the evidence demonstrates that 19 self-regulation has fostered a climate of self- 20 interest. It may protect deviant investigators in 21 institutions, but it fails to protect vulnerable 22 patients from abuse, exploitation, and harm. 633 1 CIRCare believes that existing regulatory 2 restrictions need to be enforced and strengthened to 3 protect children from medical predators. 4 Instead, we are concerned about the draft 5 policy and procedures for DHHS research involving 6 children 45 C.F.R. 46.407 which was revised March 12 7 of this year, because it redefines and weakens 8 current regulations that had been adopted to protect 9 healthy children from exploitation. 10 The draft policy would broaden the 11 criteria under which healthy children may be 12 subjected to risky research by inventing a new 13 category. Risk bearing children, what are risk 14 bearing children? And by redefining the terms, 15 "disorder" or "condition" and "reasonable 16 opportunity." 17 The DHHS indicates that for the purpose of 18 Section 46.406 the term "condition" is redefined to 19 include non-medical conditions including a 20 demographic descriptor. Does that legitimize racial 21 profiling? 22 Whatever the condition, the children are 634 1 being used to test medical interventions. By 2 twisting regulatory terminology, federal policymakers 3 would legitimize experiments that put healthy 4 children at risks of harm without scientific 5 justification or potential benefit. I will cite 6 three examples. One was fenfluramine experiment 7 which we do return to over and over because it was 8 never clarified, is it legal or not. 9 And then there was the NIH obesity study 10 which was shut down by OHRP in which 93 healthy 11 children were exposed to pain, discomfort, risks, 12 with the preposterous justification that the research 13 was, quote, safer than playing actively on sidewalks 14 and streets. 15 And then there's an Eli-Lilly experiment 16 at Yale that is exposing 32 children and adolescents 17 to serious risks of adverse side effects associated 18 with the company's powerful schizophrenia drug, 19 elanzopine to test a hypothesis. 20 The experiment has been widely criticized 21 even by NIMH researchers and by the leading proponent 22 of schizophrenia prevention research in Australia. 635 1 Dr. Patrick McGory [ph] is highly critical of 2 researchers both at Yale and Harvard for conducting 3 this experiment. He told Time Magazine, current 4 issue, "the Americans went at it like a bull at a 5 gate dispensing antipsychotic drugs to adolescents on 6 unacceptably flimsy grounds." We strongly disagree 7 with this DHHS proposed policy change and ask whose 8 children will be designated, "risk bearing" children? 9 What is the ethical and scientific 10 justification for a government oversight agency to 11 redefine existing regulations so that safeguards for 12 children are effectively diluted rather than 13 strengthened. This ill-advised policy is encouraging 14 the recruitment of thousands of helpless children 15 exposing them to drugs whose safety has not been 16 established. Whose children are being sought for 17 these painful, potentially harmful experiments? 18 And do those who profit from drug trials 19 volunteer their own children for science? 20 Also the proposed changes, is this a 21 notice of intent to regulate because then it would 22 require that it be done in accordance with federal 636 1 administrative procedure act, otherwise those 2 recommendations would be nullified if accepted. 3 DR. FLEISCHMAN: We'd appreciate receiving 4 those comments if you would -- 5 MS. SHEROV: Yes, I have the fuller ones. 6 DR. FLEISCHMAN: Give those to us so that 7 we can digest them more carefully. 8 The workgroup actually has several 9 concerns that parallel yours and in concluding this 10 part of the conversation about the workgroup's 11 report, the workgroup actually is concerned about the 12 importance of aggregating information about adverse 13 effects. The importance of coordinating the work of 14 DSNBs and IRBs for the benefit of children as 15 subjects. And would very much like that to be part 16 of the discussions of this group. It's not child- 17 specific, but is an important part of monitoring 18 adverse occurrences, and also the workgroup on 19 children is also interested in looking toward 20 additional monitoring of research studies of IRBs and 21 meaningful oversight of IRBs. 22 We've said that several times, and in the 637 1 course of the conversation that the IRBs do require 2 accountability, oversight and review and in order to 3 do that, we are going to have to be very creative in 4 terms of what are the outcome measures to look at. 5 How do we ensure that investigators and IRBs are 6 doing their jobs which is part of, I think, what 7 you're really talking about from a -- 8 MS. SHEROV: I am, but I think that part of 9 the problem that has come out everywhere where there 10 is a scandal, everywhere where there is a shutdown is 11 that the IRBs clearly cannot do it themselves, 12 particularly when some of the people that they're 13 supposed to oversee are far more powerful than they 14 who bring in the grants. I mean, we are quite 15 cognizant of reality and money is important. I know 16 that Greg has often said that one should take the "I" 17 out of the IRB and call it a research protection -- 18 what would you call it, RRB? Research review board. 19 Okay. Research review board. In other words, not 20 based in the institution who studies are being 21 evaluated. That come across very clearly from IRBs 22 and I hear a great deal from people in IRB. 638 1 DR. FLEISCHMAN: I will conclude our 2 workgroup report by remind the committee that the 3 workgroup believes that there ought to be specific 4 memoranda on a series of issues to clarify the 5 present regulatory structures to give examples. And 6 we've listed a whole host of those which we've had an 7 opportunity to talk about most of them today. And 8 the workgroup remains prepared to address other 9 issues as well as these and to help the committee in 10 developing some of these memoranda if the committee 11 so wishes. 12 And I will turn it back to our 13 chairperson. 14 DR. DORFF: Just a question. The changes 15 in the definitions of 406 and 407 to which you 16 alluded, is that -- first of all, that's not coming 17 from this committee, so where is that coming from and 18 that's not the document that we got, I take it? I 19 mean, I'm just perplexed. 20 DR. KOSKI: There are no changes. 21 DR. DORFF: Oh. 22 DR. SHAMOO: There is an advisory from FDA 639 1 how to reinterpret 407. There was an FDA ethics 2 advisory -- 3 CHAIRPERSON MARSHALL: Adil, let me 4 clarify that because I actually sat on that, what is 5 called a 407 panel. I guess in the many years since 6 the regs have been in effect, there have not been 7 many 407 panels convened or called. Requests have 8 not come from local IRBs to look at research that 9 potentially would be approveable under the 407 area. 10 There was a group of special consultants 11 to the OHRP that was asked to look at some studies 12 that may potentially have been approvable under the 13 407 regulations -- component of the regulations. And 14 the outcome of that was that the group did not review 15 any of the studies that were proposed, the group felt 16 that there was not an adequate framework for IRBs to 17 use to put studies forward, and for them to be 18 evaluated at the local level and that there was work 19 to do at the policy or the interpretation level. So 20 there was a draft document that I believe is on the 21 web; is it not? 22 Yeah. And it's in our notebooks. And, 640 1 the working group on children used that to inform its 2 thinking in terms of the request from the Department 3 of Health and Humans Services to assist them in 4 responding to the Child health Act or the request for 5 response to the Child Health Act. So there is 6 nothing that has been official in terms of any 7 changes to the regulation or any policy that has been 8 adopted by the OHRP. This document that was put 9 forth by the 407 panel, as far as my understanding 10 that the only use that has been made of it is that it 11 has been forwarded to our working. 12 DR. SHAMOO: That's not the one, Mary, I'm 13 talking about. People in FDA can correct me. If you 14 go to the FDA web site, there was a new, in the past 15 few months, FDA ethics advisory. A group of 16 ethicists got together to explain how the 407 will be 17 -- and I don't know, we are across purpose we are 18 talking. 19 They are the one who mentioned the word 20 "otitis media" is that the one? That's the one they 21 said, every child, therefore, can be considered sick 22 because they will get otitis media. Therefore any 641 1 drug for otitis media -- that is the example they 2 used -- any drug for otitis media can be tested on 3 healthy children because in the future they will get 4 otitis media. That's -- I got it out of the web 5 site. None of you know anything about it. Sorry. 6 CHAIRPERSON MARSHALL: Rosemary, could you 7 please speak to that for us? Because I'm confused, 8 I'm not sure what the facts are. 9 DR. ROBERTS: Okay. There was a pediatric 10 advisory subcommittee meeting in November of 1999 11 where there was a discussion about the use of healthy 12 children volunteers in non-therapeutic trials. And 13 basically after a discussion by a panel of six 14 ethicists, it was concluded, and their advice was, 15 that children who have the disorder or the illness 16 should be the only ones who participate in the trial. 17 Or, if they are likely to get the condition. 18 Now, for otitis media, the one time they 19 said the trial designed, or the trial that we 20 described that they agreed young children -- in this 21 country almost every child will get at least one 22 episode of otitis media. 642 1 So the trial example that we put up was a 2 single dose taste test of a new antibiotic and it was 3 agreed by those people who deliberated, that they 4 felt that kind of a single dose as a taste test on 5 healthy children who are likely to have an episode of 6 otitis media they could find that acceptable. 7 But basically nontherapeutic trials are to 8 be done in check who have the condition. 9 DR. SHAMOO: I'm glad that you confirmed 10 that there is such a thing -- and we didn't -- Abbey 11 and I didn't make it up. And although otitis media 12 was used an example which opens the door for other 13 type of examples that can be used to broaden the 14 definition. That is a problem. 15 MS. KORNETSKY: I was at that meeting and 16 participated, now that I understand what it is. And 17 I have to say that there were other -- several other 18 examples that were not, you know, permitted and there 19 was quite a bit of discussion. I don't think that 20 was totally unanimous from my own standpoint. 21 [Simultaneous conversation.] 22 CHAIRPERSON MARSHALL: We have asked, and 643 1 we really do need to move along because Felice has 2 been very patient with us. 3 Adil and Abbey, I would ask and invite you 4 to, one, help us with the task that we talked about 5 earlier relative to the concrete examples that the 6 committee -- that the workgroup -- sorry -- can move 7 forward with. If there are other things that you 8 would like for us to move forward with, then please 9 let us know. And Greg would like one final comment 10 and then we're moving on. 11 DR. KOSKI: I would just like to thank all 12 of you for your thoughts and input. Clearly this is 13 an area that not only is very complex, but can be 14 very emotionally charged as we think about those that 15 we love so much. 16 Our office is charged with putting 17 together, as I mentioned earlier, a report to 18 Congress in response to the Child Health Act of 2000, 19 and so I would urge this group to offer to us its 20 advice at its earliest possible convenience. 21 We intend to incorporate the advice from 22 NHRPAC along with advice that we've received from 644 1 other individuals, other organizations, that have 2 been broadly solicited across the country and will 3 make first an initial report to Congress that we 4 expect to deliver sometime around the first week in 5 May, and will then ultimately be following up with an 6 additional report. Clearly when and if it comes time 7 to issue either new policy or change regulations we 8 will, of course, go through the appropriate notice of 9 proposed rulemaking with public comment and so on as 10 is routine and customary for that kind of government 11 business. 12 But I just want to thank the members of 13 the workgroup and the members of the public, members 14 of the committee at large, and particularly to Dr. 15 Fleischman for his leadership in this. I'm sure 16 we're all going to benefit enormously from it. Thank 17 you. 18 CHAIRPERSON MARSHALL: Thank you, Greg. 19 And I would like to second your thanks to Alan and 20 the other members of the working group. We have just 21 begun and I think that was how Dr. Fleischman began 22 his remarks in his conversation. Our group has only 645 1 had the benefit of one meeting. 2 So, we truly have just begun. And thank 3 all of you for helping to inform our thinking today 4 and as we move along. 5 Felice, would you like to come to the 6 front, or are you happy to -- 7 DR. F. LEVINE: [Off mic.] 8 CHAIRPERSON MARSHALL: Thank you. 9 DR. F. LEVINE: We're going to run to 10 about 6:30 this evening, right? 11 [Laughter.] 12 DR. F. LEVINE: Well, we heard Alan say, 13 looking to the agenda, actually, that the children's 14 working group is a work in progress which sort of 15 took the words out of my mouth and you could see how 16 productive that work in progress was. I would say 17 that we too are a work in progress and at this moment 18 really what we want to do is really give you an 19 overview of where we're going, not where we've been 20 because we've just begun. 21 I hope that those of you who didn't pick 22 up the report, I think there are -- needless to say, 646 1 one of the hot pieces of paper to take back to your 2 homes, copies of the report that we prepared on the 3 social and behavioral science working group and I 4 think what we want to do today is just give you the 5 briefest overview of where we are and what we see 6 ourselves doing. 7 And really to sort of solicit comments, 8 advice, guidance, in particular, by e-mail at this 9 hour because I know there are a number of important 10 issues we want to get to on the agenda. 11 My co-chair, as Greg alluded to, there's a 12 hardworking group of federal officials seeming to be 13 constantly in the air advising, speaking, lecturing, 14 educating, and Jeff Cohen is the director of the 15 education division and he is absolutely phenomenal 16 and so he's here, but you don't see him. But he's 17 been very much a presence. Indeed, we count 18 backwards when he's in Hawaii and we plug him into 19 conference calls and he is -- he's just been on the 20 road a huge amount because the work that is underway 21 is rather labor intensive on human subjects issues 22 more broadly and certainly the education division is 647 1 playing the leadership role in that regard. 2 I am joined, happily, by my colleague, an 3 ex officio member of the committee, Phil Rubin, who 4 is the NSF division director of the Behavior and 5 Cognitive Science Division. And he also is an active 6 -- I'll say participant -- in the subcommittee on 7 human subjects research protection on the Committee 8 on Science. And I guess is chairing the social and 9 behavioral science subcommittee. 10 And one of the things that we want to talk 11 a little bit about is that interaction between the 12 agencies that fall under the common rule and the 13 interaction between the Committee on Science and the 14 subcommittee on Human Subjects and how we are working 15 together to integrate and glean the best set of 16 wisdom and knowledge. 17 I'm not going to repeat the outline, but 18 very much the charge of the working group really 19 emanated from this group, from the advisory committee 20 in December when I spoke to the advisory committee 21 about the common rule, the guidelines for the 22 protection of human subjects and the history of 648 1 experience with the social and behavioral sciences 2 with those rules, and both their workability and 3 their complexities really much more in their 4 implementation than necessarily the language on 5 paper. 6 And we saw as the charge in discussions 7 with Mary Faith and Kate Louise to develop guidelines 8 to help institutional review boards and I would say 9 the Human Subjects Protection System more broadly 10 reviews social and behavioral science research 11 involving human subjects and as we talked about over 12 the past two days, also to certainly not foreclose in 13 any respect, but not necessarily be led by the notion 14 of any change, per se, in the regulations, to of 15 course entertain and ask ourselves whether in 16 specific language or forms of transformation we may 17 need to make recommendations regarding additions or 18 changes with respect to the rules insofar as they 19 need to be better appreciative of the full range of 20 research that involves human participants. Not 21 because there are another set of rules, but because 22 the language that has often been used has evolved 649 1 much more in the context of biomedical research. 2 And, therefore, by illustration and 3 example we may need to develop materials that better 4 communicate both to social and behavioral scientists 5 as well as to those involved in the review process. 6 The composition of our working group and 7 all volunteers are welcome, and I guess this in a way 8 speaks to the housekeeping discussion that we will be 9 having subsequently. But the composition of the 10 working group is currently 12 strong. Three members 11 of the committee, Dr. Jennie Joe who couldn't be with 12 us today, who bring a strong interdisciplinary 13 background, as I think many of us around the table 14 indeed do in public health and nursing and in 15 anthropology. 16 Dr. Jonathan Moreno who stepped forward 17 and volunteered to be part of this -- I think -- 18 ambitious enterprise. Seven ex officio agencies, not 19 necessarily always the ex officio members, but from 20 the ex officio agencies, and you have a list in the 21 back. 22 And I'll give you an example of what we 650 1 were seeking to do and that is from the Department of 2 Justice, Dr. Sally Hillsman who is the Deputy 3 Director of the National Institute of Justice with a 4 long career as a very active bench scientist doing 5 work on various aspects of crime in the 6 administration of justice. And we were seeking in 7 this working group to be strong in the talent pool of 8 persons who have wrestled with the difficult and 9 complex issues of reviewing research which she 10 certainly is now involved in doing, undertaking that 11 research, working with subjects in different forms of 12 vulnerable populations and bringing that best wisdom 13 to bear. 14 So the seven agencies which are ex officio 15 colleagues, the three of us from this committee and 16 two active members of the research committee that -- 17 research community that don't bear any of those hats, 18 one is Dr. Joan Sever who is at California State 19 University with a long-term set of experiences in the 20 ethics of research and human subjects protection. 21 And people are shaking their heads yes. And I feel 22 like I've known Joan my whole life in this area which 651 1 is several decades and I think anyone who is 2 intersected with these issues do, and not only does 3 she bring the sophistication as a quality scientist, 4 psychologically trained, but also -- and the 5 longstanding interest in human subjects protection, 6 but a lot of interaction around IRBs and experience 7 with IRBs, and in particular some very active work on 8 issues of accreditation and other similar issues with 9 Primer. 10 And the other is Dr. Robert Hauser who is 11 at the University of Wisconsin Madison at the Center 12 for Demography on Health and Aging who has been a 13 very active primary researcher in issues that relate 14 to health and well-being of children, also the 15 education system and has had wide experience both 16 with extant data collections as well as the producer 17 of primary data including longitudinal data. 18 And we thought through that composition, 19 not to be exclusive, but to really be inclusive of 20 the range of methodologies and strategies that come 21 into play in doing quality research and in working 22 with human participants in a variety of experiences 652 1 and with a variety of intersections from the mere 2 observation of people in public places to lab 3 experiments to field experiments, et cetera. 4 Our hope is to -- I think one of the 5 things we have to control ourselves from doing as 6 social and behavioral scientists are those of us who 7 identify with these fields is not to make this a 8 research project. 9 [Laughter.] 10 DR. F. LEVINE: And I must say, my 11 constant interaction with Mary Faith and the e-mails 12 about this, because, of course, this is for us, a 13 lively subject. You know, everyone would love data 14 and what better subject to study than the human 15 subjects protection system. I think that's phase two 16 of the IOM study. 17 And we are seeking to bite the bullet and 18 I will say, be instrumental, build upon the best 19 knowledge that exists, and do it in a very wide open 20 and transparent way. So we are going to have town 21 meetings and discussions at various research 22 societies. We're going to be going to the Primer 653 1 meeting and trying to get input from a variety of 2 professionals in a variety of ways. Indeed, in my 3 own head I'm trying to think about how, without 4 creating undue additional burden. We even have some 5 input from persons who were subjects in a variety of 6 different types of studies, studies that have been -- 7 have been concluded and how we can work in that way. 8 Also, it would be very important when we 9 talk about access to public data and data sets that 10 have been made publicly available to talk with some 11 of the leading person in the social and behavioral 12 sciences we have some quality data archives and data 13 repositories and how some of those complex issues are 14 resolved when we're talking about deep interviews 15 with small samples, and under what conditions is 16 access provided. 17 And so the Murray Center for the Study of 18 Human Lives, the Interuniversity Consortium of 19 Political and Social Research provide for us 20 opportunities to build upon expertise and I don't 21 know if I should use the language "exploit it" but 22 capitalize on it so that we can move in a fast and 654 1 deliberative way and I hope you'll see the fruit of 2 that. 3 At the July meeting we're going to have 4 our first official meeting of the almost full group. 5 On May 16th we had a mini meeting talking -- thinking 6 through the logistics and the operation and sketching 7 forth the issues that we want to be able to address. 8 And I don't want to repeat in any sense the outline, 9 but if you scan the outline, you will see an outline 10 of the substantive scientific issues that we see as 11 central to grapple with, with respect to the social 12 and behavioral sciences from issues of risk to what 13 constitutes, as we talked about yesterday, what 14 constitute human subjects, what constitute 15 interaction, issues of concent, at what process, and 16 assent and with what process and what staging. 17 Complex issues involved in different forms 18 of research from longitudinal study to non-invasive 19 experiments to international research and how we -- 20 and how the system is currently operating, how 21 researchers are currently understanding it and how we 22 both have successfully, and sometimes more complexly 655 1 navigated the human subjects protection system. 2 So I really see this, for all of us, as a 3 kind of a collaborative opportunity because there 4 isn't one person around this table that -- this table 5 and those chairs that can add to the process. And I 6 think we all look forward to the evolution of how we 7 present the Human Subjects Protection System in a way 8 that truly not meets the needs, but truly 9 communicates its adequacy for all forms of research 10 involving human subjects protection. 11 Most of us involved in this process for as 12 many years as some of us have been recognize that it 13 both can and has done so. And where we need to look 14 toward is identifying those areas that have been more 15 complex, that have been less workable and trying to 16 address those challenges in a way that when that 17 system presents itself, it truly communicates 18 effectively. 19 The one hand out that I have, and I have 20 extra copies at the end of that table, is three 21 charts from the Office for Protection for Research 22 Subjects. And I think they are generically useful. 656 1 But what they help us do in the social and behavioral 2 sciences is identify what have been some of the 3 traditional fault lines. 4 One we really talked about yesterday 5 afternoon quite a bit. And that is what constitutes 6 human subjects? And what constitutes private 7 identifiable data with respect to those human 8 subjects and that's chart 1. 9 Chart 2 is, is the research exempt? Will 10 the research use solely-existing data or specimens? 11 And currently we have some complexities in the social 12 and behavioral sciences with respect to IRBs seeking 13 to review data that are essentially public-use files 14 that have already been debited as public use files 15 through IRBs. And so we have a mutual education. 16 What happens when someone is looking at the yes 17 column versus the no. And when do they identify yes 18 versus no? 19 Similarly, what does it mean, intervention 20 and interaction in chart 1. if one is observing 21 essentially an anonymous form, human interaction in 22 public places and there is no intervention or 657 1 interaction between the researcher and those being 2 observed. Is that in the no column which is 3 traditionally the case, I might say, but currently 4 the case under the fragility of the system, more 5 typically finds itself in the yes collection. That 6 can have rather challenging consequences for 7 ethnographic studies where indeed there's no intent 8 for interest in being in any way altering the 9 environments or the experiment. 10 And similarly the issue of waiver, I think 11 is similarly important. And what we want to work 12 through is examples and be able to provide not only 13 insights and information, but I think some guidance 14 as to best practices that ideally will be extremely 15 helpful to those IRBs, perhaps less experienced with 16 social and behavioral research, and also to those 17 researchers who sometimes may wonder how, indeed, 18 they need to deal with certain of the vital choice 19 points that they may not be sufficiently cognizant 20 of. And so a lot is going to go on between us. 21 I want to turn this over to Phil who will 22 give us another angle, but it's a collaborative 658 1 angle, and I think that is the strength of what we're 2 seeking to do together. 3 DR. RUBIN: Hi, my name is Philip Rubin. 4 I'm the Director, Division of Behavioral and 5 Cognitive School at the National Science Foundation. 6 That means I'm responsible for programs that range 7 from cultural anthropology through the new children's 8 -- congressionally mandated children's research 9 initiative to the new cognitive neuroscience program. 10 In addition, I'm the NSF ex officio. And, finally, 11 I'm the chair of a committee that's part of the Human 12 Subjects Research Subcommittee. 13 A couple points I want to emphasize is I 14 see my role there as one of communication. That's my 15 job and it's a complex job because there are a number 16 of agencies. The HSRS is an interagency group and 17 there are concerns across agencies. The goal is 18 protecting the participants in research. However, 19 there's a diversity of approaches. I want to 20 emphasize though that the group is called behavioral 21 and social science. The real issue from my 22 perspective is non-biomedical research. 659 1 There are a variety of agencies, as I 2 said. There is the Department of Energy, the 3 Department of Justice, and there are unique concerns. 4 What we need to do across the agencies is try to 5 identify what are the special issues in the agencies 6 in terms of what their concerns are, and in what they 7 need to do to best protect participants. So, in a 8 nutshell, what we are trying to do is identify those 9 issues by working with the individual agencies and 10 finally eventually bring a report to this particular 11 group that hopefully will have some guidelines that 12 are concrete and to try to do that as rapidly as 13 possible. It's very difficult working across a lot 14 of agencies, but to try to do that rapidly. 15 We are encouraging the other agencies to 16 follow our model. What we are doing at the NSF is in 17 May we're having a workshop, we're bringing people in 18 from a wide variety of interests and areas to try to 19 grapple with these issues and then report back. And 20 we're going to make sure we try to include 21 participants in research in addition to researchers 22 and administrators. There's a whole spectrum of 660 1 interests, ideas, and issues. 2 Those issues, as Felice has stated, are 3 really broad. They range from things like 4 confidentiality, to issues of what is -- what exactly 5 is informed consent. A final issue -- and then I'm 6 going to turn it over -- that we grapple with is 7 because we also fund a lot of international 8 collaborative research we want to, at least from our 9 perspective at the NSF, make it very clear that there 10 are a lot of varying international and cultural 11 concerns. How we work with individuals and groups 12 has to be a joint effort and it has to be an effort 13 in which we're informed by those individuals that are 14 going to engage in the research process about what 15 their needs and concerns are. 16 And, finally, the regulations then or the 17 guidelines that are proposed have to reflect those 18 concerns. So we'll try to do that and pass that 19 information on to this group and we invite any agency 20 that is not participating to get in touch with us. 21 We have a list serve that we're running. We have a 22 workshop that we're holding and Stu Platner, who is 661 1 the main person doing the work, would be glad to hear 2 from you and if you need to find out how, I'll be 3 outside after the meeting to give you my business 4 card. 5 Thank you. 6 CHAIRPERSON MARSHALL: I think that we 7 have time for some questions for Felice. 8 Let's do this, in terms of procedure. Why 9 don't you take 15 minutes for question and I promise 10 that all of us will be -- at least the meeting will 11 be over at 4:30. Whether all of us leave at 4:30 is 12 another thing. But we will finish at 4:30. I know 13 there are flights. 14 Thank you, Phil, very much for your 15 remarks. And I want to add on and make sure that 16 it's understood that the invitation that was extended 17 is also extended to our public members in terms of 18 participation. 19 DR. DORFF: What I'm about to say may be 20 completely unrealistic. Certainly from the 21 presentation that you made in December, and from the 22 paper that we read from the American Association of 662 1 University Professors, at least I had the impression 2 that the common rule was sort of a *percustian bed 3 into which you found yourselves and that you needed 4 to somehow make the most of it. And I sort of had a 5 sense that this was really imposed on you and that 6 you were -- and that what the AUP, at any rate, was 7 doing was trying to say, "no, but" you know this that 8 and the other thing. 9 What I'm wondering, and that's one of your 10 goals, right, in other words to talk about, as you 11 put it, to make specific recommendations regarding 12 additions or changes to the common rule rather than 13 to the social behavioral sciences. And politically 14 that might be the easiest thing to do. But what I'm 15 wondering is, what would happen if you sort of 16 thought out of the box and were trying to create the 17 ideal world in which social science researchers 18 should be operating, vis-a-vis and including the 19 regulations to protect human subjects. 20 And the reason why I ask this is because 21 you would not be the first ones to think of this. 22 Presumably -- I mean, one of the things that you list 663 1 as information useful to obtain is, are the ethical 2 guidelines of scientific studies of societies in 3 social and behavioral sciences. So presumably other 4 people in the various social sciences have thought 5 about this issue. And it would be sort of 6 interesting to see -- I mean, I thought in particular 7 that was really important, to see, you know, people 8 who -- you know, we're not thinking government and 9 we're not thinking common rule, we're not thinking 10 all of the law, we're thinking ethical guidelines. 11 And it would be interesting to see if 12 there are major distinctions between what they 13 thought would be reasonable moral rules to govern 14 social sciences as opposed to what the government has 15 thought to be reasonable rules. 16 Now, it may turn out that they're all the 17 same, or that they're very similar in which case, 18 fine. But if they're not, I would urge you to, you 19 know, not to be timid in this. But rather to -- you 20 know, to really state the things -- state the way 21 that it ought to be in order to do best kind of 22 research that social scientists can do. Because 664 1 after it's all said and done, that's what serves all 2 of our interests. 3 DR. F. LEVINE: Those are challenging 4 questions. I promise not to be -- 5 Let me also say -- a new hat -- not the 6 hat of a committee member, although that too, that I 7 was presenting the AUP report and very much central 8 that AUP report was a strong interest, although the 9 language specified that it was talking about the 10 social sciences. A lot of it was really grounded in 11 the humanities. And that was in part some of the 12 social scientists in that group and myself included 13 were really brought to the group to really kind of 14 create some synergies between the social and 15 behavioral sciences that had much more history of 16 experience with the human subjects protection 17 guidelines and system, and those traditions of 18 scholarships including, and especially those that 19 really didn't fall under the common rule, in part, 20 because much of that scholarly work had fallen within 21 the traditions of NHA funded which is not one of the 22 agencies. 665 1 Now, from the social and behavioral 2 science point of view, which I thus was trying to 3 walk two lines in December -- this isn't a new 4 system, this isn't a *prescrestian system that indeed 5 we've been plopped into, the social and behavioral 6 scientists, from the outset, we're really a part of 7 the system. 8 The system itself, however, just in terms 9 to the sheer magnitude of the numbers of grantees and 10 the dollars of funding and its origins being much 11 more concerned about the troubled cases of medical 12 experimentation, et cetera, that much of the way it 13 operationalized in examples not ethical guidelines, 14 per se, but in examples and in rules of thumb were 15 much more grounded in the experience of the 16 biomedical sciences. And, indeed, the infrastructure 17 tends to be much more dominated by the biomedical 18 sciences including the IRB's. 19 So that what we have and what I was trying 20 to address in December, though it was probably 21 clearer in my testimony before IOM when I talking 22 about the Institute of Medicine in January when I was 666 1 talking about the social and behavioral sciences is 2 that we don't necessarily have a set of principles 3 that are workable, indeed I have advocated on behalf 4 of the common rule when faced with various efforts to 5 fly in the face of those principles on other 6 occasions; as I referred to the Family Privacy 7 Protection Act that would have essentially regressed 8 in its process by which parenteral consent was 9 obtained in it having an absolutely one-size-fits-all 10 solution and not permitting any kind of process by 11 which you could undertake research on adolescents or 12 on children and youth without a written parental 13 consent. And we invoked the history of experience 14 with the common rule and the operations of the IRB's 15 and how functional it was to have a system in place 16 that had those elements. 17 So, now, that said, I think all of us in 18 all of our working groups contexts the children's 19 this morning yesterday when we were talking about 20 genetics and families want to think outside of the 21 box and Mary Faith emphasized that at every turn in 22 the road. 667 1 The ethics codes, however, aren t 2 something that have evolved separate and apart from 3 the common rule. And indeed I passed out the 4 American Sociological Association's code of ethics 5 at the last meeting. There s really a synergism 6 between the two. 7 Some of us have studied these documents. 8 We want to go back and restudy to see almost how 9 certain things are articulated where the common rule 10 might not have adequately articulated. So for 11 example recordings in public places seems to be a 12 rub, and how can we better educate from those ethical 13 guidelines to say there are guidelines when you are 14 doing recording in public places to preserve that 15 material. 16 And so I think we will have a lot to say 17 but not because we are going to develop a new set of 18 moral guidelines, although were we to encounter some, 19 I think they would be generically sharable. I don t 20 think this is something that is idiosyncratic to the 21 social and behavioral sciences and that is why I said 22 yesterday that I don t see myself as representing 668 1 those fields of science exclusively. I see myself as 2 knowledgeable about them and what I have to say I 3 hope will have broader applicabilities. 4 CHAIRPERSON MARSHALL: I have Greg. Who 5 else had a -- okay. Abbey and then Jonathan and then 6 I want to open the floor up after that. 7 DR. KOSKI: I just very quickly add that 8 the Belmont Report, the National Commission, actually 9 as the report is entitled and it includes behavioral 10 and biomedical sciences and the fundamental ethical 11 principles that are delineated there I think in fact 12 it is important for everyone to recognize that they 13 do indeed apply across the entire domain of human 14 research. 15 So I think the last thing in the world 16 that we would want to do would be to somehow say that 17 research that is done in the behavioral and social 18 science somehow subscribes to a different set of 19 fundamental ethical standards for research. That 20 would be a serious flaw. 21 So I think indeed our efforts are toward 22 focusing on the many instances misapplication of the 669 1 biomedical model to the social and behavioral 2 sciences realm. We benefit actually in multiple ways 3 from that in that we recognize that the burdens that 4 these processes place in many instances both on 5 investigators and IRBs. 6 Where we are having unnecessary 7 misapplication of provisions that would and basically 8 they don t result in enhanced protections for human 9 subjects, but rather are miss guided attempts to do 10 the right thing often through a lack of appropriate 11 understanding is where we ve gone astray. So I think 12 that this working group will help to focus on those 13 areas where we can productively make our system work, 14 both more efficiently and effectively. 15 CHAIRPERSON MARSHALL: Jonathan. 16 MS. MEYERS: Quickly. The National 17 Bioethics Commission, I haven t heard much mention of 18 it in the last couple of days and I m wondering is 19 there anything among the many reports that they have 20 issued and would apply to this area, so that we don t 21 have to go and reinvent the wheel and start from 22 ground one. 670 1 DR. F. LEVINE: To the extent either 2 because of our shared lack of awareness of some of 3 the social behavioral research it gives some of you 4 the feeling that we are starting from square one. I 5 could not have put better what Greg just said. I 6 don t see us as starting from square one at all and I 7 actually don t see the social and behavioral sciences 8 as a particularly unique challenge. I think some of 9 our complexities raise some important challenges. 10 The NBAC report fully addressed to social 11 and behavioral scientist and I think probably 12 received lots of commentary about those portions of 13 the report that did so just so as it in other areas. 14 A indeed Marjorie Spears who was central to the 15 staffing of that committee is a talented psychologist 16 that was detailed from CDC that is central to social 17 and behavioral scientists at CDC and is an active 18 member of the social and behavioral science research 19 community. 20 I think actually that report even where I 21 may feel with my personal hat on that it hasn t quite 22 hit the boat or maybe missed the boat in certain 671 1 areas. Certainly it didn t miss the boat in being 2 inattentative to the social and behavioral sciences. 3 It certainly sought to address those issues and I 4 think will give us material as it will give this 5 committee material in other areas. 6 DR. MORENO: I actually want to endorse 7 that last point and suggest that not only that 8 report, but also the human biological materials 9 report in the context of the genetic stuff we're 10 doing. We need to have someone come from NBAC and 11 perhaps a principal staffer and do a little briefing 12 on that for us. 13 I think that you re absolutely right about 14 the history, none the less, I have to say when I go 15 up the hill from the medical school to the grounds at 16 UVA and on the few occasions when I m asked to go up 17 there to talk about ethics with my colleagues in 18 behavioral sciences, I sometimes feel the way I did 19 when I walked in a room full of doctors 22 years ago 20 when I started when I started teaching medical 21 ethics. There's at the very least there's less 22 intellectual energy devoted it seems to me 672 1 anecdotally among the rank and file behavioral 2 investigator to ethical issues then even among many 3 of our physician colleagues, several of whom are here 4 who have made such a change in the culture. 5 I'm being a little bit facetious, but I 6 mean to say that I think that the medical world has 7 thought more about these issues than the social 8 science world among the rank and file, not among the 9 leaders perhaps. 10 Having said that and gone out on that limb 11 I also do want to say that my understanding is 12 entirely another matter that our charge is specific 13 with respect to the common rule but that there are 14 some federal agencies that conduct what some people 15 would consider to be behavioral research, at least 16 survey research who are not signatories to the common 17 rule. I guess I'm asking for point a clarification 18 about that. And whether that ought not also to be a 19 part of what, a question at least that we raise as 20 part of this work. 21 DR. F. LEVINE: Survey research 22 methodology is so pervasively used in society that it 673 1 may be that there is an agency that either funds or 2 undertake surveys that may or may not fall under the 3 common rule, but as a method and as a generic set of 4 issues that it raises in terms of ethical guidelines 5 it will be interrogated, I think, in our group so 6 fully and that probably is one of the mature areas of 7 work that I think that that would have a spillover 8 effect even to contexts that aren't under the common 9 rule just as so much of the research currently that 10 isn't a common rule funded project. It is certainly 11 reviewed by local IRBs. 12 DR. KOSKI: Actually, Rachel, I don't know 13 whether or not HUD is actually a signatory to the 14 common rule. You may know, but I guess whether or 15 not it is I would mention that the new charter for 16 the Human Subjects Research Subcommittee as I 17 mentioned in yesterday's discussion has actually been 18 enhanced to include among its members not only the 19 signatories of the common rule but every federal 20 office, department, and agency that's engaged or 21 involved in human research in any way. So that for 22 instance the Social Security Administration has come 674 1 forward as part of that group and then we have an ex 2 officio member here. 3 So we are truly trying to work toward a 4 fully integrated process across all the government 5 agencies. 6 CHAIRPERSON MARSHALL: I'll allow one 7 question for Bob and then I went to open floor for 8 public commentary. 9 DR. R. LEVINE: I won't take the time. 10 CHAIRPERSON MARSHALL: Let me ask if 11 whether there are ex officio members who have 12 questions or comments? 13 DR. ROSE: Susan Rose from the Department 14 of Energy. First of all I am grateful to this 15 committee which I think is very wise and deliberative 16 and I hope from my prospective that we can hide under 17 your wings. So I was also hurt today by the NSF 18 folks bringing the table the fact that there's a lot 19 of science still not on you agendas. 20 I think it came a lot closer today, but 21 there is a huge amount of research that goes beyond 22 or is totally not behavioral and is not biomedical 675 1 and has to follow these rules or else hides from the 2 rules because we can't fit it under the current 3 category, so I have both problems. 4 I think I talked yesterday with Dave 5 Cloughman a little bit at the Department of Justice. 6 They do a lot of work at our sites. A lot of the 7 stuff that I'm talking about is using people to test 8 stuff or a thing or some sort of implement there may 9 be a risk involved. In some cases there's a large 10 risk. It's not a privacy issue, folks obviously know 11 that they're doing whatever it is, if it's a test 12 driver or something like that it's not a secret to 13 them. So I would like to know -- Phil mentioned that 14 the other agencies should be heard from. I would 15 like to know how to go about that. 16 I would also like to say, and I think this 17 is true of the Department of Justice and probably NSF 18 as well as DOE, we do a lot of traditional stuff so 19 I'm only asking for help on the stuff that's not 20 traditional. 21 One of the other things that I think my 22 problem is the sole human subjects person at the 676 1 Department of Energy, at headquarters at any rate, 2 the definition of research leaves me wide open for 3 people who don't want to be research and people who I 4 want to fall under this and don't. So I have two 5 problems, I need help with inclusion, occupational 6 health studies where they claim it's an occupational 7 study and it's not research, and yet they have people 8 from other sites coming in, Boston Med School, for 9 example, and looking at workers 2000 miles away and 10 going into very private medical records. 11 The other kinds of things are these 12 engineering studies where it never crosses an 13 engineer's mind that he's using people and putting 14 them at risk in his human subject research; he's 15 never heard of that. So those are the kinds of 16 things. 17 And then my last issue, and I think I 18 could use this as a weapon, if you guys could help, 19 the issue of science. A lot of these things -- my 20 worst problems are politically motivated studies 21 where there's no -- I could stand on my head I can't 22 find any scientific value. So some addressing at 677 1 least in this committee where the way you weigh that 2 science is going to be a little tougher than in the 3 strictly biomedical research. So any help that you 4 could provide, Phil. Thank you. 5 MR. RUBIN: Let me respond in part because 6 I totally agree with everything that you're saying 7 and it is a real problem and a real issue. A couple 8 of suggestions, then I can talk to you after. First, 9 you can't be reactive, you have to be proactive. One 10 of the things we find out is that at the National 11 Science Foundation people seemed unaware. In the 12 research community not necessarily our program 13 officers but even there you have to be proactive that 14 any time a human being is involved, not even 15 directly, indirectly, after the fact in anyway and in 16 any possible way if there's human there at all, 17 potentially human there's an issue that you have to 18 face and think about seriously. 19 One of the things that we do, and once 20 again, we all operate under limited budgets but we do 21 and we try to do within the constraints we do 22 outreach. You can't just wait till something happens 678 1 you have to go out there in advance. We do outreach 2 both to the research communities by going out and 3 trying to talk to them about these issues and to 4 listen to them about what they are. But also within 5 the foundation we try to meet regularly with program 6 officers because they change frequently and say, do 7 you realize that what you're engaged in involves 8 human beings potentially and, so for example, in 9 engineering, nanotechnology, computer science there 10 used to be less of an awareness. 11 Now at least, every program officer 12 understands this. They complain at the same time 13 that the communities they deal don't. But our 14 response is, well it's your obligation to make it 15 clear, that this is a two-way street. So that is one 16 thing is that that's an issue that's a real one and 17 you have to try to grab it and bring it to you and 18 work with it. 19 I don't want to -- the time is short I 20 would happy to -- and there were in number of 21 questions I'd be happy to discuss additional issues. 22 The other thing is, in terms of the agencies all we 679 1 can do is beg all the agencies in the federal 2 government to take this issue seriously. All of them 3 are involved. There's not one agency that's not 4 involved people, and we cannot force them, the 5 National Science Foundation cannot be a big gorilla 6 either. We don't want to be seen as the way we view 7 the NIH as the big guerrilla; we want to all be co- 8 equal in this thing and try to realize that to 9 participate. So we encourage you to participate. We 10 will work with you and what we are trying to do is 11 actively go out and find people at agencies, if 12 they're not the official person, who are willing to 13 be a part of this enterprise. 14 CHAIRPERSON MARSHALL: Please go ahead and 15 respond and then a I think Greg has a response on 16 point and then I have Bob. You need to be at the 17 microphone because we are -- your words are going 18 down for prosperity. 19 DR. ROSE: Oh great, I m sure they ll love 20 that at DOE. 21 [Laughter.] 22 DR. ROSE: I didn't mean to sound like I 680 1 don't do outreach in education. That's probably what 2 I spend 85 percent of my life doing and I would feel 3 terrible if you don't have copies of our educational 4 materials. That's the most important thing I do but, 5 nonetheless, the areas I mentioned wouldn't have to 6 be a continual fight if you guys could help produce 7 some guidance. That's all I'm saying. 8 I would like to help but I need to know 9 how. Well, sitting on a behavioral and social 10 science committee isn't going to help me, that's my 11 only -- 12 DR. KOSKI: First of all, I would like to 13 recognize that Susan Rose is actually the one who has 14 picked up the ball to leave the effort to create a 15 federal-wide handbook for human research as one of 16 the projects of the human subject research 17 subcommittee. 18 But to the specific point that she raises, 19 how do we get there. Well, in fact, I think that the 20 800-pound gorilla here could be indeed the human 21 subjects research subcommittee. I frequently talk 22 about that as sort of the awakening of a sleeping 681 1 giant because it has that capability, but it may need 2 in fact to have the additional recognition and 3 support that would come from appropriate testimony 4 before Congress with respect to the need to have all 5 of the federal agencies stepping up to the plate and 6 exercising their responsibilities in this area. 7 That's an opportunity that also coming. 8 CHAIRPERSON MARSHALL: Bob, and please 9 stay at the microphone. 10 AUDIENCE PARTICIPANT: I'm a member of the 11 public, I don't want to get lost in the shuffle here. 12 CHAIRPERSON MARSHALL: Please just stay 13 there and we will -- I've got Bob and then the floor 14 is yours. 15 DR. R. LEVINE: On the topic that Susan 16 was talking about there have been other agencies that 17 have gotten started on this. I think one that has 18 interest very much in common with social behavioral 19 sciences is CDC. I was chair of their committee to 20 evaluate and make recommendations on their human 21 subjects protection system and one of the big issues 22 that came up was so many of their activities used 682 1 devices that are indistinguishable from research as 2 they do their outbreak investigation their 3 surveillance and things of this sort. And we came up 4 with a set of recommendations that might have some 5 value for your group since they do overlap. 6 Another area where there's been a lot of 7 issues is in the area of evaluating public benefit 8 programs. And what happened in the 1980s is that the 9 common rule adopted an exclusion or an exemption for 10 public benefit -- evaluation to public benefits 11 programs and this exemption has been used over and 12 over again in the programs that are most prominently 13 evaluating new approaches to Aid For Dependent 14 Children. 15 The recommendation of my group to CDC was 16 that they should stop trying to define research so 17 that it fits exactly what they want it to regulate. 18 But what they should do instead it identify some 19 categories of activity that are either clearly 20 research or that look enough like research so that 21 somebody raises the issue and go the exemption route. 22 The rationale for developing exemption for 683 1 evaluation of public benefits programs could apply 2 equally to doing such things as outbreak 3 investigation and so on. 4 If you want to see that report you'll be 5 able to see the line of reasoning that went into it. 6 Thank you. 7 DR. F. LEVINE: I think we all would like 8 to see that report. When I referred to field 9 experiments I was thinking about some of the large- 10 scale evaluations when in my conversations with Susan 11 I think she's talking about a band of testing that 12 may or may not, and is as much not than is social and 13 behavioral science research and how that falls within 14 a system. I think that one -- Greg s very helpful 15 starting point meaning the subcommittee on human 16 subject research protection is a starting point. 17 I think her additional question is, how 18 does that graft into our process. But perhaps by 19 starting there by getting different agencies together 20 that have that articulated interest that doesn't 21 neatly fit into biomedical sciences health sciences, 22 social and behavioral sciences as they intersect with 684 1 health or other phenomena, if you could sketch out 2 something, perhaps in a working memoranda, then it 3 may be that some of us who empathize with the falling 4 between multiple stools of science if there is no one 5 left to fall within could help articulate where that 6 fits and whether that fits this or whether that fits 7 something else. 8 And I could tell from your e-mail and from 9 our conversation that you knew you had an issue that 10 involves humans but that it wasn't classically within 11 a research regulatory regime. 12 CHAIRPERSON MARSHALL: Thank you. Please 13 tell us who you are. 14 DR. NOBLE: Hi. My name is Jack Noble 15 I'm a professor at Catholic University. I'm on 16 sabbatical this year doing a study of human subjects 17 protection and I have not had IRB review of my 18 project even though my sabbatical has been approved 19 by the university including the Provost. Isn't that 20 interesting? 21 Am I investigator reporter? Am I a spy? 22 You know, systematically documenting the -- and 685 1 reporting systematic deception or opportunities? 2 There are any number of very interesting questions 3 that I have asked myself as I went off on this little 4 sabbatical. But here I would like to ask you to 5 consider an issue from a look at your process and 6 what you are about the from a political economic 7 standpoint. 8 Obviously you are a part of a very large 9 and expanding marketplace wherein there are 10 transactions, wherein things of value are exchanged, 11 subject are exchanging their lives and increased 12 risks in exchange for something that they view may 13 benefit them. 14 Now, the subject of public accountability 15 has come up. And, you know, as I view the process 16 and how far this goes I think public accountability 17 and gets very difficult for an industry. In fact the 18 only way you could do it right would perhaps be like 19 Swift's suggestion to the starving Irish that they 20 eat their own children. 21 I don't think that will happen. It's too 22 horrendous. So in that circumstance I don't think 686 1 you're going to get much public accountability unless 2 you have some sort of an external system that is 3 automatically in place. 4 Now, where does this leave me? It leads 5 me to the suggestion that might be considered by this 6 whole advisory committee of putting in place some way 7 of compensating those individuals who suffer death, 8 injuries, or illnesses that arise out of and in the 9 course of participation in research. That has been 10 suggested by one of the earlier national advisory 11 commission's bioethics advisory commission it was not 12 implemented. But it gives an opportunity to deal 13 with the risky business that researchers involve 14 human subjects in. 15 The definition of condition, I listened to 16 very carefully, includes a situation where an 17 individual becomes involved in a piece of research. 18 And how do you deal with those injuries and illnesses 19 that happened in the course of participation. Well, 20 justice would require that there be some level of 21 compensation or indemnification, no-fault, good 22 people make mistakes. The estimation of risk is 687 1 wrong. But somebody pays the price and it's not the 2 investigator it is that human subject. 3 So if you had -- you want to know about 4 adverse events, you want to know where they occur and 5 with what frequency and how bad they are, look at the 6 dollar costs of compensating deaths, injuries, 7 disabilities, and the echogenic illnesses. The 8 insurance industry is quite capable with its large 9 sets of actuarials plus a mechanism, certainly all 10 those workers' compensation carries, would be able to 11 carry policies very well and if they're not willing 12 to carry a policy for an institution based upon risk 13 rating the Office of Human Research Protection would 14 not have to come to the rescue. 15 The marketplace would define what is an 16 unacceptable financial risk for it to continue to 17 provide coverage for that type of practice. So I 18 just throw this out, it's a little bit out of the box 19 but not too far. It's only as far as workers' 20 compensation for injuries -- accident and injuries 21 that arise out of and in the course of employment. 22 And the last statement, most of your 688 1 subjects are more like employees than volunteers if 2 you really look at it. They provide a service. Now, 3 I don't want to get into the analogy too far because 4 those services of children are prescribed by child 5 labor laws with some very small exceptions. So let's 6 not carry that analogy too far, all examples limp. 7 This is one that limps right at that point. But I 8 just throw this out. Consider it and maybe it will 9 help you a little bit. 10 CHAIRPERSON MARSHALL: Thank you very 11 much. You have raised an issue that I think is dear 12 to all of us and it is something that we will have on 13 our agenda at some point. So thank you. And I think 14 Abbey also would like to speak to your remarks. 15 MS. MEYERS: I don't think the risk of 16 injury has been a major thing in the past. Back in 17 1989 we had a National Commission on Orphan Diseases 18 and at that time we said to the drug industry you're 19 just not stepping up to plate on pediatric drug. 20 You're not testing them, you're not labeling your 21 drugs for pediatric uses. And the industry defended 22 itself by saying the liability issue is so big we 689 1 don't want to test drugs on children. 2 So we did a search on some legal databases 3 to find out how many lawsuits there had been for 4 investigational drugs, whether in adults or children 5 and we found only one case in the whole country. And 6 that case, the case was a malpractice case against 7 the physician because he didn't adequately tell the 8 patient that she was in a trial and it was not 9 against the company that manufactured whatever 10 product was being tested. 11 So as time went on of course we see a lot 12 of pediatric research on drugs now and liability 13 doesn't seem to be a problem, but I think that in 14 cases where patients felt that they were harmed they 15 felt that this was, in most cases, a risk they took 16 when they signed the informed consent document. That 17 informed consent document does a lot to tell people I 18 accepted the risk and very few cases have come to 19 court. 20 MS. MEYERS: Thank you, Abbey. I have 21 Bob. 22 DR. R. LEVINE: We have examples of 690 1 attempts to set up no-fault compensation programs. 2 The University of Washington at Seattle ran such a 3 program for eight years. The total amount of money 4 they paid out without contesting any claims -- the 5 total amount of money they paid out was under 6 $10,000. The biggest claim was $1,500 from a normal 7 volunteer who fainted while blood was being drawn and 8 struck his teeth on the radiator. 9 We have one other example. There are many 10 examples. I'm only going to mention one more. When 11 John Arnold set up his so-called "alternate subject 12 population program" in Kansas City he had normal 13 volunteers enrolling in one Phase I drug study after 14 another, and after a while he decided that he wanted 15 to have workers compensation for his employees just 16 as he had for the other employees in the building, 17 and he brought in a real insurance company who 18 studied the books and came out with a premium workers 19 compensation for phase one subjects that was very 20 slightly higher than it was for the secretaries in 21 the office there. 22 Now, about 20 years Pat Patello of Harvard 691 1 wrote me a letter saying, why are they trying to make 2 behavioral research look like that very dangerous 3 biomedical research? He said do you have any data on 4 the dangers of biomedical research? And I sent him 5 the Arnold story among others. And a couple of days 6 later I got a handwritten note on yellow paper 7 saying, "I had no idea. I fired my secretary and 8 it's for her own good don't you know." 9 CHAIRPERSON MARSHALL: Please, tell us who 10 you are. 11 MR. CLOUGHMAN: Hello, my name is Dave 12 Cloughman, I'm from the National Institute of Justice 13 and I guess the social science group we do a lot of 14 research in the area of criminology and Sally is 15 serving on the panel, I think that's great. A couple 16 of things that I would encourage the panel to 17 consider, and Phil and I have talked about this. One 18 is, I think at some point the social sciences you 19 come out with almost like a good laboratory practice 20 document that basically lays out that types of 21 studies they do, the types of risk that run the gamut 22 from no risk to some number of X risk; how those are 692 1 handled, and what types of issues there are. And I 2 think the big issue is going to be confidentiality 3 and breaches of confidentiality is where I think the 4 major risk lie in most of these studies. 5 And that brings up a couple of issues for 6 me. One, at the Department of Justice we have a 7 confidentiality regulation that applies to all 8 research we sponsor. Actually it's under the omnibus 9 of crime control access not all of Justice but it's 10 the National Institute of Justice and it's much more 11 restrictive than the certificate of confidentiality 12 that people know under the Public Health Service Act. 13 And that raises some problems with investigators and 14 IRBs that don't understand those restrictions and we 15 are working at educating them on that. It also 16 raises some conflicts with mandatory reporting issues 17 such as child abuse, domestic violence, et cetera. 18 But on the other hand the confidentiality 19 rule that we have has allowed me to stick my nose 20 under the tent, so to speak on some technology 21 development areas where you wouldn't define them as 22 human subject research under Part 46, but because we 693 1 have the confidentiality rule and require 2 notification I can ask the investigators to make sure 3 that people understand the risk of the studies that 4 they are involved in. And there's things like 5 technology development and law enforcement areas. 6 There's some advantages in that as well as 7 shortcomings. Thank you. 8 CHAIRPERSON MARSHALL: Thank you very 9 much. 10 DR. F. LEVINE: I think that s in an area 11 compatible with your language is a topic we will 12 interrogate thoroughly. 13 [Laughter.] 14 CHAIRPERSON MARSHALL: Felice and Phil, 15 thank you very much. We know that you truly are just 16 beginning, so we look forward to hearing from you in 17 the future. 18 [Applause.] 19 CHAIRPERSON MARSHALL: We have about half 20 an hour left and I do want to talk about some 21 housekeeping things relative to our working and 22 moving forward as a committee. I think probably I am 694 1 not going to recap or review recommendations that 2 were already at least done this morning in terms of 3 what we did yesterday in lieu of time. I may just 4 touch on children and social science. 5 But I want to have us as a committee to 6 talk about how some issues that I would like for us 7 to think on, some issues that have arisen yesterday 8 and today in terms of how we proceed doing our work. 9 So I have a list. I want to start with, I am going 10 to save the composition of our workgroups and put 11 that a little bit further down the list because I 12 know there's going to be discussion on that. 13 So there are a couple of things I would 14 just like to move forward with before that, and they 15 are these: One of them is that we have ex officio 16 members from I believe from 25 agencies appointed to 17 this committee. Obviously not all of you are in 18 attendance. 19 [Laughter.] 20 CHAIRPERSON MARSHALL: But I want to 21 emphasize the fact that we need our ex officio 22 members here, we want them here, they should be a 695 1 working and an integral part of our committee. You 2 do comprise our committee in a very fundamental way. 3 So I'm putting the message out there gently in the 4 form of a call but also an expectation. And my 5 expectation is this, the ex officio members will 6 attend this meeting or they will send a designee from 7 each of the agencies that are delineated in our 8 charter. 9 We by the rules of our charter are 10 required to have a majority of our ex officio members 11 just as we are required to have a majority of our 12 committee members in order to convene and have a 13 meeting. So here is the expectation. Our meetings 14 begin at 8:30. They end at least when they are 15 formally supposed to end according to our schedule. 16 I think in the future we will have a 17 second layer of tables with names microphones and so 18 forth so that it is easier for our members to 19 participate, or ex officio members, so the call is 20 out there the expectation is that every agency will 21 have a representative here at our meeting. And I 22 look forward to that and fruitful participation. 696 1 The second has to do with our own 2 committee, and I hope you take this in a constructive 3 spirit. I know that each of you wears not just one 4 and not just two, but many hats and that you have 5 professional lives and personal lives and you have 6 graciously given up time out of both of those to be a 7 member of this committee. 8 I would ask that in the future -- I know 9 that our first two meetings have been scheduled so 10 that you're teaching schedules and other events in 11 your lives were already done before you were even 12 appointed to this committee but we are working very 13 hard to plan our schedule far enough in advance that 14 you can, I hope, work your professional life, you're 15 teaching schedules, around our committee meetings. 16 And I don't want to be unrealistic or 17 unfair in terms of expectations, but we will meet 18 quarterly and I truly would urge you to be here both 19 days, the full day, for all of our meetings because 20 we need each and every one of you. So I hope that 21 you can do that and that if I can help intervene with 22 deans or whomever, if that needs to be for you to be 697 1 here, then I will be happy to do that. 2 And my second piece of encouragement is 3 that we hear from each and every one of you at this 4 meeting. And I know that not all of us as an 5 expertise in research ethics, per se, none of us is 6 certainly Bob Levine who has the breadth of knowledge 7 and experience in this area that I think probably as 8 a group none of us could surpass if we put our 9 collective brains together we still wouldn't reach up 10 to the mark that Bob has. 11 But you're here for a reason and I need to 12 have active meaningful participation from each of 13 you. So if you're feeling unfamiliar with an area, 14 read the background materials. We will try and get 15 them to you in a more timely fashion in the future. 16 So that is a call, a plea, an expectation 17 for active meaningful participation from each member 18 of this committee, don't be shy there's no reason to 19 be. 20 I want to talk about resources. Again, 21 our committee was begun at the end of a former 22 administration. It happened rather quickly. We live 698 1 for the moment within the constraints that were 2 originally set out, but as those of you who were at 3 the research summit that occurred recently now I made 4 the statement that I am going to assume that the 5 resources are there that we need to do our job. And 6 I'm going to do more than assume that. We are going 7 to work very hard with the new administration now 8 that the hiring freeze has been lifted and some of 9 the constraints that Greg and his office and Kate 10 have been under are lifted to make sure that we have 11 the resources that we need both the fiscal, the 12 financial resources to convene working groups and to 13 have consultants and to have papers written by 14 scholars and authorities that we need to have done. 15 Those will happen. 16 So I want you to know that we're aware 17 that we have been constrained and that Kate Louise 18 Gottfried has been working 22 hours a day, seven days 19 a week for a long time and that needs to change. She 20 needs to have staff assistance. We as a committee 21 need to have the resources we need to do our job. 22 And I think Greg has put it well also, in the past, 699 1 and is an ardent advocate for that. 2 So I'm going to assume the resources are 3 there and I'm going to make sure that the resources 4 of there. 5 I want us to think a little bit about the 6 regulations. I've mentioned this before. Within the 7 various working groups it has become clear that we 8 may want to consider or we may identify an area where 9 the common rule, where the regulations may need 10 clarification, explication, or where we may even want 11 to make a recommendation that they be changed. 12 So I would like for us, as a committee, to 13 be thinking about the fact that that moment in time 14 may come, and whether we want to do it on a piecemeal 15 basis or whether at some point in time we want to 16 make a large, more wholesale recommendation, but I 17 would ask that each workgroup chair, and all members 18 of the workgroup, as you're doing your work, if there 19 is a component of your work that has to do with the 20 regulations and a recommendation that may bear on 21 changing the regulations in the future, that you 22 bring that to our attention so that we at least have 700 1 all of those nicely explicated as we move along in 2 the process. 3 I would also ask you, as a committee, to 4 be thinking about the best process for advising that 5 the regulations might be changed if any of you comes 6 to that consensus in your work. 7 Yes, Abbey? 8 MS. MEYERS: It covers 17 agencies; right? 9 So if we want to change regulations, it would have to 10 be approved by 17 agencies; right? 11 CHAIRPERSON MARSHALL: Absolutely. And 12 remember, we are an advisory group only. So what I'm 13 asking is, within the purview of our work, if we were 14 to recommend to any of the folks to whom we advise, 15 in our charge, our charter, that we would make that 16 recommendation. Yes, changing rulemkaing, lawmaking, 17 you know, there's an established procedure which Greg 18 can speak to. Certainly others have alluded to it, 19 whether they're in fear of it, or in support of it. 20 But we don't make regulations, we don't 21 set policy, but we do make recommendations, and we 22 can make recommendations to change the regulations if 701 1 we see fit. 2 So I just want you to bear that in mind 3 because there's a current that underlies probably 4 almost each working group that we've had so far that 5 may result in that sort of recommendation, or has the 6 possibility for resulting in it. 7 Yes, Susan. 8 MS. KORNETSKY: In line with that, I think 9 it would be helpful in the working group, I mean, 10 obviously a change in the regulations, I understand 11 and I appreciate that we can do that. But I sort of 12 look at things as long term and short term and things 13 that are pressing. And so in our working groups, I 14 think that if there is something that's pressing, we 15 may have to tackle it from two points. And I think 16 -- because, if there is something pressing, changing 17 the regulations is not going to happen that quickly. 18 CHAIRPERSON MARSHALL: Well said, and you 19 made that point earlier. We do need to think about 20 plan A and also be thinking -- looking forward to 21 plan B. So I agree with you wholeheartedly. 22 I have Kate and then Elliot. 702 1 DR. KIRSCHSTEIN: Indeed, that's how we 2 have been proceeding with all the workgroups and 3 we've had a two-tiered sort of process where we deal 4 with the immediate and then the long term. And I 5 think all of the working groups will end up doing 6 that because of that fact, that regulation revision 7 if it's required would take a while. 8 CHAIRPERSON MARSHALL: I just don't want 9 us to lose sight of the long term if it's there. So 10 thank you very much, Susan. 11 Elliot. 12 DR. DORFF: Just in terms of the first 13 things we were talking about in terms of scheduling. 14 I understand July 30th and 31st is our next meeting. 15 Have our meetings for the rest of the year been 16 scheduled or not? 17 DR. KIRSCHSTEIN: No, because the 18 committee members have not been able to supply us 19 with their available data for the forthcoming 20 meetings. But we are -- what we may do, because we 21 had wanted to schedule them all in advance is just 22 start scheduling them and have you put them on your 703 1 calendars. 2 My concern, though, is that I really want 3 to have, you know, as much representation as 4 possible. And so I'm a little hesitant to go ahead, 5 but we'll do that and then see what happens. 6 CHAIRPERSON MARSHALL: It sounds as though 7 the committee is saying, please go ahead and 8 schedule. Okay. 9 All right. And, again, if we can help you 10 in any way. Obviously this is my biased perspective, 11 but I'm not sure that any of us is engaged in 12 anything that is more important than the charge to 13 this committee which is ensuring the protection of 14 human research subjects. 15 Let me ask, in terms of workgroups, we 16 talked about them earlier today, and we are 17 establishing our own mechanisms. There's nothing 18 that's been handed to us in terms of you will do it 19 this way. So, we are discovering these mechanisms or 20 creating them as we go along. It's vitally 21 important, I think, as I said yesterday and at our 22 first meeting that our process be excellent, that it 704 1 be exemplary. Because the outcome of our work 2 depends wholly on the excellence of our process. And 3 we have made a promise that we will work in a 4 transparent way and in a inclusive way. And that is 5 and will be how we work. 6 So let me ask, we began the conversation 7 within the last two days with the workgroup on 8 financial relationships. Whether the way that we 9 have outlined that working group's work to proceed 10 fits well with you, whether you have suggestions for 11 changing how we're going to proceed, and just to 12 remind you, there is a document -- a draft document 13 that has been presented to the committee as a whole. 14 We have had input on that today. 15 It is -- or if it's not already, will be 16 on our web site for further comment from ex officio 17 members, from members of the public, from committee 18 membership who may not have had the chance to weigh 19 in today, or yesterday, there will be a revision 20 incorporating those remarks that will subsequently be 21 put on the web with, again, a chance for comment -- 22 open comment before what we hope is a penultimate 705 1 draft will come back to the committee as a whole. 2 Working groups do not have final products. 3 Our committee has a final product. 4 So does that seem like a good procedure to 5 you? Obviously I'm aware that a different working 6 group may need to work in a different way, but I'm 7 asking whether this seems fair and transparent in 8 terms of our goals? 9 DR. FLEISCHMAN: I would recommend that 10 each of the working groups identify their products as 11 from the working groups. 12 CHAIRPERSON MARSHALL: Thank you. Thank 13 you. 14 We did have a little -- it was unfortunate 15 that the report from the financial relationships 16 group came as a letter. Kate and I actually tried to 17 have that. When we thought that we had had those 18 first and last pages removed because they looked like 19 a fait accompli and they didn't smell right and so I 20 was rather dismayed to see that wonderful piece of 21 work come in the form that it did. So in the future 22 I will say now, the rule is that working groups are 706 1 bringing products and that the product should have no 2 -- in no way imply that they are a fait accompli. 3 Alan and then Bob. 4 DR. FLEISCHMAN: And might I suggest, if 5 that document -- is it on the web site at this point? 6 If it is not, we might wish to change that language 7 so that we can give everyone who reads it the 8 understanding that it's a product of a working group. 9 This committee, I'm not suggesting that it's not a 10 wonderful product. I mean, this committee may bless 11 it and not change a word, and all we'll have to do 12 then is to change working group to NHRPAC. But I 13 think it would be helpful for the public to view it 14 as a work in progress. 15 CHAIRPERSON MARSHALL: Yes, it has to be 16 that way. Kate. 17 DR. KIRSCHSTEIN: It's just if you note 18 what's in your notebook, that's the way it should 19 appear on the web site, and that's what we had 20 intended. That was the first draft. If you look at 21 the first draft that's in the notebook, it's a 22 different format than what you got as a revision. 707 1 DR. FLEISCHMAN: But it still says NHRPAC. 2 At least the thing I read. 3 DR. KIRSCHSTEIN: It says, "To NHRPAC 4 Committee Members from the working group." 5 DR. FLEISCHMAN: No, I understand that. 6 But the document -- 7 DR. KIRSCHSTEIN: Oh, okay, got you. I 8 understand. 9 DR. FLEISCHMAN: -- assumes NHRPAC has 10 approved it. 11 DR. KIRSCHSTEIN: No, I understand. 12 DR. FLEISCHMAN: And that's quite 13 confusing to the not-so-naive reader. 14 DR. KIRSCHSTEIN: Yes, I agree. Right. 15 We'll take care of that. 16 CHAIRPERSON MARSHALL: Thank you, Alan. 17 DR. R. LEVINE: My comments address to the 18 same point. My belief is that the working group that 19 Marc headed was trying to do us a service by drafting 20 language for our signature. And I was going to 21 propose that if it is going to go on the web site in 22 its current form, that there be that explanatory lead 708 1 in that this is drafted as if it came from NHRPAC, 2 but it hasn't yet. 3 CHAIRPERSON MARSHALL: Adil and then 4 Felice. 5 DR. SHAMOO: Do I understand you correctly 6 that the working group procedure is not going to 7 change, for example, we do teleconferencing, et 8 cetera, et cetera, and then the working group meeting 9 is private, not open to the public. And my thinking 10 is that really the working groups are working as a 11 subcommittee. I'm very familiar with NBAC because I 12 attended a lot of their meetings. We were a part of 13 the NBAC "groupies" they're called. 14 The subcommittees met. A lot of people 15 from the committee, even though they are not members 16 of that subcommittee attended the meeting, 17 participated in the discussion, and they have the 18 same material. And here we don't have that 19 opportunity. We don't have the material, we don't 20 know when they meet, and the public definitely does 21 not have any access to the deliberations. 22 The important thing is accountability and 709 1 deliberation and both now are lacking. The working 2 group, as I understood from Kate, is collect 3 information. And none of the working group so far I 4 have seen is really purely collecting information, 5 rather they were trying to develop a product. So 6 they are really functioning as a subcommittee. So 7 it's up to the committee and you, Mary Faith, to 8 decide that. But my thinking is that we should 9 consider making at least when we have in person 10 working group that the meeting is open to whoever 11 want to attend that meeting. 12 CHAIRPERSON MARSHALL: I think that's a 13 good suggestion. We talked about it a little bit, 14 you know, we do need mechanism to put words on paper. 15 But that's a good suggestion. That if a working 16 group convenes, you know, physically in a place that 17 that is advertised and that it's open to whomever 18 would like to attend. So we will ensure that in the 19 future that happens. 20 And I do hope that in terms of access that 21 we are fair in that regard also. These meetings are 22 public. The public has the opportunity, you know, 710 1 via the e-mail to comment on any product. So I 2 recognize that letting all members of the public know 3 that they have access is a problem. And I do 4 remember at the first meeting asking that if there 5 are any suggestions and certainly asking advocates 6 and professional associations -- advocacy 7 associations to please put the word out, let your 8 membership know via whatever communication mechanism 9 you have what our web site is and that anyone is 10 invited to weigh in. 11 And if there are further suggestions in 12 terms of the way we can get the word out, please let 13 us know. 14 Greg. 15 DR. KOSKI: Again, Kate is the expert on 16 this, but this committee obviously as a federal 17 advisory committee is governed by the requirements of 18 the FACA, you know, Act, or the Federal Advisory 19 Committee Act. There are provisions within that act, 20 as I understand it, for working groups that are not 21 open public meetings. They're certainly nothing 22 secret or that's non-transparent or in any way 711 1 deceptive about the working group structure as it has 2 been used to this point. After all, every single 3 piece that comes back from any of them is openly 4 discussed clearly before this group. 5 And I would urge that the committee retain 6 the option for utilizing working groups in an 7 appropriate manner so as to not encumber the progress 8 of the group, recognizing that the principal and the 9 goal has been so clearly delineated, not only by the 10 members, but by the chair is to have an open, robust, 11 and inclusive process. So, don't cut off your nose 12 to spite your face. 13 CHAIRPERSON MARSHALL: Felice? 14 DR. F. LEVINE: Let me just comment that 15 I, of course, share the common view that's emerged 16 that when we put the financial relationships report 17 up that I'll say we should go with the one that's in 18 the book. But I think in that spirit, I think with 19 the informed consent of that working group, I that 20 cover memo will need to be shifted because it still 21 sounds like it's the first paragraph of the letter. 22 But I think working groups are different 712 1 from subcommittees. As I said in December, 2 biographically, I sit on the Secretary of Commerce's 3 Decennial Census Advisory Committee and we have 4 working groups extremely productively to do leg work. 5 But I think all of us are now articulating and 6 reaffirming that it's a subvehicle of getting stuff 7 to this group as things go back and forth and 8 ultimately what is owned is owned by this group. 9 In that context, when we have had meetings 10 in and around our Decennial Advisory Committee which 11 also meets more or less quarterly and if there's a 12 scheduled time for working groups, you know, anybody 13 can sort of sit in who might like, but obviously 14 because a lot is done by conference call and other 15 vehicles that while the products are transparent and 16 widely disseminated, and the whole notion of these 17 groups is to bring input from wide audiences, I think 18 there is a role for that leg work that just couldn't 19 happen as a committee as a whole. And I think that's 20 why FACA permits that to happen that way. 21 CHAIRPERSON MARSHALL: Thank you Felice. 22 I think that just to clarify that in the 713 1 future that if our working groups are physically 2 getting together in a geographical location, we will 3 make that known ahead of time so that whoever would 4 like to attend that can attend. 5 Abbey, I also wanted to just speak to your 6 concern about proportionality or the ratio of perhaps 7 public members isn't the right term -- but I want to 8 make sure that your concerns are adequately spoken 9 to. I do have a note from Marc who says, "I think 10 that Abbey is right. The Committee should" -- he 11 says, "consent to any appointment of a noncommittee 12 member to a committee working group." And I'm not 13 sure whether that's what you were getting at, so 14 could you just clarify so that I'm clear about the 15 point that you wanted to make? 16 MS. MEYERS: It is proportionality because 17 there should be more members of this committee on any 18 subcommittee than there are members of the public. 19 And we should be sure that it's evenly balanced so 20 that the people on the committee, if we're talking 21 about regulations, that pediatricians are going to 22 have to abide by in the future, we should not have 714 1 100 percent pediatricians on that committee. Because 2 they're not going to vote to regulate themselves. 3 CHAIRPERSON MARSHALL: Thank you. Do you 4 feel as though what we've talked about today in terms 5 of process and procedure adequate addresses those? 6 We certainly can put on our web site the composition 7 of any committee. Do you think that as we are 8 convening initially our committees that we need to 9 get that information to the full committee to consent 10 to in terms of what the group looks like? 11 MS. MEYERS: The way this committee is 12 right now, it looks like we have four committee 13 members and 11 non-committee members on the 14 committee. 15 CHAIRPERSON MARSHALL: But remember that I 16 consider our ex officio members as members. I mean, 17 we can't convene a meeting by our charter without the 18 majority of them present. So are you considering 19 them in a different light than I am? 20 MS. MEYERS: I don't know. What's the 21 number of the government liaison? 22 CHAIRPERSON MARSHALL: I think we have 25 715 1 -- 22, thank you. Twenty-two ex officio -- 22 2 agencies that are represented. 3 MS. MEYERS: Okay. This subcommittee 4 doesn't have 22 ex officio members on the 5 subcommittee? 6 CHAIRPERSON MARSHALL: No, but are you 7 asking that every working group be sort of a small 8 duplication in terms of proportionality? I mean, I 9 think that we need to be fair that we have the 10 expertise and the voices of those who should be at 11 the table, at the table. And that's my primary 12 concern rather than direct proportionality, is that 13 everyone who should have a voice is there. 14 MS. MEYERS: Yes. 15 CHAIRPERSON MARSHALL: Then we don't laeve 16 people out. That's my big worry. I don't want 17 someone who wants to be at the table not to be at the 18 table. 19 MS. MEYERS: I'm afraid to say, but the 20 members of this committee should be increased on that 21 committee so that more people -- and I'm not 22 volunteering for it, because they already -- they got 716 1 me for another one. 2 CHAIRPERSON MARSHALL: I had Greg, and 3 then Denyse, and then Adil, and Alan. And you've got 4 about four minutes. You each have a minute. 5 DR. KOSKI: I have to take issue with the 6 assertion, Abbey, that pediatricians couldn't vote to 7 regulate themselves in a sense. I'm sorry, I think 8 it's an important point and I don't mean to quibble 9 here, but the important point is to have the 10 necessary expertise and the thoughtful -- you know, 11 the wisdom, the collective wisdom of the people 12 there. Indeed to adopt the position that because one 13 happens to care for children one is incapable of 14 putting the interest of the children somehow ahead of 15 their -- I think it makes a statement that I don't 16 think you intended to make. 17 You know, these working groups are not 18 voting groups, or anything. These are groups that 19 are working toward a product that comes back to this 20 committee. And, indeed, there are numerous examples. 21 In fact, you know, many of the regulations and all 22 there are things that the scientific community have 717 1 developed in consult with the public and others, 2 emphasis specifically for the purposes of regulating 3 themselves and recognize the value there. 4 So, again, I don't mean to quibble, but I 5 think it does a disservice to the dedicated members 6 of a variety of communities if we somehow impugn 7 their reputations or their judgments saying that they 8 wouldn't be able to act in a responsible manner. 9 CHAIRPERSON MARSHALL: Kate. 10 DR. KIRSCHSTEIN: I don't want to belabor 11 this, but I just want to indicate that both from a 12 philosophical and a logistical perspective, I agree 13 with what Greg is saying. But in particular, from a 14 practical perspective, again, we had 17 members of 15 the committee. You can't have many more than five 16 committee members on each workgroup. It's just not 17 feasible. 18 And the issue is, I think, I'd love to 19 talk with you more about this independently. But the 20 issue is, do we have, as Greg said, adequate 21 representation with respect to the issue we're 22 addressing and do we have a reflection of the public 718 1 of say consumer person as we did, we looked for one, 2 two and three consumer type people for the workgroup 3 and diversity as well. And I think that's what you 4 really are getting towards is the issue of balance 5 and objectivity. And that's what we've been striving 6 for and I think we should continue to do so. 7 CHAIRPERSON MARSHALL: Denyse. 8 DR. THORNLEY-BROWN: [Bad mic.] I 9 basically wanted to say two things. We don't need to 10 be worshiping at the altar of numbers. Ultimately 11 the product -- important and that's the thing that we 12 all bring to the table. So we have this product -- 13 CHAIRPERSON MARSHALL: Thank you. Adil. 14 DR. SHAMOO: Well, I was the one who 15 brought the assent issue. Regardless of what the 16 composition is, I think the committee should -- there 17 should have been a proposal. Here is the 18 composition. Here are the members, and I said, most 19 likelihood we will give the nod for it. But that 20 hasn't happened and I think that was missing. And it 21 still is missing. To be very honest these working 22 groups were appointed by a process where the 719 1 committee had no ownership in them. 2 CHAIRPERSON MARSHALL: If I'm remembering 3 the process, I asked at the last meeting people who 4 are interested and those sort of were the people who 5 ended up on the committee, I hope, and then we, as 6 Kate said, tried to balance it in terms of looking 7 for outside expertise. But, what we will do in the 8 future, Adil, is for the members of the committee, we 9 will post the names of those who have been appointed 10 to working group and ask that via the e-mail or a 11 call to Kate, or whatever, if you have -- you want to 12 register a concern about the composition of the 13 committee that you let us know. How does that sound? 14 DR. SHAMOO: Well, I have mentioned to 15 you, I would like to see Vera Sharov be in the 16 children's group. She has worked for two years 17 studying that issue and I think she has an input. 18 And I think the committee really does not have 19 someone like her with her point of view on the 20 committee and I think she should be. 21 CHAIRPERSON MARSHALL: Thank you, Adil. 22 And Alan, you were next on the list. 720 1 DR. FLEISCHMAN: I just wanted to give us 2 some evidence here. The committee consisted of the 3 executive director who both was participant and staff 4 of NHRPAC. Five NHRPAC members, three 5 representatives of ex officio groups, one public 6 advocate, and six academic pediatricians representing 7 different expertise ranging from neonatology to 8 public policy to infectious diseases to diversity and 9 adolescent issues in mental health. 10 So, the actual mechanisms of having 11 thought about those six members, had to do with the 12 recommendations to the Secretary from the Congress 13 about the kinds of pediatricians that ought to be 14 considered in helping to analyze the regulations. 15 And, in fact, that was part of the conversations that 16 we had in trying to put together this committee so 17 that we could fulfills some of the obligations that 18 were part of the request. And I certainly felt that 19 those different types of pediatric scientists and 20 ethicists were important -- you know, gave us 21 different groups. 22 And, then finally, the American Academy of 721 1 Pediatrics has a bioethics committee. Skip Nelson 2 happens to, I think, chair it at the moment. And 3 they have been -- not anymore. He just shifted and I 4 haven't been on it for a few years. 5 That bioethics committee tries to create 6 ethical guidelines for the practice of pediatricians 7 and is dramatically criticized by pediatricians for 8 being overly concerned with ethical regulatory 9 structures. So it isn't that pediatricians haven't 10 had that role previously in trying to regulate their 11 own practices. 12 CHAIRPERSON MARSHALL: Thank you very 13 much. And we need to wind down. We don't have a 14 quorum anymore. And I'm sorry people have had to 15 drift off. 16 Alan, thank you very much for your work in 17 chairing the pediatrics group. And I would like to 18 thank each and every one of you for being here and 19 for your work during the interim. And I look forward 20 to hearing from you soon on our work products and to 21 seeing you at our next meeting. 22 Thank you all. 722 1 [Whereupon, at 4:35 p.m., the meeting was 2 adjourned.] 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22