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.


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          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.


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          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


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          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


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          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