1 1 2 3 NATIONAL HUMAN RESEARCH PROTECTIONS 4 ADVISORY COMMITTEE 5 6 Thursday, December 21, 2000 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 2 1 ATTENDEES 2 MARY FAITH MARSHALL, Ph.D., Chairperson, Director 3 of Program in Bioethics, University of Kansas Medical Center 4 5 GREG KOSKI, Executive Secretary, Ph.D., M.D., 6 Director, Office of Human Research Protections, 7 Office of Public Health and Science, OS 8 9 MARK BARNES, J.D., LL.M., Partner, Proskauer Rose, LLP 10 SANFORD CHODOSH, M.D. 11 12 ELLIOT N. DORFF, Ph.D., Rector, Distinguished 13 Professor of Philosophy 14 15 JENNIE R. JOE, Ph.D., M.P.H., R.N., Professor, 16 Family and Community Medicine, University of Arizona 17 18 ROBERT LEVINE, M.D., Professor of Medicine, Yale 19 University School of Medicine 20 21 ABBEY S. MEYERS, President, National Organization 22 for Rare Disorders 3 1 ATTENDEES (Continued) 2 MARY Z. PELIAS, Ph.D., J.D., Professor, Department 3 of Genetics, Louisiana State University Health 4 Sciences Center 5 6 ROBERT R. RICH, M.D., Executive Associate Dean of 7 Research, Emory University School of Medicine 8 9 ADIL E. SHAMOO, Ph.D., Professor, Department of 10 Biochemistry and Molecular Biology, University of 11 Maryland School of Medicine 12 13 JUDITH L. SIEGEL, Ph.D., Vice President, Head U.S. 14 Clinical Operations, Hoffman-La Roche, Inc. 15 16 DENYSE THORNLEY-BROWN, M.D., Assistant Professor, 17 Division of Nephrology, University of Alabama at Birmingham 18 19 KATE-LOUISE GOTTFRIED, J.D., M.S.P.H., Executive 20 Director, National Human Research Protections 21 Advisory Committee 22 4 1 ATTENDEES (Continued) 2 JACKIE COLEMAN, Personnel Specialist, Program Support Center 3 DONNA E. SHALALA, Secretary of Health and Human Services 4 5 EDWARD M. KENNEDY, Senator of Massachusetts 6 FELICE J. LEVINE, Ph.D., Executive Officer, 7 American Sociological Association 8 9 STUART L. NIGHTINGALE, M.D., Senior Medical Advisor 10 to the Assistant Secretary for Planning and Evaluation 11 12 DAVID SATCHER, M.D., Ph.D., Assistant Secretary for 13 Health and Surgeon General 14 15 DIXIE E. SNIDER, M.D., M.P.H., Associate Director 16 of Science, Centers for Disease Control and Prevention 17 18 ALAN FLEISHMAN, M.D., Senior Vice President, New 19 York Academy of Medicine, Clinical Professor of 20 Pediatrics and Clinic Professor of Epidemiology & 21 Social Medicine, Albert Einstein College, New York 22 ROBERT COOKE DEAGAN, National Institute of Medicine 5 1 P R O C E E D I N G S 2 [Time noted: 9:10 a.m.] 3 CHAIRPERSON MARSHALL: Welcome back, all 4 of our visitors from yesterday and folks who may 5 have not been here yesterday, welcome to the second 6 day of our committee meeting. 7 Our agenda for the morning calls for a 8 recap of yesterday's proceedings, and we're handing 9 out to each of you a summary of the action plans 10 that were discussed yesterday. They will also be 11 discussed and assigned priority at the end of the 12 day today and based on the business at hand on our 13 agenda, which includes a discussion of the 14 Declaration of Helsinki and research involving 15 children. 16 I'll make you a couple of promises, 17 committee members and community members and our 18 liaisons with federal agencies, and that is that we 19 will end on time. We actually perhaps made history 20 yesterday and ended 15 minutes early. 21 So I know that people have flights to 22 catch and things to do and we will finish on time, 6 1 if not slightly before. 2 So you have in front of you this document 3 that tells you what we did yesterday. 4 The focus of our discussions yesterday, 5 the first item to which we assigned the highest 6 priority had to do with the relationship of the 7 social and behavioral sciences to the system for 8 reviewing human research subjects protections, and 9 I think that it was a very fruitful. I am sure 10 will be more discussion as we move along because 11 there are some very serious concerns among members 12 of the social and behavioral sciences community. 13 And Jennie Joe, who is a member of our 14 committee, was, unfortunately, unable to be here 15 for part of that discussion or for that discussion 16 yesterday morning, but she will be integrally 17 involved as we proceed in this area. 18 So what we decided to do in terms of 19 action plans relative to non-biomedical research 20 was that we would make a formal request of the 21 American Sociological Society, as well as other 22 social and behavioral sciences organizations for 7 1 guidance on how to proceed with both the how and 2 the what, the concrete approach to human subjects 3 protections in non-biomedical research. 4 And we will, as well as was suggested by 5 Robert Levine, review the existing paper that was 6 written 20 years ago by Jerry Mashaw on social and 7 behavioral sciences research, and -- I'm sorry, 8 Bob? 9 DR. ROBERT LEVINE: I'm so sorry. I'm 10 sorry if I created a misunderstanding. His paper 11 was on the structure of IRBs, generally. 12 CHAIRPERSON MARSHALL: Oh, okay. Okay. 13 So we will ask him to revisit that then, perhaps, 14 and commission a paper that would include the 15 social and behavioral sciences. 16 Is that correct? 17 DR. ROBERT LEVINE: That's good. Thank 18 you. 19 CHAIRPERSON MARSHALL: Thank you for 20 correcting me. 21 And we need data. We need information in 22 terms of proceeding on this issue, and a spectrum 8 1 of issues. 2 It was suggested that we look at the 3 relationship between the number of persons who are 4 engaged in social and behavioral sciences research 5 and how many social scientists there are who serve 6 as members of IRBs or administrators or Chairs, and 7 how often are social and behavioral sciences 8 protocols disapproved because of risk and harm to 9 the subject. 10 And something that came up thematically 11 throughout the discussion on the social and 12 behavioral sciences had to do with risk and the 13 definition of "risk" relative to the review 14 process. And so we felt that it was vitally 15 important to explore this issue of risk and where 16 it fell out relative to the review process or the 17 exemption process. So we will also ask, probably 18 commission, some work on the definition of "risk" 19 as it applies to subjects of research in the social 20 and behavioral sciences, and how that would relate 21 subsequently to the review of that research. 22 So those are our current plans for non- 9 1 biomedical research. 2 Yes, Bob? 3 DR. ROBERT LEVINE: I just want to make 4 one additional suggestion on that, and that is I 5 believe that the survey conducted by OPRR, Charles 6 McKay was in charge of it, done with the Jayvel 7 Corporation, may have information on social and 8 behavioral scientists and IRBs. So we might be 9 able to -- maybe someone here knows for sure? 10 No? Well, I think it would be worth 11 checking that before we started to do it again. 12 CHAIRPERSON MARSHALL: Thank you, Bob. 13 Bob? 14 DR. RICH: I'd like to just again 15 reiterate my concern about getting a better sense, 16 more clarity as to where the boundaries of IRB 17 responsibility to the social and behavioral 18 sciences really extend. 19 At least I know in my university, I have 20 had concerns that a fair amount of things that are 21 out there in the non-biomedical arena that may 22 perhaps properly come to an IRB is basically not 10 1 being thought about as being IRB appropriate. 2 And I think that in universities, for 3 example, even that have other kinds of professional 4 schools, I had previous discussions with Greg about 5 the situation at Harvard where some of the non- 6 biomedical professional schools, I believe the law 7 school, for example, or the business school, have 8 IRB-mandated activities. 9 And I think that as we look at the social 10 and behavioral sciences, it would be good for the 11 community to begin to try to draw the boundaries 12 because particularly I think we blur the boundary 13 between research and education in the undergraduate 14 university. 15 A lot of things that you and I might 16 regard as research in another context might be 17 simply seen as part of the educational process, and 18 as we all are painfully aware at least that the 19 previous work from OPRR, actually, shut down 20 universities on the basis of not having the clarity 21 about some of those issues, so -- 22 CHAIRPERSON MARSHALL: Right, and so let 11 1 me ask you about, then, in looking at this, 2 revisiting the commissioned paper by Jerry Mashaw, 3 and perhaps asking him to revisit this issue, 4 whether that could be something that would be 5 incorporated into his charge? 6 Yes? 7 DR. RICH: If that works. It's clarity in 8 my mind, and I suspect I'm not the only person who 9 has that issue. 10 CHAIRPERSON MARSHALL: Bob? 11 DR. ROBERT LEVINE: I doubt that Professor 12 Mashaw would agree to do that. He's a professor in 13 the law school, and he was much more interested in 14 decision-making bodies than exactly what decisions 15 they were making. 16 So I think -- 17 CHAIRPERSON MARSHALL: So we will find the 18 appropriate person. Thank you very much, Bob. 19 Greg? 20 DR. KOSKI: The umbrella organization for 21 many of the social and behavioral sciences, COSSA, 22 the Coalition of Social Sciences Associations, may 12 1 be a group to go to in terms of getting some 2 guidance on how to proceed with this as with 3 respect to, you know, appropriate people and so on. 4 And it would be a shortcut way to do this, so we 5 should contact them. In fact, we already have 6 connections with them. I'm sure we can take 7 advantage of that. 8 CHAIRPERSON MARSHALL: Thank you, Greg. 9 DR. CHODOSH: Can I just make a slight 10 modification, and that is on the one about 11 collecting the data, and I don't know if we took it 12 out intentionally, but the idea was to look at how 13 many social science protocols are looked at by an 14 IRB, as compared to how many social sciences they 15 have on the board. 16 CHAIRPERSON MARSHALL: You are correct. 17 We need to look at that ratio. Thank you for 18 keeping us honest, Sandy. 19 The second half of the day was also 20 interesting in terms of its discussion, and I think 21 it was a little easier for us to come up with a 22 working plan. 13 1 In general, the discussion about financial 2 relationships and conflicts of interest started out 3 perhaps in a narrow fashion, but it very quickly 4 broadened. 5 And the committee felt that there are many 6 forms of conflict of interest, some of them hidden, 7 some of them that are more subtle, but just as 8 insidious as others that may be more blatant. 9 And so part of our concern is that we 10 address all of those financial relationships in 11 addition to obvious conflicts of interest, so we 12 will do that. And to that end, we have created a 13 working group that Mark Burns has agreed to chair, 14 to draft a response to the draft interim guidance 15 that was presented yesterday by Stuart Nightingale. 16 And that working group that you can see includes 17 Sandy Chodosh, Elliot Dorff, Adil Shamoo and Judy 18 Siegel. 19 And Stuart Nightingale will be available 20 as a consultant to the working group and may -- I 21 think we could say will -- also assist in the 22 reviews since this is an incorporation of incoming 14 1 comments from the web and draft or otherwise to the 2 draft guidance. 3 And we want to let you know then the final 4 item. As you can see, there is that as soon as 5 possible, I might say immediately, if not sooner, 6 that draft interim guidance will be posted on the 7 Office for Human Research Protections web site for 8 public comment. 9 And we also want to provide access to the 10 guidance so that organizations and other 11 association will assure dissemination to their own 12 constituencies. Abbey, yesterday, raised a vitally 13 important point and that is that there are many 14 people in the world who don't read the Federal 15 Register, and there may be many people in the world 16 who don't read the OHRP web site. 17 So I would call upon our professional 18 associates who are here today and our public 19 members to please help us either in letting us know 20 of organizations with which we could link or other 21 venues that would be appropriate for communicating 22 with groups and organizations so that we can assure 15 1 the best possible dissemination and the fullest 2 response to what we are about, and input into the 3 draft guidance as possible. 4 MS. GOTTFRIED: There was a paper outside 5 with that. We'll make sure it's available, that 6 has the OHRP web site, as well as a couple of other 7 links. 8 DR. KOSKI: Madam Chairman, we will 9 actually talk with our technical people in OHRP and 10 see if we can't establish a separate web page for 11 NHRPAC that will be something that pops up so that 12 when people search, they'll actually find, you 13 know, human research protections and come to the 14 NHRPAC. 15 I think that will be valuable both to 16 emphasize the important role of this committee, but 17 also, in the pragmatic sense of being able to go to 18 one spot to get this information. So we'll work on 19 that. 20 CHAIRPERSON MARSHALL: And, in that 21 spirit, I'll repeat what I said at the close of 22 yesterday, and that is, I would encourage any and 16 1 all of you, if you have particular concerns, to 2 contact members of the committee, to contact me, to 3 contact Greg and Kate. We want to hear from you. 4 Our philosophy is that this is your 5 committee. This is a public committee. We very 6 much value your input, and it will be taken to 7 heart. 8 Just to give you a sense, for those of you 9 who weren't here yesterday, about the proceedings 10 today, and I hope that it worked well yesterday -- 11 my sense in the discussions afterwards was that it 12 did work well -- is that during -- that we will 13 have two papers presented. Afterwards, there is a 14 discussion period and I will break that discussion 15 period down as follows: 16 I will give precedent to committee members 17 to ask questions of the presenter and to have 18 discussion among themselves. Then I will give time 19 to our ex officio members and our agency liaisons, 20 and then there will be time for our public members 21 also to ask questions and to participate in the 22 discussion. 17 1 One of our cardinal rules is that we want 2 to insure that everyone who should be at the table 3 is at the table, and not only that they are at the 4 table, but that they are heard. And so that is a 5 promise from us to you. 6 So let me ask just before we begin with 7 our first paper presentation if there -- we've 8 heard from committee members, but if there's anyone 9 who's an ex officio member, who is a liaison from 10 an agency or one of our public members, if there is 11 anything that you have to say about out action 12 plans that we've presented this morning that 13 doesn't hold true to the discussions that we had 14 yesterday? 15 And, please, do identify yourself and your 16 affiliation or your interest. 17 MS. BLEVINS: Sure. Sue Blevins, 18 Institute for Health Freedom, and I'm interested in 19 helping the public become aware of their basic 20 human rights involved in participating in research. 21 So just so that you know what my agenda is 22 and not to in any way stop medical research. I 18 1 just want to make that clear. I want to support 2 you all, but basically we get questions about what 3 are individuals' rights. 4 To that end, yesterday, I just want to 5 share this one comment, and that is to make sure 6 that you mention fairness and transparency, and I 7 know to be efficient, you need to go off and do 8 things in small groups to make it efficient. 9 People constantly want better efficiency in 10 government. 11 But I would like to make sure that the 12 minutes, the notes and all the themes that are done 13 behind closed doors are made available as if it 14 were done in the open. So that's just a 15 suggestion. 16 CHAIRPERSON MARSHALL: It's a wonderful 17 suggestion and it is something that we have 18 discussed. And we promise you that everything that 19 this committee does will be transparent. 20 So even though there may be work that's 21 done by conference call or via the Internet, as 22 soon as there is a draft product, it will be out 19 1 there. 2 So thank you so much for bringing that up 3 and we will do that. 4 MR. SHELTON: Yeah. Jim Shelton, U.S. 5 Agency for International Development. 6 Just two reactions from yesterday. One 7 is, I really like the point I think that Dr. Shamoo 8 was making yesterday, at least I took from it, 9 about trying to get as much evidence and sort of 10 see the whole picture before kind of going, making 11 too many decisions. 12 And I think it's really important to be 13 evidence based, and I think it's very easy to see a 14 very small piece or a pretty big piece, but not the 15 whole piece. 16 And I would just encourage people to 17 really look at the whole thing before, because it 18 is very complicated. It's very, very different. 19 So that's one thought. 20 The other thought is very specific. The 21 issue of the 26 percent overhead, it occurred to 22 me, and I guess it's occurred to others, I don't 20 1 actually see why some of the funding for some of 2 the activities couldn't be directly funded and 3 wouldn't necessarily have to come out of the 26 4 percent. 5 And I understand this issue came up in the 6 context of research integrity, and, in fact, NIH 7 was on record as saying that there might be ways of 8 supporting it more directly, which I think would 9 make a lot of difference in the university context. 10 CHAIRPERSON MARSHALL: Thank you, Jim, and 11 we'll respond to both of those. 12 I guess relative to your first point, it 13 is well taken, and I think we are extremely 14 sensitive to the fact that to do things in haste 15 would be tragic, and that we want the products and 16 the work of this committee to be well thought out 17 and to be excellent. 18 So I guess our thinking is this: We do 19 have a charge. We do have issues that we need to 20 look at, but the agreement that I have made with 21 Greg and with Kate and with those who have given us 22 our charge is that although we may make 21 1 recommendations that we will have the prerogative 2 of going back and revisiting them or that we will 3 establish them from the outset as interim, and that 4 they do need to be factually based and evidence 5 based. 6 Someone asked yesterday, "What's the 7 difference between our committee and between the 8 National Bioethics Advisory Committee," and I think 9 one difference is this: 10 The National Bioethics Advisory Committee 11 looks at issues and is charged to look at issues 12 from, in a sense, a theoretical perspective. They 13 do some applied work, but they are doing a lot of 14 intellectual heavy lifting. 15 Greg has talked about taking the "I" out 16 of IRB. Our sense is that our job is to put the 17 "A" back in applied ethics, so that's what we're 18 going to do, and thank you very much. 19 And if you feel that we're moving off 20 course, then, please, do let us know. 21 And Greg wanted to respond to your second 22 question. 22 1 DR. KOSKI: Yes. Thank you, Jim. 2 As I've mentioned before, there have been 3 ongoing discussions about that, and I'm certain 4 that the folks at NIH have expressed an interest in 5 finding appropriate mechanisms for funding. 6 There has been some suggestion of, you 7 know, the possibility of looking at the 26 percent 8 cap. Certainly there are types of activities that 9 are protocols or, you know, project specific that 10 would be very legitimate direct costs for 11 individual research grants and so on. 12 On the other hand, there are other aspects 13 of this whole process that would not be 14 appropriate. So it's going to be a process of, you 15 know, continuing to work on it and look to make 16 sure that there are adequate resources available in 17 order to meet these very important 18 responsibilities. 19 So that would be an ongoing project, but 20 it's convincing the Office of Management and Budget 21 that, you know, we should sort of soften the cap is 22 not a minor undertaking, but it's certainly that 23 1 people are looking at, so we'll go forward. 2 CHAIRPERSON MARSHALL: Thank you for that? 3 Yes? 4 MR. MESA: John Mesa with the VA. 5 I just want to go back to Jim's point very 6 briefly where he used the word, "evidence based," 7 in your response. 8 One of the things that impressed me 9 yesterday about the deliberations was that you were 10 really clear and straightforward in trying to get 11 to the heart of where the facts and the data were. 12 I also think you had an opportunity, also, 13 to identify where the gaps are and where the 14 knowledge base is weak, insufficient, or even 15 absent, and thereby promote, in essence, the 16 gaining of that knowledge in some manner or 17 another, either through professional testimony or 18 through the literal collection of data, and 19 possibly even promoting the establishment of 20 research agenda in the area of human rights 21 protection. 22 I say that in the sense that I think one 24 1 of the things that convinces researchers maybe 2 there's robustness to all of this activity is there 3 some research data that proves to them, at least in 4 their minds, that this is solid kinds of stuff. 5 So I would encourage you that where there 6 are honest gaps, that those get put on the table, 7 explicated, captured into themselves. 8 CHAIRPERSON MARSHALL: Thank you. And one 9 last. Paul, we'll give you the last word here. 10 MR. RUBEN: Philip Ruben, ex officio, 11 National Science Foundation. 12 Following up on something Greg said, as to 13 distribution of information, COSSA has an excellent 14 newsletter that gets very wide distribution and 15 high visibility, so I would suggest sending stuff 16 to Howard Silver to be included in there. 17 And another point that came up in the 18 summary yesterday in the recommendation section was 19 the consideration of the bouncing of risks and the 20 definition of "risk." 21 Thank you. 22 CHAIRPERSON MARSHALL: Yes. Thank you 25 1 very much. 2 Elliot? 3 DR. DORFF: I mention this only because 4 it's not on our agenda, at least for this meeting, 5 and maybe it ought to be. 6 The last night I spent with an old camp 7 friend, who happens to be in charge of the NIH, 8 happens to be in charge of the drug and alcohol 9 abuse programs, and one of the points that he made 10 to me was that, when you're talking about drug 11 abusers, you're not talking about -- the way that 12 the regulations are set up is that they assume a 13 one-time entrance into a correctional facility, and 14 that's it, whereas in a point of fact, it's a 15 revolving door. 16 So I think that one of the things, 17 especially since there is a special subpart about 18 prisoners in the regulations, that one of the 19 things we can ask COSSA and whoever else is writing 20 that report to address is the kind of research that 21 goes on in terms of drug abuse, dealing with people 22 who are in and out of prison centers. 26 1 CHAIRPERSON MARSHALL: Elliot, you may not 2 know this, but my own area of research is perinatal 3 substance abuse, and you've spoken to my heart. 4 So, well said. We will make sure that that's done. 5 Adil, last word because we need to move 6 on. 7 DR. SHAMOO: One question I had to put our 8 mission in perspective, and I think our liaison or 9 ex officio may be able to provide us, how many 10 human subjects we're talking about earlier within 11 the federal sector, the public sector and the 12 private sector, whether it's 100,000, millions or 13 tens of millions. 14 And I think NIH and FDA may be able to 15 provide us those numbers to put boundaries to what 16 our mission is. 17 CHAIRPERSON MARSHALL: That's an excellent 18 point. It would probably also be helpful to the 19 IOM Committee that's looking at systems for 20 protections of human subjects. Those would be 21 incredibly important data. 22 Thank you, Adil. 27 1 So let us move on, then, to our first 2 presentation regarding the declaration of Helsinki. 3 Dixie Snider is going to present that paper, and 4 Dixie is the Associate Director of Science at the 5 Center for Disease Control and Prevention. 6 Welcome, Dixie. 7 MR. SNIDER: I was asked a few days ago by 8 Greg to introduce this topic to the committee. I 9 want to make it clear that we have not developed a 10 departmental position about the Declaration of 11 Helsinki, nor do we have an agency position. So 12 these are my personal reflections at this point. 13 We did have a meeting a few weeks ago 14 among several representatives from the op-divs, as 15 we call them, within the Department of Health and 16 Human Services, at which we discussed the 17 declaration, but we've not produced any document. 18 I'm sure that everybody here is aware of 19 the Declaration of Helsinki which was first adopted 20 in 1964. It certainly has been an extraordinary 21 document in terms of helping scientists throughout 22 the world to conduct ethical research. 28 1 It's gone through several revisions, most 2 recently in October of this year, the 52nd World 3 Health Assembly General Assembly, which met in 4 Edinburgh, Scotland, approved this latest version. 5 In this week's Journal of the American 6 Medical Association, the document is reproduced, 7 and along with it is a medical news and 8 perspectives article which says, "Helsinki Discord? 9 A Controversial Declaration." 10 By way of a very brief background, I need 11 to tell you where I'm coming from because, as they 12 say, you know, where one stands often depends on 13 where one sits. 14 I am trained in immunology, internal 15 medicine immunology, but quickly was converted to 16 public health more than 25 years ago now. 17 I have been a research subject. I have 18 been a researcher. I have been an IRB member. I 19 have been an IRB Chair, and I apparently serve as a 20 research administrator, I suppose you would say. 21 I have done a number of things since 22 become Associate Director for Science at CDC. One 29 1 is, I hope, increasing the visibility of human 2 research protections, increasing the visibility of 3 ethical conduct and research at CDC. 4 I spent about two and a half years working 5 very hard on the Presidential apology for the 6 Tuskeegee study and was a pest and refused to take 7 "no" for an answer for a long period of time until 8 people finally gave in. 9 I worked for an organization that has 10 about 8,000 employees, although over 2,000 11 scientists, who were stationed throughout the 12 world. So the work that we do is not done just in 13 the United States, but is done in many countries 14 throughout the world. 15 Most of the time when we're involved with 16 some things because we're invited, it's a different 17 paradigms than many others, but we're asked to come 18 because we possess some expertise. 19 So with that as a way of introduction, let 20 me just say that this new Declaration of Helsinki 21 has, as far as I'm personally concerned, some good 22 changes and some areas of concern, at least areas 30 1 that have confused a number of the researchers who 2 work at CDC, as well as researchers who worked in 3 some of the other agencies in HHS. 4 This latest iteration was, of course, 5 completed only after a very lengthy period of 6 discussion and debate, and what we're asking you 7 today, the focus of this discussion from our 8 standpoint, is how the Department of Health and 9 Human Services should use and react to the current 10 version of the Declaration of Helsinki based on 11 some of the observations that I'll make. 12 First of all, in your notebooks, you have 13 several documents. You have the Declaration of 14 Helsinki. You have the NBAC Report on 15 International Research. You have some side-by-side 16 comparisons of the 1996 version, compared to the 17 year 2000 version that Glenn Drew of NBAC was able 18 to put together for us. 19 Some of the very positive things I think 20 is that the declaration has moved from being 21 recommendations guiding physicians to ethical 22 principles. It's a stronger statement. 31 1 Bob? 2 DR. ROBERT LEVINE: Dixie, the agenda book 3 has two documents that give by side-by-side 4 comparisons by Glen Drew with two different dates. 5 Superficially, they appear to be about identical, 6 but which one are we going to be reading from? 7 MR. SNIDER: I'm using the one that has 8 the 1996 on the left and the 2000 on the right. 9 DR. ROBERT LEVINE: All right. That's the 10 December the 13th view. 11 The 14th reverses that. 12 MR. SNIDER: Okay. 13 DR. ROBERT LEVINE: Thank you. 14 MR. SNIDER: And I had planned to go 15 through it word by word. 16 DR. KOSKI: Can I just quickly comment on 17 this? 18 We included both of those because Glen 19 Drew found that some people preferred to have the 20 old version first and then the new version, others 21 like to have, you know, the other way around. We 22 figured we'd try to make everybody happy, but like 32 1 they say, you can't please all the people all the 2 time. 3 MR. SNIDER: Just to try to be efficient 4 with our time, let me just hit what I think are 5 some of the high points on the positive side. 6 I think item number six, for example, in 7 the 2000 version, which talks about the fact that 8 even the best proven prophylactic diagnostic and 9 therapeutic methods must continuously be challenged 10 through research, addresses an issue that Dr. Rich 11 brought up yesterday that in a lot of these 12 documents, we need to point out that research 13 usually is, certainly can be a societal good when 14 done properly. 15 On item eight, a whole new section is 16 added, particularly focusing on vulnerable 17 populations, which is not something that was 18 elaborated on as well in the earlier version. 19 One of the things I would draw your 20 attention to an item number nine, which is also 21 new, is that it indicates researchers should be 22 aware of the ethical, legal and regulatory 33 1 requirements for research on human subjects in 2 their own countries, as well as applicable 3 international requirements. 4 I would say that from the international 5 standpoint, they obviously should be aware of the 6 requirements within the countries in which they do 7 the research, as well. 8 Item number 13 I think has significant 9 enhancements in that it talks about IRB review 10 here, and the protocols should be submitted for 11 consideration, comment, guidance, and where 12 appropriate, approval to a specially-appointed 13 ethical review committee. 14 And, here, emphasizing that committee 15 should be independent of the investigator, the 16 sponsor, or any kind of undue influence. I think 17 this gets into some of the conflicts we were 18 talking about, and that the independent committee 19 should be in conformance with the laws and 20 regulations of the country in which the research 21 experiment is performed. 22 It also emphasizes an area that many 34 1 people have been critical of with regard to IRBs, 2 and that is the monitoring, the ongoing monitoring, 3 of the trials. 4 Now, as many of you know, there are data, 5 safety and monitoring boards which have been 6 created for certain clinical trials, which that 7 takes place outside the context of the IRB, but it 8 doesn't happen that the IRB -- that there is a DSMV 9 or a data monitoring board, and, certainly, the IRB 10 has responsibilities. 11 Again, in view, I think, of some recent 12 events, they had the wisdom to include the 13 statement that the researcher has the obligation to 14 provide monitoring information to the committee, 15 especially any serious adverse events, and that the 16 researcher should submit to the committee for 17 review information regarding funding, sponsors, 18 institutional affiliations, other potential 19 conflicts of interest and incentives for subjects. 20 So, again, this document, I think, is 21 moving forward with regard to some of the concerns 22 that were expressed yesterday. I think this is 35 1 very positive. 2 Item 27, which is on the next page of the 3 version I have, talks about publication in more 4 detail than the previous version, and that both 5 authors and publishers have ethical obligations, it 6 states. 7 The publication, the results of the 8 research, the investigators are obliged to preserve 9 the accuracy of the results, and negative, as well 10 as positive results, should be published or 11 otherwise publicly available, again a theme that 12 most of us who are familiar with research know has 13 been a shortcoming and I think a very positive 14 contribution by adding these new words to the new 15 2000 version of the declaration. 16 And sources of funding, again, are 17 mentioned in here in the context of being declared 18 in the publication. This has become a common 19 practice, of course, among the international 20 medical journal editors, but to have it as an 21 ethical principle I think is a very positive 22 statement. 36 1 And just one last point. There are many 2 points I could make about positive things here, but 3 on the last page, at least the last page I have 4 printed out from my computer, which is number 19 in 5 the 2000 version, medical research is only 6 justified if there is a reasonable likelihood that 7 the populations in which the research is carried 8 out stand to benefit from the results of the 9 research. 10 Much concern has been expressed recently 11 about that particular issue, and I think it's very 12 good that the 2000 version has been more explicit 13 on that particular point. 14 Now, there are, on the other hand, some 15 major concerns. The two largest concerns that I'll 16 discuss have to do with numbers 29 and 30. But 17 before I talk about that, let me just say that we 18 have noted that the document does not seem to, at 19 any point, deal with the issue of waiver of 20 informed consent. I think that perhaps was an 21 oversight, but it's silent on that point. 22 And most of you know, in our own federal 37 1 regulations at 45 CFR 46, or in the common rule, 2 there are conditions under which waivers for 3 research can be obtained. 4 But getting to the major issues of 5 concern, number 29 states that, "The benefits, 6 risks, burdens and effectiveness of a new method 7 should be tested against those of the best current 8 prophylactic, diagnostic and therapeutic methods. 9 This does not exclude the use of placebo or no 10 treatment in studies where no proven prophylactic, 11 diagnostic or therapeutic method exists." 12 Number 30 states that, "At the conclusion 13 of the study, every patient entered into the study 14 should be assured of access to the best proven 15 prophylactic, diagnostic and therapeutic methods 16 identified by the study." 17 And I think in most cases, we would all 18 agree that those wouldn't present problems. But 19 there are a number of situations in which this new 20 version and these statements in the new version 21 create some problems for some of us. 22 In calling for new treatments tested 38 1 against the best existing treatments, we would 2 agree that when trials with untreated or placebo 3 treated controls are used, when the condition being 4 treated is very serious and results in death or 5 some serious consequence, that it would clearly be 6 unethical. 7 On the other hand, placebo-controlled 8 trials are widely used in settings in which proven 9 treatment is available, as long as participants are 10 at little risk from the time that they have on 11 placebo. 12 For example, if they have allergic 13 rhinitis and they're going to suffer that for a 14 week or so until there's a crossover to an active 15 therapy. 16 There are so-called proven therapies that 17 have marginal value, and in some populations, may 18 have little or no value. And if you compared your 19 new intervention to the so-called best proven 20 therapy, you may get equivalent results. But what 21 it may show is that neither one of them are working 22 and if you have no placebo control. 39 1 And so there are some situations in which 2 we have some real concerns that it would be 3 appropriate to use placebo controls. 4 In my own setting, I have people who are 5 working overseas who have responded to this. These 6 folks are working in developing countries, some 7 people who are collaborating with the Kenyan 8 government and carrying out a multi-faceted program 9 of malaria research. 10 And part of that program involves the 11 ongoing project, studying a cohort of women and 12 children who are exposed to malaria. There is an 13 area of intense malaria transmission. And we're 14 assisting the Kenyan government in implementing the 15 first phase of a large-scale insecticide 16 impregnated bed net trial. 17 And we're going to assess whether children 18 under five years of age who sleep under those nets 19 have a lower crude and specific mortality compared 20 with children who don't sleep under those nets. 21 That's obviously a placebo control of sorts. 22 Now, we, like everyone else I think in 40 1 public health, would love to deliver the best 2 proven method, which would be to have a strong 3 vector control program in that country, to have 4 everyone have housing that has screens, preferably 5 air-conditioned homes, but we are unable to provide 6 that, either as individuals or as an institution. 7 And so I have investigators coming back to 8 me, saying, "Are we behaving unethically? Should 9 we not be involved in this trial?" 10 Similarly, we have people working in 11 developing countries. We have a project that's 12 going on to provide potable water in households, 13 and it involves teaching people how to use a 14 specially designed container that they can use to 15 have water that they can drink. 16 Again, it's being compared against a 17 placebo, which is what they have in the community, 18 nothing. 19 We know what the best proven intervention 20 would be, which would be a filtered, piped water 21 system. We would dearly love to provide it. 22 We, like many of the other people in this 41 1 room, would like there to be better economic and 2 social equity in this world, but given the fact 3 that we are operating in a world with these kind of 4 inequities, we're trying to do what we can do 5 incrementally to help improve the lot of people in 6 developing countries in these particular 7 situations. 8 There's also the issue of what is the 9 definition of best proven therapy. An example that 10 comes to mind a few years ago were the acellular 11 pertussis vaccine trials. 12 Many of you may be aware that, for some 13 time, Sweden had decided to do away with DPT 14 vaccine, the wholesale pertussis, because they felt 15 the harms from the vaccine were worse than the 16 disease. And so the government and the public 17 stopped using wholesale pertussis vaccine. 18 Consequently, it was with some enthusiasm 19 that they embraced the trial of the acellular 20 pertussis vaccine, which is now on the market here 21 and in other developed countries, and, hopefully, 22 will be available in developing countries before 42 1 long, which is a much safer vaccine. 2 And the fact that we were able to compare 3 the acellular pertussis vaccine to placebo, of 4 course, was an important thing for Sweden, and 5 allowed them to begin to vaccinate against 6 pertussis, which had been, during the period that 7 they were not vaccinating, a significant public 8 health problem. 9 So I think the issue of best proven 10 therapy presents us some problems in terms of 11 definition. It presents us some problems in being 12 able to deliver in certain circumstances, and it 13 presents some scientific issues in terms of whether 14 you can, through alternative designs, actually get 15 the answers to the questions that you want. 16 Or, in some cases, it may conflict with 17 another of the principles in the Declaration of 18 Helsinki, which says that the research, as I 19 pointed out, should be relevant to the country. 20 Well, if the hypothesis being tested is 21 one in which you're comparing the best proven 22 therapy to a new intervention, but that best proven 43 1 therapy will not be available in that country, one 2 would say that research hypothesis and that study 3 is not relevant for that country. 4 So does that mean you don't do any studies 5 in that country, or is an alternative design one 6 that can be entertained under those circumstances? 7 With regard to item number 30, which is 8 the last point I'll make, I've already alluded to 9 it, but, again, at the conclusion of the study, 10 every patient entered into the study should be 11 assured of access to the best proven prophylactic 12 diagnostic and therapeutic methods identified by 13 the study. 14 Again, on the surface, it sounds like 15 something we should adopt, and, again, I'm not 16 here, at least from my personal standpoint, to say 17 that that's not a good general rule to follow. 18 On the other hand, I think all the 19 scientists in the room know that one study doesn't 20 always prove unequivocally that one intervention is 21 better than another. And so it may or may not be 22 appropriate to apply such an intervention 44 1 immediately if there are some questions about the 2 adequacy of the study and whether it has proven 3 unequivocal results. 4 There are also issues about research, 5 where you put the responsibility here, too. You 6 know, are the researchers going to be in a positive 7 to actually make this intervention available? 8 Are they going to have the resources? Are 9 the funding agencies going to provide those 10 resources, or where are those resources going to 11 come from? 12 Is it appropriate for those circumstances? 13 So, providing the best proven methods 14 identified by the study, yes. In many cases, 15 perhaps it should be done. 16 But there will be obstacles to doing that. 17 The sponsors themselves, for example, may have to 18 go through a period in which there is regulatory 19 approval. 20 There will have to be marketing efforts 21 undertaken to make it available. For certain 22 interventions, there will have to be training of 45 1 health care providers. 2 So it's a major undertaking, and it would 3 involve, in many cases, not just sponsors, but many 4 development agencies, the local host government. 5 And so the question is, how much of a 6 burden do you put on the individual researcher to 7 carry this out, and how much of the responsibility 8 falls on other entities? 9 And what can you reasonably expect a 10 researcher to do? How far down the road do we want 11 researchers and sponsoring agencies to go to help 12 insure the availability of these interventions when 13 they're not completely under their control? 14 So, with that, I think I've raised a few 15 issues for discussion. I'm sure there are folks 16 from some of the other op-divs who have some other 17 things that they would like to say somewhere, Madam 18 Chairman, during the course of the discussion, but 19 I think that's enough to get us started. 20 CHAIRPERSON MARSHALL: Thank you very 21 much, Dixie, and please stay and join us for the 22 discussion and for the recommendation discussion 46 1 afterwards. 2 It is now 10:00 and we are scheduled to 3 have discussion and recommendations between now and 4 11:30, and are scheduled to have a break at 10:30. 5 So let me ask this, that this is an 6 incredibly important topic. There are many people 7 here who have serious interests in the topic at 8 hand. 9 So, in order to be fair and to have a 10 thorough discussion, I would ask that you think 11 through your question before you ask it. 12 I don't want to have a chilling effect, 13 but I want us to be efficient and I want us to hear 14 from everyone. So, please no disquisitions. Have 15 your questions be on point, clear and concise, and 16 I will, again, give precedence to members of the 17 committee and then our ex officio and members who 18 are advisory to us or liaisons from other agencies, 19 and then to our public members. 20 So, let us begin. I have Bob and Adil, 21 right, and Elliot and Abbey. Thank you. 22 Bob? 47 1 DR. ROBERT LEVINE: Thank you very much. 2 Dixie gave a splendid exposition of some 3 of the good things and bad things in the revision 4 of the Declaration of Helsinki. And as some of you 5 know, I've written very extensively on this. If I 6 just read one of my shorter papers, we'd use up all 7 the time Mary Faith gave us. 8 I want to make two points, though, to 9 really emphasize the importance of some things 10 Dixie said. 11 First is, this is an unfortunately written 12 document. It's logically incoherent. It 13 contradicts itself within itself. 14 It talks in Article 6 about the need to do 15 research on the pathogenesis and etiology of 16 disease, and it says in Article 28 that you're not 17 allowed to do it because you have to justify 18 everything you do on a patient in terms of benefit 19 for that patient. 20 That's just one of the inconsistencies. 21 The only topic -- I'm going to bring up 22 two subtopics related to placebo, and that's all 48 1 I'm going to say. 2 The first one is, as Dixie pointed out, 3 this document rules out all of the research that's 4 done where there is no risk whatsoever in placebo 5 controlled in the development of new hypnotics, 6 analgesics, anti-inflammatories, and in other areas 7 where the conditions of the research convert what 8 looks like it might be a bit of risk into 9 essentially no risk, oral hypoglycemics and 10 anxiolytics, anti-hypertensives, and so on. 11 The only thing we accomplish by adhering 12 to the new Declaration of Helsinki, which, 13 incidentally, is no different on this point than 14 the old Declaration of Helsinki, is that we would 15 run up the expense and inefficiency, and run down 16 the reliability of clinical trials in these fields. 17 The second point is the most controversial 18 point, and Dixie talked in terms of water filters 19 and bed bugs and so on. 20 But the thing that started all the recent 21 commotion was criticism of the short duration 22 regiment of AZT to treat or to prevent perinatal 49 1 transmission of HIV in developing countries. 2 The reason this was done at the request of 3 the developing countries that participated in this 4 was because they couldn't afford the standard of 5 the United States, the O76 regimen, which at the 6 time they did these studies, cost $800 per woman. 7 In sub-Saharan African countries, the 8 upper levels of annual per capita health 9 expenditure in the order of magnitude of $10 per 10 person. So we're talking about spending 80 times 11 the annual per capita health expenditure to provide 12 what is the established standard in the 13 industrialized countries. 14 The people who criticized in the most 15 strident and belligerent terms, the people who 16 criticized on grounds that it violated the 17 Declaration of Helsinki spoke only of providing the 18 chemical. 19 As Dixie has pointed out, if you did 20 provide the chemical in these countries, you would 21 be developing data that might be of interest in the 22 United States or the United Kingdom, but would be 50 1 of no value whatever to the people of Africa, 2 Thailand and other places where the trial was 3 coming out. 4 But what they left out and what's left out 5 of all of these arguments is what do you have to do 6 to make the O76 regimen work in a developing 7 country? 8 Well, the first thing you have to do is 9 you have to be able to buy $800 worth of chemicals. 10 The second thing you have to do is to 11 change the prenatal care pattern of the entire 12 pregnant population. 13 The reason they can't take the full- 14 fledged, long-term AZT, as in the O76 regimen, is 15 they don't come in for prenatal care in time to 16 start it. 17 The third is, in the O76 regimen, the drug 18 is administered intravenously during delivery and 19 during labor. And in the countries in which this 20 was tried, with the possible exception of Thailand, 21 there is almost no facility for intravenous 22 administration of anything. 51 1 Now I'm getting to the important points. 2 The O76 regimen trials were done in women 3 who did not breast-feed. We know from other 4 studies that breast-feeding is an efficient way to 5 transmit the virus. 6 It's about 14 percent of women who are HIV 7 infected who breast-feed their babies transmit to 8 the babies the virus. And so that would have to be 9 calculated into the baseline of what was being done 10 in other countries. 11 Well, people say, you could tell them to 12 stop breast-feeding and give them formula. They 13 don't have formula. 14 Well, if you give them formula to put the 15 AZT in, they've got to mix it with water, and the 16 local water supply in these countries is more 17 dangerous to the infants than HIV. 18 At the time the trials were done, the 19 number of cases of death from infant diarrhea, 20 largely due to ingestion of the local water supply, 21 was approximately four million infants a year in 22 sub-Saharan Africa. 52 1 All of this shows how truly bizarre it is 2 to say that we must make the best proven 3 therapeutic method available in trials of this type 4 that are designed to help people in developing 5 countries develop affordable alternatives to the 6 expensive therapies that are used in the 7 industrialized countries. 8 Thank you very much. 9 CHAIRPERSON MARSHALL: Thank you, Bob, and 10 your scholarship is evident. We really thank you 11 for the facts that are guiding us. 12 I have Adil next, and Elliot and Abbey. 13 DR. SHAMOO: Thank you, Mary. 14 I guess everyone sees in the declaration 15 what they want to see. I see item number five of 16 the Declaration of Helsinki been reemphasized since 17 '64 till now. It says, "A medical researcher human 18 subject consideration related to the well-being of 19 the human subject should take precedence over the 20 interest of science in society." 21 That's an excuse that's been used to 22 justify some of the experiments which I think they 53 1 were unethical, conducted in the past 20, 30 years. 2 The other, it says, "When obtaining 3 informed consent" -- I'm going to read the whole 4 thing -- "that there should be a well-informed 5 physician who is not engaged in the investigation, 6 and who is completely independent of this 7 relationship." 8 We have suggested that in the early 9 nineties and was attacked by a lot of my colleagues 10 in this country for suggesting such an arduous 11 method of obtaining informed consent. 12 I won't go over the other points I like, 13 but we will go to the heart of the issue, which is 14 placebo. 15 Dixie, you gave good examples of how 16 placebo should be used. My question is two parts: 17 Could you give me examples, past examples, where 18 the use of placebo was abused, and how in the 19 future we could prevent the use of placebo which 20 could be unethical, also? 21 Because blanket license to use placebo 22 sometimes becomes the norm rather than unique and 54 1 compelling circumstances. 2 I will not sit here and face you and tell 3 you the net experiment you're doing, you should not 4 do. There would be nobody in their right mind 5 would tell you. 6 But I could also tell you, a lot of 7 placebo experiment should never be done because 8 what you're creating a whole house of poor 9 countries that are the dumping ground for our 10 unethical experiments in order to provide cheap and 11 fast methods of producing drugs. 12 That's my question to you, Dixie. 13 CHAIRPERSON MARSHALL: Well said, Adil. 14 MR. SNIDER: I don't think we're in 15 disagreement, Adil, and the issue I think is how, 16 again, can we deal with this issue of the unethical 17 use of placebos, and articulate it in a way so that 18 it doesn't convey to researchers who are 19 appropriately using placebos, under, you know, very 20 difficult circumstances, that they're somehow doing 21 something unethical? 22 And I think our worry is that in an effort 55 1 to try to be succinct and to get at a particular 2 paradigm of research that I and you would find 3 objectionable, that there are other types of 4 research that just were not on people's radar 5 screens, and, consequently, have created this 6 confusion. 7 So, you know, I think our goal is the 8 same. I don't have the words in front of me of how 9 to explain that, and the issue for us is what 10 process would the committee recommend that we use 11 to be able to articulate what we find objectionable 12 and still permit, and even encourage, what would be 13 appropriate when it comes to the use of placebo 14 control. 15 CHAIRPERSON MARSHALL: Dixie, let me just 16 interject, take the prerogative here to ask you -- 17 so Adil has asked, in a sense, for some methodology 18 for fact finding. 19 Do you have any suggestions to the 20 committee for how to go about that? 21 MR. SNIDER: Well, I really don't. I 22 think the question that was raised earlier about, 56 1 you know, how many -- that you raised earlier, how 2 many research subjects are there? 3 How many studies are there out there, and 4 what types of studies are going on, both in the 5 public sector and the private sector? 6 We don't have an answer to that. We don't 7 know all the studies that are going on, even those 8 that are funded by federal agencies. We don't have 9 a central registry of all of that. 10 And I think the fact is that we're going 11 to have to develop a system for finding out about 12 these kinds of studies and, at the moment, we don't 13 have such a system for finding out about those kind 14 of studies. 15 We need some better information system. 16 CHAIRPERSON MARSHALL: Thank you. So 17 we'll we mindful of that in terms of our action 18 plan. 19 Now I'm going to allow -- I have Elliot 20 and Abbey, but because these questions are on point 21 and because they're going to be brief, I have Greg 22 and then Bob. 57 1 DR. KOSKI: Thank you, Mary Faith. 2 I just wanted to mention that, in fact, we 3 do have an opportunity right now, and that OHRP 4 recently introduced a unified federal registration 5 system for institutional review boards that's been 6 developed in close cooperation with the other 7 operating divisions in the FDA. 8 That registration system includes the 9 collection of information about the numbers and 10 types of studies and things that are being done, 11 and it can be a source, then, of creating a data 12 base for a lot of this, and we may want to look at 13 that as an opportunity for collecting more 14 information in order to help us. So it's something 15 that we should consider in going forward. 16 CHAIRPERSON MARSHALL: Thank you, Greg. 17 Bob? 18 DR. ROBERT LEVINE: Thank you. The point 19 that Adil raises about exploitation is a very 20 important point, and something we have to be on 21 guard against. 22 It was true in the past that various 58 1 people ran their trials in developing countries, 2 one, because it cost less, and two, because of 3 their less well developed regulatory systems, they 4 didn't have to jump through so many hoops. 5 We begin to see the correction for that in 6 the 1993 CIOMS International Ethical Guidelines, 7 which providing justifications for carrying our 8 research in developing countries, including being 9 responsive to the health needs and priorities 10 defined by the country in making a product 11 reasonably available. 12 The current draft of the CIOMS 13 International Ethical Guidelines, which will 14 probably be dated in 2001 or 2002, has a new 15 standard that I think is a much more valid 16 safeguard. The standard now has the ungamely name 17 of highest attainable and sustainable therapy. 18 Highest attainable means you can't simply 19 do what's going on in that country, anyhow, which 20 is usually nothing. You got to do the best you 21 can. 22 Sustainable means you can't go to such a 59 1 level that the country can't possibly sustain it 2 after the researchers leave with all their extra 3 resources. 4 As one man from Thailand put it, "You guys 5 come to Thailand. You build a Rolls Royce and you 6 leave, and we can't even afford the petrol to run 7 it." 8 Thank you. 9 CHAIRPERSON MARSHALL: Thanks. Thank you, 10 Bob. 11 Elliot and then Abbey. 12 DR. DORFF: My question is just a question 13 of the status of the Helsinki agreement, to begin 14 with. 15 Is this a law for us in the United States? 16 Is this just simply a suggestion of a world body, 17 and we are then free to change it in any way we 18 want, in which case, this might be guidance for 19 what we might want to do or not want to do? 20 Where is this in terms of -- is this some 21 kind of a statement of policy for worldwide 22 research that we have to adhere to in some way? 60 1 In other words, what is this? 2 MR. SNIDER: Well, I'll take the first 3 crack at it. Greg may have some additional 4 comments. 5 My understanding is that we -- when I say, 6 "we," I mean certainly FDA, CDC, NIH, I think the 7 pharmaceutical companies, have generally accepted a 8 statement from a group of investigators that if 9 they were following the principles of the 10 Declaration of Helsinki, that would be a 11 satisfactory pledge of conducting ethical research. 12 And this comes back, again, then to the 13 point I was making earlier. You know, I had some 14 investigators, and could name additional studies, 15 who now, with this particular version of the 16 Declaration of Helsinki, wondering if they can, you 17 know, really certify that they are following the 18 Declaration of Helsinki. 19 So I think the document asserts itself as 20 applying to all physicians throughout the world, 21 and, in fact, you could read it as asserting itself 22 as being above whatever this group would say, or 61 1 NBAC or FDA. There's a statement in there that, 2 something to the effect that -- 3 DR. SHAMOO: No local or national law. 4 MR. SNIDER: Yeah. No local or national 5 law. "No national, ethical, legal or regulatory 6 requirement should be allowed to reduce or 7 eliminate any of the protections for human subjects 8 set forth in this declaration." 9 Now, again, you know, depending upon how 10 one interprets that, I think the spirit of it was 11 certainly well, intended, but a reader of it could 12 come to a conclusion that perhaps anything that 13 NBAC might say is ethical, that might be in 14 conflict with some principle articulated in the 15 Declaration of Helsinki, would -- I mean it would 16 be trumped by the declaration. 17 And so that's another area that's 18 troubling to investigators. 19 It's a final document, so I don't know, 20 Greg, if you have anything else you want to add. 21 CHAIRPERSON MARSHALL: I think Bob has an 22 answer to that question, as well. 62 1 DR. ROBERT LEVINE: The three major 2 international documents, Nuremberg Code, 3 Declaration of Helsinki, CIOMS International, 4 Ethical Guidelines, have no legal status anywhere 5 in the world, except to the extent that some 6 countries have incorporated some passages from some 7 of them into their national legislation. 8 And to the extent that regulatory agencies 9 have built them in, researchers around the world 10 have been violating the Declaration of Helsinki 11 since the day it was first published in 1964. They 12 don't even know they're violating it. 13 For example, in the United States, we have 14 had placebo-controlled trials in many categories of 15 drugs since 1964, and people still sign these 16 things. 17 The World Association of Medical Editors 18 has agreed to this article that says they will 19 refuse to publish anything done that's not in 20 compliance with the declaration, and yet they 21 routinely publish the results of placebo-controlled 22 trials, studies on the pathogenesis, etiology, 63 1 epidemiology of disease, and all the other things 2 that are flat out violations of the Declaration of 3 Helsinki. 4 The reason Dixie's colleagues are finding 5 they have trouble now attesting to their following 6 of the Declaration of Helsinki is that until 7 recently, most people didn't know what was in it. 8 But all of the fuss that began with the fuss over 9 the short duration AZT trials has had the good 10 effect of making larger numbers of people aware of 11 the document that they're not conforming to. 12 Thank you. 13 CHAIRPERSON MARSHALL: Thank you, Bob. 14 I have Abbey and -- well, let us do this 15 now, then. I was going to do this later. 16 Bern Schwetz, do I see you here? Yes. 17 Thank you. 18 Do you have some commentary to offer, some 19 wisdom to give us, or -- 20 DR. KOSKI: I ask -- excuse me -- or I 21 recommended to the Chair that we ask Bern, who's 22 the Deputy Commissioner of FDA, to address this 64 1 because, in fact, there has been reference, I 2 believe, in FDA guidance and all to the 3 declaration. But I thought you could provide some 4 expert information on this, Bern. 5 MR. SCHWETZ: I can comment on our current 6 status of discussions on the declaration. 7 DR. KOSKI: Bern, excuse me. I think, 8 specifically, the question is in reference to what 9 Bob just said. 10 To what extent has the Declaration of 11 Helsinki been sort of incorporated by reference 12 into FDA regulations? So it's a specific question, 13 and then the Chair will take us back to the more 14 general discussion. 15 MR. SCHWETZ: Well, then I would defer 16 that question to David Lepay and Bob Temple because 17 they'll know exactly what the answer is to that. 18 MR. LEPAY: I'll take a start -- is this 19 on? I'll take a start on this and let Bob continue 20 from there. 21 In fact, our regulations at FDA do 22 incorporate within the provisions for acceptance of 65 1 non-IND, that is, research that is not conducted 2 under a U.S. research permit, investigational new 3 drug application for drugs or biologics from 4 totally non-U.S. sources, so trials conducted 5 outside of the United States, outside of the IND 6 process. 7 We do have a series of conditions under 8 which we'll accept that data for review pursuant to 9 the regulations. And one of the provisions that is 10 included in this particular section of the 11 regulations, as it was written back in the 12 eighties, and I believe that's what it dates from, 13 is a provision that, in fact, the ethical 14 principles of the research that is conducted are in 15 accordance with the Declaration of Helsinki or with 16 the local standards, whichever provides greater 17 protection. 18 Now, there are a couple of caveats 19 associated with that particular regulation. First 20 of all, by virtue of the fact that this is a 21 regulation, in order to change this, and it was put 22 in, in the 1980's and incorporates in it an earlier 66 1 version of the Declaration of Helsinki. 2 In order to for us to go through the 3 process, if you will, of being able to say that 4 this applies to subsequent versions of the 5 Declaration of Helsinki, we cannot do that legally. 6 So the reference still remains to the old version 7 of Declaration of Helsinki. 8 We cannot, in any way, incorporate inter- 9 regulation to this new version without going 10 through a notice and comment period and proceeding 11 with it. 12 Of course, since that time, we've also 13 gone through the process, if you will, of 14 developing or working on other harmonized standards 15 that bear on ethical principles in clinical 16 research, part of this through the International 17 Conference on Harmonization. 18 And if one goes through the good clinical 19 practice principles that are embedded in the ICHE6 20 document, what one finds is they encounter the same 21 problems in the thinking about these passages of 22 the Declaration of Helsinki, that it is, in fact, 67 1 very difficult to adopt these particular passages 2 in the applicability for various reasons that Dixie 3 has pointed out earlier. 4 And if you read the E6 document, it very 5 clearly states that, in fact, the ethical 6 principles incorporated therein have their origins 7 in the Declaration of Helsinki, but nowhere is 8 there a direct citation in E6 that, in fact, 9 Declaration of Helsinki has, in fact, become 10 incorporated verbatim just for these very reasons. 11 So, in fact, we have a lot of regulatory 12 dilemmas right now. We have a series of harmonized 13 documents that represent the thinking of a large 14 number of people. 15 They have been out for public comment. 16 They've included comments from ethicists. They 17 were developed in accordance with regulators, in 18 accordance with industry, out for public comment, 19 in the form of the ICH guidelines. 20 They recognized the problems with 21 Declaration of Helsinki. They're the basis by 22 which we do now, in fact, harmonize a lot of our 68 1 research. And in countries, in fact, that have 2 ascribed to ICH, those are the expected standards 3 we have for conduct of research. 4 We also have the parallel dilemma, of 5 course, that we have a regulation out there that, 6 in fact, is based and reads from an earlier version 7 of the Declaration of Helsinki that until we make 8 some kind of definitive move forward, remains this 9 way and doesn't, in any way, embed this new 10 provision. 11 CHAIRPERSON MARSHALL: Thank you very 12 much, Bern. Thank you. 13 I have Abbey and I have Mark and I have 14 Elliot, and I'm mindful of our time. We're 15 scheduled at 10:30 to take a break. 16 And what I would like to do is to take, 17 not a 15-minute break, but a 10-minute break, 18 because I would like to use the 20-minute time 19 period following that to hear from our ex officio 20 and liaison members, and also from our public 21 members. 22 Abbey? 69 1 MS. MEYERS: Yeah. My first thought when 2 I heard about the mosquito net thing is that, years 3 ago, I believe there was a Senator Proxmire used to 4 give the Fickle Finger of Fate Award, and I would 5 give it to that experiment because, when you think 6 about it, I don't think any researcher would want 7 to go into a room with a bunch of mosquitos, or 8 sleep in that climate down there without a net over 9 it. 10 So the fact that the United States 11 government is spending any money to determine 12 whether children do better sleeping better without 13 a net or with a net is just insanity. Everybody 14 knows the answer to it, and if you took the money 15 you're spending on this study and bought nets for 16 all of these children, we'd be much further ahead 17 in the end. 18 So the first thing it points out is that 19 whoever is making these decisions, whoever is 20 giving these grants, whichever IRBs are approving 21 these projects, they should have some bio-ethicists 22 mandated on their review boards, so that something 70 1 like this would never be approved in the first 2 place. It's like studying whether the sun should 3 come up. 4 But the thing that I want to know out of 5 this whole discussion is, what is the national 6 imperative to adopt the Declaration of Helsinki? 7 What will be the punishment? What will be the 8 price that we have to pay if we just say we are not 9 going to adopt it? 10 CHAIRPERSON MARSHALL: Wonderful question. 11 MR. SNIDER: Well, let me just respond to 12 the first part. 13 It is not at all clear to the malaria 14 scientists, nor their ethical consultants, which 15 they did consult with, that spending a small amount 16 of time of their day sleeping in a mosquito net 17 would necessarily have any major impact on 18 transmission of malaria, which can occur, you know, 19 during other periods when the children are not 20 asleep. So what impact, if any, it would have on 21 morbidity or mortality, the scientists believe and 22 their ethical consultants believe, was a valid 71 1 scientific question. 2 I'll ask Greg or someone else to comment 3 about what the impact would be. 4 DR. KOSKI: Well, obviously, no one knows 5 precisely what the impact would be, but I don't 6 know whether, you know, acceptance or rejection is 7 a simple binomial function here. 8 Indeed, there are multiple codes of 9 conduct and regulations and so on, all of which 10 come to bear on the way we conduct our activities. 11 My sense in many of the discussions that 12 I've listened to, and I've seen it reflected here, 13 is that everyone can agree that there are specific 14 situations in which the provision, for instance, 15 regarding the use of placebos, would apply without 16 question. And, you know, certainly a situation 17 where it would be a group of patients that had a, 18 you know, disabling or potentially fatal condition, 19 or if there was a known effective therapy 20 available, it would truly be unethical and 21 unconscionable to use a placebo-controlled trial. 22 On the other hand, there are situations, 72 1 some of which we've heard described, where, in 2 fact, there is good, both scientific and ethical 3 justification, for using placebo-controlled trials. 4 And so we want to be, I would think, 5 careful not to throw all of that out. It's the 6 sense that, as written, the revised version of the 7 Declaration of Helsinki, in fact, it's taken a very 8 narrow approach to a very complex problem. 9 I mean we don't have to work through all 10 of the examples again, but, certainly, there are 11 instances where there is a group of patients that 12 have a condition for which there is known effective 13 treatment, but the only treatments that are 14 available are things that carry, you know, severe 15 adverse side effects, or a patient may be 16 intolerant of them. 17 And so, in order to find a drug that would 18 work for them, you would have to subject them to 19 taking another drug that could have serious 20 consequences. 21 But we don't want to do senseless things 22 like that, so I think that one thing that this 73 1 group could be very effective in doing is sort of 2 recognizing and putting into context where those 3 specifics provisions of the Declaration of Helsinki 4 do work. 5 Certainly most everyone here, I believe, 6 would endorse most of the provisions that are 7 there, but much as we heard from the social 8 scientists yesterday that, you know, one set of 9 regulations may be constructed in a narrow context 10 so that it becomes less applicable in the broad 11 context, seems to be something that happens here. 12 My own sense is that need to recognize 13 that sometimes the use of a placebo can actually 14 have therapeutic effects. Placebos will reduce 15 blood pressure. Placebos will improve mood. 16 Placebos will reduce anxiety, and so on. 17 And if you see an improvement in mood or a 18 reduction in blood pressure or better sleep, 19 whatever, as a result of taking a placebo, that's a 20 therapeutic benefit that's every bit as real as 21 what you would have if you were taking a drug that 22 had an active chemical in it. 74 1 So I think there is a general 2 misunderstanding of a lot of the science behind 3 placebo that's been lost in this debate, so we want 4 to be careful there. 5 But in the final analysis, it seems to me 6 that we should recognize that, again, there can be 7 appropriate and inappropriate uses. If we're going 8 to propose the use of a placebo, then it seems to 9 me it ought to be justified on both ethical and 10 scientific grounds. 11 And, if, in fact, we're going to use a 12 placebo that involves risk, let's say we used it in 13 a blood pressure trial where the blood pressure may 14 go up instead of down, then we need to have 15 protections that are commensurate with the risks to 16 which we would be subjecting people as a result of 17 participation in that trial. 18 So, you know, I guess that would be the 19 kind of shell I would try to put around it. 20 CHAIRPERSON MARSHALL: Mark, final 21 question. 22 MR. BARNES: I just wanted to make a 75 1 couple of brief points. One is in regard to 2 Abbey's question and I think Elliot's question as 3 to the legal status of this declaration. 4 I think, just to put it in context, the 5 real sanction, in terms of the FDA here, it would 6 be a decision to disregard or exclude the data in a 7 new application. That would be -- that's the 8 essential sanction that's been talked about. 9 There are a range of other sanctions 10 through another regulatory mechanism, though, that 11 I think it's important to understand, which is that 12 all physicians who are licensed in the U.S. are 13 licensed by their various state and medical boards. 14 And if there were an incident -- and there 15 have been some recent incidents in which a 16 privately-funded research, not federal research, 17 came under some kind of ethical scrutiny from 18 colleagues, peers, hospitals or patients which are 19 subjects themselves, they have filed complaints 20 with state medical boards. And then the state 21 medical boards, in turn, looked to prevailing 22 professional ethics in terms of evaluating the 76 1 patient or their colleagues' complaints. 2 And one of the sources that they could 3 look to might be the Declaration of Helsinki. It's 4 not necessary and it has no force of law, but it 5 might be one of many pieces of evidence. 6 And especially what the AMA positions 7 would be, to the extent that the AMA signed on, 8 either in whole or in part other the Declaration of 9 Helsinki or had separate guidance documents, all 10 those things could be considered within the state 11 medical board complaints. 12 So that's yet another source of 13 enforcement, authority, if you will, would simply 14 be the tort system because if there really were a 15 patient harmed, even a patient overseas harmed, 16 they could presumably file a lawsuit, and one of 17 the kinds of evidence they would try to trot out of 18 their plaintiff's lawyer, would try to trot out 19 would be the Declaration of Helsinki as being one 20 of the guides. They would try to say it was an 21 authoritative guide, and obviously, defense counsel 22 would say the opposite. And it would be fought out 77 1 in that realm. 2 MS. MEYERS: But have we ever, and is it 3 written in any law that we have adopted the 4 Declaration of Helsinki? 5 MR. BARNES: No. 6 MS. MEYERS: It's totally voluntary, then? 7 It's like a code of conduct? 8 MR. BARNES: Like a guidance document or a 9 code of conduct among many codes of conducts, and 10 many codes of conduct and many guidance documents 11 that are promulgated by many different medical 12 associations. 13 A second very brief -- I'm sorry? 14 DR. ROBERT LEVINE: I'm sorry. Go on. 15 MR. BARNES: Just a second very brief 16 point about the clinical trials registry that Dr. 17 Koski was referring to. 18 I just want to point out that there is 19 another clinical trials registry being built up 20 right now, being developed by HCVA in regard to the 21 national coverage determination under Medicare by 22 which Clinton and Secretary Shalala extended the 78 1 coverage, Medicare coverage, for medical services, 2 associative clinical drug trials, and that is being 3 developed itself. 4 And so I would just encourage all the 5 agencies that are in the room, since they're 6 developing registries of clinical trials, please to 7 harmonize those registries, okay? 8 CHAIRPERSON MARSHALL: Yes, you may, but 9 you may not get a break. 10 DR. ROBERT LEVINE: Mark, has there ever 11 been a reported case in which a court ruled against 12 a physician for violating the Declaration of 13 Helsinki? 14 MR. BARNES: If there is, I'm not aware of 15 it. 16 CHAIRPERSON MARSHALL: Greg, a quick final 17 word, and then we're going to break for ten 18 minutes. 19 DR. KOSKI: Thank you, Mary Faith. 20 The final word is that I think the 21 critical point here is that we cannot remain in a 22 state of limbo. We need to have clear guidance on 79 1 exactly how to apply the provisions of Helsinki in 2 an appropriate context, and also that that's what 3 needs to come out of this group as where we need to 4 go. 5 So thanks. 6 CHAIRPERSON MARSHALL: Thank you very 7 much. So let us be back here at quarter till the 8 hour. Thank you. 9 [Whereupon, a break was taken at 10:35 10 a.m.] 11 CHAIRPERSON MARSHALL: And what I would 12 like to do now is to ask our ex officio members, 13 our agency liaisons if they have comments or 14 questions for us, if you would come to the 15 microphone and introduce yourself and let us know 16 what agency you represent. 17 And, again, cogent and concise would be 18 helpful. 19 MR. SHELTON: Okay. I guess -- can you 20 hear me? He's going to turn it up, okay. 21 Just to get us started, I think -- you 22 know, I thought about this placebo issue for a long 80 1 time -- 2 CHAIRPERSON MARSHALL: Can you tell us who 3 you are because we have some folks here today -- 4 MR. SHELTON: Oh, sure. 5 CHAIRPERSON MARSHALL: -- who weren't here 6 yesterday. 7 MR. SHELTON: Yes. Jim Shelton, USAID. 8 I think it's kind of important to put 9 yourselves in somebody's shoes to understand this 10 issue, at least as I frame it. And from sort of 11 the classical, medical perspective, the value is do 12 absolutely the best that you can for your one 13 particular patient, at least in the abstract. I 14 don't think it necessarily works out that way. 15 But that's the value that you hear coming 16 through in this document. But I think you also 17 need to come and look at the other value, the other 18 perspective. 19 If you look at sort of ground level public 20 health perspective, let's say Uganda, and you say, 21 "Nobody's getting the best possible therapy. 22 Nobody is getting it," why would I possibly want to 81 1 have something used in this context? 2 First of all, it's even an ethical issue. 3 Why would these people be so very special compared 4 to everybody else with this condition that they 5 would get the best therapy? 6 Why is it ethical to give them the best 7 therapy and other people get nothing? We could be 8 using those additional resources for something. 9 So they're either ethical problems on the 10 other side, and then, in addition, there is the 11 scientific issue. 12 That's not helpful to me. If I'm 13 interested in an appropriate technology, if I want 14 to know, for example, how something less than that 15 standard would work -- the term we use is 16 "appropriate technology." It's a very widespread 17 issue -- it doesn't help me to know that it's less 18 effective that than best therapy because what I 19 want to know is, is it effective at all? 20 It doesn't help me to know that, so I just 21 kind of wanted to put on the table that you can 22 kind of see these two different very valid, in a 82 1 sense, perspectives, at least as I understand that 2 issue. 3 CHAIRPERSON MARSHALL: Thank you, Jim. 4 That's quite a challenge. 5 Dixie, do you -- committee members? 6 MR. SNIDER: No, not a lot to say except 7 that the public health perspective and the clinical 8 perspective are clearly perspectives that allow 9 you, much of the time, to have concordance in your 10 thinking and do the right thing for individuals and 11 do the right thing for society at large. 12 But in many cases, and many cases because 13 of the social economic inequities in the world, you 14 can't do the best for a single individual and do 15 the best thing for an entire country. 16 And this conflict is something that people 17 who, you know, haven't worked in both arenas can't 18 feel torn about. But the folks on the ground feel 19 torn about it, as Jim knows, and it's very 20 disconcerting to them, and it's even further 21 disconcerting if they read a document that has the 22 authority, as the Declaration of Helsinki does, 83 1 that gives them the impression that, in trying to 2 do the best they can for the most people to improve 3 the health, as admittedly marginally, but with the 4 resources they have at hand, to improve their 5 health as best they can, as quickly as they can, to 6 be given a message that perhaps they're doing 7 something wrong is not the message that should be 8 sent to these people who are working under 9 extremely difficult circumstances. 10 It's not the message we should be sending 11 to the collaborating investigators in those 12 countries, that they shouldn't be trying to make 13 marginal improvements in the health of their 14 populations, even though it might not be the best 15 possible therapy that exists. 16 So I would just second what you had to 17 say. 18 CHAIRPERSON MARSHALL: Thank you. 19 MR. TEMPLE: Bob Temple. I'm from FDA. 20 The new version of the declaration 21 represents actually a very important change with 22 respect to placebos. The previous version used to 84 1 have a phrase that went approximately like this, 2 since 1975: 3 In every study, every patient in the 4 trial, including those on the control, if there is 5 one, should be provided with the best available 6 therapy. 7 For a lot of reasons, although some people 8 interpret that as barring placebos whenever there 9 was existing therapy. Others did not. 10 When that change was added in 1975, there 11 was not a word about placebo controls. What they 12 said when they made that change was that they 13 wanted to remind people that there was a patient in 14 there and you need to take care of their needs. 15 So, since 1975, for 25 years, you could 16 say people had just been ignoring the declaration 17 because they've been doing placebo control trials, 18 even when there was existing therapy, but I think 19 people didn't interpret it that way. 20 The new version, however, is unequivocal. 21 It says absolutely, without reservation, for 22 allergic rhinitis, erectile dysfunction or anything 85 1 else, if there is existing medical therapy, you 2 must do an active control trial. 3 That is a very important difference, and 4 for reasons that I obviously don't have time to 5 explain now, there are many situations in which an 6 equivalence or a non-inferiority trial in those 7 settings, such as allergic rhinitis, depression, 8 are -- non-inferiority trials are non-informative 9 because the active control in that situation is not 10 always superior to placebo in well done trials, for 11 reasons that we don't always know. But it is a 12 fact of life when you're studying anti-depressants, 13 about a third to a half of the trials fail, and 14 it's not for any obvious reason. 15 So an equivalence or non-inferiority trial 16 which shows equivalence doesn't tell you the drug 17 works. Putting ineffective anti-depressants out 18 into the world something FDA wants to do, and it's 19 obviously not good for the community. 20 So, the declaration, to the extent people 21 pay attention to it, could sharply inhibit the use 22 of trials that are informative in many, many 86 1 symptomatic treatments. 2 Having said that, nobody doubts that where 3 a therapy is known to improve survival or make a 4 major difference in morbidity, you can't expose 5 people to -- you can't deny people therapy that's 6 available to them. 7 Now, what "available" means in a Third 8 World context is a much more thorny question. But, 9 at least in the United States, you're not going to 10 do long-term trials of any hypertensives against 11 placebo or anything like that. 12 The issue is on symptomatic treatments 13 where the patient ought to be able to understand 14 what they're giving up when they give up active 15 therapy, and it has long been the FDA's position 16 that you can do trials in that arena, as long as 17 the patient is properly informed they can leave the 18 study and doesn't come to harm. 19 I just want to flag a document that you'll 20 eventually need to look at. It's an international 21 conference on harmonization document on choice of 22 control group which gives an alternative to what 87 1 the declaration says. 2 It basically says, if people are going to 3 come to harm, you can't do placebo control trials, 4 and by denying them available therapy. If what 5 they're being denied is a symptomatic benefit, they 6 ought to be smart enough to make a judgment, 7 properly informed, et cetera, about whether they 8 want to participate in those trials. 9 And so I can see that everybody at the 10 table is very interested in the trials in Third 11 World countries where denial of therapy is a 12 potential health problem. 13 A lot of cases that at least FDA worries 14 about, we're not really worried about the health 15 consequences of not getting your drug for allergic 16 rhinitis, but the declaration bars those, too, and 17 seems to do it absolutely, which is very 18 troublesome for us. 19 CHAIRPERSON MARSHALL: Thank you, Bob. 20 Elliot? 21 DR. SHAMOO: Can we ask some questions? 22 CHAIRPERSON MARSHALL: Yes. Bob, please 88 1 stay. Bob, would you mind coming back? Some of 2 the committee members have questions for you. 3 And I have Elliot, Abbey and Adil. 4 DR. DORFF: Mine was not a question to 5 him. 6 My own view of this, and from what I'm 7 hearing around the table, is that it's very similar 8 to the kinds of things that I've been very much 9 involved in my own professional life in terms of 10 valuing ethical codes of a variety of different 11 professions. 12 What it seems to me is what we have here 13 is a stab at, in the Helsinki Declaration, I mean, 14 is a stab at a statement of what constitutes moral 15 norms. 16 And any time you do that, simply because 17 human beings are fallible and not omniscient, there 18 will always be improvements in the code that are 19 necessary. That's why you have revisions of 20 ethical codes, and refinements, and for that 21 matter, changes. 22 And I'm already hearing that in addition 89 1 to that Helsinki thing, there's this other thing 2 that you just mentioned on harmonization, which is 3 also international. 4 So I mean I think that the way that we 5 ought to see these codes, even though I understand 6 completely that lacking anything to the contrary 7 courts might use these things or the FDA might use 8 these things as a kind of backup statement of, 9 well, this is what are the moral standards in the 10 field, I think the duty of this committee is to 11 evaluate those statements and to say, you know, 12 they're good in these ways and they're not good in 13 these ways. 14 And the kinds of standards that we would 15 want to adopt here in the United States and that we 16 would suggest to the next Helsinki conference would 17 be the following kinds of revisions. 18 And I think that, if this committee came 19 out with such a statement, then it's precisely that 20 kind of a statement that might be used in state 21 trials, you know, that about removing a physician's 22 license because they didn't follow the standards of 90 1 the practice, or that they might get into FDA 2 regulations instead of Helsinki. 3 I mean it seems to me that's just the 4 nature of evolving ethical codes. 5 CHAIRPERSON MARSHALL: Thank you, Elliot. 6 Abbey? 7 MS. MEYERS: The words, "Declaration of 8 Helsinki," appears in the FDA regulations 9 somewhere. 10 Now what would it involve, let's say, if 11 we reject the Declaration of Helsinki? What does 12 it involve in changing those regulations so that 13 nobody has to conform to them? 14 MR. TEMPLE: Well, Abbey, David tells me 15 that we have an opinion from general counsel that 16 is eminently sensible which said that we couldn't 17 have guaranteed the World Medical Association the 18 right to give us advice in perpetuity without 19 seeing it, and that what's in the regulations is 20 the 1975 version. That has the phrase about, "in 21 every study, every patient needs to be assured the 22 best available therapy." 91 1 However, we have interpreted that as not 2 invariably requiring placebo-controlled trials, and 3 apparently, certainly everybody behaves that way. 4 We have tens of thousands of them, and they all get 5 published, as Bob pointed out. 6 So we may or may not need to do something 7 about the presence of the declaration in our rules 8 for accepting foreign data, but at least at the 9 moment, that version doesn't, in our view, bar the 10 conduct of placebo-controlled trials. 11 Now as Stuart points out, we give advice 12 to investigators that refers to the declaration 13 that doesn't particularly put the version in it, 14 and maybe we need to modify that so people are 15 aware of that controversy. 16 CHAIRPERSON MARSHALL: Abbey, I'm sorry. 17 I'm going to move on and give Adil a chance to ask 18 his question. 19 DR. SHAMOO: I have a question. The U.S. 20 Pharmacopeia is a private publication. But 21 throughout the years, through court cases, have 22 gained some legal status. 92 1 And the Declaration of Helsinki, by being 2 mentioned in the regs, in the international court 3 cases, and maybe even domestic court cases, sooner 4 or later, will become embedded. It may not be the 5 law, the statute, the way the Congress passes, but 6 will gain legal status somehow. 7 And I think what we got the opinion of our 8 colleagues here sitting, that first was dismissal. 9 That has no legal stand. 10 Slowly, we found out, and I would like 11 Mark to answer that question, that analysis is 12 right. And, second, I have a question to Bob 13 specifically to him, because it's relevant. 14 CHAIRPERSON MARSHALL: Very brief because 15 I want to get Jim and then I want to open the 16 discussion up, also, for our public members. 17 MR. BARNES: I don't want what I said 18 before to be over interpreted or too aggressively 19 interpreted. 20 I think that it's not a foregone 21 conclusion that courts or state medical boards 22 would ultimately regard the year 2000 revision of 93 1 Helsinki as binding. 2 There have been, I mean I know in the 3 scholarly literature, I know that primarily it's 4 one of the primary disputants in the scholarly 5 literature has been Dr. Levine here, in regard to 6 this issue of the international trials and the 7 standard of care. 8 So I think -- I mean it's not a foregone 9 conclusion that these things would be the 10 prevailing norms. I mean that happens over a 11 period of time. 12 I mean I think that what we can say for 13 sure, or with some certainty, is that given the 14 multiplicity of research efforts, given the amount 15 of money, both private and public going into 16 research, that there will be some ethical standards 17 developed of some sort that will ultimately be 18 recognized as being the binding standards. 19 So I think we can't -- now we can only, 20 you know, we know in part and we prophesy in part, 21 and what we know is that there will be standards, 22 and we can't really prophesy what they might be. 94 1 DR. SHAMOO: My specific question to Bob 2 is, in cases where there are scientific evidence 3 that placebo may be therapeutic, especially in 4 behavioral health issues, the current existing 5 statement of the 2000 Helsinki Declaration, will 6 that fit the placebo that even though it's called 7 placebo, that it's therapeutic in nature, and it 8 will be allowed, therefore, under the same 9 statement, so you don't need any modification? 10 MR. TEMPLE: Well, if it doesn't mean what 11 I think it means, then we don't have to worry about 12 it. 13 But I think there are very few cases where 14 placebos are really known to be therapeutic. This 15 is a long discussion, but the change in the placebo 16 group in a trial is not the effect of placebo. 17 If you were, for example, going to study a 18 cold and you noticed that by 12 days, everybody is 19 better, that's not a placebo effect. That's the 20 cold going away. 21 Similarly, many diseases, anxiety, 22 depression, are cyclical and the placebo is there 95 1 to correct, yes, for placebo effects, but also for 2 spontaneous improvement, regression to the mean, 3 and a whole bunch of other stuff. 4 So where placebo is effective is not clear 5 to me. There's certainly pretty good evidence that 6 in some analgesics, short-term analgesic settings, 7 it is. But I don't know that there is a real 8 placebo response in depressions, schizophrenia or 9 any of those things. 10 There's improvement in the placebo group. 11 In depression, quite a substantial improvement, but 12 I don't know. Maybe that is a way to deal with the 13 declaration. But I think it's not as 14 straightforward as saying it's wrong. 15 CHAIRPERSON MARSHALL: Bob, thank you very 16 much. 17 Greg, did you have a question of Bob? 18 Okay. Bob, thank you so much. I'm going 19 to give Greg the floor for just a moment, and Tim. 20 Then we'll move to -- 21 DR. KOSKI: Thanks. I just wanted to sort 22 of respond to Abbey's comment about rejecting the 96 1 Declaration of Helsinki. 2 I think it would be unseemly for, you 3 know, the federal government to formally reject the 4 Declaration of Helsinki. I think at least my sense 5 of the discussion here is that what we're talking 6 more about is recognizing the very positive things 7 that the Declaration of Helsinki, in its present 8 version, bring to this responsible conduct of human 9 research. 10 But to recognize that it has limitations 11 and it needs to be put into a proper context. And 12 I think that would be the most desirable direction 13 to go. 14 So, rejection, I don't think is something 15 that is really so much on the table. 16 CHAIRPERSON MARSHALL: Thank you very much 17 and we will revisit that sentiment very shortly 18 when we talk about our recommendations. Thank you. 19 Jim? 20 MR. SHELTON: Yeah, this relates to that 21 point and I think Elliot's point in a way, which is 22 I mean I actually think in formulating the Helsinki 97 1 position, it went beyond what I would call 2 principle. 3 I think there is an error here to take 4 light of. We've already seen that there is so many 5 different kinds of situations that if you get too 6 specific, it's almost sort of like a Heizenberg 7 principle. You try to cone in too much on it 8 because, oh, I'm thinking a sick person with cancer 9 chemotherapy, and I'm not thinking this other 10 thing. 11 I think the way to go at these things is 12 to try to think of what are the fundamental 13 principles. And there really is a lot of common 14 ground here, Greg. There is a principle of 15 respecting human beings and being careful about 16 placebo trials and so forth. 17 I mean I think that's the way to really go 18 about these kind of things, not to say, "Never do 19 such and such." 20 CHAIRPERSON MARSHALL: Thank you. 21 John? 22 MR. MESA: You asked us to be concise and 98 1 cogent. That's a tough order. 2 But I want to put on my hat as a regulator 3 for just one moment. 4 CHAIRPERSON MARSHALL: And just, John, if 5 you can remember we have folks in the audience who 6 weren't here yesterday, so if you could just tell 7 us -- 8 MR. MESA: I'm sorry. 9 CHAIRPERSON MARSHALL: -- who you are? 10 MR. MESA: John Mesa with the VA. Heads 11 the Office of Research Compliance and Assurance, 12 and I'm going to put on my hat as a regulator for a 13 moment. 14 When you talk about the bedrock of what 15 our offices, Greg and so forth have to do, we have 16 to assure compliance with a common role. And for 17 FDA, there are key 21 CFR regulations that lay it 18 right out. That becomes de facto of the law of the 19 land. 20 Everything sort of on top of that is like 21 best practices, it's a good idea, you know, and I'm 22 not sure if I want to put a hierarchy here, but 99 1 presumably, you're one of the better ones, and that 2 would be the Declaration of Helsinki, maybe the 3 Nuremberg statement, and maybe the CRMS in which 4 there are two brands and varieties, and then others 5 have had best practices beyond that which actually 6 operationalize the common rule within our agencies. 7 And we have a manual that defines, you 8 know, this is what you're literally supposed to do. 9 The question that keeps coming back, 10 though, in my mind is, okay, what is it the de 11 minimus that we would be willing to accept, and in 12 fact, operationalize, and say, "Look, if you don't 13 meet this de minimus standard, then I'm sorry. 14 You're not conducting yourself in an ethical manner 15 as an institution, as an IRB, or as an 16 investigator." 17 Now this is very cogent at this point in 18 time because of the discussion about the human 19 subjects protection accreditation process. And of 20 itself, is that going to be something which is de 21 minimus, or is it something that's going to help 22 people reach for the stars to do better and better 100 1 things because of best practices? 2 So it's not an intellectual discussion 3 what you're doing right now. So I'm asking you as 4 a plea, broaden it just beyond Helsinki for a 5 moment and think about all the other sort of 6 standards that are sort of wafted around, and what 7 kind of standing do those have? 8 For those of us who have to send out, like 9 FDA does, investigators to look at IRBs, 10 investigators, or else send out, you know, 11 surveillance proactive compliance teams, or for 12 cause, you know, reviews where somebody said, "Hey, 13 this bad thing is going on, either through a hot 14 line or whatever I is." 15 And my plea is just broaden your thinking 16 a little bit beyond Helsinki. What do all these 17 other things really mean? 18 CHAIRPERSON MARSHALL: Thank you for that 19 call for establishing a benchmark. 20 Let me ask our public members if anyone 21 has questions or comments, would like to join the 22 discussion? And, again, if you could just tell us 101 1 who you are and what your interest is. 2 MR. WOLF: Sid Wolf, Public Citizens 3 Health Research Group. 4 A couple of comments. One, ever since the 5 publication back I guess five, six, seven years ago 6 in the New England Journal by Ken Rothman and Karen 7 Michaels of their, to use Bob Levine's term, 8 strident insistence of placebos at every single 9 instance, even when you had what we would call a 10 placebo effect known, we've disagreed with that 11 publicly, and every other way. 12 And as I told Bob Temple during the break, 13 we will be glad to provide him with public 14 statements, including, I believe, some letters to 15 the editor over the years, where we essentially 16 believe as Bob does, I think largely, if not 17 completely, that in a number of situations, the 18 most recent one of which has to do with irritable 19 bowel syndrome, where a drug which did not look 20 like it was much better than the placebo, would 21 only have been known to be very little better than 22 the placebo because of a placebo-controlled trial 102 1 that was done. Allergic rhinitis is, of course, 2 another one, mild pain, and so forth. 3 So I think that there are a number of 4 conditions, and we disagree with Helsinki if it's 5 going to be strictly interpreted that way. 6 On the other hand, since '75, as Bob 7 Levine pointed out, even if the language wasn't as 8 precise as it is now, there has been this tendency 9 in the way you could interpret Helsinki to simply 10 say that you should never use a placebo. So we 11 think there are proper uses of placebo. 12 The second point has to do with this whole 13 issue of best available therapy, an issue that we 14 raised several years ago in an article in the New 15 England Journal of Medicine. 16 And I think that the best answer to this 17 comes from researchers in the developing country 18 who, themselves, rejected the use of a placebo for 19 treating HIV positive pregnant women. This is a 20 letter published over two years ago in the New 21 England Journal by researchers from Harvard and 22 Thailand who said it was unethical to do a placebo. 103 1 While designing a Thailand clinical trial 2 in early 1994, we felt that both, scientifically 3 and ethically, the only controlled study design 4 option was an equivalency study. They were 5 comparing the long expensive route of treating 6 perinatal transmission, or preventing it, with a 7 short course. 8 They had access to data, as did anyone 9 else would wanted to back, six years ago, that a 10 short course already worked that was already in 11 part of the design of the original O76 study. A 12 subgroup analysis planned in advance showed that it 13 worked. 14 So they said that it was unethical. They 15 also said no data supported -- their study got 16 started later than it should have because NIH would 17 have liked to have them do a placebo-controlled 18 trial. 19 And they say again in this letter in the 20 New England Journal, "No data supported the 21 reviewers' -- the NIH reviewers -- fear that the 22 shorter regimen might be no more efficacious than 104 1 nothing, and that our results could leave 2 developing countries stranded if the short 3 treatment turned out to be less efficacious than 4 the complicated expensive standard was unfounded." 5 So I think that the fact that the Harvard 6 IRB refused to allow a placebo-controlled trial 7 points out that some other researchers -- 8 I would say that one of the reasons that 9 we publicly raised this issue was because there was 10 a specific concrete example in the developing world 11 where someone else who knew much more than we had 12 thought that it was unethical. 13 And I think that the issue of best 14 available therapy really should be a scientific 15 issue, not an economic one to condemn people in 16 countries where the government can well afford, in 17 the context of an experiment, to provide the best 18 available therapy in a control group, as well as 19 the experimental group getting the new therapy, I 20 think is just really unconscionable. 21 So I would stick with that part of the 22 Declaration of Helsinki that says, "best available 105 1 therapy." 2 Dixie alluded briefly to the whole issue 3 of post-trial availability for those in the trial. 4 Again, I think that is very, very important 5 because, otherwise, people are going to be sort of 6 left in the lurch, and the larger issue of post- 7 trial availability for people in the country. 8 Hepatitis B was experimented on in Africa, 9 and it was found to work. The countries where it 10 was experimented on don't really have access to 11 hepatitis B. 12 And I think that when one decides where to 13 do studies, particularly if the people in that 14 country could benefit, one has to think about post- 15 trial availability, and that's certainly an issue 16 that is discussed in more detail in the National 17 Bioethics Advisory Commission report than in 18 Helsinki. 19 Anyway, thank you for the opportunity 20 again. I'd be glad to try and answer any 21 questions. 22 CHAIRPERSON MARSHALL: Thank you. I think 106 1 that we are running close to the time, and I'm 2 mindful of it simply because we are not cutting 3 into lunch. We are cutting into our next speaker. 4 But, again, there will be time at the end 5 of the day when we are recapping things. So one 6 more question, and then I do want to talk briefly 7 about recommendations. 8 MR. CHADWICK: Yeah. I'm Gary Chadwick 9 from the University of Rochester, and also with 10 Applied Research Ethics National Association, the 11 Association of IRBs. 12 I think yesterday, it was pointed out that 13 the United States is unique in its emphasis on 14 individual rights versus societal good and how that 15 has all become more and more important since the 16 civil rights movement and so forth. 17 But we're also unique in that we've 18 developed our own national standard of ethical 19 principles, the Belmont Report and the Belmont 20 principles. 21 So I would suggest, in looking at 22 recommendations, that the committee needs to look 107 1 at the World Medical Association's Declaration of 2 Helsinki in juxtaposition to the national standard 3 here, which is the Belmont Report, and those 4 principles. 5 I think IRBs and investigators and 6 probably OHRP, as well, really could use guidance 7 on what to apply and how to apply in the way of 8 principles for research, both in the United States 9 and internationally. And we also could use 10 guidance on applying those principles, not only in 11 biomedical research, which is what the Declaration 12 of Helsinki focuses on, but also in behavioral and 13 social sciences research, as well. 14 CHAIRPERSON MARSHALL: Thank you very 15 much. 16 Last? Yes. We will give you the final 17 word. 18 MS. FISHER: Dr. Snider, I am glad you 19 brought up the acellular pertussis vaccine trials 20 -- I'm sorry. Barbara Lowe Fisher. National Value 21 Information Center. 22 I am glad that you brought up the 108 1 acellular pertussis vaccine trials in Sweden, 2 because the first trials in the 1980's were 3 conducted with a true placebo in that it was 4 comparing the acellular vaccine against no vaccine. 5 And those trials did show that the acellular 6 vaccine was much less reactive and more effective 7 than was known about the DPT vaccine at the time. 8 However, the CDC did not accept these 9 trials as adequate and required eight more years of 10 trials to be conducted on babies, comparing the 11 more reactive DPT to the safer DTAP. 12 And after the safer DTAP was licensed in 13 1996 and recommended for all babies, an 14 experimental trial of pneumococcal vaccines was 15 conducted on babies in this country where more than 16 50 percent of the babies got the old, more reactive 17 DPT vaccine, and the seizures and other kinds of 18 reactions that those babies suffered, which were 19 suffered by many more babies in the DPT vaccine 20 group, were used by the manufacturer to exonerate 21 the pneumococcal vaccine in terms of its potential 22 seizure producing capability. 109 1 In our view, the use of placebo in this 2 trial, that is, the use of the more reactive 3 wholesale pertussis vaccine, when a safer vaccine 4 was licensed and available, was unethical and 5 resulted not only in unnecessary harm to the babies 6 in that experimental trial, but also confounded the 7 adverse reaction profile of the experimental 8 pneumococcal vaccine. 9 And so the use of placebo does have to be 10 carefully considered for scientific, as well as 11 ethical reasons. And I hope very much that this 12 committee will devise some sort of mechanism to 13 sort these issues out because, in that trial, I 14 wonder if the parents really did have informed 15 consent and, you know, who was there to speak for 16 those babies? 17 CHAIRPERSON MARSHALL: Barbara, thank you 18 very much. 19 And that leads us, beautifully, I think, 20 into the recommendation phase. And, committee, let 21 me say this: 22 I think that there is a consensus within 110 1 the room at large that there are some merits to the 2 recent revisions of the Declaration of Helsinki, 3 and there are some parts of it that are broken. 4 What I would propose that we do in terms 5 of an action plan for our committee is this, and 6 it's something that Dixie and Greg and I have 7 discussed, and it seems to be an obvious solution. 8 The subcommittee of the Committee on 9 Science of the Office of Science Technology Policy 10 has already formed an ad hoc, inter-agency working 11 group. And I would propose that for our action 12 plan, relative to the Declaration of Helsinki, that 13 we ask that group to give us a thoughtful and well- 14 reasoned response to the revisions of the 15 declaration. And that, once that's done, then we 16 can move forward. 17 The other suggestion that I have and point 18 that I would like to make is that the document that 19 we have been working from and that the committee 20 members had the benefit of having ahead of time, 21 the side by side comparison of the '96 and 2000 22 Declarations of Helsinki that was written for the 111 1 NBAC by Glen Drew, will be made available on the 2 OHRP web site. 3 And so I am encouraging those of you who 4 are ex officio and liaison members, and who are our 5 public members, to please send us your comments so 6 that we can get them to this working group so that 7 they can have the benefit of your wisdom and your 8 concerns. 9 And I have Elliot and then Greg, and we've 10 got about two minutes because we have our next 11 presenter here in the room. 12 DR. DORFF: No. That's fine. 13 Just as a matter of information for us, 14 there have been two other ethical standards on 15 these issues that have been mentioned this morning. 16 One is the Belmont Report and the other is the 17 International Commission on harmonization 18 statement, and I would at least like to see those. 19 CHAIRPERSON MARSHALL: Done. 20 Bob and then Greg. 21 DR. RICH: I think your action plan is an 22 excellent one. I would suggest that we incorporate 112 1 in that analysis of the Helsinki report the other 2 contextual reports that we have before us, and I 3 would include the NBAC report that immediately 4 proceeds this as part of something that we should 5 also put into that context. 6 I think the other comment that I would 7 make about the Helsinki report from the discussion 8 I've heard this morning is that I think there is an 9 important distinction between rejecting the 10 Helsinki report and not endorsing it. And I would 11 hope that because I think the problems that we have 12 heard about are sufficiently substantive in 13 concept, that I hope that by not rejecting it, 14 we're not misconstrued as having endorsed it with 15 some provisos or something, because I think it 16 would put OHRP in a difficult situation, and the 17 FDA, for that matter, in a difficult situation if 18 we were to say we basically endorse in principle 19 with these concerns. I think we're far from ready 20 to do that. 21 CHAIRPERSON MARSHALL: Thank you so much 22 and an excellent point. 113 1 Greg? 2 DR. KOSKI: It sounds like we're getting a 3 charge from this. 4 I would just like to perhaps suggest that 5 we do two things. One of them actually happens 6 automatically and that is the fact that the human 7 research subcommittee has as part of its makeup, 8 representation, or at least links to the National 9 Bioethics Advisory commission. 10 They way that commission works is that 11 they come out with an advisory paper, and then 12 somebody in, you know, one of the departments gets 13 charged with translating that into some effective 14 action. So we will just join those at the hip. 15 But I think the other important point is 16 that recently, NIH conducted a conference on, you 17 know, placebo and scientific design and all that. 18 I think we would miss the boat here if we didn't, 19 at the same time we're dealing with this issue on 20 the ethical guidelines and everything, not tap into 21 that in order to come out with perhaps some useful 22 and clarifying information on how placebo studies 114 1 are best designed, how they can be used, so it goes 2 kind of hand in hand to get people in the right 3 direction. 4 And with the consensus of the group, we 5 would work with them to try and do that. 6 CHAIRPERSON MARSHALL: Thank you very 7 much, Greg. And if we need further refinement of 8 this action plan, then we do have time at the end 9 of the day. 10 Thank you very much, Greg. 11 Dixie, thank you for a beautiful 12 presentation and for all of your thoughtful help 13 and for the help that you're going to offer us in 14 the future. 15 MR. SNIDER: You're welcome. 16 CHAIRPERSON MARSHALL: And I would like to 17 welcome Alan Fleishman, who is Senior Vice 18 President of the New York Academy of Medicine. He 19 is clinical professor of pediatrics and clinical 20 professor of epidemiology and social medicine at 21 the Albert Einstein College in New York. 22 Welcome, Alan. 115 1 MR. FLEISHMAN: Thank you, Mary Faith. 2 I actually do have a few slides, if you 3 would please set the slides up. But, you see, 4 since I saw you move the projector away, I thought 5 maybe you could move the projector back. 6 I can begin without the slides. Actually, 7 the slides are just trigger slides, and they'll 8 help a little bit to keep our attention. 9 As a physician and an ethicist, physicians 10 always use slides. Ethicists rarely use slides. I 11 use a few. 12 CHAIRPERSON MARSHALL: No. That's the 13 definition of a true medical humanist, is someone 14 who does not use slides during grand rounds. 15 MR. FLEISHMAN: But all the doctors fall 16 asleep. 17 Now, let me begin by saying that Dr. Koski 18 has asked me to talk a little bit about and trigger 19 your discussions about some of the problems 20 inherent in research with children, presently 21 regulated through the federal common rule. 22 I'd like to say, first of all, that 116 1 children are a broad category, having done research 2 with children for many years. I am a pediatrician 3 and a neonatologist and a bioethicist. 4 Children come in various sizes, starting 5 from about one pound in the neonatal intensive care 6 units, up to the 300 pound high school football 7 linebackers. And, clearly, we need to understand 8 that that developmental trajectory is important, 9 and we may need some different thinking for those 10 different groups of children. 11 Secondly, surrogate decision making by 12 parents for children is both conceptually and 13 socially different from surrogate decision making 14 for incapacitated adults. 15 Parents are the decision makers for their 16 children and are given broad range of 17 responsibility and authority in our society. We do 18 not allow them unlimited authority. We do ask them 19 to act responsibly, but we give them a broad range 20 of authority in our society, and we assume that 21 they will determine the risks that they allow their 22 children to take as long as they can control them. 117 1 And at some point in time, they lose 2 control of their children, and their children 3 choose to take risks that even their parents 4 wouldn't even wish them to take. Those of us who 5 have had adolescents understand this concept. 6 And, you know, I'm not going to be able to 7 control those slides from here. It just dawned on 8 me, so I am going to have to ask for some help. 9 Excuse me? 10 PARTICIPANT: PowerPoint? 11 MR. FLEISHMAN: No. It's just slides. 12 It's just a remote. 13 What's been debated for the entire post 14 World War II era is whether is it ever ethical to 15 do research on children. 16 Thank you very much. 17 And I think that we need to answer that 18 question as, "yes." In fact, one would argue, it's 19 unethical not to do research on children because 20 children are unique. Children are different from 21 adults. They're not just small humans. 22 And we have so many therapeutic 118 1 misadventures in children that are the result of 2 well-intentioned physicians, doing what they 3 thought best for children and hurting them 4 directly. 5 We also have assorted history of research 6 in children in this country, so we don't allow just 7 well-intentioned investigators and parents to 8 decide what is acceptable in terms of research. 9 And we do meet standards, and we do have 10 some at this point. 11 Children are unique because their diseases 12 are unique. Respiratory distress syndrome of the 13 premature, the greatest killer in infant mortality, 14 basically is a disease of immaturity of the lung. 15 Critically important for us to study such issues 16 only in premature infants. 17 They're unique also because they have 18 different metabolism. They have different 19 developmental stages, and these things go without 20 saying almost to people, but we need to remember 21 this when people say, "Well, we don't want to have 22 research because we take these vulnerable children 119 1 and we subject them to risks." 2 The children require this research, and I 3 think one of the things that I'll talk about a 4 little bit later is the importance of questioning 5 so-called standard therapies that have never been 6 evidence based in children. In fact, as a 7 practicing pediatrician, pediatricians know that 8 probably, at least a few years ago, 80 percent of 9 the drugs they prescribed on a daily basis were 10 never studied in children, which is very 11 problematic. 12 We avoid studies in children. We avoid 13 them because they're expensive. It is more 14 expensive to study things in children. 15 The consent processes are complex. We're 16 going to talk a little bit about that. 17 The liability issues are very great for 18 the pharmaceutical industry and others, and the 19 economic gains are slim since, thank God, there are 20 fewer sick children than there are sick adults. So 21 the economic gains for new treatments tend to be 22 less important. 120 1 We should remember, and we were talking 2 about the Declaration of Helsinki, we should 3 remember that the Nuremberg Code in 1947 precluded 4 research in children by specifically stating that 5 the voluntary consent of the subject was required. 6 Now it's argued whether they were just not 7 talking about children or whether they intended it 8 to preclude research in children, but we do 9 remember many of the atrocities that occurred 10 during the war were atrocities on children. And, 11 here, the feeling was that this ought not happen. 12 In the United States, we developed our 13 National Commission. We looked at the Belmont 14 Report, and the National Commission, and Dr. Levine 15 was a consultant to the report on research 16 involving children, and I would strongly recommend, 17 if you're interested in research involving children 18 and the regulatory structure, that you go back and 19 read this document, which I had read several times 20 in the 1970's, once in the 1990's, and then again 21 last weekend. 22 And I have to say that it is a very fine 121 1 piece of work. 2 And in 1978, I put together this document 3 and the federal regulations in a side-by-side 4 analysis, in 1978, and I pulled that out again this 5 weekend to look at. And part of the issues that 6 I'm going to raise today actually have to do with 7 the federal regulations not fully complying with 8 the recommendations of the National Commission and 9 leave us with some unanswered questions and 10 problems, which I'd like to talk about. And there 11 are seven areas that I would like to highlight for 12 your thought and review. 13 Before I get to that, and the Belmont 14 Report has been talked about, and we know that it's 15 the very basis upon which we think about research 16 ethics. 17 But in the Belmont Report, both in the 18 Benefices and the Justice discussions, research in 19 children was specifically spoken about, 20 specifically spoken as justifiable with appropriate 21 concerns for risk and appropriate concerns for 22 consent. 122 1 And I think that we moved very far forward 2 from the Nuremberg Code as the writers of the 3 Belmont Report did embrace the idea that parents 4 would be the decision makers for their children in 5 terms of research. 6 Now, in the federal regulations, there are 7 four permissible levels or permissible types of 8 research for children. You have those regulations 9 in your packets, the so-called subpart D of the 10 regulations. 11 These four permissible levels start with 12 the concept of minimal risk. 13 Now, minimal risk actually is defined in 14 the general regulations of the Federal Register. 15 It wasn't only defined around children, but it is 16 spoken of in the children's regulations as a 17 permissible level of risk. And we all know this 18 definition, but I remind you that it talks about 19 both the magnitude and likelihood of risk. 20 If you read the documents of the National 21 Commission and if you look at how this term has 22 been used, it has been my experience, having worked 123 1 in two major IRBs for 19 years, and now chairing a 2 less major IRB, that this definition was used to 3 encompass the risks of daily life for the average 4 child, for the ordinary child, for the normal 5 child. 6 There are many people who have criticized 7 this definition as vague, have created straw men to 8 be easily struck down because there isn't such a 9 specificity in this regulation or in this 10 definition. 11 I believe that it is an anchor. It is a 12 good anchor, and that we could benefit in all of 13 the IRBs around this country from a clear, not new 14 regulation, but a clarification of what this means. 15 I had the opportunity to look at NBAC's 16 most recent draft report. I have to say I have not 17 analyzed it carefully since I only saw it 18 yesterday, but I think, here, they're pushing for a 19 new definitional structure. 20 I'm not sure that's necessary, but I do 21 think this group could benefit, all of the IRBs, by 22 clarifying what the intent of this definition was 124 1 and how it ought to be used. And I think that 2 ought to be those risks of daily life in the 3 average, ordinary child. Not the child under 4 siege. Not the child in Biafra. Not the child 5 when bombs are falling in Israel or anywhere else. 6 Having worked in the Bronx for many years, 7 we felt that our risks of daily living might be 8 greater than some, but we absolutely understood 9 that in our IRBs what this concept meant. 10 And I think that this concept has 11 normative, as well as descriptive, force. It 12 basically says that our society allows these risks 13 for children in general, and that we ought to allow 14 them as a permissible level of risk in defining 15 such. 16 The next issue is the issue of direct 17 benefit, so if there is the prospect of direct 18 benefit for children, we allow this as permissible 19 level of research. 20 Here, I think we have several issues we 21 need to deal with. You've already talked a good 22 deal about the placebo-controlled trials question. 125 1 Placebo-controlled trials often come up in 2 the arguments at IRBs in terms of is this potential 3 risk, is it a prospect of direct benefit if half 4 the subjects will be in a placebo arm of a study, 5 the other half of the subjects in a more active 6 arm. And I think we need clarification here again, 7 and I think we can benefit from the NIH analysis 8 here. 9 But this group here, again, could clarify, 10 could help IRBs to place placebo-controlled trials 11 in their appropriate perspective. 12 My feeling is it does belong in the 13 prospect of direct benefit research, but I think 14 that needs to be argued, discussed, and then 15 clarified with some specificity. 16 The other area where the prospect of 17 direct benefit is used is in the Phase I trials, 18 particularly in cancer chemotherapeutic studies. 19 Now most of us realize that Phase I trials 20 have no direct therapeutic benefit, but it's hard 21 to justify Phase I trials for children when risk is 22 possible and benefit is not in this consideration. 126 1 So I believe this group will need to think 2 very carefully and directly about Phase I trials 3 for children. I think they're absolutely 4 important, in fact, critical because children's 5 research requires new drugs, particularly in the 6 cancer area. 7 But unless we have a clear delineation 8 about how to justify those trials, we will have 9 problems. 10 Now perhaps the most debated issue in 11 child regs is the question of minor increment over 12 minimal risk. This, I think, artful, intelligent 13 and thoughtful approach from the National 14 Commission allows IRBs for research without the 15 prospect of direct benefit to allow parents to 16 enroll children if several things occur. 17 One is that it's just a little more than 18 minimal risk, and it's contextual; that the 19 subjects have some experience with these kinds of 20 problems, commensurate with actual or expected 21 medical situations, and it's a very high standard 22 to ask the researcher to assert that this 127 1 information is likely to yield generalizable 2 knowledge of vital importance. Not just of 3 importance, but of vital importance to the 4 subject's disorder. 5 Now, here we have several issues that I 6 think need clarification. One is, what is a 7 subject and what is a disorder? 8 If I am now increasingly going to be in 9 the predispositional testing business, as we learn 10 more and more about genetics and the powerful 11 influence of genetics and our genetic 12 predispositions, if I am phenotypically not 13 affected, but genotypically predisposed, do I have 14 a disorder which would allow me, as a child, to be 15 subjected to a minor increment over minimal risk 16 without direct therapeutic or without direct 17 prospect of benefit? 18 I believe we need to clarify that this 19 does place such children into the category of the 20 subject with a disorder. I do believe that 21 children in families who have had the experience of 22 understanding disorders because another sibling or 128 1 a cousin or a relative or others have been affected 2 with this problem, or a child who has a 3 predisposition within a family who has learned this 4 problem I think has the ability to understand and 5 to fit into this category. And the words were 6 "actual or expected," and here, again, this 7 predispositional study might well be expected 8 medical conditions of the child. 9 We need clarification here. I think that 10 this will be an important thing for this group to 11 do, remembering as Francis Collins has said, that 12 we are at a miraculous time in what we will learn 13 about children and the potential to predict and 14 prevent as we move the fields of pediatrics even 15 further into preventive health than it is 16 presently. 17 NBAC has also talked about this, and I 18 think that we would benefit from looking carefully 19 at that report, and, you know, we could have the 20 argument about genetic exceptionalism and whether 21 we ought to treat this differently, but I think the 22 public believes that this information is different 129 1 and important and we need to think about that. 2 The sixth issue is child assent. For me, 3 the concept of child assent is a respect for 4 children's issue. We ought to respect children. 5 We ought to respect all children from the moment 6 that they're born and a child, and we ought to 7 consider what they ought to be told if they're 8 going to be enrolled in a research project. 9 However, in giving a talk at a grand 10 rounds recently, an oncologist came up to me and 11 said he had a child who refused to be part of a 12 research study that was clearly in the child's 13 benefit. 14 And as most people know, there is almost 15 no cancer treatment of children outside of academic 16 medical centers today. You can, as an adult, get 17 cancer treatment outside of an academic medical 18 center, but virtually all children are at least 19 approached to enroll in research studies. 20 And, here, this oncologist said, "Well, 21 this youngster didn't wish to be in this research 22 study. His parents wanted him to. He was just 130 1 being ornery. 2 We informed him that he ought to be in the 3 study because we would learn about which arm of 4 these study arms were better. 5 The investigator was quite concerned about 6 the concept of assent, particularly in the area of 7 direct benefit research. 8 So we need to clarify the concept of 9 informing, of respecting children, appropriately 10 getting their positive assent for those trials 11 where there is no potential benefit, and dealing 12 with the idea of informing and the level of assent 13 required in those trials where there is direct 14 potential benefit. 15 Assent is an evolving concept. We need to 16 think about it developmentally. We can't put 17 absolute rules on it, and we have learned in our 18 thinking about it. 19 We don't always have to inform the child 20 about his diagnosis. We've learned that in the HIV 21 world that it was sometimes harmful to the family 22 to inform a youngster that he had HIV. 131 1 Even though the American Academy of 2 Pediatrics, and I helped write their policy on 3 this, believes that children ought to be informed 4 at the appropriate level about their diagnoses, we 5 also have to respect family privacy and understand 6 the potential of this youngster with this new name, 7 telling other people and causing great problems for 8 his family. 9 So with the assent forms, we need to be 10 careful and to explain to IRBs what we try to 11 accomplish with informing children and respecting 12 them, without putting the family and the child at 13 greater risk than necessary. 14 And, finally, the seventh point that we 15 need to look at is the adolescent consent issue. 16 It's what I call the "research paradox." 17 The National Commission, in its wisdom, 18 suggested that adolescents ought to be allowed to 19 consent when they could consent for therapeutic 20 intervention. The federal regulations dropped that 21 comment and only commented, and you can look at 22 your regulations, but I'll just quote quickly the 132 1 one sentence that is relevant here is, "Parental or 2 guardian permission is not a reasonable requirement 3 to protect the subjects, for example, neglected or 4 abused children." 5 So IRBs may waive parental requirement for 6 permission and have waived parental requirements 7 for permission, but we need clarification as to the 8 extent with which they may, particularly in the 9 adolescent area. 10 Let me be very specific. Adolescents in 11 New York and almost every other state, as far as I 12 know, can have sexually transmitted diseases 13 treated. So if they go to their doctor, they can 14 consent for the treatment of sexually transmitted 15 diseases, gonorrhea, syphilis, without informing 16 their parents. 17 Now that doesn't say that we don't want to 18 talk to their parents, if it's appropriate, that we 19 don't counsel them about the importance of family 20 involvement and such things, but we are allowed, as 21 pediatricians, to treat such youngsters without 22 informing their parents. 133 1 If we do like to do a randomized clinical 2 trial of two appropriate therapeutic arms for 16 3 year old to 17 year old to below 18 year old 4 children, there is real question as to whether we 5 may enroll those same children in a randomized 6 clinical trial which might tell us more about how 7 to treat such children, and particularly, children 8 with these characteristics because we might want 9 shorter therapies. 10 We might want therapies we could give in 11 one shot in the clinic. We might want ways of 12 dealing with such children so that we can take care 13 of their problem, and we might want to enroll such 14 children in therapy. 15 Most IRBs are quite reluctant to do that. 16 Now I've given your Executive Director a 17 document that I think she will distribute to you. 18 It's from the Journal of Adolescent Health. It's a 19 document written by and for the Society for 20 Adolescent Medicine which argues that, within that 21 single sentence in the federal regulations, we 22 could develop a system in which IRBs could develop 134 1 a process which could capacitate, if that's a word, 2 and I don't like it, but could develop a 3 methodology to find out whether this adolescent has 4 the capacity to make these kind of judgments, could 5 then develop special protections for these 6 adolescents, perhaps a social worker or others who 7 would be available to the adolescent, other than 8 their families, and allow them to consent to such 9 research studies. 10 Certainly, many IRBs have done that in the 11 HIV area, and I think it's very important that we 12 clarify to IRBs that they may do that so that they 13 may, in fact, continue. 14 Now, basically my thought is that in these 15 seven areas that I've tried to highlight, the 16 federal regulations I believe are not clear, but 17 are sufficient in order for us to clarify using, as 18 a primary source, the National Commission's report. 19 And that if we created from the Office of 20 Human Research Protection a series of memoranda to 21 IRBs, that we could, as we do in departments of 22 health across the country, clarify regulations, 135 1 clarify legislation, and create a case law or an 2 ability to inform IRBs. 3 And then, as we went around to look at 4 IRBs, we could see whether, in fact, they were 5 consistent with those memoranda. 6 For 15 years, I've been on the New York 7 State Task Force on Life and the Law, the Bioethics 8 Commission in New York. Some of you may have read 9 some of the monographs that we've done, and we've 10 actually had seven laws passed in New York, based 11 in the nexus of the interaction between medicine, 12 law and ethics. 13 One of our first tenets of that task force 14 since 1985 has been if we don't need to go toward 15 legislative or regulatory help, we don't because we 16 understand the complexity of that approach. 17 If we can do it by education, if we can do 18 it by interpretation, by memoranda from important 19 groups like the Commissioner of Health or the 20 Governor, we choose that route, and only go the 21 route of changing the structural fabric of 22 regulation or legislation if we have to. 136 1 Thank you very much. 2 CHAIRPERSON MARSHALL: Alan, thank you. 3 That was just beautiful. Very clear, well thought 4 out, and I think that it will assist us in terms of 5 our discussion and also our action plan. 6 Please stay with us for our discussion. 7 Our time frame is that we will have some discussion 8 now. We will break for lunch, then reconvene for 9 more discussion and for working on our 10 recommendations and our action plan. 11 So I have Bob. Bob is first on my list. 12 Okay. Sandy, Bob and Adil. 13 DR. ROBERT LEVINE: Alan, that was truly a 14 splendid piece of work. You took what I considered 15 the National Commission's best product and you 16 found every difficulty there is in it, and that's a 17 great service to us all. 18 I'm only going to make three comments. 19 Your comment on the minor increment above minimal 20 risk issue was right on target. 21 What you didn't mention, and I think what 22 you already know, is that this research rules out 137 1 developing normal values for anything that presents 2 a minor increment above minimal risk because the 3 subjects had no condition that -- because they 4 don't meet the three contextual criteria you 5 mentioned. 6 I think when you talk about advocating 7 that being genotypically at risk counts as having a 8 condition, I'm sympathetic with this. But it's 9 necessary to point out that that would call into 10 question the recent OHRP move to criticize and put 11 a stop to the studies of the children of obese 12 parents, and that could be a focal point for our 13 discussion. 14 Just two more comments. One is that, and 15 I don't have any advice on this point, that when 16 we're working with small children, their need to 17 get parental permission often stands as an obstacle 18 when we have to warn the parents that in the course 19 of the studies, if the researchers find anything 20 that raises a suspicion of child abuse, they will 21 have to report that to the authorities. 22 My colleagues in psychology tell me every 138 1 time they want to do a study to explore the origins 2 of child abuse, they have to issue that warning, 3 and this virtually guarantees that the only 4 families they'll get to look at are the ones that 5 they're not interested in, because they've warned 6 all the ones they're interested in to stay out of 7 the study. One problem. 8 Another problem that relates to your 9 concern about adolescent consent is there are many 10 studies that are trying to look at, for example, 11 the acculturation of what I call "middle-aged 12 adolescence," you know, 14, 15, 16, into, for 13 example, a hard drug abusing culture, where 14 ethnographers, anthropologists just want to follow 15 the kids around and find out how they are caught up 16 into this culture, and describe what the events are 17 all about. 18 If these people -- now, you know, with 16 19 year olds, as you pointed out, they may have the 20 authority to seek treatment on their own. But with 21 14 and 15 year olds, we're not so sure. 22 And so when these anthropologists are told 139 1 they might have to get parental permission, that 2 kills the study because no child who is eligible 3 for a study in such a protocol will say, "Yes. I'd 4 love it if you talked this over with my mother." 5 Again, Alan, thank you very much. 6 CHAIRPERSON MARSHALL: Yes, Alan, please. 7 MR. FLEISHMAN: Two issues: The child 8 abuse problem is a real one. We, as pediatricians, 9 are legally mandated, as are other people who 10 interact with children, like teachers and social 11 workers and others and researchers, to inform state 12 authorities if, in fact, we see neglect or abuse in 13 progress, or even a suspicion. 14 And, therefore, when we engage people in 15 research, we need to tell them that's going to 16 happen. It's one of the few legal steps we have to 17 take, we're mandated to take, and it does, in fact, 18 impact on the research into some of these issues. 19 Again, one has to be creative in design. 20 One has to go to families who, in fact, have 21 already been involved in abusive situations to 22 learn more about them. 140 1 But I'm sympathetic to it, but I'm not 2 sure that I would, for the sake of those children, 3 not continue the obligation of the physicians to 4 report, and, therefore, I'm not sure that I would 5 take out of the informed consent the reality that I 6 will report if I do observe it. And, you know, 7 I've dealt with that in longitudinal studies that 8 I've been involved with in children. 9 So I think it is a problem. I'm not sure 10 that ought to be one that we try to overcome. 11 The first issue that you talked about in 12 terms of developing normative standards, one of the 13 first studies that I reviewed in 1975 when I first 14 became a member of an IRB had to do with some 15 nephrology colleagues wanting to do some fairly 16 sophisticated nephrologic physiology on normal 17 children, and we just didn't let them. We really 18 didn't. We really felt that the risks to those 19 children far outweighed the greater benefit of 20 developing physiologic norms. 21 And, in fact, having -- you know, they 22 went to war, and I was a new member of that 141 1 department, and, you know, I figured I was history. 2 But they were able to creatively develop 3 methodologies that decrease the risk and got us 4 closer to be able to define those norms. And I 5 think there is a balancing here that we're going to 6 need to maintain. 7 And, lastly, concerning the adolescent, we 8 presently, at the New York Academy of Medicine, are 9 doing very large studies in ethnography and in 10 early drug abuse in Harlem and East Harlem, and we 11 believe that adolescents ought to be able to 12 consent for those studies, based on an 13 interpretation of these regulations, as they stand. 14 We think there are methods in order to 15 allow them both to be examined for capacity. We 16 believe there are methods to allow them to have 17 counselors to help them make this thoughtful 18 decision, and we think it's critically important, 19 hepatitis C, HIV, to learn about what are the 20 social determinants of those diseases in this 21 cohort so we can then develop the interventions to 22 prevent them. 142 1 So we are, in fact, doing them. We 2 believe -- and I'm saying it publicly -- we believe 3 that we're doing it within the regulations. We 4 believe we're doing it well intentioned. 5 So IRBs would benefit from knowing whether 6 they are or aren't doing it within the regulations, 7 but we would make the case that it is possible to 8 do this. 9 CHAIRPERSON MARSHALL: Thank you, Alan. 10 I have Sandy, Bob, Adil and I am also 11 going to ask Mary and Jennie if they would put 12 themselves in line because I would like to hear 13 from you relative to your areas of expertise and 14 your background on this issue. 15 Sandy? 16 DR. CHODOSH: I have two comments or 17 questions, and that is that we deal with 18 adolescents. When you talk about adolescent 19 mothers, at least in the state of Massachusetts, 20 one has a problem that, in many respects, they are 21 treated as adults. 22 And it gets to be quite confounding when 143 1 you look at this from an IRB point of view, and you 2 get into very complex studies, particularly when 3 you're trying to study exactly the motherhood and, 4 in fact, the fatherhood aspects of that kind of 5 relationship. 6 So its something I think that needs to be 7 addressed about, you know, how do you determine 8 that to be adult as opposed to all the other 9 aspects? 10 It just wipes out the age factor once you 11 become a mother. It doesn't help the father 12 because it this help him to become an adult by 13 having fathered a child. 14 MR. FLEISHMAN: I would say it does in New 15 York, Sandy. 16 DR. CHODOSH: Oh, it does? Oh, well. And 17 I'm sure it varies from state to state. 18 The other has to do with the Phase I 19 trials and the risk involved. But this is not just 20 unique to children. I mean there are clearly 21 situations where it's unethical to use normal 22 volunteers to do Phase I trials with very toxic 144 1 stuff. 2 With children, you're talking about almost 3 anything being more toxic than what they should be 4 getting, and some of the ways around this would 5 combine really Phase I aspects into a Phase II 6 trial so that the people who don't come into the 7 study have, in fact, some benefit in that. At 8 least they have the sense of at least doing 9 something about their disease, not their personal 10 disease, the disease that they suffer from. 11 It is one possibility. I don't know that 12 our regs allow it, but I think that certainly if 13 we're going to move ahead with research in children 14 that we need to find some innovative way to get 15 through this kind of information and still be 16 productive. 17 MR. FLEISHMAN: Just a quick comment on 18 the distinction between emancipated minors and 19 mature minors. 20 Within each state, there are a group of 21 minors less than 18 who are legally emancipated. 22 In New York, I know that they are pregnant or 145 1 apparent. They are in the military, and in 2 general, they are independent and employed, not 3 throw-aways, runaways, cast away children on the 4 streets, but are independent of their families, 5 employed and functioning like adults. And those 6 children ought to be treated like adults. 7 Now, those of us who are prudent in health 8 care delivery understand that, on occasion, and 9 it's a rare occasion, we see a 13-year old mother 10 or a 14-year old mother, and it is rare, although 11 we talk a lot about it. And those children need 12 protection, and we are careful about how fast we 13 allow them to be called emancipated. 14 But 16-year old parents pretty much are 15 treated as adults in terms of emancipation, 16 particularly because we respect their right to make 17 judgments for their children. And having dealt 18 with a large number of those youngsters, I think 19 there are ways to help them to do that and to put 20 them in a context so that they can. 21 I have no question in my mind that they 22 love their children and have the same ability to 146 1 weigh the risks and benefits for their children, as 2 most of us have for our children, perhaps sometimes 3 even better. 4 So I think that's an important issue. I 5 share your concern about the Phase I. 6 CHAIRPERSON MARSHALL: Bob? 7 DR. RICH: Sandy actually stole my 8 question completely about the Phase I issue, which 9 is to say that it seems to me that one of the 10 things that we can actually take advantage of is 11 that, by and large, trials in children -- excuse me 12 -- will follow the development of some normative 13 data in adults. 14 And so it's not as though one is starting 15 a Phase I trial in children without a context. And 16 I think that by acknowledging that, the fact is 17 that one can start a Phase I -- one can move what 18 would be nominally a Phase I trial in a childhood 19 population where there are data that may be 20 relevant, but arguably different from adults, and 21 still move quickly into a Phase I/II kind of 22 context where the possibility of benefit to the 147 1 child actually might be realized. 2 DR. CHODOSH: Could I just add something 3 to that? 4 CHAIRPERSON MARSHALL: Yes, please do, 5 Sandy. 6 DR. CHODOSH: But turn that around, Bob, 7 and now the thing you're developing has no benefit 8 to adults and is only used in children. You don't 9 have to find a way around that. 10 DR. RICH: No. I don't disagree with 11 that, and I'm just basically saying that the vast 12 majority of drugs will develop in that kind of a 13 sequential way. But I certainly appreciate the 14 exceptions. 15 CHAIRPERSON MARSHALL: Bob has a comment 16 on point. 17 DR. ROBERT LEVINE: I've also seen, over 18 the last few years, ten or 15 years, the tendency 19 to call studies done in children "Phase I/II." And 20 that gets around the minor increase above minimal 21 risk that Alan was talking about. 22 However, if it's got a dose escalation 148 1 design and it says that it's looking for the 2 maximum tolerated dose, this is not a Phase I/II 3 study, no matter what the title says. 4 I'm not opposed to it. I side with Alan. 5 I think it's essential that these studies be done. 6 But we've got to find some vocabulary for 7 describing some of these things that really are 8 ethically justified. 9 CHAIRPERSON MARSHALL: I think we need a 10 rhetorician on our committee. 11 Greg? 12 DR. KOSKI: Well, just to address 13 something here that I've heard in several of the 14 comments, and as well as in one of the remarks Alan 15 made, what we're hearing increasingly is talk about 16 how studies are being designed in order to get 17 around the regulations, in order to do things that 18 we somehow believe, as a society, we ought to be 19 doing. 20 Well, that tells me that maybe the 21 regulations, as they are currently cast, may not be 22 serving our interests. So that, as I'm listening 149 1 to the discussion, this sounds like the first time 2 during this meeting where I'm hearing basically the 3 need to actually consider I mean a possible 4 revision of the regulations because they may not be 5 serving the greater interests here. 6 But I can tell you, as the Director of 7 OHRP, putting on my other hat, you know, the 8 prospect that we have things set up so that people 9 have to basically try to find a way around the 10 regulations for protection of human subjects is an 11 unsavory situation. 12 MR. FLEISHMAN: I just want to reassure 13 Greg that I'm not suggesting we need to go to 14 change or rewrite the regulations. I think, within 15 these regulations, we can forthrightly come to 16 grips with this problem. I believe we can, and we 17 can clarify how one could design ethically 18 acceptable, justifiable studies. 19 I, too, share your concern about going 20 back to the well. I am not suggesting that we need 21 to rewrite the regulations. 22 CHAIRPERSON MARSHALL: Abbey? 150 1 MS. MEYERS: You know, it's very 2 interesting, looking back on the history of this 3 pediatric testing, for years and years, especially 4 for rare diseases, we were begging pharmaceutical 5 companies to sponsor these trials. They absolutely 6 refused. And the excuse across the board was 7 liability. 8 Suddenly, when FDAMA was passed and they 9 gave them six months' exclusivity for studying an 10 adult drug in children, they're tripping over each 11 other to do pediatric studies. 12 And I think things will arise in the 13 future that are really so terribly unethical. I 14 can't wait for somebody to decide they want a 15 pediatric study on Viagra, not that they care what 16 it does to the children, but just because they want 17 the six extra months of their patent. 18 What do you think about this new phenomena 19 about paying parents? I mean we've heard about 20 parents being paid $1,000 and kids being given gift 21 certificates at Toys 'R Us. What do you think is 22 going on here? 151 1 MR. FLEISHMAN: I'm sorry I missed the 2 discussion yesterday about what I call, "follow the 3 money," but I think conflict of interest, coercive 4 payments and financial incentives that go far 5 beyond appropriate levels are a real serious 6 problem today in all research, not just with 7 research with children, and I think this group 8 would greatly benefit the public by looking 9 carefully at those parts of the research problem. 10 MS. MEYERS: Do you think it should be 11 banned? 12 MR. FLEISHMAN: I think compensation to 13 children for being subjects of research, or to 14 their parents for the time it takes to bring them, 15 and some of the discomforts and all, are 16 appropriate. 17 So I don't think that the word, "banned," 18 is a word that I would use, but I think they need 19 to be regulated. I think there need to be 20 standards. I think there need to be appropriate 21 balancing. 22 I don't think it's inappropriate for the 152 1 child to have, you know, a Toys 'R Us coupon for 2 some number of dollars to go over there and choose 3 a book or a toy for participating in a research 4 study. I mean I think that's appropriate, just as 5 we would ask if we adults being normal volunteers 6 in a study, you know, we had to take half a day 7 away from our work or take a vacation day or 8 something that we would, you know, want some 9 appropriate level of compensation that's not 10 coercive. 11 I think that many IRBs have set those 12 standards. Those are generally in academic centers 13 where those standards have been maintained, and we 14 need to generalize from that experience to try to 15 help set appropriate levels. 16 MS. MEYERS: So you're saying set 17 standards? 18 CHAIRPERSON MARSHALL: Greg and then Judy. 19 DR. KOSKI: Yes. One of the very 20 difficult problems with children is that, as you 21 know, if you've got kids, you know, by the time 22 your kid gets old enough to cut the law, you know, 153 1 you can get your son or your daughter to cut the 2 lawn for three bucks, whereas it costs you $35 to 3 get the crew to come in there. 4 So that the ease with which children could 5 be induced to do something with perhaps a lack of a 6 full understanding of the dimensions of what their 7 participational, you know, involve is I think the 8 concern here. 9 Some IRBs and others have recognized that 10 as the main problem, and when you come with the 11 argument, "Well, wouldn't it be disrespectful to 12 the children not to give them some compensations, 13 the other side of it, the approach that's sometimes 14 taken now is to take the potential coercive element 15 out of the signing up assent process, and instead, 16 you know, for those children who independently, 17 with their parents, decide that they want to do it, 18 give them a thank you gift afterwards so that it 19 doesn't put them in a coercive position. 20 And I think that, you know, introduces a, 21 you know, different kind of approach. It expands 22 our thinking a little bit in a way that could be 154 1 valuable as we consider alternatives to the current 2 arrangements or guidance that might come out to 3 help people. 4 CHAIRPERSON MARSHALL: Judy? 5 DR. SIEGEL: Yeah. I have a couple of 6 points to the testing and pediatric trials, 7 especially, from my perspective, which is 8 pharmaceutical. 9 I think you're correct. I think that the 10 pharmaceutical industry, for many years, actually 11 did not actively pursue testing for pediatrician 12 patients, as well as it did not pursue the testing 13 of geriatric patients, difficult issues in both. 14 I think, clearly, the geriatric issue is 15 addressed much earlier, but, again, there are still 16 issues of assent-consent in the geriatric 17 population. 18 I think that, at least from my own 19 perspective, I would argue that there has been no 20 race, at least on the part of the company I belong 21 to, to rush into pediatrician trials for the same 22 reasons. 155 1 The issues of liability are huge. 2 However, also, the issues of pediatrician 3 methodology are enormous, and at this point, still 4 unknown to us. 5 To do a clinical trial in children that 6 parallels the clinical trial in the same indication 7 in an adult, it is not a parallel process, 8 necessarily. 9 And so I think that the issues involved 10 with developing good, ethical research in children 11 are just beginning to be addressed. 12 I think this is being pushed, actually, by 13 FDA, which is now looking at drugs that are in 14 development, and actually suggesting which one of 15 those should be identified as a drug that should 16 have pediatric indications, whether it be as a 17 first indication, which we've all discussed. 18 If it's just particular to that age group, 19 for instance, or whether this is an indication that 20 could be used in trials, should it be used in 21 trials, and when in the course of development of 22 the drug should that decision be taken? 156 1 And I think that most companies now 2 clearly have that discussion with FDA early in the 3 development of drugs. 4 So I would argue that it's not necessarily 5 the six months' exclusivity that is making people 6 race forward. I think my own feeling is that the 7 time has come, and now the question is how to do it 8 in a way that actually protects the child, protects 9 the parent. 10 There are major issues with what a parent 11 will accept for their child. Also, there clearly 12 are issues that we've never dealt with before. And 13 so how do you develop something that is ethically 14 appropriate for the child, and also something that 15 a parent can actually support? 16 CHAIRPERSON MARSHALL: Thank you, and one 17 last question on point here, Greg, and then Adil, 18 Mary and Jennie. 19 DR. KOSKI: I think, Judy, you just raised 20 a very important point when you talked about the 21 assessment of whether or not a trial should be done 22 because what that implies -- I mean ethics is all 157 1 about what we should and should not do, and by 2 saying that, you know, the sponsors and the FDA 3 need to involve or engage in a discussion of 4 whether or not something should be done means that 5 we are beginning to have actually the introduction 6 of an ethical review part as sort of a formal part 7 of the process of developing clinical trials which 8 could be an extremely valuable approach, whereby as 9 part of the actual development of a clinical trial 10 protocol, there is actually a formal discussion of 11 the ethical basis for the experimental design. 12 And rather than putting that in as an 13 afterthought or part of a review process 14 subsequently, it's actually to make it an inherent 15 part of the actual process of developing the trial. 16 And I would imagine, Abbey, that in a 17 situation where, let's say that some, you know, 18 evil drug company did want to propose a Viagra 19 trial in children, it would be very difficult to 20 probably justify that unethical ground. 21 So I think that there is a very important 22 kernel of future development and opportunity in 158 1 what you just said that really deserves further 2 exploration. 3 CHAIRPERSON MARSHALL: Thank you, Judy, so 4 much. 5 Adil? 6 DR. SHAMOO: Alan did a great job at 7 summarizing the whole issue and children, and 8 there's going to be great help. And I've asked the 9 staff to give us a copy of your presentation, if 10 possible. 11 My impression, and correct me if I'm 12 wrong, and I have a series of questions for you is 13 that the last category of allowed research with 14 children; that is, that one must go to the 15 secretary for approval, has not really been 16 utilized well. A lot of them, they have been 17 pushed below that, even though it should be the one 18 to go to HHS. And that is of concern to me, and I 19 hope there will be some gratification. 20 Two questions are, what do you think the 21 threshold should be in children where genetically, 22 we're going to know that genotypically, they'll 159 1 have one percent, five percent, ten percent, 50 2 percent or 90 percent chance of getting an illness? 3 What should be the practical threshold 4 that we put those children through hell of 5 experimentation in order to prevent only one 6 percent or five percent? 7 There are experiments now being conducted 8 and approved by IRBs where the potential risk is 9 sure like five percent or maybe ten percent that 10 they will get the illness. 11 And the last question I have to you is -- 12 I may have misunderstood you, and that is, you 13 know, we have other values besides promotion of 14 science, and that is family. And it disturbs me to 15 hear that 12, 13, 14 years old, if they're not 16 emancipated, if they're not court ordered to be 17 taken away from their children, that we enroll them 18 in research without the consent of parents, 19 regardless of what that topic is because its 20 implication to the value of family unit is much 21 more destructive than the value we gain from 22 science progress. 160 1 I just need to see your comments. 2 MR. FLEISHMAN: My understanding of the 3 first comment you made is that the fourth 4 permissible level of research going to the 5 secretary has been used twice in the 15 years. 6 When pediatric investigators have been 7 polled about their desire to do what is basically 8 risky research, more than a minor increment of 9 minimal risk, there are no investigators who wish 10 to do that. 11 So I think it was an interesting approach 12 that was used when the regulations was created. It 13 I think adds some merit, as we look back at their 14 time. 15 But I'm not very worried about that 16 category because I don't see people coming out, 17 looking to do that work. 18 Second, oh, and by the way, I'm on record 19 at other forums suggesting that the national review 20 suggested by NBAC as a way to get around for 21 incapacitated adults, the issue of minor increment 22 over minimal risk is not an appropriate mechanism 161 1 and will be actually hurtful, both to the subjects, 2 as well as to the research enterprise. But we can 3 get into that at a different point. 4 The threshold issue, I'm never in favor of 5 putting anybody through the hell of 6 experimentation. I don't believe that that level, 7 as you have suggested, of risk or discomfort ought 8 to be in any experiments that we use. 9 But I do think that we will greatly 10 benefit from understanding more about 11 predisposition to disease as we study the genetic 12 component of children and adults and we learn more 13 about their natural history. 14 Last week, in Washington, a large group of 15 people convened to discuss the potential to do a 16 longitudinal cohort study of children over the next 17 30 or 40 years, a study that would have great 18 benefit to the children of America, but has some 19 ethical concerns that need to be dealt with in 20 order to be justified. 21 So I think that we have the potential to 22 learn in order to develop the potential to prevent 162 1 illness to help children without risking them 2 unduly. 3 So I don't know what the right threshold 4 is, but I do think that we need to evaluate the 5 studies from where we stand, what we know about 6 things today, and we need to be flexible as we go 7 forward as we learn more. 8 The third point is I'm absolutely in 9 agreement that the promotion of science is only one 10 good and that the promotion family is critical. 11 Children come in families. Children benefit from 12 families. 13 I use the word, "family," very broadly 14 when I use it. It isn't the Marcus Welbyian 15 concept that I have of it. 16 Families come of different kinds. They 17 are places where children are nurtured, and they 18 may have different groupings within them. 19 But I believe children are best nurtured 20 in families and that we ought to involve parents 21 for permission for children when they're in 22 research. 163 1 However, there are times when research 2 studies are of benefit to the children. The 3 children have ascertained that in applying the idea 4 that asking their parents for permission would be 5 hurtful to the children. 6 And as a society, I think we need to think 7 about that and respect it. We need to continue to 8 foster children within families, but at the same 9 time, know that there are some children who are 10 estranged from their families. There are some 11 children who will be hurt from informing their 12 families, and yet they have problems, disorders, 13 diseases, social problems which we, as a society, 14 need to study in order to help those children or 15 prevent future children from becoming those 16 children. 17 So I'm quite aware of the issue of family, 18 and I think as you begin to come down in the age 19 range, the first step for me is that we must have a 20 process by which we determine whether youngsters 21 have the capacity to make these judgments. 22 And we could think chronologically about 164 1 that, although within the chronology, we also have 2 to think about whether the children have a chronic 3 illness, because I think children who are 13 and 4 have had cystic fibrosis and who understand 5 something about their illnesses are different than 6 children who are 13 or if they see something new or 7 just a normal volunteer. 8 So I do think we need to sort out a 9 methodology to think about whether they have the 10 capacity to get involved in making a decision like 11 this, and that has to be a threshold point. 12 And 12 year olds, in general, will not 13 have that capacity, and 13 year olds probably 14 won't, and 14 year olds probably won't, but some of 15 them will. And as we get toward 17, most of them 16 will, I think, as we develop these methodologies. 17 CHAIRPERSON MARSHALL: Thank you very 18 much, Alan. And I think relative to that last 19 point there, there are data out there and studies 20 that are developing relative to the decision-making 21 capacity of children and adolescents. And that's 22 something that this committee, I'm sure, can 165 1 benefit from as we work forward in terms of action 2 plan. 3 Mary? 4 DR. PELIAS: If I can do this without 5 getting too choked up, I'd like to go to the 6 question of genetic predispositions, and my refusal 7 to acquaint a genetic predisposition with a 8 disorder in a child. I think that's a very, very 9 dangerous thing to do because while we know that 10 there are familial predispositions and things run 11 in families, for the kinds of diseases or disorders 12 we're talking about in terms of predispositions, 13 these are problems that are usually caused by lots 14 of genes and genes that we haven't identified yet. 15 So I think we have to be very careful when we use 16 the phrase, "genetic predisposition." 17 In the world of genetics, we, first of 18 all, acknowledge that testing well children or 19 genotyping well children can be extremely 20 stigmatizing, depending upon how the information is 21 used. 22 With that said, we also say that if a 166 1 child stands to realize an immediate or an imminent 2 medical benefit from genotyping, then it's okay to 3 go ahead and do it. 4 However, we have also cautiously 5 recognized that there are other reasons for 6 genotyping children, including a parent's wish to 7 have a child typed so that he or she can be 8 included in financial planning or estate planning 9 and so on and so forth. 10 We also recognize that there are some 11 reasons why parents might request testing of their 12 children that are completely off the wall. For 13 example, the mother who wants her nine year old 14 daughter tested for breast cancer genes so that her 15 breast buds can be removed right away. That kind 16 of is unacceptable. 17 So I think the world of genetics 18 approaches genotyping children very cautiously and 19 allows for some exceptions. We certainly allow 20 genotyping of all infants in newborn screening 21 programs because we know that we can bring 22 immediate benefits to those children. 167 1 Now, this has not addressed any of the 2 questions of experimentation with children that 3 we're talking about right now, but youngsters have 4 occupied a great deal of our attention in the world 5 of medical genetics, and we are cautious a little 6 bit, yes, but very cautious about stigmatizing 7 them. 8 CHAIRPERSON MARSHALL: Alan? 9 Thank you. Thank you very much. 10 I have 12:30 on my watch, and it's -- 11 DR. KOSKI: Jennie. 12 CHAIRPERSON MARSHALL: No. I haven't 13 forgotten Jennie, but here's what I would like to 14 do. 15 We actually have the luxury of having a 16 fair amount of time left, not only for discussion, 17 but for talking about our recommendations and 18 making an action plan. 19 I don't want to cut Jennie short. I want 20 to give her ample time. So what I would like to do 21 is to break for lunch, reconvene at 1:30. 22 Jennie will be first on the agenda in 168 1 terms of her question, and we will continue the 2 discussion and open the floor up. 3 And, again, I think that we will be out of 4 here on time, if not earlier. 5 So thank you very much, Alan, for a 6 stellar, stellar report. 7 [Applause] 8 [Whereupon, at 12:35 p.m., lunch was taken 9 to reconvene at 1:30 p.m.] 10 11 12 13 14 15 16 17 18 19 20 21 22 169 1 2 3 4 5 A F T E R N O O N S E S S I O N 6 [Time Noted: 1:50 p.m.] 7 CHAIRPERSON MARSHALL: We didn't have to 8 bolt our lunches today. It's our reward for 9 following our time schedule. 10 We are in the midst of the discussion 11 period on research involving children, following 12 Alan Fleishman's beautiful presentation, and we 13 have ample time for discussion and also to 14 formulate recommendations and a work plan. 15 At the moment, we're still considering 16 comments and questions from committee members, and 17 Jennie Joe has the floor. 18 DR. JOE: Thank you very much. 19 I have probably just a comment, as well as 20 a question. 21 I certainly support the idea in the 22 clinical trial. I think we desperately need it. I 170 1 see this firsthand because of my work with children 2 with Type II diabetes. It's a very important 3 emerging epidemic, I think particularly noticeable 4 among minority children. 5 And we get quite a bit of communication 6 from family members who, to a large extent, also 7 have been experiencing the disease, and they feel 8 like that whatever treatment is available doesn't 9 work for them, why should they consent to have 10 their child participate in these clinical trials 11 that hold no promises for adults. 12 And it's an interesting question, and I 13 would hope that somewhere along the line, more 14 effort is given to this issue. 15 The other one I think is a little bit more 16 vague, and I'm not sure exactly how to put it. 17 Except that we do have considerable amount 18 of research taking place in various communities 19 that are under the rubric of the word, 20 "prevention," and we don't seem to hold the 21 researchers accountable when they pull out and 22 their projects are done. 171 1 It isn't like leaving something behind 2 that says, "This is the efficacy test, and this is 3 a particular pharmaceutical drug that seems to 4 work." 5 We impose these research projects on 6 communities, and when the dollars are gone, the 7 researchers move on and nothing is left. And 8 they're not held accountable to putting their plans 9 some way of continuing these programs so that the 10 benefit remains. And that's the part I'm not 11 really sure how to do this. 12 And I'm particularly thinking about 13 school-based programs for children. The school 14 administrators and the teachers may be committed as 15 long as research is taking place in their midst. 16 But once the research investigators leave 17 the community, it's back to business as usual, 18 despite the fact that maybe the results indicated 19 that there was considerable benefit as a result of 20 this. 21 CHAIRPERSON MARSHALL: Thank you. So the 22 issue of sustainability, which really is important 172 1 and I think emerging as within the consciousness of 2 the research community. 3 Bob, did you want to respond to that? 4 DR. ROBERT LEVINE: I'm sorry I didn't 5 raise my hand to respond to that. I agree with 6 that, and there is quite a bit of commentary in the 7 1993 CIOMS International Ethical Guidelines that 8 have to do with responsibilities to the community 9 and continuing obligations. 10 I wanted to say something that is 11 partially responsive to the concern Abbey presented 12 this morning: What are the consequences of not 13 accepting Helsinki. 14 When Alan Fleishman gave his splendid 15 presentation based upon the 1977 report of the 16 National Commission, one thing that was not said is 17 that it was in the process of writing that report 18 that the National Commission explicitly repudiated 19 the Declaration of Helsinki's illogical distinction 20 between therapeutic and non-therapeutic research. 21 That's the distinction that creates all of 22 the internal contradictions that you find within 173 1 the Declaration of Helsinki that make it so very, 2 very difficult to follow because if you adhere to 3 one principle, you're violating another one. And 4 that's part of the problem that we in North America 5 -- Canada at the same time rejected this, acting 6 through a very different route, but we're now 25 7 years down the road of having departed from that. 8 CHAIRPERSON MARSHALL: Thank you, Bob. 9 Abbey and then Adil. 10 MS. MEYERS: It seems to me that there 11 should be some international body that everybody 12 respects. I mean this is a group of private people 13 who got together and they decided to make this 14 declaration, I guess. And they really don't have 15 the stamp of approval from any official government 16 bodies. 17 Has anybody ever thought about approaching 18 the world health organization to come up with 19 standards? 20 DR. ROBERT LEVINE: The CIOMS guidelines 21 are -- the last two rounds of them have proclaimed 22 that they are issued by the Council for 174 1 International Organizations of Medical Sciences, in 2 collaboration with the World Health Organization. 3 That point notwithstanding, they still 4 have no legal status. The only way they develop 5 any enforceable status is if countries decide to 6 enact parts or all of these guidelines in their own 7 legislation, or as Mark suggested this morning, if 8 professional societies adopt some of these 9 standards in the policy of their own professional 10 society, then what he said, that in case there is a 11 legal dispute over whether or not somebody violated 12 it, it's at that point that you're more likely to 13 see, or even more importantly, would be if a 14 hospital put it in its policy, then judges would 15 have a tendency to take that very seriously. 16 The other thing is that I've heard 17 reference to the Nuremberg Code today. The people 18 who wrote Nuremberg were very clear that they were 19 only developing principles to guide research 20 involving healthy adults, people who had no 21 disease. And for this reason, they made no mention 22 whatever of anything in the research that could 175 1 benefit the individual because, medically speaking, 2 you can't benefit an individual who has no disease 3 to begin with. 4 Now, it's not that they just simply 5 overlooked this. One of their American 6 consultants, Leo Alexander, a psychiatrist from 7 Boston, said, "You can't do this," what Alan showed 8 us, "the voluntary consent of the human subject is 9 absolutely essential," the psychiatrist said. 10 "That means much of the research in my field can't 11 be done." 12 And they responded, "That's not the job 13 for this tribunal. That's a job for someone else. 14 CHAIRPERSON MARSHALL: Thank you, Bob. 15 I have Adil next. 16 DR. SHAMOO: I think since Bob has -- Bob 17 Levine, that is, has given a lot of anti-Helsinki 18 statement, it's important to remember the 19 perspective. 20 All of us know the Monroe Doctrine. The 21 Monroe Doctrine is over 100 years old, and the 22 historians criticize it that it's just a staff 176 1 person, and President Monroe just approved it and 2 read it. 3 It's the historical perspective that that 4 part of our history, that Monroe Doctrine, that is 5 no one can invade any country within North America 6 without all of us coming to its defense, it's that 7 perspective which gave it the power and the force 8 by which, 'till today, we comply with the Monroe 9 Doctrine. 10 The same thing with the Nuremberg Code was 11 that period of time when the atrocities of the 12 Nazis toward human subjects was unveiled, and the 13 world was repulsed by it. And that's why the 14 Nuremberg Code, if it was written in any other 15 time, would have never had that force. It evolves 16 into a force. 17 The same thing with the Helsinki 18 Declaration. It's the World Medical Association 19 that is representing the National Medical 20 Association from every country in the world came 21 together in '64, and then, subsequently, and 22 including this just few months ago. And Bob Levine 177 1 and others went there and represented their views 2 before the world body, and they were rejected. 3 So it's important to note that they had a 4 chance to be heard by all their colleagues, and 5 they did not agree with them. 6 And I'm not saying I agreed with 7 everything they said, but that perspective is 8 important for us to know. 9 The question I have, which is not relevant 10 to that one, is the discussion when we said about 11 education and research. I think Bob Rich, that is, 12 talked about it. 13 I have a question to my colleagues here: 14 What do you call that researcher education when you 15 decide autistic children in first, second or pre- 16 schoolers, you're going to do certain methodology, 17 how you're going to treat them, behavior during the 18 whole year, and eventually, they write papers about 19 it. Is that research or is that education, and 20 should it go to an IRB? 21 This is the gray area where it really 22 disturbs me because within one year, that autistic 178 1 child's subsequent development would be influenced 2 within that year. 3 CHAIRPERSON MARSHALL: Thank you, Adil. 4 A couple of things that I would like to 5 say. One is, I would like to thank you for the 6 paradigm example that you just gave us of the 7 importance of having all voices heard and open 8 mindedness and respect for the opinions of others 9 or other committee members, and our liaisons and ex 10 officio members and our community members. So 11 thank you very much for that. 12 I also would like to welcome Dr. 13 Alexander, who is in the back of the room. 14 Dr. Alexander, I just would like to tell 15 you procedurally where we are in terms of our 16 afternoon discussion. 17 Dr. Alexander is the Director of the 18 National Institutes for Child Health and 19 Development at the National Institutes of Health. 20 We are in the midst of concluding the 21 discussion among committee members, per se, 22 relative to research involving children, and are 179 1 about to open the floor to discussion and questions 2 and remarks from our ex officio members and from 3 our organizational liaisons. 4 And after we do that, then we will open 5 the floor for discussion to the public members of 6 our committee, and so that's where we are. 7 So let me ask members of the committee 8 here at the table if there are others who would 9 like to be heard. 10 Alan? 11 MR. FLEISHMAN: Let me just echo Professor 12 Shamoo's concerns about masking behavioral research 13 around educational interventions. 14 We do that in medical interventions, as 15 well as. We create new innovative standards of 16 care without randomized trials. 17 In the field of pediatrics, we've done 18 that in neonatology, post-World War II a great 19 deal. Oxygen was used to prevent children who were 20 getting apneic from having a decrease in oxygen, 21 when they stopped breathing. And we then learned 22 that use of oxygen haphazardly in that way caused 180 1 blindness and serious problems. We used 2 medications that way. 3 And I think what you're suggesting is that 4 all major interventions, innovative interventions, 5 ought to be subject of research. 6 That doesn't mean I don't think you're 7 implying that those children couldn't be in a 8 research study which would study whether this 9 methodology actually was of benefit. And they 10 might spend the whole year in that study, as 11 compared to some other children, but it certainly 12 is a very important lesson about the importance of 13 research protocols, reviews and data which base is 14 the evidence of the outcome. 15 DR. SHAMOO: But the protocol would be 16 reviewed, et cetera, et cetera, whereas now, it's 17 not. 18 MR. FLEISHMAN: I was saying at lunch that 19 one of the great moments in my career as an IRB 20 member was when a major division chief of a 21 department in a hospital that will remain nameless 22 was having an argument with the IRB. He pounded 181 1 his fist and he said, "Well, okay. I withdraw the 2 proposal. And tomorrow, instead of having a 3 randomized clinical trial, this will become 4 standard practice in my cath lab, and we'll see 5 what happens." 6 And no one sought to stop that since it 7 was now the chief of the service declaring what was 8 now the standard approach in his cath lab. 9 CHAIRPERSON MARSHALL: Elliot? 10 DR. DORFF: Yeah. I just want to assert 11 the other side of this side, because remember, in 12 the regulations themselves, one of the six things 13 that are specifically exempted from IRB approval is 14 the first one, research conducted and established 15 in commonly-accepted educational settings involving 16 normal educational practices, which is specifically 17 exempted from IRB approval. 18 So I mean we don't want to have this 19 become, you know, all of the educational techniques 20 that are used to teach math or whatever thing being 21 referred to IRBs. 22 And I think that we have to -- I grant the 182 1 problem of masking what is really psychological 2 research or psychiatric research in educational 3 settings, but I think you have to be careful to see 4 the other side of it, as well. 5 CHAIRPERSON MARSHALL: This reflects back, 6 also, on the discussion that we had yesterday 7 relative to the social and behavioral sciences. 8 Jennie, did you want to weigh in on that 9 at all? 10 All right. Alan, any? 11 Mark? 12 MR. BARNES: This is not about pediatrics, 13 per se, but just to pick up on the point that Alan 14 Fleishman just made. 15 One of the topics that I wanted to bring 16 up at some point in this committee is deliberations 17 over the next few years, is the issue -- I might as 18 well bring it up now because it's come up -- is 19 this issue of the distinction between medicine and 20 surgery. 21 And the fact that, you know, most of the 22 people around this table, in fact, I think all of 183 1 them who are medical professions really are -- this 2 one is in medicine rather than from surgery. 3 And I don't know what the answer to this 4 is, but I just put it to you that, in my experience 5 with counseling IRBs and research administrators, 6 that there is a tradition in surgery that 7 significant changes in technique, even in medical 8 devices or whatever, is regarded as tinkering, 9 rather than as research. 10 And I think that there are, you know, 11 there is a real potential for abuse there, in 12 general, and I don't want to cast dispersions on 13 surgeons. But, in general, there is less 14 solicitude, at least in my experience, from 15 departments of surgery than there is from 16 departments of medicine in various medical centers 17 in regard to taking the IRB's role seriously and 18 trying to understand what is tinkering and what is 19 research. What's an acceptable variation on a 20 surgical technique, on the one hand, versus what is 21 a new or innovative surgical technique for which 22 there ought to be some consent and some review. 184 1 And I think that this is a general area 2 that really has not been explored fully. And, you 3 know, even in the literature, frankly, and it 4 really deserves in the future some manner of 5 concern and attention. 6 CHAIRPERSON MARSHALL: Thank you. 7 Greg, I have you next, but I want to 8 respond to that, as well. 9 In my former life as a critical care 10 nurse, I directed what I call the "Vietnam of ICUs" 11 at the University of Virginia, which was a surgical 12 intensive care unit. So I can relate very much to 13 what you have to say. 14 And I think, in some respects, the same 15 critique holds for critical care medicine, in 16 general. 17 And, Dr. Koski, who, in his former life, 18 was an anesthesiologist, knows surgeons well, too. 19 So I'm sure that he has something to say about this 20 issue. 21 DR. KOSKI: Great knowledge and respect 22 for my colleagues, of course. 185 1 I think there is a lot of truth to the 2 notion that there is variation that is done in the 3 course of surgical practice that's generally done 4 in the context of care in order to improve the 5 outcome for an individual patient and some for 6 their interest. That's medical care. 7 Of course, the federal regulations for 8 research, protection of human subjects in research, 9 are not intended to direct or restrict medical 10 care. 11 I think, on the other hand, it's also very 12 clear that when there is systematic variation in 13 technique and assignment in some way, other than 14 the usual clinical procedure of discussing all of 15 the various options with a patient and deciding 16 with them which of the procedures they choose to 17 undergo, that goes beyond the practice of clinical 18 medicine and enters into the realm of research. 19 And I think that point is becoming increasingly 20 clear. 21 CHAIRPERSON MARSHALL: Having just moved 22 to Missouri and the recent sanction against a 186 1 surgeon at the University of Missouri, for this 2 very sort of reason, it is becoming increasingly 3 clear. 4 Bob? 5 DR. ROBERT LEVINE: The National 6 Commission attempted to deal with this problem. It 7 recognized it in a couple of fields. It did not 8 recognize critical care medicine, probably because 9 it was in its infancy, but it recognized that in 10 surgery and in talking psychotherapy, as 11 distinguished from psychopharmacology, that there 12 was a tendency to innovate without review. 13 This is covered in the Belmont Report 14 where it defines a set of activities that are 15 called "innovative practices," and it says that, in 16 general, innovation, in practice, is not to be 17 considered research. 18 However, it called attention to the fact 19 that, in institutions, there are medical practice 20 committees, hospital staff, hospital board, they're 21 called variously, and it's their responsibility to 22 say what is acceptable surgery or psychotherapy or 187 1 any other practice in the hospital. 2 And they may say at some times that an 3 innovation may be permissible, but only if it's 4 evaluated in a research protocol to see whether or 5 not it's all that the innovator hopes it will be, 6 and that's what creates the bridge between -- for 7 all of the other things, radio biologicals, you 8 know, drugs, biologicals, devices. 9 There are federal agencies, or primarily 10 the Food and Drug Administration, that has the 11 authority to say when something passes from 12 innovative or non-validated into the realm of 13 accepted practice. 14 Anyway, I would just say that that might 15 be worth looking at. 16 CHAIRPERSON MARSHALL: I agree. Future 17 agenda item, perhaps. 18 Thank you very much, Mark. 19 Other committee members? 20 Sandy? 21 DR. CHODOSH: You know, the education part 22 and the education research was touched on, but, you 188 1 know, it seems to me that when my kids were going 2 to school, periodically, they would be introduced 3 new programs, quotes, like new math, et cetera. 4 And you never were quite sure whether this was 5 experimental or whether this was -- 6 CHAIRPERSON MARSHALL: That's right, and 7 it didn't work. 8 DR. ROBERT LEVINE: Well, that's exactly 9 right. And depending on where my children were, 10 since they were scaled along the way, some did very 11 well because they didn't have it, and others who 12 had it never did do very well. 13 And there are real risks involved in that 14 kind of, quote, research, and I'm not sure they 15 called it "research." It was very unclear, and I 16 think it is today. So that, you know, maybe some 17 of this needs to be discussed a little bit, you 18 know. 19 DR. DORFF: But that's exactly what the 20 rules exempt. 21 DR. CHODOSH: I know. 22 DR. DORFF: Research conducted and 189 1 established are commonly accepted educational 2 settings involving normal educational practices 3 such as research on regular and special educational 4 instructional strategies. The new math, okay? 5 So whatever damage that did, okay, it's 6 exempt. 7 CHAIRPERSON MARSHALL: Let us then, if 8 there are no further questions at the moment from 9 committee members, let me ask our ex officio 10 members and our liaisons with other agencies to 11 please let us hear from you. 12 I will. Yes, I will. And just please 13 remember to tell us who you are and whom you 14 represent. 15 MR. GRAVE: Yeah. My name is Gilman 16 Grave, and I chair the IRB for the National 17 Institute of Child Health and Human Development. 18 And at the break, I called the FDA, Victor 19 Ruskowski, to find out what the latest information 20 is about pediatric trials under the FDA 21 Modernization Act of 1997 that Abbey referred to 22 this morning as FDAMA. 190 1 Prior to that, in 1994, there was a 2 pediatric rule that asked that drug companies do 3 drug trials in children, and the results were 4 extremely disappointing. Probably fewer than 10 5 trials were initiated because of that pediatric 6 rule. 7 Following the 1997 passage of the FDA 8 Modernization Act, as of December 1st, the FDA now 9 has 211 requests from drug companies to do drug 10 trials in children, and 170 of these have resulted 11 in a written request from the FDA to the drug 12 company to go ahead with such a trial. 13 Twenty-four of these are cardio-renal 14 drugs. Eighteen of them are anti-hypertensives. 15 And it's very interesting that the six 16 month exclusivity that applies really applies to 17 marking a drug for adults. Ninety percent of what 18 the company is going to accrue, or maybe 99 19 percent, is not going to be from children, and the 20 use of any hypertensives is going to be from the 21 adults. 22 But the adult incentive to make more money 191 1 is what's causing them to be willing to do a trial 2 in children. 3 So I just thought you ought to have some 4 data as of December 1st. 5 Thank you. 6 CHAIRPERSON MARSHALL: Gil, would you mind 7 staying at the podium and perhaps entertaining some 8 questions? 9 I don't know whether there are members of 10 the committee who might have questions of you. I 11 do. 12 MR. GRAVE: Well, you know, we have FDA 13 people here that are probably better capable of 14 answering, but our institute is very interested in 15 drug trials in children. That's why I decided to 16 present this. 17 CHAIRPERSON MARSHALL: Thank you very 18 much, and I want to just, if this is a fair 19 question. I hope so, ask you whether you think the 20 regs relative to children are broken? 21 MR. GRAVE: No. I -- 22 CHAIRPERSON MARSHALL: Or do you have 192 1 advice for us in terms of our proceedings, perhaps 2 might be a more apt way to put that question. 3 MR. GRAVE: No. I was simply giving 4 information because Abbey had mentioned FDAMA, but 5 she did it very quickly and presented no data. 6 And we heard from Dr. Siegel that there 7 wasn't a great rush of companies to do research in 8 children. So I just think that I wanted to show 9 that maybe not a rush. It depends on what you mean 10 by "rush." 11 It looks like they're at least 20 times 12 the number of drug trials that have been requested 13 by industry. 14 Actually, we're very grateful that 15 industry is doing drug trials in children, and I 16 hope they're not breaking any regulations. 17 CHAIRPERSON MARSHALL: Abbey? 18 MS. MEYERS: One of the shortfalls of this 19 system is that the rush, and it's wonderful, 210 20 trials, they're all on patented drugs, where 21 somebody wants to extend the patent. 22 MR. GRAVE: Right. 193 1 MS. MEYERS: And one of the big problems 2 is a lot of drugs that children use are off patent, 3 and nobody wants to sponsor those trials. 4 MR. GRAVE: Yeah. 5 MS. MEYERS: This is now -- 6 MR. GRAVE: That's a very big problem, you 7 know. 8 MS. MEYERS: A very big problem. 9 MR. GRAVE: You're right on target, there. 10 MS. MEYERS: And so these things are never 11 going to be sponsored by commercial companies, and 12 it's an area where the government should absolutely 13 step in, when you talk about old asthma drugs, for 14 example, things like that. 15 MR. GRAVE: We meet periodically with 16 members of the FDA to try to figure out a way to 17 bring generic companies or some sponsor to the 18 table to be willing to sponsor a drug that's off 19 patent. You're right. 20 MS. MEYERS: Well, the generic companies 21 will never be able to do that because if they would 22 be the only ones to get the labeling changed on 194 1 their drug. 2 However, when a mother takes a 3 prescription to the pharmacist, he fills it with 4 whatever brand is on his shelf. He doesn't look at 5 the labeling and say, "Okay. This one is labeled 6 for asthma in children and this one isn't." 7 MR. GRAVE: Right. 8 MS. MEYERS: So there will be no economic 9 advantage to doing that research by a generic 10 company. 11 MR. GRAVE: It's a very big problem, and 12 anybody that has an idea, please contact me or Dr. 13 Alexander because we're very interested in this 14 problem. 15 CHAIRPERSON MARSHALL: I think that Judy 16 perhaps had a question for you, as well. Sorry. 17 DR. SIEGEL: Yeah. Actually, my question 18 is maybe not to you, but to anyone from FDA who is 19 here. 20 It is my understanding that as part of the 21 approval -- it's on. Yeah -- that as part of the 22 approval now, pediatric trials are, in fact, 195 1 mandated, and that as a condition of approval. 2 So the issue of this huge increase -- 3 MR. GRAVE: If it fits. I mean if there 4 is a possibility of -- 5 DR. SIEGEL: Yeah. 6 MR. GRAVE: -- use of -- 7 DR. SIEGEL: But what I'm saying is I 8 think what possibly one of the reasons for this 9 huge increase is it is now mandated. Six months' 10 exclusivity notwithstanding, it is, at least in one 11 specific example that I know that we're working on, 12 it was a condition of approval that we also -- and 13 this is where the discussion -- 14 MR. GRAVE: This is for new molecular 15 entity. You're right. 16 DR. SIEGEL: Yeah. 17 MR. GRAVE: Pediatric drug trial is 18 applicable for pediatrics would be mandated. 19 You're right. 20 DR. SIEGEL: Right, and so my question, I 21 guess we can find out, is this huge increase that 22 you've seen, is it as a result of now this new 196 1 mandate on the new molecular entities? 2 And, again, FDA getting into the 3 discussion with the companies much earlier, now at 4 the beginning of development programs, it says, 5 "Okay. Is this a drug that would be appropriate? 6 At what point in the development would be 7 appropriate, and what kind of development would be 8 appropriate for children?" 9 MR. GRAVE: Right. I think that this was 10 all drugs that are already patented. This is not 11 molecular entities, the 211 figure. 12 Rosemary Roberts is right here. Maybe she 13 wants to say something. 14 MS. ROBERTS: I'm Rosemary Roberts from 15 the Center for Drugs, and I'm on the pediatrics 16 team. 17 Clearly, the 211 requests that have come 18 in from industry indicates industry saying, "We 19 want to study this drug for this indication." 20 We have issued 170 written requests. Each 21 one of the proposals that comes into the agency is 22 reviewed by the appropriate review division or 197 1 divisions, if there is more than one indication it 2 may reside in more than one review division. 3 The agency looks at these proposals, looks 4 at the drugs and the indication. And the mandate 5 that we have from the statute is that we are to 6 look to see if there would be a public health 7 benefit to studying the product, and if so, what 8 information is needed and what kind of trials are 9 needed to get that information. 10 So the agency is in the driver's seat 11 here. The agency issues the written request. It 12 stipulates what type of trials are to be done and 13 the end points in that, and the time frame it's to 14 be done. 15 Industry, if it meets the conditions 16 outlined in the written request, they can qualify 17 for the six months of marketing exclusivity. 18 Now, you are correct. There are 19 significant gaps. There are products that are not 20 getting studied under this FDAMA incentive. 21 And, right now, there is a report to 22 Congress that is sitting down at HHS and being in 198 1 its final review. It is due to go to Congress on 2 January 1st of 2001, as it was mandated in the 3 statute. 4 And one of the things that we were asked 5 to comment on was the incentive, and was it 6 adequate in that. And one of our comments is that 7 there are gaps. There are products that are not 8 getting studied, just as you've outlined, those who 9 have no patent or exclusivity left or the 10 antibiotics that never had a patent you could 11 attach to. 12 And so one of the areas we've pointed out 13 is our concerns that those are not getting 14 addressed. And one of the reasons that the agency 15 went ahead with the regulation which requires 16 studies, and I think Dr. Siegel was referring to 17 that, is that it was to address the fact that we 18 had these gaps. 19 And one of the beauties of this regulation 20 is that, as products are in development, we are 21 talking about the sponsors about is this product 22 going to be used in children? 199 1 Is it appropriate to design trials in 2 children? 3 At what point should we actually begin the 4 trials? 5 And there is a lot that has to be thought 6 about as you do that with each particular product. 7 And this is one way of trying to get the 8 information on those products. 9 The majority of the activity we have seen 10 to date is secondary to the incentive. And we have 11 27 products that have been granted exclusivity, and 12 14 of those now have pediatric labeling. They have 13 labeling that's been approved and will be 14 disseminated. 15 One of our biggest concerns is how do we 16 disseminate this information? 17 Of the 14 products labeled, three of them 18 have dosing recommendation changes. Others have 19 pointed out that there are certain high-risk 20 populations that are more likely to have adverse 21 events if you don't start at a lower dose when you 22 titrate up. Some have pointed out adverse events 200 1 that are particular to the pediatric population. 2 So we have very, very good information. 3 This incentive is getting good information. 4 How do we get that disseminated? We've 5 talked to the American Academy of Pediatrics about 6 how we can go about doing that because, clearly, we 7 know people don't read the labels. 8 CHAIRPERSON MARSHALL: Let me just ask 9 David Lepay -- you're in my line of vision -- 10 whether you have any thoughts or advice for the 11 committee? 12 MR. LEPAY: Well, I think Rosemary has 13 done a very good job of summarizing -- 14 CHAIRPERSON MARSHALL: Beautiful job. 15 Yes. Thank you, Rosemary. 16 MR. LEPAY: -- much of the information 17 that we need to take forward here. 18 Of course, I would imagine I -- 19 unfortunately got a bit detained, so I didn't hear 20 all of the earliest deliberations after lunch. 21 I would imagine some of the discussion, I 22 would hope, centered on the Children's Health Act 201 1 of 2000 and where we are required to go, vis-a-vis 2 legislation that has come forth from Congress. 3 Am I being repetitive here? 4 CHAIRPERSON MARSHALL: No. 5 Okay. There are two requirements that are 6 particularly pertinent in the area of children's 7 protections here. The first actually, and 8 certainly this is a very comprehensive bill. I'm 9 focusing in on a couple of regulatory requirements 10 that affect FDA directly, as well as HHS from the 11 standpoint of dealing with protections for 12 children. 13 The first of these requirements is that 14 any HHS agency -- or that may be federal agency. 15 I'd have to go back to the regulation itself or the 16 law -- that either funds, conducts or regulates 17 research involving children is to adopt Subpart D 18 within six months of the enactment of this 19 legislation, which I believe was October 12th. 20 So, in effect, FDA, of course, which has 21 never formally adopted Subpart D as regulational, 22 though it certainly alluded to our guidance 202 1 document but has not been formally incorporated 2 within the regulation. We do mention additional 3 protections for children. 4 We are in a position now, of course, by 5 the legislation -- we had already started on this, 6 in fact, and Rosemary was very much involved in 7 this, as well -- in moving forward with adopting 8 Subpart D as regulation for FDA. 9 DR. DORFF: Excuse me. What is Subpart D? 10 MR. LEPAY: Subpart D is the portion of 11 Title 45, CFR Part 46, that is the regulations that 12 govern -- Subpart A is the common rule. Subpart B, 13 C and D involve different protections for various 14 populations, prisoners, for pregnant women and 15 fetuses, and Subpart D is additional protections 16 for children. 17 So, in effect, based on this legislation, 18 FDA is required, and we were proceeding to do that 19 in any case, is required to adopt Subpart D as FDA 20 regulation. 21 That will go, as well, for any other 22 federal agency that is involved in regulating 203 1 research, which, up until now, has not necessarily 2 been in the position where they have had to do so. 3 The second requirement, and, in fact, part 4 of the reason, from our standpoint, that we're very 5 interested in the dialogue, and especially the 6 points that were raised this morning that requires 7 some additional discussion is the second provision 8 of the Children's Health Act of 2000, which 9 requires us to report back to Congress within six 10 months, which means, again, somewhere around April 11 12th, if my calendar is correct in mentally 12 figuring these -- to report back on some of the 13 terminology, if you will, that was always very 14 difficult for FDA indirectly adopting Subpart D or 15 for any of the agencies, in fact. 16 And some of this deals with the exact 17 issues you've mentioned earlier, the issues of 18 assent and the issues of parental consent, if you 19 will, as part of the food, drug and cosmetic -- or 20 as part of the legislative act that governs FDA 21 regulations. 22 We have some specific provisions where we 204 1 require informed consent. We have to be able, 2 again, because Subpart D is not based on the Food, 3 Drug and Cosmetic Act, Subpart D talks about 4 parental permission. 5 So we have to somehow be able to reconcile 6 this terminology as we go forth in adopting Subpart 7 D. 8 We have the basic issues that you 9 mentioned earlier, the concept of what is minimal 10 risk? What are minor increases over minimal risk? 11 How does this relate to drug studies? 12 And so, again, these are issues that we're 13 required to report back to Congress on. 14 And, in effect, there was a number of 15 similar terms that were used in the original 16 Subpart D, as it's been adopted by NIH, by those 17 agencies that have otherwise adopted it, that, 18 again, going back to the history of Subpart D and 19 when it was first developed, were contentious from 20 the standpoint of FDA's other regulations or FDA's 21 mandates, vis-a-vis the Food, Drug and Cosmetic 22 Act. 205 1 So one of the hopes in the deliberations 2 here is that we're starting to gain some 3 information, if you will, through the committee of 4 how to approach back to Congress an answer to that 5 second provision as to what is our thinking, if you 6 will, on these issues that may result in some 7 changes in wording across the board that will 8 affect NIH, that will affect us, that will affect 9 other agencies that have adopted Subpart D to, in 10 fact, make Subpart D more compatible with the 11 advice, the recommendations, if you will, from the 12 community, from our advisors. 13 So that's pretty much the state of our 14 current legislative mandate, and I guess, as I 15 would say, Rosemary gave you a very good summary of 16 where we stand with regard to pediatric labeling 17 requirements and exclusivity. 18 CHAIRPERSON MARSHALL: David, thank you so 19 much. 20 And let me ask Dr. Alexander for comments. 21 DR. ALEXANDER: The American Medical 22 Association provided a half a million dollar gift 206 1 to NICHD for research. 2 I stated at the time that we would set 3 aside these funds for doing testing of drugs on 4 children, but had never achieved testing in 5 children and labeling. 6 We would do this in the network that we 7 had set up, the pediatric pharmacology research 8 unit network, specifically for drug testing in 9 children. And since there wasn't a logical 10 industry slot -- 11 [Problems with microphone.] 12 DR. ALEXANDER: -- to select which drug 13 trials we would give priority to, I asked our PPRU 14 people to work with the Academy of Pediatrics 15 Committee on Drugs, and also to work with the U.S. 16 Pharmacopeia to determine what additional data 17 might be necessary in order to achieve this kind of 18 labeling. Then we came up with a priority list. 19 We basically had the units in place to do 20 the testing. We have the funding available to do 21 the testing, but we have no assurance that if we do 22 this testing, that pediatric labeling will, indeed, 207 1 be sought. 2 And, in fact, as we have made the 3 inquiries, the answers have been negative, that we 4 will not seek pediatric labeling for these drugs, 5 even if you do the testing that shows what the 6 appropriate dose is and the safety and everything 7 else, and do everything that is necessary for the 8 pediatric labeling. 9 Why? Because -- 10 [Problems with microphone.] 11 CHAIRPERSON MARSHALL: Excuse me. I have 12 Bob, Abbey and Elliot. 13 DR. ROBERT LEVINE: Alan, I've been with 14 you all along, but I'm going to have to part a 15 little bit now. 16 The National Commission's purpose was to, 17 in a time when there were very powerful arguments 18 against doing any research on children, during the 19 famous Ramsey McCormick debate, they wanted to take 20 a stand and say, "We really want to have good 21 research on children encouraged." But they did not 22 say that the IRB had to review science for its 208 1 design. 2 There's a consensus among all of the 3 documents that speak to research ethics, beginning 4 with Nuremberg, continuing through Helsinki, and 5 explicated in the CIOMS guidelines where it says, 6 "Good scientific design is the number one ethical 7 requirement. If it's not well designed, we don't 8 care about informed consent. We don't care about 9 risks and benefits. It's the number one 10 requirement. You review that before you do 11 anything else." 12 However, the IRB is designed to be 13 incompetent to review scientific design, and now 14 I'm talking about competence at the level that we 15 expect from an OIG or a study section. 16 In an institution the size of Yale, we 17 might have one or two people on our faculty who are 18 sufficiently expert to give review at the level we 19 expect of an OIG. These people are generally 20 investigators, and so the rules say, as they should 21 say, these people must be excused from the 22 discussion. 209 1 Now, the point you made that's vitally 2 important is the IRB then requires consultation. 3 How this consultation will be accomplished is up 4 for grabs right now. 5 But I think, I hope I'm sensing a movement 6 around the country to have scientific review 7 committees that look at protocols before the IRB 8 does, or simultaneously, so that the IRB, with 9 advice from the scientific review committee in the 10 relevant field can say, "We can use this 11 information to calculate the risk benefit, you 12 know, relationship." 13 I think I'm seeing, as I look around the 14 country, we're seeing the scientific review 15 committees developing first in oncology, in 16 psychiatry and in cardiovascular areas because 17 these are the people that provide a high volume of 18 rather esoteric research. But I'm hoping to see it 19 more widely generalized in the future. 20 Thank you. 21 CHAIRPERSON MARSHALL: Thank you, Bob, and 22 Greg has a response on point. 210 1 DR. KOSKI: Bob, I think you raised a very 2 important point, and I know very disturbing 3 instances where IRBs have actually been given a 4 directive by the people at the top of the 5 institution that, "Look, don't worry about the 6 science. We'll take care of that. You just, you 7 know, do your thing," and that's a serious mistake. 8 As many of you know, and I don't think 9 we've talked about it directly, we are currently 10 engaged in the process of this overall evolution 11 and sort of remodeling of the system for protection 12 of human subjects, and a major part of that focuses 13 on the development of accreditation standards that 14 actually exceed minimal regulatory requirements to 15 get to the real purpose here of not compliance, but 16 actually, you know, doing good research and 17 protecting human subjects. 18 And although I don't know it for a fact, I 19 believe that one of the elements in those 20 accreditation standards will be, you know, 21 something to the effect that there will be, you 22 know, a mechanism to assure appropriate review of 211 1 the science. 2 Now there are several ways in which that 3 can be achieved. One is by using a specific 4 scientific review board. Another is if, in fact, 5 an IRB is so constituted, such as an oncology IRB, 6 that it has all of the experience within it to do 7 that job, then that's appropriate, as well. 8 But consistent with the recommendations of 9 the OIG report that we try to move toward a system 10 that has greater flexibility in order to achieve 11 these goals, but to have greater accountability, as 12 well, it means that we have multiple ways to 13 achieve the end point, the end point being the 14 effectiveness of the system. 15 So I think that this will be very helpful. 16 But the message that you said of the need to insure 17 that the science is good science as a fundamental 18 criteria for doing it is important. 19 And we've heard a great deal of discussion 20 of this from the corporate or the private funded 21 research side, as well. Particularly, some of it 22 focuses on, you know, certain drug trials that are 212 1 sponsored by pharmaceutical companies, and I'm not 2 bashing here, but it's concern that some trials are 3 put forth primarily as a legitimate part of the 4 business interest of establishing a particular 5 niche in the marketplace. 6 Now a pharmaceutical company is in 7 business to develop and sell drugs. There's 8 nothing wrong with that. 9 But there is this difference between the 10 intent, if you will, of the particular protocol. 11 There's one side of science that's looking at the 12 discovery aspect of new things. There's another 13 side of science that's more applied in nature. 14 So you get into a number of issues that 15 you have to consider, but this is going to be an 16 ongoing discussion, so we'll see where it leads. 17 CHAIRPERSON MARSHALL: Yes, Sandy? 18 DR. CHODOSH: Actually, the performance 19 standards, as they exist right now, very clearly 20 address the business of establishing the science, 21 but leaving it open because it will depend. Yale 22 will have one kind of problem, but the hospital 213 1 that's doing ten studies a year, you're going to 2 have a different kind of problem. 3 So that to actually say, "This is the way 4 you have to do it," what's important that you 5 document that the science was reviewed and any 6 comments that were made, and they're made part of 7 the minutes so that it's clear that even though 8 that particular IRB did not do the scientific 9 review, they have reviewed a review of the 10 scientific science. 11 CHAIRPERSON MARSHALL: Bob has another 12 comment on point. 13 I have not forgotten those of you who have 14 asked to speak. 15 DR. ROBERT LEVINE: The CIOMS guidelines 16 as of '93 give the IRB, or what they call the 17 Research Ethics Committee, the responsibility to 18 assure that scientific design has been evaluated by 19 some competent review body. 20 It does not rule out the possibility that, 21 in some cases, that competent review body could be 22 the Research Ethics Board. 214 1 And when Bob Temple, for example, brought 2 up studies on, you know, nose drops and things of 3 this sort, probably you could find sufficient 4 competence within the IRB. 5 Thank you. 6 CHAIRPERSON MARSHALL: Abbey? 7 MS. MEYERS: Well, I just wanted to 8 comment on what Joy and Alexander said in terms of 9 the overall problem here. And the overall problem, 10 I think, is it doesn't do any good to do research 11 if you can't apply it, really. Even in the long 12 term, you do basic research and you hope that, 20 13 years down the road, it turns into a treatment or a 14 diagnostic test or something, you know. 15 And here, we have this whole area in 16 pediatric research where we can't really apply it 17 because you have no commercial sponsorship. And it 18 just magnifies the importance of the industries. 19 Not just drugs, but devices and health care 20 industries, in general, that are the end part of 21 this pipeline that we're looking at. 22 And if they're not there and they're not 215 1 willing to bring these things to the bedside, then 2 something is very wrong with the whole research 3 system. 4 That's all. 5 CHAIRPERSON MARSHALL: Thank you, Abbey. 6 Elliot? 7 DR. DORFF: Three things about three 8 different things. One is you had mentioned the 9 CIOMS guidelines, whatever, okay. Along with the 10 other two things I mentioned earlier, I would like 11 to see those, too, if possible, right? 12 CHAIRPERSON MARSHALL: I'd like to see a 13 list of acronyms. 14 DR. DORFF: Yeah. That's right. 15 CHAIRPERSON MARSHALL: I'm serious. 16 DR. DORFF: That's exactly right. 17 CHAIRPERSON MARSHALL: Yes. 18 DR. DORFF: Exactly. Okay. But I mean, 19 and along with the Belmont Report and the 20 International Congress or something that we heard 21 about before, I'd like to see those, primarily 22 because of what I had mentioned earlier, namely 216 1 that, in each of these cases, you're getting people 2 who are trying to articulate what good, moral norms 3 should be in these areas. 4 And we ought to learn from their efforts, 5 even if we ultimately criticize some of their 6 efforts. So I mean it would be good to have these 7 things in front of us as we try to create our own 8 effort in shaping these guidelines. 9 The second thing I wanted to say is that, 10 unless I'm hearing this altogether wrong, in this 11 world, children seem to be sort of the abandoned 12 population in the sense that drug trials 13 specifically for children are apparently either not 14 economically advantageous to companies, and not 15 mandated by law, so that you've got all these drugs 16 on the market with no specific recommendations as 17 to dosage for children. 18 Is that right? 19 CHAIRPERSON MARSHALL: That's right. 20 DR. ROBERT LEVINE: There's one thing. 21 They're not the only abandoned population. There 22 is a population that has even further drugs 217 1 approved for use in them, and that's pre-menopausal 2 women. 3 DR. DORFF: Uh-huh. 4 DR. ROBERT LEVINE: Pregnant women are 5 even less -- 6 DR. CHODOSH: No. Women with childbearing 7 potential. 8 DR. ROBERT LEVINE: I don't like to use 9 that term. 10 DR. DORFF: Okay. All right. 11 In that case, it seems to me that our 12 report must make mention of this. I mean if we're 13 talking about protecting human subjects, here, we 14 have now two very important subsets of the 15 population that are, frankly, being not only not 16 protected, but it seems to me, ultimately attacked 17 by drugs that are not meant for them, or at least 18 not in those dosages, and that are ultimately 19 dangerous for them. 20 So I mean I think our report has to talk 21 about these things and make recommendations. 22 You know, if it's not commercially 218 1 advantageous, one possibility is to have government 2 grants for these things. Another possibility is to 3 make it mandated by law. 4 If you want to get FDA approval for use in 5 adults, you have to also test them on children. 6 Whatever -- I don't know exactly what the answer 7 is, but something's got to be done to protect 8 children and whatever you want to call the women 9 that you were just talking about. 10 And then the third thing I wanted to say 11 was in response to Alan's point and the story that 12 he told. 13 I'm not -- you know, I've been on a higher 14 beat, and I've been on hospital ethics committees 15 and all that, but I know nothing about the inner 16 politics of how these things work in hospitals and 17 in, you know, medical centers and so on. 18 And although what I'm hearing is that IRBs 19 are sort of very low on the totem pole. And so I 20 don't -- the question is, if that's, indeed, true, 21 then what does that mean in terms of their ability 22 to protect human subjects? 219 1 And what can be done to insure that they 2 do, indeed, function in the role that I guess they 3 were intended to function to be able to protect 4 human subjects? 5 And I don't know the answers to that. I 6 don't even know if I'm right in saying that they're 7 low on the totem pole, but that's exactly what I've 8 just been hearing. 9 CHAIRPERSON MARSHALL: I hope you're going 10 to bear those in mind also for our discussion 11 that's going to begin shortly in terms of action 12 plans and so forth, so, thank you very much. 13 And I know Alan wants to respond to you, 14 and I have other names on the list, as well. 15 MR. FLEISHMAN: Let me respond in reverse 16 order. 17 If IRBs were low on the totem pole, 18 they're at least rising, and they're going up 19 pretty fast. So I think we've, where your 20 committee could seek to do that and you'd be very 21 successful and you'd have an outcome measure of 22 success because I think there's a lot of pressure 220 1 now. The world is attending to this issue, so I'm 2 not too worried about that. 3 CHAIRPERSON MARSHALL: John? Thank you. 4 MR. FLEISHMAN: The other question, and, 5 you know, I'm just a country doc here observing, or 6 a city doc. Anyway, and I'd be the first on line 7 to join a group who wants to protect children, help 8 children and do lots of good things for children, 9 and I'm on that line. 10 But if I were this group, I'd be very 11 careful about what you bite off as your 12 responsibility. 13 It is important for some of the research 14 kind of things to go on that Dr. Alexander. It's 15 critical. 16 But I don't know that the committee that 17 relates to the Office of Human Research Protection 18 is the place that ought to drive or carry that 19 water. 20 I think that any subjects of any research 21 ought to be very carefully involved in this 22 committee's concern and protection, but driving 221 1 research to protect children and then being the 2 committee that is protecting subjects of research, 3 I'm not sure that you want to bite off that and let 4 somebody else -- no. Not even conflict of 5 interest. I'm not sure you want to bite off that 6 responsibility. 7 I could be wrong and maybe Dr. Koski wants 8 to do that, but, hey, I'll be happy to help, if I 9 could. 10 But there's a difference here as to what 11 the agenda is, and I would be thoughtful about how 12 you set your agenda. 13 CHAIRPERSON MARSHALL: Thank you, Alan. 14 I have Adil and then I have Bob. 15 DR. SHAMOO: Thank you, Mary. 16 Alan really said most of what I wanted to 17 say, but let me just add for Elliot's benefit, and 18 maybe others, that the issue of using children in 19 research is inherently difficult. Not too many 20 parents will allow their two, three, four, five, 21 six years old and not sick, or even slightly sick, 22 to be used for drug testing. 222 1 It's inherently very difficult to recruit 2 children, and the liability that Judy is talking 3 about is very scary to industry. So it's 4 inherently difficult, no matter what you do about 5 it and how we slice it. It's not the same as 25 6 years old who is willing to volunteer for 7 altruistic reasons. 8 You cannot conscript children to donate 9 their bodies for research, but I could do it as an 10 adult and somebody else can do it as an adult. 11 CHAIRPERSON MARSHALL: Thank you, Adil. 12 Bob. 13 DR. RICH: I'd like to return to a comment 14 that Bob and Elliot both alluded to, which is the 15 issue of pre-menopausal women, because I'm old 16 enough to have been doing clinical investigation at 17 a time when we avoided studies in pre-menopausal 18 women exactly for the reason of protection of 19 children, which is to say that I think most of us 20 were very concerned about the woman with a very 21 early pregnancy who did not know she was pregnant, 22 at a time when drugs might have profound 223 1 pyretogenic activities. 2 And I think there remains a serious 3 ethical question about drug trials in pre- 4 menopausal women, at least absent fail safe birth 5 control, and I think there are a lots of pyretogens 6 that we don't know about, that political pressures 7 are now forcing us to put very early embryos at 8 risk. 9 CHAIRPERSON MARSHALL: Yes, Bob, if you're 10 on point. Thank you. 11 DR. ROBERT LEVINE: If I can just mention 12 what I think is the paradigm case in striking fear 13 in the hearts of clinical investigators. It was 14 the Thalidomide experience. And for those who 15 don't recall, this was a drug that was found to be 16 one of the best sedatives known. And after it had 17 been distributed -- this was in the mid-1950's -- 18 after it had been distributed to thousands of 19 women, primarily in Europe, it began to get clear 20 that it was associated, as a scientist's whimpy way 21 of saying there is probably a cause and effect 22 relationship, with phocomelia, which means that the 224 1 babies were born without arms and legs. They had 2 flippers that superficially resembled those of a 3 seal. 4 After that, everybody was very, very 5 careful about giving any drugs to anybody who could 6 become pregnant, even to the extent of refusing 7 religious celibates as research subjects. 8 The change we've had in recent years is 9 that, first, it's required, both by FDA and the 10 common rule, or the guidelines issued by the U.S. 11 Public Health Service, that you must include women 12 in all kinds of research, except where you've got a 13 very clear reason to not include them. So we do 14 have the beginnings of progress in that field. 15 In part, what this requires is that when 16 women tell you they're taking precautions not to 17 get pregnant, that you have to believe them and 18 consider them responsible for their decisions. 19 Thank you. 20 CHAIRPERSON MARSHALL: Abbey? 21 MS. MEYERS: I think that that's the 22 point. This whole group of people, pre-menopausal 225 1 women, were left out of medical research for more 2 than 20 years. 3 It's also interesting to note that 4 Thalidomide is finally on the market. It's an 5 approved orphan drug. It's being sold under FDA's 6 very, very tightly controlled distribution system. 7 You have to have two pregnancy tests. 8 You know, every month, when you go back 9 for another prescription, you have to take another 10 pregnancy test. It's wonderful. It's working 11 wonderfully, and it's a very, very good drug, if 12 you don't use it -- as a tranquilizer. 13 But the point is, we also have -- Hoffman- 14 La Roche has Acutane on the market, which also 15 causes the same type of birth defects. It's being 16 given to teenagers, you know. 17 So the question is, when you look at a 18 woman, she shouldn't be treated differently than a 19 man because you have to take her word for it that 20 she is going to do everything in her power not to 21 become pregnant if she knows the whole truth, if 22 she's informed. 226 1 DR. ROBERT LEVINE: We agree on that, but 2 I have to add one more -- it's much more than 20 3 years. 4 Another reason that women were kept out of 5 even basic research, which was not designed to 6 develop anything, is that they have cyclic 7 variation in various physiological and biochemic 8 measurements. So it was always much more difficult 9 to establish a control group in women. You had to 10 study many more of them, and it was expensive. 11 That's why, if you look back into the 12 medical textbooks, until recent times, the normal 13 values for everything, from hematocrit to sodium, 14 are values they got from men. And women are then 15 identified as femaleness as one cause of deviation 16 from what was portrayed as normal. 17 If I could make stories like this up, I 18 would make a lot more money than I do. 19 But I think we're overcoming that now, 20 too. 21 MS. MEYERS: But it's taken a civil rights 22 battle to get here, and it's not right. 227 1 And we have another minority, and that's 2 the pregnant women. We don't do any kind of 3 research on pregnant women. Can't even get 4 anything for nausea in pregnancy because of that. 5 And children. Children are still being 6 left out, and there's got to be some way for this 7 committee to address that. 8 CHAIRPERSON MARSHALL: I agree with that 9 wholeheartedly, and I want to weigh in on that 10 sentiment, Abbey. 11 If there is -- there have been black holes 12 in terms of subjects of research, and I do think 13 that pregnant women probably today represent the 14 largest black hole. And it's a very complex issue, 15 and it involves a lot of deliberation in terms of 16 -- I don't want to say, "competing interests," but 17 balancing of interests, and I would, at some point 18 in the future, like for us to take a look at that. 19 Adil has one brief point that he wants to 20 make, and then I would like to do this: Because we 21 still have a few moments left, I want to see 22 whether Sue or any other folks who are there who 228 1 are appellate members have anything to say. 2 And then, also, Dr. Alexander, if you 3 could put on your historian's hat for a moment. I 4 understand that your President at the National 5 Commission, when they worked on Subpart D of the 6 regulations, and part of our conversation this 7 morning focused on physiologic and Phase I research 8 in children, and whether you had any thoughts or 9 guidance that you might want to offer to the 10 committee along those lines. 11 So, Adil? 12 DR. SHAMOO: This is in defense of NIH. 13 Since '96, the ratio of women, in general, to men 14 is two to one. So let's not say that they are not 15 being tested upon. Two to one ratio. 16 MS. BLEVINS: Sue Blevins, Institute for 17 Health Freedom. 18 And I just want to preface this statement 19 with this is not meant to be personally directed at 20 anyone, but I'm sitting here, and this day has been 21 more disturbing than probably any day I've been to 22 a government meeting in a number of years, and I'll 229 1 tell you why. 2 I went home last night, and I thought, 3 "What's wrong with this picture?" 4 This committee is working on conflicts of 5 interest. Do not any of you have conflicts of 6 interest? Are you not working for either industry 7 or research or scientific community? 8 Where are the victims? Where are the 9 parents of children that have been affected, that 10 have been deceived or misled? 11 Maybe, you know, Mark, nothing personal, 12 but, you know, you're representing academic medical 13 centers. 14 I don't feel like this is the voice of the 15 people, and I don't -- I mean it as a system 16 approach. I do not mean it personally. 17 Having said that, this "we," Dr. 18 Fleishman, how do you define "we"? You use the 19 word, "we," so many times. 20 Do you mean, "we, the people"? And if you 21 do, we, the people should be involved in every 22 regulation that is written. 230 1 And it really disturbed me to hear you 2 talk about using this memorandum approach and 3 writing this here and writing this here. We've 4 gone through a lot of that with medical privacy 5 rules. 6 Any rule or any code that anybody in this 7 room or any publicly funded research is going to 8 come down with, the voice of the people and every 9 voice of every person should be counted, and we 10 should have the rule of law with any regulation 11 that affects my health, my family's health, any 12 child's health. 13 This can't be done behind closed doors, so 14 -- and, again, I don't mean that personally. This 15 is from the heart, and I'm disturbed that there 16 aren't -- in my opinion, I don't see the public 17 here. I really don't. 18 Again, I've been involved and supported 19 academic researchers, worked at wonderful 20 institutions, and I highly respect the surgeons 21 that I worked with, worked for, continue to respect 22 them. But, by golly, people need to be heard and 231 1 their input needs to be involved in any rule or 2 regulation. 3 Thank you. 4 CHAIRPERSON MARSHALL: Thank you very 5 much, Sue, and, Mark, I'll give you a chance in 6 just a moment. 7 In terms of the composition of the 8 committee, let me just say this, that those who 9 serve on the committee or who are asked to serve on 10 the committee represent a variety of constituencies 11 of interests or areas of expertise. 12 I think that it's unfortunate, although 13 you will be able to find them on the web, the 14 biographical information relative to each member of 15 the committee, but I think they are on the web 16 currently. 17 I think Abbey Meyers has been a very 18 articulate spokeswoman as an advocate for human 19 subjects of research, and that is the reason that 20 she's present with us today. 21 Also, I hear you, and as I have said 22 before, we want these proceedings to be open and 232 1 transparent and for there to be ownership by the 2 public at large. So I do solicit, not only that 3 critique, but concrete ways in which we can reach 4 out to the public at large. 5 And perhaps part of the constraint and 6 part of the reason that there aren't more members 7 of the public here today have to do with the 8 relative haste in which this first meeting was 9 established. But we do hope to implant or rectify 10 that in the future, and we need to hear from you in 11 terms of how best to reach out to others. 12 And Greg may wish to speak to that. 13 Mark, let me give you the floor and then 14 perhaps ask Greg to speak to this issue, as well, 15 because it is very important. 16 MR. BARNES: Yeah. I don't take what you 17 say personally, but I do want to respond to it 18 because I think it's important. I have a couple 19 of, I think, important points to make. 20 First of all, the status that each of us 21 has in our various walks of life does not preclude 22 us from thinking outside of the box and from being 233 1 able to think about and appreciate other points of 2 view. 3 And I can tell you, certainly from me, 4 that you say I represent -- the comment was I 5 represent academic medical centers. 6 I do represent academic medical centers 7 right now. I represent individual physicians. I 8 represent patients sometimes in fights with their 9 insurance companies. 10 I've work on behalf of women with 11 metastatic breast cancer to get autologous bone 12 marrow transplants. 13 I've done all sorts of things, and I've 14 spent the last 15 years of my life, aside from what 15 I do every day, as an advocate for people with HIV- 16 AIDS, including being the chief lobbyist in 17 Washington in 1995-96 for people living with HIV 18 and AIDS. 19 So I mean and I'm just one person. 20 Everybody here has a different story, and you don't 21 know but that everybody here doesn't have a child 22 that's affected with muscular dystrophy and 234 1 everything else. 2 So I mean, you know, I really take great 3 exception to that, the thought that would, you 4 know, impugn our motives in serving on this 5 committee and tainting us by the roles that we 6 occupy in our kind of daily occupations. 7 I don't think that's right to do that to 8 me. It's not right to do it to Judy or Abbey or 9 anybody else. 10 I expect that Abbey is going to take 11 account, or Bob or anybody, but I expect that Abbey 12 is going to take account of all the other 13 perspectives on the committee. I know that I'm 14 going to do that, and that's the way that we work. 15 Everyone has a built in conflict of 16 interest because if you want someone with no 17 conflict of interest, then you wouldn't have 18 anybody serving on this committee at all because 19 they would have no interest in even serving. They 20 would have no information, no expertise or anything 21 else. 22 So, you know, I reject it completely and 235 1 utterly. Transparency is fine. You can go on the 2 web. Anyone in the public can go on the web. They 3 can look at our resumes. They can understand our 4 perspectives. 5 They may impugn our motives on individual 6 points, but just to give you one example, what I 7 just said about 30 minutes ago about surgeons, I 8 represent a lot of surgeons. 9 If they knew that I said that, they would 10 hang me. That was against my interests to say 11 anything about it, but I was trying to participate 12 as a member of the committee in an honest way to 13 give an honest issue that I think needs to be put 14 forth about the difference between medicine and 15 surgery and the historical approaches to research. 16 So, you know, I reject what you said 17 completely. 18 MS. BLEVINS: Well, I'd like to respond to 19 that, and, again, this was saying, not personal, 20 but I will respond. 21 Yesterday, when you said that you 22 suggested removing liability from IRBs, I was 236 1 stunned. 2 If you went out and took a poll of the 3 American public and asked them, should people that 4 are responsible for determining whether or not that 5 risk and benefit is good for your child, should be 6 held accountable and liable, let's take this out to 7 the public and ask them. 8 Now you went and created a committee 9 privately. If you were a private association 10 setting out your agenda, or a non-profit group 11 where people -- you went out and you raised money 12 and you said -- where people voluntarily gave it, 13 and you had your own agenda and set your agenda, I 14 wouldn't even be here. That's none of my business. 15 But when this committee is setting policy 16 that is going to affect my life, whether or not I 17 will be allowed to give informed consent for a 18 study, that's different. You are responsive to me, 19 and I do have a right to know where my public 20 leaders and coming from and what their agendas are. 21 You know, and you're not elected. It's 22 sort of a self-anointed -- I mean I know you're 237 1 appointed by Secretary Shalala, and I don't mean 2 this personally. 3 I've worked at NIH. I've been in 4 government. I know what it's like to be in an 5 official position. 6 But when a system is going to be affecting 7 my life, then I have a say in that system and I 8 have a say in the players and where they're coming 9 from and what they're going to be doing with that 10 system. 11 CHAIRPERSON MARSHALL: I'm going to 12 interject here, and I have Greg and I have Adil, 13 but I do want to say this, and I'm going back to 14 the way that I -- my opening remarks to this 15 committee and to those of us in the room, and that 16 is that we will be respectful of our guests, of our 17 fellow committee members, and that we will be civil 18 in our deliberations. And my expectation is that 19 will be the case from committee members and from 20 our community members, and I want the discourse to 21 be civil, and it will be civil. 22 And let me just, sort of in a lighthearted 238 1 way, tell you that my sport is boxing. I've been a 2 boxer for many years, and I think I'm a relatively 3 good one. And if I have to, I will, in the words 4 of my hero, Muhammed Ali, I will take you to -- I 5 will give you a whipping and a verbal whipping will 6 be much more painful and embarrassing than the 7 physical variety. 8 So I will insist on civility in the 9 discourse of this meeting. 10 Greg and then Adil. 11 DR. KOSKI: Thank you, Mary Faith. 12 I'd also like to go back to the comments 13 that I made at the opening of this committee's 14 sessions, and that is that we are in the process of 15 moving toward a new paradigm in this whole endeavor 16 of human research, and I use the example of, you 17 know, the time when mankind felt that the earth was 18 the center of the universe. 19 And I indicated that what we're trying to 20 do is to move toward a universe where the well 21 being of those who are participating in this human 22 research endeavor as the subjects of the research 239 1 are actually the center of our attention. They are 2 -- obviously, we depend upon them. Otherwise, we 3 simply won't be able to do research, and so our 4 first obligation is to protect them. 5 I also indicated that it's critical that 6 we recognize that institutional review boards are 7 not the sole bodies that have responsibility for 8 protecting human research subjects. It's each and 9 every one participating. 10 And whether it's an institutional 11 official, whether it's a drug company that's 12 sponsoring this study, or a biotechnology company, 13 whether it's an investigator or a research nurse, 14 an IRB member or a parent, it makes no difference. 15 We all have shared goals and responsibilities, and 16 this is the time for us all to recognize those and 17 work together. 18 Now the membership of this committee, 19 indeed, was selected by Secretary Shalala, based in 20 part upon recommendations made me. And those 21 recommendations, okay, which, well, basically, they 22 were drawn from a group of nominees, including 240 1 self-nominees, as well as organizational nominees. 2 They came from every sector of the community, and 3 some from the public at large. 4 My directive, if you will, if I could be 5 so bold as to say I directed Donna Shalala to do 6 anything -- my recommendation was that this 7 committee have the broadest possible composition in 8 order to insure that every perspective possible was 9 reasonably represented, okay, and also to make sure 10 that we had balance. 11 I think, again, if you will go and look at 12 the individual biographical sketches for each 13 member, you'll see that, in fact, it covers the 14 very, very broad range. In many instances, 15 individuals were drawn from representative 16 organizations, okay, because they have a large 17 constituency behind them to express a certain view. 18 I can tell you that Adil Shamoo, okay, 19 long ago -- he's been involved in this as an 20 advocate for patients in research, for, what, 30 21 years. 22 He represents an organization known as 241 1 CIRK. He helped define that. Okay. That has been 2 a very powerful group in bringing some of the 3 issues involved in human research before this 4 community. 5 Perhaps on the other extreme might be 6 someone like Bob Rich, who is, I believe, one of 7 the Presidents of one of the largest science 8 organizations in the country, FASEB, okay? 9 So that we have really tried to cover the 10 entire thing. And as we've heard many times during 11 this session, this is an open public meeting, and 12 we have encouraged at every turn, the participation 13 of the public and everyone else, and we want more 14 of that. 15 And we're delighted that you're here, and 16 we're delighted to, you know, hear the concerns 17 from the public. 18 We have to listen to those because if we 19 don't -- as I said at the very opening of the 20 session, the only way we're going to succeed in 21 this is by going forward together. 22 So let's do it in that sense, and I'm sure 242 1 that we will, indeed, succeed. 2 CHAIRPERSON MARSHALL: Thank you. 3 MS. FISHER: Thank you for saying that. 4 Barbara Lowe Fisher, National Vaccine Information 5 Center. 6 I have been both up there, and today, I am 7 here, and I think that what you're hearing is a lot 8 of fear, in a way, from the public. And this is 9 exactly why I think it's important to say that this 10 is open or that you want participation by the 11 public because the public is very afraid of what is 12 happening in science and medicine today, the 13 technology, the advances in biotechnology. They're 14 afraid that their loss of control over their lives 15 and over the lives of their children is getting out 16 of their control. 17 And so, if you sense this frustration, 18 there is frustration. But, most of all, there is 19 fear that people in positions of power are somehow 20 going to have control over their lives. 21 And in that regard, I'll make a brief 22 point. 243 1 I was very interested in the discussion 2 about the suspension of informed consent from 3 parents in some circumstances because of what that 4 may mean for the future in research. 5 People know the difference between 6 participation and exploitation, and the brightest 7 line that ensures the separation between the two in 8 scientific research is voluntary informed consent. 9 And I think once you start making 10 exceptions, particularly where the consent of 11 parents of minor children is concerned, no matter 12 what societal or individual good is used for 13 justification by those in control of the system, it 14 is a slippery slope that opens up the potential for 15 exploitation. 16 And, in the end, if a scientific study 17 results in harm to a child, it is the mother and 18 father who will bear the grief and burden of what 19 happens to that child, not the clinical 20 investigator or the IRB board of officials with 21 rule-making authority here in Washington. 22 I don't think you will get the support of 244 1 most parents for an informed consent ethic that 2 leaves them out of the decision-making process 3 under any circumstances. 4 And if the public starts to suspect that 5 their children are going to be used in research 6 without their knowledge or consent, you are going 7 to be in big trouble with regard to public trust of 8 scientists and health officials. 9 CHAIRPERSON MARSHALL: Thank you very 10 much. Well said. 11 MS. MEYERS: Can I just agree with this? 12 CHAIRPERSON MARSHALL: Please do. 13 MS. MEYERS: Okay. I want to agree with 14 you wholeheartedly that the public is very fearful. 15 Right now, we have this six-part series in 16 the Washington Post, for example, about clinical 17 research which will probably scare off thousands 18 and thousands of people will be afraid to go into 19 clinical trials. 20 The death of Jesse Gelsinger is another 21 one that scared a lot of people, and it may take us 22 many, many years to overcome what's happening, 245 1 xenotransplantation with pigs' viruses, and what's 2 going on in Europe with Yakob [ph] disease. These 3 are very scary things. 4 And I think the purpose of this committee 5 is to talk about that, to bring it all out and to 6 say, "We have to find a way to protect people so 7 they'll have more confidence in the system," and 8 that is the rule. 9 And I have to tell you that I'm not a very 10 patriotic person, but this is the greatest country 11 in the world when it comes to public input. No 12 matter what this committee decides, it will 13 eventually end up in that horrible little book 14 called the Federal Register. 15 And if you can possibly get through it, 16 you will find that the reason it's in there is 17 because they want you to comment. And once you 18 comment and it's in writing, those government 19 officials -- and I've said some pretty ridiculous 20 things in my comments to the Federal Register 21 things, but they don't ignore them. They pay 22 attention, and it does have an impact on what 246 1 eventually happens. 2 MS. BLEVINS: Sometimes. Sometimes, they 3 don't, and -- 4 MS. MEYERS: But sometimes you express an 5 opinion that many other people are going to 6 disagree with, you see, and that's why it won't be 7 put in there. 8 But what we need is the incremental 9 changes because the system is broken. And I say 10 that knowing that my children have been in clinical 11 trials and my grandchildren will be in clinical 12 trials. 13 I must have faith in the system, and I 14 don't have faith in it now, and neither does the 15 public. And all this horrible publicity that's 16 going on out there is going to make it even worse, 17 so it's very imperative that we act now, okay? 18 CHAIRPERSON MARSHALL: Thank you very 19 much, Abbey. 20 Can I call on you, Dr. Alexander? I hate 21 to put you on the spot, but we really would benefit 22 from your wisdom. 247 1 DR. ALEXANDER: Hopefully from experience, 2 anyway, not necessarily wisdom. 3 Let me, if I may, just say something about 4 the issue of drug testing and pregnant women and 5 then give you a few observations on research with 6 children and the commission's report and the 7 regulations. 8 As people had said, the problem of testing 9 drugs in pregnant women is an even greater one in 10 terms of magnitude than in children. 11 We are seeing some progress, real 12 progress, significant progress in testing drugs 13 with children with the FDA Modernization Act and 14 some of the other things. 15 There are still some problems on the edges 16 that we haven't solved yet, but we're making 17 progress, and have hopes of solving them, as well. 18 But the problem of testing drugs in 19 pregnant women is one that still we can cite almost 20 no progress on, and these are the most 21 disenfranchised part of the population in terms of 22 adequacy of studies of safety for the drugs that 248 1 they're taking in their condition. 2 It's not for lack of trying. We, at 3 NICHD, have been addressing this for a number of 4 years with very limited success. 5 We have a maternal fetal medicine network 6 that have full capabilities of doing drug studies 7 in pregnant women. 8 Several years ago, the Office of Research 9 in Women's Health, and I keep talking about these 10 gifts that we get, gave the institute $350,000 11 specifically for doing drug testing of two entities 12 in pregnant women. 13 We were all set to do this. We had the 14 protocols reviewed and approved, and asked the 15 companies if they would provide the drugs for the 16 testing, and the answer was, not only would they 17 not provide the drugs for testing, but if we got 18 evidence of their safety, their appropriate dosage 19 and everything else, they still would not seek 20 labeling for use in pregnant women. 21 Why not? Because of the same liability 22 issue that I described to you in children, only 249 1 worse. 2 The issue of liability is one that totally 3 scares drug companies with regard to pregnant women 4 and it's because not just of the risk to the woman 5 herself, but anything that is abnormal with the 6 child can be blamed on the drug, and we have seen 7 many instances of litigation with little evidence 8 to support the claim in which awards were made to 9 the plaintiff. 10 As long as we fail to solve that problem, 11 we are not going to make much progress. 12 We had a conference last week -- two weeks 13 ago, excuse me, in Washington where Ruth Kirchstein 14 from NIH, Jane Henney from FDA, members of Congress 15 and a variety of other people participated, 16 addressing specifically this issue of drug testing 17 in pregnant women and trying to solve it. 18 We're still going to keep at it, but this 19 is an order of magnitude more difficult to solve 20 than just drug testing in children. 21 Now, let me get to the issue of major 22 focus here, which is the children's regulations. 250 1 I'm just going to comment on three particular 2 areas. 3 One, first of all, is the definition of 4 "condition" in the regulations. 5 The regulations talk about the ability to 6 do research of minor increase over minimal risk in 7 children if it's relative to their disease, 8 disorder or condition. And there has been a 9 considerable amount of debate, discussion, 10 disagreement over what is meant by "condition." 11 The commission, in its discussions, 12 clearly meant condition to be something different 13 than disease or disorder, or would not have put the 14 word in there, and that condition means their 15 condition as children. 16 This is an opportunity to allow research 17 in this category to be done on children related to 18 their condition as children. Not sick people or 19 disordered people, but information that needs to be 20 gathered on them because of their status as 21 children. 22 And if this group could help to clarify 251 1 this issue, I think it would be a significant 2 contribution. 3 A second area of confusion and differences 4 of opinion relates to the issue of minimal risk 5 itself. And, here, the commission spent a lot of 6 time discussing and trying to come up with the 7 definition that could be applicable. 8 And what they finally did was come up with 9 a definition that said, "Risks comparable to those 10 experienced in their daily lives or in the course 11 of physical or psychological examinations of 12 healthy children." 13 Now there's a lot to be said for this 14 definition which had a lot of thought go into it, 15 and they did not say that the only things that were 16 minimal risk were these things, but that the risks 17 were comparable to these things. 18 And that gives a standard of comparison 19 that IRBs have a lot of ability to consider in 20 their assessment of risk to children. So that it 21 is the risk that is comparable to these experiences 22 of children, not just the things that go into 252 1 physical exams of healthy children or psychologic 2 exams or just their daily life. 3 So, again, some clarification here would 4 be useful, as well as the idea that both the 5 commission, in its recommendations, and in the 6 regulations, as they were eventually written, there 7 was the clear intent that there not be any fixed 8 national standard of what minimal risk was; that 9 there would be differences of opinion from one IRB 10 to another, and that this was healthy and to be 11 encouraged, and that the IRBs were the best judges 12 of what, at their institution, in the experience of 13 their institution, constituted minimal risk, and 14 that this might differ from one institution to 15 another. 16 And this was a concept that was embedded 17 in the recommendations, in the discussions of the 18 commission, and in the regulations as they were 19 finally written. 20 One final comment and that is the idea of 21 assent of children and permission of parents, and 22 this was a significant departure, and I think a 253 1 major contribution from the commission, that it did 2 away with the idea that there had to be informed 3 consent and that the old binders of consent, as 4 defined, were off. 5 And we just said, "Okay. You can't get 6 informed consent in children, but what we will get 7 is permission and assent." 8 And permission kind of speaks for itself, 9 but I'm going to say something about assent 10 because, again, the commission spent a lot of time 11 on this and there's been a lot more experience 12 gained since then. 13 And the idea was, you know, what are you 14 going to be able to get from a child? What can a 15 child really, truly assent to? How much can they 16 understand? When can they understand it? 17 And the commission gave some general 18 guidelines based on the best information we could 19 get at the time, which suggested maybe sort of 20 around sevenish, a child is capable of 21 understanding enough to give assent. 22 I think that our experience since that 254 1 time has informed us that children are able to 2 understand a lot more than we maybe gave them 3 credit for, and that well before the age of seven, 4 they can understand an awful lot, and that we ought 5 to, to the greatest extent possible, even at much 6 younger ages, explain things to them in terms that 7 they are capable of understanding, enlist their 8 participation as co-venturers with us in the 9 research enterprise. 10 This applies not just to research related 11 to their disease or disorder, but also to their 12 condition as children. 13 Children are far more altruistic than we 14 often give them credit for being, and we experience 15 this over and over again in the normal volunteer 16 program that we have at NIH where we have 17 participation of children with their parents' 18 permission and with their parents' involvement much 19 of the time. 20 And I think that we really need to 21 recognize increasingly from the experience that we 22 have gained over the years the ability of children 255 1 to think for themselves, to make judgments at 2 earlier ages than we maybe have given them credit 3 for in the past, and to really be made co-venturers 4 with us in the research enterprise. 5 Thank you. 6 CHAIRPERSON MARSHALL: Hear, hear. Thank 7 you very much. 8 Let us move on then to a discussion of 9 recommendations. 10 Oh, I'm sorry. Bob, last word. 11 DR. ROBERT LEVINE: There was one point 12 Dwayne made that he didn't explicitly tie it to our 13 earlier discussion, but Abbey called attention to 14 the fact that no drugs have been approved for 15 treatment of nausea and vomiting in pregnancy. 16 Actually, there was a drug that was approved way 17 back then called Vandactin. 18 Those of you who support liability 19 litigation as a cure for things will probably be 20 interested in knowing that there was one litigation 21 after another in which it was asserted or claimed 22 that Vandactin had induced a condition in newborn 256 1 babies that looked exactly like what you got with 2 Thalidomide. 3 The corporation that owned Vandactin kept 4 going into court, and they won case after case. In 5 one case, they actually got a judgment against the 6 plaintiff's lawyer for abusive process, and Mark 7 can tell you how rare that is. The lawyer in 8 question was Melvin Beli. 9 And, finally, the drug company pulled the 10 drug off the market because it cost more to win the 11 suits against it than the drug was bringing in. 12 Thank you. 13 CHAIRPERSON MARSHALL: Thank you. 14 Gil? 15 MR. GRAVE: One quick comment about 16 experimentation. 17 In normal children, exposing them to new 18 molecular entities, it's my understanding, and 19 maybe I'm wrong here, but aside from vaccines, it's 20 my understanding that most IRBs do not approve the 21 use of new a molecular entity in a child without a 22 condition or a disease. 257 1 I know that in our pediatric pharmacology 2 research units, we don't, and I don't think that 3 this is common practice. So I just thought I'd 4 like to get that on the record. 5 CHAIRPERSON MARSHALL: Thank you. I 6 believe that's true, as well. That's a belief. 7 A couple of people have to go. We really 8 need to move on to our recommendation phase, and I 9 have asked Alan -- he's doing some yeoman's work 10 for us today -- if he would, because he gave us 11 such a beautiful presentation today, and it was a 12 saint, especially in terms of his seven key points 13 at the end of his discussion, to lead off the 14 discussion in terms of recommendations. 15 MR. FLEISHMAN: And Greg has a point. 16 CHAIRPERSON MARSHALL: And Greg has a 17 point. Yes. 18 DR. KOSKI: Dwayne, are you still here? 19 Oh, good. I'm sorry. 20 I just wanted you to help us with this 21 because you made the point in talking about the 22 condition. 258 1 One of the things that I felt was very 2 important for this group to address and try to get 3 to some clarity on is, of course, the issue of 4 minimal risk and having a condition. And the 5 reason I wanted to -- 6 CHAIRPERSON MARSHALL: Greg, can I just 7 stop you? 8 DR. KOSKI: Yes. 9 CHAIRPERSON MARSHALL: Barbara and Sue, 10 thank you very much. Appreciate it. 11 MS. BLEVINS: 1,536 pages of the federal 12 regulations on medical privacy, that my privacy and 13 your privacy, and having to make this available by 14 the report, these key minutes, and I'd like to 15 again say, Mark, there's nothing personal. I've 16 been where you are, all of you, but please listen 17 to the system, okay? 18 CHAIRPERSON MARSHALL: Greg? 19 DR. KOSKI: Thank you very much. 20 Dwayne, the reason I wanted to 21 specifically catch you before you left, because I 22 don't want to leave any misimpressions, the actual 259 1 wording in the regulation says, "Subject's disorder 2 or condition." And so can you -- 3 You know, I think that that wording, okay, 4 has led to a general conception that what they're 5 actually talking about with respect to condition is 6 not the fact that a person happens to be under the 7 age of 18 or something like that, but, in fact, its 8 context, the way it's used in the regulation, sort 9 of ties it directly to a disorder. 10 So that the interpretation that many apply 11 is medical condition or medical disorder. 12 I think I have personally gone back, of 13 course, as you know, and read the full text of the 14 discussions, the transcripts from the National 15 Commission. But because you're here and you were 16 there for those discussions, I think it would be 17 extremely helpful to have you sort of expand upon 18 that to let us know what the thinking was 19 originally of the National Commission, and then to 20 sort of advise us as to how we should go forward in 21 this committee, if necessary, and providing, you 22 know, greater clarity and all, because I think the 260 1 sense that we've heard from the group is that 2 clearly everyone believes that there is a need to 3 do important meaningful research in children, but 4 this is an area where we need greater clarity and 5 guidance, okay? 6 PARTICIPANT: Yeah. Bob Levine should 7 comment on this, as well, because he also was 8 present for all these discussions with the 9 commission. 10 But it's my recollection from the 11 commission's discussion and from the discussions 12 that went on during the writing of the regulations 13 themselves that we had meant just disease or 14 disorder, that's all that would have been said, and 15 that the word, "condition," which carries a broader 16 connotation, was put in there specifically to 17 encompass condition as children, and so that should 18 be encompassed, as well. 19 Bob, you might want to comment, too? 20 DR. ROBERT LEVINE: I can't improve on 21 that. 22 CHAIRPERSON MARSHALL: Bob, what are you 261 1 doing back there? Are you having an identity 2 crisis? 3 DR. ROBERT LEVINE: I'm just getting some 4 water. 5 CHAIRPERSON MARSHALL: One more question 6 of Dwayne. 7 DR. KOSKI: Dwayne, I think one of the 8 concerns that's been raised is the studies that are 9 designed to obtain physiologic data, particularly 10 in normal, healthy children, okay, which is 11 certainly relevant to their condition as children. 12 Much as we heard Bob talk about the 13 unavailability of information about normal women, 14 where, you know, to some extent, have been in a 15 condition of having no information on normal 16 children, which, you know, is problematic in 17 itself, so I would assume that your interpretation 18 would be that normal or that physiologic studies in 19 children, I mean obviously once there is clearer 20 definition as to what we could call "minimal risk" 21 or not minimal risk would be something that would 22 be appropriately done under this particular part of 262 1 Subpart D? 2 PARTICIPANT: That's the interpretation, 3 and, again, that's part of the reason that it was 4 written that way. 5 CHAIRPERSON MARSHALL: Brief, and then 6 Alan has the floor. 7 DR. ROBERT LEVINE: Dwayne, I agree with 8 you on the meaning of including the term, 9 "condition." 10 Even if you didn't have the history or the 11 memory here, if they meant condition as a subset of 12 disorder, they would have probably said, "disorder 13 and condition." 14 I think, though, that the big obstacle to 15 doing research that presents -- in which procedures 16 that do not hold out the prospect of direct benefit 17 are presenting minor increases above minimal risk. 18 The big stumbling block is the sentence right 19 before that, that the intervention or procedures 20 presents experiences to subjects that are 21 reasonably commensurate with those inherent in 22 their actual or expected medical, et cetera. 263 1 And so you could say, for example, that a 2 child with leukemia could have a bone marrow 3 aspiration, a procedure that's generally 4 interpreted as presenting a minor increase because 5 that trial, this is commensurate with what this 6 child would encounter in his or her regular 7 experience. 8 I want to emphasize that the 9 commensurability standard was not set because they 10 said, "Well, the kid's going to have ten bone 11 marrows anyway. What's another one going to" -- it 12 was really because the child would have experience 13 to draw on, to know whether or not he or she was 14 willing to go through one that was not necessary, 15 one that was being done for altruistic reasons. 16 However, the normal or the child without 17 leukemia, most children without leukemia, this bone 18 marrow aspiration would not be commensurate with 19 what goes on in their actual expected. And that's 20 the real -- that's the thing that stands in the way 21 of developing information about children who may 22 have conditions but not experiences. 264 1 CHAIRPERSON MARSHALL: Thank you, Bob. 2 Alan. 3 MR. FLEISHMAN: Well, I think the most 4 important thing you can do is to realize the 5 vastness of the test you're about to undertake 6 here. 7 CHAIRPERSON MARSHALL: I think you used 8 the word, "miracle" earlier. It's apt here. 9 MR. FLEISHMAN: And in order to do justice 10 to each of these issues, and I was talking about 11 this before lunch and before our comments from the 12 public commentators, I think we need a good deal of 13 dialogue and information about each of these areas 14 that was raised. 15 There is a literature, as well as people 16 with critical thoughts about the definition of 17 "minimal risk," minor increment over minimal risk. 18 This dialogue we've just had about the 19 word, "condition," I think is actually quite 20 interesting. I've actually not heard this dialogue 21 before, but requires unpacking and more discussion. 22 Because if this group would like to share 265 1 their views as to what the regulations mean, then 2 we need a tremendous amount of input. 3 So we need information. We need the 4 literature that's out there. We need the people 5 who've been the most critical in those discussions 6 to come and talk to the group, and we need the 7 public to give us those views. 8 I think we do need some data on the extent 9 of research that's going on in children. I think 10 Dr. Alexander could probably help us to achieve 11 those data. They exist between the FDA and the 12 NIH. 13 I think we need the research societies of 14 the pediatricians to come and talk before the group 15 so people understand what their goals are and how 16 they, I think, are attempting to do research in an 17 ethical manner. 18 But still, just as the public are fearful, 19 they are also very demanding. And when children 20 are admitted to hospitals with serious diseases, it 21 is expected that we will treat them and fix them. 22 They are our future, so they are demanding of new 266 1 interventions at the same time that they're 2 fearful. 3 So I think we need all of those people to 4 come and to talk to the group for each of these 5 issues. 6 I would not have children carry the water 7 of placebos or Phase I's because those are 8 discussions you can do, in general, and then see 9 what the specific issues of children are, after 10 you've kind of carved out the general issues. So I 11 would focus specifically on the regulations and the 12 definitions and try to come to grips with 13 clarifications. 14 MS. FITZSIMMONS: I just -- 15 DR. KOSKI: Yes. 16 MS. FITZSIMMONS: -- would like to make a 17 comment as you're developing your work plan. My 18 name is Lorraine Fitzsimmons. I'm with the 19 Neurology Institute at NIH, but I'm not speaking 20 for NIH. 21 But the Child Health Act of 2000 which was 22 mentioned briefly before does have a requirement in 267 1 it within six months of a report back to Congress, 2 and it does direct that the Secretary of HHS must 3 look at the regulations Subpart D and specifically 4 identify several areas that must be very carefully 5 examined and addressed, including things like 6 assent versus consent. 7 So in developing your work plan, there is 8 a requirement, too, that a committee, and it 9 specifies who must be represented on that 10 committee, including children who have been in 11 research and parents of children who have been in 12 research. 13 So to kind of think about how the 14 department is involved in an implementation plan 15 right now, and the agencies are looking at how they 16 need to implement certain parts, so I don't know 17 where that is. 18 But certainly to capitalize and not have 19 redundancies in what you're doing and to maximize, 20 to consider whether or not you can expand so that 21 you have like a working group that might include 22 the people legislatively mandated, or what the 268 1 nexus might be between what you're doing, and if 2 there's a separate committee, what it is they're 3 doing because some of the issues, you've brought 4 up. 5 And some very sticky issues that require a 6 lot of research, including developmental maturity, 7 need to be addressed by this group in looking at 8 the regulations. 9 So that's the only point I wanted to bring 10 up. 11 CHAIRPERSON MARSHALL: Thank you very 12 much. It's a beautiful idea. 13 Greg. 14 DR. KOSKI: Well, since Secretary Shalala 15 has the good sense to get out of here January 20th, 16 I can tell you exactly where that responsibility 17 falls. And we recognize our responsibility to do 18 that. 19 I think, just off the cuff, my sense is 20 that we clearly would have to follow the specific 21 dictates in the Child Health Act that tells us what 22 we must do there. 269 1 I think we would be well served by making 2 sure that whatever committee we're obligated under 3 law to assemble there be interfaced with this group 4 in a very important way. That's why, in fact, I 5 chose to make sure that we could get this topic out 6 there soon so that we could make sure these efforts 7 are integrated as we go forward. 8 And so we will do that. I don't know the 9 precise form that it would take. But, clearly, we 10 would like to do that, and I suspect that this 11 would be a reasonable thing to continue the 12 discussion on at the next meeting of this group, 13 which is likely to coincide, more or less, with the 14 time frame of actually producing that report under 15 the Child Health Act. So it all comes together 16 pretty nicely and gives us our marching orders, I 17 believe. 18 CHAIRPERSON MARSHALL: Other committee 19 members, comments on -- yes, Bob. 20 DR. ROBERT LEVINE: I think we have to 21 listen to Alan Fleishman. He has pointed out that 22 -- he has laid out for us an amount of work that 270 1 might be the equal of all the time we plan to spend 2 meeting for the next two years, and we also have 3 other projects. 4 We have to understand what the Secretary's 5 office would consider -- 6 CHAIRPERSON MARSHALL: Denyse. Denyse. 7 DR. ROBERT LEVINE: -- our agenda. 8 CHAIRPERSON MARSHALL: Thank you. 9 DR. ROBERT LEVINE: What's happening? 10 CHAIRPERSON MARSHALL: Thank you so much. 11 We'll see you next time. 12 Sorry, Bob. 13 DR. ROBERT LEVINE: We have to understand 14 what the Secretary would like us to do, and then we 15 probably would be well advised to figure out how 16 much of that we can actually do and to establish 17 some priorities. 18 It's almost like setting up a human 19 subjects protection system within the university. 20 Thank you. 21 CHAIRPERSON MARSHALL: Thank you. So let 22 me just recap a bit. 271 1 Earlier today, and I think that there is a 2 list that has been distributed, a summary of our 3 action plan from day one, what we have just heard 4 from Alan. And I think what we have agreed to is 5 this. 6 That we have a definite need for 7 information, for data gathering, for clarification 8 so that we need some scholarship and some research 9 to be done that we will ask for help with and/or 10 commission. 11 That we need to have a public forum of 12 some sort, be it a public hearing or a workshop, 13 that involves leaders or professional societies, 14 children's advocacy groups, et cetera, so that we 15 can hear from them and have their guidance, as 16 well. 17 That we do need to take a look and a focus 18 on the regulations and clarification of 19 definitions. 20 So with those as sort of broad, general 21 descriptions of a working plan, we will go forth, 22 and within, I'm sure, a short period of time, 272 1 define those more clearly and make them available 2 on our web site for input from all. 3 So a couple of things that I would like to 4 do in conclusion, because I think that we have 5 perhaps done our work for the first few days. 6 This is my sense, that we have had a very 7 successful beginning to our endeavor. I feel very 8 positive about it. I hope that members of the 9 committee feel positive, as well, and that our 10 liaisons and ex officio members and public members 11 feel as enthusiastic and celebratory in a way as I 12 do. 13 We have daunting challenges ahead of us, 14 and I think that we're well positioned to meet 15 those. 16 There are a number of people I would like 17 to thank for helping us bring this meeting together 18 and making it possible, and because I'm thanking 19 them in advance because they're going to be doing 20 some very hard work in a very short order. 21 And I think that two people who are the 22 most important to thank are Kate Gottfried, who has 273 1 truly done a yeoman's amount of work. 2 [Applause] 3 CHAIRPERSON MARSHALL: And Greg Koski. 4 [Applause] 5 DR. KOSKI: Actually, I'm sorry, but I'll 6 retract it. I reject that completely because I 7 think, in fact, the real credit goes down also 8 there to Tony Goodwin. 9 CHAIRPERSON MARSHALL: That's coming. 10 Yes. Right. 11 DR. KOSKI: Yeah. It's coming? 12 CHAIRPERSON MARSHALL: Yeah. 13 DR. KOSKI: All right. Good thing. 14 CHAIRPERSON MARSHALL: It's coming. Yes. 15 Thank you. 16 And, Tony, I would like for you to please 17 stand. 18 [Applause] 19 CHAIRPERSON MARSHALL: And Carla. 20 [Applause] 21 CHAIRPERSON MARSHALL: Please, thank you. 22 [Applause] 274 1 CHAIRPERSON MARSHALL: And Irene and Steve 2 Coleman. Stand up. 3 [Applause] 4 CHAIRPERSON MARSHALL: Stand up, please. 5 [Applause] 6 CHAIRPERSON MARSHALL: Thank you, Irene. 7 Others, Stuart Nightingale is front and 8 center. 9 [Applause] 10 CHAIRPERSON MARSHALL: Stuart, thank you. 11 And thank you in advance. You're not off 12 the hook. 13 And those who aren't here but who have 14 done a great deal of work to make this happen are 15 Jeanie Makall and Gary Rice and Barbara Smith. So 16 I would like to thank all of them and put that on 17 the record. 18 I would like to thank our presenters, 19 Felice Levine, Stuart, again, Dixie Snider and Alan 20 Fleishman just for their superb scholarship in a 21 very short amount of time, and you've given us 22 wonderful guidance and food for thought. So, thank 275 1 you as well. 2 Committee members, Mark, Jennie, Abbey, 3 Elliot, Sandy, Bob, Bob and Adil, thank you very 4 much. 5 My sense is that we are forming a 6 personality as a group and that that's a good 7 thing, and that there is ownership evolving in a 8 good way, not only among the folks who are sitting 9 around this table, but everyone in the room. And 10 so I would like to commend you for all of your hard 11 work. 12 Yes, for all of your hard work, and that 13 includes the ex officio members and our liaisons 14 with other agencies and our public members. 15 And I think we sort of owe ourselves a 16 round of applause. 17 So thank you very much and I'll see you 18 next time. 19 [Applause.] 20 [Whereupon, at 3:50 p.m., the meeting 21 adjourned.] 22 276 1 CERTIFICATE OF OFFICIAL REPORTER 2 This is to certify that the attached 3 proceedings before the NATIONAL HUMAN RESEARCH 4 PROTECTIONS ADVISORY COMMITTEE held Thursday, 5 December 21, 2000, were held as herein appears, and 6 that this is the original verbatim transcript 7 thereof, and is a full correct transcription of the 8 proceedings. 9 10 11 Gerald T. Brooks, Sr. 12 Official Reporter 13 14 15 16 17 18 19 20 21 22