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  CT 
                  
                  
                  
                  
                  
                  
                  
                  
                  
                            Department of Health and Human Services 
                  
                  
                                        Meeting of the 
                              NATIONAL HUMAN RESEARCH PROTECTIONS 
                                  ADVISORY COMMITTEE (NHRPAC) 
                  
                                    Tuesday, April 30, 2002 
                  
                  
                  
                                           VOLUME II 
                  
                  
                  
                  
                  
                                 Hilton Washington Embassy Row 
                                        Ambassador Room 
                                 2015 Massachusetts Avenue, NW 
                                    Washington, D.C.  20036 
                  
                  
                  
                   

                 

                  
                  
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                                          A G E N D A 
                  
                  
                 Tuesday, April 30, 2002 

                  
                 AM Session 
                  
                 8:30-8:45      RECAP 
                                     Mary Faith Marshall, Ph.D. 
                  
                 8:435-10:15    UPDATE AND DISCUSSION GENETICS WORKGROUP 
                                     Mary Kay Pelias, J.D., Ph.D. 
                                     Chair, Working Group 
                                     Professor of Genetics, Louisiana State 
                                     University, HSC 
                  
                 [10:15-10:30]  Break 
                  
                 10:30-12:30    PRAXIS AND ACTION:  CONDUCT OF RESEARCH IN 
                                THE AFTERMATH OF BIOTERRORISM 
                                     Moderator: 
                                     Jonathan Moreno, Ph.D. 
                                     Monica Schoch-Spana, Ph.D. 
                                     Senior Fellow 
                                     Center for Civilian Biodefense 
                                     Strategies 
                                     Johns Hopkins University 
                                     John Livengood, M.D. 
                                     Deputy Associate Director for Science 
                                     Centers for Disease Control and 
                                     Prevention 
                  
                 PM Session 
                 12:30-1:30     LUNCH 
                  
                 1:30-2:30      WORKGROUP ON DECISIONAL CAPACITY 
                                     Jonathan Moreno, Ph.D. 
                                     Director, Center for Biomedical Ethics 
                                     University of Virginia Health System 
                  
                 2:30-4:15      UPDATE AND DISCUSSION:  SOCIAL & BEHAVIORAL 
                                SCIENCE WORKGROUP 
                                     Felice Levine, Ph.D. 
                                     Co-chair Working Group  
                                     Executive Officer 
                                     American Sociological Association 
                                     Jeffrey Cohen, Ph.D. 
                                     Co-chair, Working Group 
                                     Director, Education OHRP/HHS 

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                 AGENDA - Continued 
                  
                  
                  
                 [3:00-3:15]    Break 
                  
                 4:15-4:30      WRAP-UP 
                                     Mary Faith Marshall 
                  
                 4:30      Adjourn 

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                                       ROSTER OF MEMBERS 
                  
                 MARY FAITH MARSHALL, Ph.D., Chairperson, Professor of 
                 Medicine and Bioethics, University of Kansas Medical Center 
                  
                 GREG KOSKI, Ph.D., M.D., Executive Secretary, Director, 
                 Office of Human Research Protections, Office of Public 
                 Health and Science, OS 
                  
                 MARK BARNES, J.D., LL.M., Partner, Ropes & Gray 
                  
                 MS. MARGARET BORWHAT, President, Women's Cancer Advocacy 
                 Network 
                  
                 SANFORD CHODOSH, M.D. 
                  
                 ELLIOT N. DORFF, Ph.D., Rector and Distinguished Professor 
                 of Philosophy, University of Judaism 
                  
                 ALAN R. FLEISCHMAN, M.D., Senior Vice President, The New 
                 York Academy of Medicine 
                  
                 JENNIE R. JOE, Ph.D., M.P.H., R.N. 
                 Professor, Family and Community Medicine 
                 Director, Native American Research and Training Center, 
                 University of Arizona 
                  
                 SUSAN Z. KORNETSKY, M.P.H., C.I.P., Director, Clinical 
                 Research Compliance, Department of Clinical Investigation 
                  
                 FELICE J. LEVINE, Ph.D., Executive Officer, American 
                 Sociological Association 
                  
                 ROBERT LEVINE, M.D., Professor of Medicine, Yale University 
                 School of Medicine 
                  
                 ABBEY S. MEYERS, President, National Organization for Rare 
                 Disorders 
                  
                 JONATHAN D. MORENO, Ph.D., Emily Davie and Joseph S. 
                 Kornfeld Professor of Biomedical Ethics, Director, Center 
                 for Biomedical Ethics, University of Virginia Health System 
                  
                 MARY KAY PELIAS, Ph.D., J.D., Professor, Department of 
                 Genetics, Louisiana State University Health Sciences Center 

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                   Roster of Members (Continued) 
                    
                   ROBERT R. RICH, M.D., Executive Associate Dean of 
                   Research, Emory University School of Medicine 
                    
                   ADIL E. SHAMOO, Ph.D., Professor, Department of 
                   Biochemistry and Molecular Biology, University of Maryland 
                   School of Medicine 
                    
                   JUDITH L. SIEGEL, Ph.D., Vice President, Head US Clinical 
                   Operations, Hoffmann-La Roche, Inc. 
                    
                   KATE-LOUISE GOTTFRIED, J.D., M.S.P.H., 
                   Executive Director, NHRPAC 
                   Office of Human Research Protections, Office of Public 
                   Health and Science, OS 
                    
                   EX-OFFICIO MEMBERS 
                    
                   Dr. James Shelton, USAID 
                   Robert B. Ochsman, Ph.D., CPSC 
                   Dr. Joseph Spence, USDA 
                   Dr. Susan L. Rose, DOE 
                   Dr. Dixie Snider, CDCP, DHHS 
                   Dr. David A. Lepay, FDA, DHHS 
                   Dr. Belinda Seto, NIH 
                   Mr. Thomas G. Raslear, DOT 
                   E. Donald Sussman, DOT 
                   John H. Mather, M.D., DVA, VHA 
                   Joan Porter, D.P.A., M.P.H., DVA, VHA 

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              1                      P R O C E E D I N G S 

              2                                    [Time noted:  8:38 a.m.] 

              3               CHAIRPERSON MARSHALL:  Good morning. 

              4               Well, I thought we had a superb day 

              5     yesterday.  And I think the best thing about yesterday 

              6     is the fact that there is obviously very good work 

              7     coming out of this committee.  Everybody is working so 

              8     hard and so well.  It was really kind of delightful to 

              9     see how fruitful we are.  So I want to thank all of you 

             10     again for your hard work and for having such a 

             11     successful day yesterday, and I think it will be just 

             12     as successful today. 

             13               I did want to make one observation and that 

             14     is that I think during the afternoon discussion about 

             15     pesticide testing in humans which itself is kind of on 

             16     the surface perhaps a gruesome or strange idea that 

             17     doing work in bioethics means that you need to let 

             18     emotions inform your reason, but you also have to let 

             19     reason inform your emotions in order to do good work 

             20     and critical thinking.  

             21               So, perhaps we could bear that in mind today 

             22     in terms of our civility towards one another and we 

             23     promise that we won't pick on Bob Levine because he's 

             24     devine as well as Levine --  

             25               [Laughter.]  
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              1               CHAIRPERSON MARSHALL:  -- and --  

              2               DR. SHAMOO:  Oh, God, now we're really in 

              3     trouble.  

              4               CHAIRPERSON MARSHALL:  Okay.  Adil, now --  

              5               [Laughter.]  

              6               CHAIRPERSON MARSHALL:  Bob, I was just saying 

              7     that there are no jokes allowed that you're define as 

              8     well as being Levine, so I'm not letting anyone pick on 

              9     you today or make jokes unless they come from Susan 

             10     Kornetsky who is the youngest member of the committee. 

             11      She's allowed.  

             12               [Laughter.]  

             13               [Simultaneous conversation.]  

             14               DR. R. LEVINE:  Is that because I've been 

             15     telling jokes?  

             16               CHAIRPERSON MARSHALL:  No.  I'm just making 

             17     sure that we don't pick on you too much.  

             18               So, Abbey, or not Abbey.  I'm sorry.  Mary 

             19     Kay, my brain is not in gear obviously.  

             20               Genetics this morning.  Yes. 

             21               DR. PELIAS:  Should I come up there? 

             22               CHAIRPERSON MARSHALL:  Yes, please do come up 

             23     here.   

             24               [Pause.]  

             25               CHAIRPERSON MARSHALL:  Please turn to Tab 8 
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              1     in your notebook. 

              2               DR. PELIAS:  Folks, I would to start out this 

              3     morning with a little bit of a review of where we were 

              4     and where we are now.  When the working group on 

              5     genetics decided to start putting together information 

              6     in anticipation of putting information into a new 

              7     edition of the IRB guidebook we kind of fumbled around 

              8     for a while until we decided that the place to start 

              9     would be with the chapter on human genetics research 

             10     that appeared in the 1993 edition of the IRB guidebook. 

             11      So we got this document out and gave copies of it to 

             12     all the members of the working group and then arranged 

             13     to have a conference call. 

             14               There in 1993 approximately 22 pages of 

             15     advice about how to do human genetics research with 

             16     respect to IRBs, and I anticipate that we'll have a 

             17     document when we get finished with this go round that 

             18     we'll have a document of approximately the same length, 

             19     but with considerably different content.  

             20               After we had a bit of a chance to study the 

             21     chapter on human genetics research we had a conference 

             22     call on April the 8th and during that conference call 

             23     we pretty much dissected the outline of that 1993 

             24     chapter.  And to prove to you that we dissected, I 

             25     usually take pretty clear notes, but this page came out 
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              1     of the conference call on April the 8th and then we 

              2     were charged with making some sense out of all of the 

              3     suggestions that were made to modify the outline.  

              4     Essentially what happened was that we distributed in 

              5     the outline of the 1993 chapter and asked people to 

              6     comment on it.  

              7               I have not reproduced for you today the 

              8     outline of the 1993 chapter.  I have given you two 

              9     later versions of an outline that came out of our April 

             10     8th conference.  

             11               During that conference we all agreed that 

             12     there is a need for a shift of emphasis in what is 

             13     included in genetics research.  The reason for this is 

             14     that genetics research has changed dramatically in the 

             15     last 10 to 15 years.  

             16               Before 1993 the emphasis in genetics research 

             17     was on family studies, on pedigrees, on locating genes, 

             18     linkage studies, and I would say primarily directed 

             19     toward identifying single genes and single gene 

             20     disorders. 

             21               And since 1993, or let's say in the last 15 

             22     years, we have seen a molecular revolution which has 

             23     brought us into an era of what I call "technical 

             24     wizardry" in microarrays and bioinformatics, and we are 

             25     now doing work that is considerably different from the 
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              1     kind of work that we were doing 15 years ago. 

              2               So we are in a new technological age and we 

              3     are also, with regard to what we're looking at in terms 

              4     of hereditary problems, health problems, we are looking 

              5     to identifying genes that contribute to complex 

              6     diseases.  And I think the first one that everybody 

              7     ever talks about, the complex diseases, cardiovascular 

              8     disease, sometimes diabetes and so on, generally when 

              9     we hear the phrase "complex disease" we are talking 

             10     about what we have traditionally called 

             11     "multifactorial" diseases which for the most part are 

             12     caused by contributions of alleles or genes at many 

             13     different loci that are acting in concert with 

             14     environmental factors.  So we are in a much different 

             15     age than the kinds of problems that we were looking at. 

             16      We're still looking at them, but the emphasis now is 

             17     on considerably more convoluted or complex problems 

             18     with regard to genes and health problems. 

             19               So with acknowledging that, the shift in 

             20     emphasis that we've seen in genetics research, we took 

             21     to a practical approach of reworking the outline of the 

             22     chapter that appeared in 1993. 

             23               And for this part of our discussion, I would 

             24     ask you to refer to the two outlines that are in your 

             25     materials.  The first page -- I've only given you two 
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              1     outlines.  This is not a particularly difficult 

              2     problem.  The first page is just simply informational. 

              3      On the back of that page is an outline that I put 

              4     together after a conference call when I had this 

              5     completely unreadable, scribbled over outline from the 

              6     1993 edition. 

              7               And we went through this -- the old outline 

              8     step-by-step and wrote down these notes and then right 

              9     after the conference I put together a new outline which 

             10     is what you see here on the back of the first page of 

             11     the two pages that you have in your materials. 

             12               I generally followed the suggestions of the 

             13     committee and made a few changes and also included in 

             14     this outline the writing assignments that went out to 

             15     various people who were participating in our telephone 

             16     conference.  

             17               If we work our way down this a little bit we 

             18     would see some similarities.  Of course, you want an 

             19     introduction, I think, with definitions.  In the 

             20     definition sections of the introduction we have added 

             21     three more terms which are extremely important these 

             22     days in the world of genetics research and that 

             23     includes associations, pharmacogenetics and 

             24     bioinformatics. 

             25               And before we get finished with this and if 
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              1     you have any ideas, I entertain all of them because we 

              2     want to do as complete a job as we can.  If you want to 

              3     add more terms to this, I am completely willing to do 

              4     that as long as it doesn't get so convoluted that the 

              5     average IRB won't know what we're talking about.  And 

              6     this is something that I have to keep in mind because 

              7     I'm always doing battle with my own IRB about genetics. 

              8      So we have added three terms to the list of 

              9     definitions and I don't have concise definitions for 

             10     these last three terms yet, but we'll get there. 

             11               One of the suggestions of the folks on the 

             12     conference call was that we should deemphasize pedigree 

             13     studies and we have done that.  The second part of the 

             14     original outline was called pedigree studies.  Like 

             15     everything we do is pedigree studies, and that's no 

             16     longer so. 

             17               There were a number of general concepts that 

             18     were listed under pedigree studies in the previous 

             19     outline and the general feeling on the conference call 

             20     was we should pull out a lot of the general concepts 

             21     and just have this as our second section.  So you see 

             22     here under II, General Concepts, and for the most part 

             23     these are the same topics that were included in the 

             24     last one, but they would be rewritten with a bit of a 

             25     shift toward what we are doing these days.  And what 
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              1     I've done with regard to the materials that we're going 

              2     to be working with all day tomorrow is rewrite these 

              3     sections from the old version of the IRB guidebook into 

              4     something that is a little bit, perhaps more 

              5     contemporary. 

              6               After we got finished pulling out the so-

              7     called general concepts, we had some things left over 

              8     that we needed to sort of put together.  We couldn't 

              9     describe them entirely, but then on the other hand we 

             10     didn't have to have a major shift in these things. 

             11               So we have another section called 

             12     "identifying genes" and what I have here are topics 

             13     that represent traditional approaches to genetics which 

             14     are still used, in some situations they're just not the 

             15     focus of a great amount of attention now.  These 

             16     include our pedigree studies and linkage studies.  And 

             17     we have continuing issues that are waxing and waning 

             18     these days depending upon what the current hot issues 

             19     are. 

             20               A very important aspect of this are the 

             21     issues related type access to data, particularly access 

             22     to research data that has not been confirmed clinically 

             23     and is not rigorous enough to, for example, fall under 

             24     clear regulations, but they may well be data that 

             25     people might want to have access to. 
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              1               And also under this section of identifying 

              2     genes, we are going to deal with the question of 

              3     disposition and secondary use of tissue samples.  This 

              4     is something that for me is a very, very important 

              5     topic because I believe that people are going to want 

              6     to have access in the future to information that is 

              7     generated in the future from samples that were stored 

              8     last year or whenever.  So surplus samples is a very, 

              9     very important topic. 

             10               Moving on down the list to genetic testing, 

             11     I've put these things more or less under a rubric of 

             12     genetic testing, including newborn screening, carrier 

             13     status, pre-implantation and prenatal testing, risk 

             14     assessment testing, and then when we get down into 

             15     these last three categories here in the outline we are 

             16     moving into the newer areas that we're going to have to 

             17     expand very completely or as well as we can. 

             18               The first three under this heading of genetic 

             19     testing are generally, I would say, concern with 

             20     monogenetic, single gene disorders and picking up 

             21     things that people would want to know for their own 

             22     personal management and relatively -- maybe I should 

             23     say, relatively easy testing compared to the kinds of 

             24     testing that are associated with complex diseases.  

             25               So we have the first three related primarily 
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              1     to monogenic problems and then the last three that are 

              2     related to our newer technologies and what we are doing 

              3     these days in the area of complex diseases.  

              4               I have continued to keep gene therapy 

              5     separated out from the rest of everything because it's 

              6     our anticipation that there will be a chapter in the 

              7     new IRB guidebook, a whole chapter dedicated to gene 

              8     therapy and we will acknowledge this here, but we will 

              9     not usurp or try to repeat what's going to appear 

             10     elsewhere in the new IRB guidebook on gene therapy. 

             11               And then the last two points down there were 

             12     just -- will be things that should be brought in later 

             13     on.  But anyway, this is the outline that I put 

             14     together from my notes and from what I thought was our 

             15     mandate with the conference call of the working group. 

             16               And then a couple of days later, if you'll 

             17     look to the second page, the second page of your -- the 

             18     second sheet that's included in the two pages in your 

             19     materials, I received from two of the people who were 

             20     on the working group conference call another outline 

             21     suggested for revising this chapter on human genetics 

             22     research.  So we have a somewhat different approach 

             23     which I will tell you generally contains all of the 

             24     information, all of the topics that are included in the 

             25     first outline I just somewhat rearranged and they are 
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              1     very much expanded in the area of more complex genetic 

              2     considerations. 

              3               Now, I have a note, Jonathan -- yes, I'll 

              4     try.  Oh, okay. 

              5               If you will just look over this second 

              6     outline, I think you will find that it's much more 

              7     rigorous in setting out topics for consideration with 

              8     complex diseases and the major difference, I think, in 

              9     what I had proposed and what these two members of the 

             10     working group proposed was that I took general 

             11     considerations and placed them at the beginning of my 

             12     outline and generally they are included toward the end 

             13     of this second outline.  And I think our task this 

             14     morning and I hope we come out of this with something 

             15     that we can work with tomorrow, is to create an outline 

             16     that will be satisfactory for filling in.  I believe 

             17     it's always rather expeditious to first write an 

             18     outline and then start filling in the paragraphs and 

             19     the topics rather than doing a haphazard thing and 

             20     trying to glue it all together in one way or another 

             21     later on. 

             22               So when Kate and I talked about these two 

             23     outlines Kate said, "let's turn this over to the 

             24     committee" and that's what we are going to do today. 

             25               And I will take your suggestions to the 
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              1     working group tomorrow and we'll spend all day and then 

              2     considerably more time after that getting together a 

              3     draft chapter which I will -- I hope I will have to you 

              4     by the end of July, even actually much sooner. 

              5               Okay.  Jonathan. 

              6               DR. MORENO:  Just a couple of suggestions, 

              7     Mary Kay.  Under 1(b) under your lexicon, I think you 

              8     should probably add pharmacogenomics, pharmacogenetics 

              9     and pharmacogenomics are sometimes identified, but my 

             10     understanding is that pharmacogenetics refers to 

             11     hereditary basis of disease and pharmacogenomics refers 

             12     to the designing drugs for particular groups or 

             13     individuals if I'm not mistaken. 

             14               DR. PELIAS:  Okay.  

             15               DR. MORENO:  I really want to focus on 3(c), 

             16     tissue samples and I'm sure you guys have already 

             17     thought about going back to NBC biomaterials report.  I 

             18     think it's a very useful report.  And they have many, I 

             19     think, sound things to say about this.  A couple of 

             20     specific points, and this come out of my experience 

             21     with working with an NHLBI sponsored tissue registry. 

             22     Two things have come up that you might help think 

             23     about. 

             24               One is, when a person has decided to donate a 

             25     tissue sample for study purposes, if the individual 
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              1     later on decides they don't want to be part of the 

              2     study anymore, does that mean that their tissue can be 

              3     retrieved, particularly if it's already been 

              4     distributed to another entity, another -- an 

              5     investigator or a commercial entity? 

              6               DR. PELIAS:  Well, it's my understanding that 

              7     samples can be retrieved if they haven't yet had the 

              8     identifier stripped from them, but data cannot be 

              9     retrieved.  

             10               DR. MORENO:  Right.  Well, my question is, I 

             11     guess, how to inform people that their data -- their 

             12     samples may not even be retrievable if they're not 

             13     identified.  I mean, this is kind of an interesting 

             14     paradox here because on the one hand you may not want 

             15     them to be identified for privacy reasons, but you 

             16     might want to get them back later so people may find 

             17     themselves in a bit of a crunch on that.  That's just 

             18     something to think about how to --  

             19               DR. PELIAS:  This is something that I've been 

             20     thinking about for a while.  And I don't know all the 

             21     nuances of all the government regulations and writings 

             22     that have been done on this.  But I have, I think, an 

             23     intuitive feeling that when people are enlisted in 

             24     research projects and they're going to give samples, 

             25     they can be -- this can be discussed up front.  
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              1               DR. MORENO:  Yes. 

              2               DR. PELIAS:  And people can be told that we 

              3     would like to keep your samples and use them.  The 

              4     individuals who are donating the samples can have 

              5     choices about whether or not they want to have their 

              6     identifiers retained with the sample or not, and if 

              7     they say no identifiers, then they give up any right to 

              8     further information or further disposition of what 

              9     comes out of those samples.  

             10               DR. MORENO:  Interesting.  Right.  

             11               DR. PELIAS:  This is something -- I realize 

             12     that there is controversy about this because when I 

             13     first mentioned this back around 1995, we were having a 

             14     meeting here in Washington and I said, we could do 

             15     this.  And the response was very loud and I was told 

             16     that you cannot consent to anything that you don't know 

             17     exactly what it is.  You can't consent to future 

             18     research if it's not yet defined.  And these ideas have 

             19     been percolating in genetics community since then. 

             20               DR. MORENO:  This actually -- my last comment 

             21     goes to exactly that point.  If consent forms for these 

             22     donations can be designed and in fact are designed in 

             23     some cases to give the donor the following three 

             24     options:  You may agree to donate your tissue to any 

             25     scientific research; which is basically what you just 
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              1     said. 

              2               DR. PELIAS:  Yes.  

              3               DR. MORENO:  Which you think you can't do. 

              4               DR. PELIAS:  I think you can, but other 

              5     people don't. 

              6               DR. MORENO:  Well, all right.  

              7               DR. PELIAS:  Go ahead.  

              8               DR. MORENO:  The second option is only for 

              9     the disease or diseases that are relevant to me.  And 

             10     the third is only for a specific protocol.  So you can 

             11     call me back later to ask me about that.  And I guess 

             12     it would be useful for us to know what the workgroup 

             13     thinks about that array of options. 

             14               DR. MORENO:  I have Bob over here.  

             15               DR. R. LEVINE:  Thank you.  That's a very 

             16     interesting pair of outlines.  I don't know if -- you 

             17     seem to be concentrating your attention on the first 

             18     outline.  But in some respects I prefer the second 

             19     outline partly because it mentions some topics that I'm 

             20     not sure would have been included in the first and 

             21     maybe, for example, population genetics which are very 

             22     important topics.  It could have been included in the 

             23     first, but buried in another -- as a subtopic through 

             24     one thing that was there.  I also like the general 

             25     structure of outline number two.  It's, I think, 
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              1     conducive to locating problems, perhaps better than the 

              2     first one. 

              3               I think the topic that Jonathan was talking 

              4     about, withdrawal from participation, one of the 

              5     complexities that's come up in that is that when you're 

              6     dealing with data that are either identified or linked, 

              7     you know, the so-called one-way link so you can find 

              8     it, there has been a lot of argument over the aspect of 

              9     the -- you and Jonathan were discussing -- can you 

             10     withdraw your tissue.  But there's also been a lot of 

             11     argument about whether or not you can withdraw your 

             12     data, if your data are still like -- for example in 

             13     psychology they say in the debriefing if you don't like 

             14     what the investigator did deceptively you can order 

             15     them not to use your data.  

             16               But I think the controversy over genetic 

             17     data, particularly when geneticists can invest hundreds 

             18     of hours and thousands of dollars in developing a 

             19     dataset, it's not as easy.  There's a lot more at 

             20     stake, and I look forward to your dealing with that. 

             21               The last point I would like to make is that 

             22     in both of your outlines you talk about the subject's 

             23     right not to know the results.  I think an equally 

             24     important thing is the circumstances under which the 

             25     investigator should not reveal results. 
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              1               For example, early in an exercise in 

              2     attempting to determine a linkage between a set of 

              3     genetic findings and some disease or predilection to 

              4     some disease you really don't have enough data to know 

              5     what the data mean.  And it would be, I think, 

              6     destructive in many of those cases to say, well, you, 

              7     you know, according to our preliminary evidence you 

              8     have a gene that might result in Alzheimer's, but we 

              9     don't really know if that's accurate.  That's really 

             10     worse than giving no information.  So I hope that can 

             11     be --  

             12               DR. PELIAS:  I appreciate that, but I would 

             13     like to also consider the possibility of, say, a gene 

             14     frequency study for breast cancer that I know about 

             15     that was done in this area when there is information 

             16     that is revealed from the gene frequency study that 

             17     maybe perhaps 10 or 15 of the women out of the whole 

             18     sample ha a suspicious allele for breast cancer, is 

             19     there a great burden on the investigator to inform only 

             20     those persons that they may wish to look into this 

             21     further.  They may wish to have further testing done or 

             22     do wait until one of those women comes down with 

             23     metastatic cancer and goes to a lawyer?  I'm worried 

             24     about lawyers in all of this business.  

             25               DR. R. LEVINE:  I think that you're making an 
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              1     important point and that point illustrates that it's 

              2     not a simple issue --  

              3               DR. PELIAS:  It's not. 

              4               DR. R. LEVINE:  -- that I'm asking you to 

              5     resolve.  

              6               [Laughter.]  

              7               DR. PELIAS:  Thank you very much.  I 

              8     appreciate the assignment.  

              9               DR. PELIAS:  Elliot, Susan and then Bob Rich, 

             10     and then Margaret. 

             11               DR. DORFF:  I also like the second outline a 

             12     little bit better, because in particular at the very 

             13     beginning you spell out when genetic research is exempt 

             14     from review and when it's for expedited review and the 

             15     like.  And after it's all said and done, what we are 

             16     charged to do is to talk about exactly those issues.  

             17               All right.  So, I mean, it's -- the other, I 

             18     have several points.  One is that the word or the 

             19     phrase "genetic engineering" doesn't appear anywhere 

             20     here.  And I don't know if that's political reasons or 

             21     if that's because the research just simply doesn't deal 

             22     with that, or -- what I can tell you is that it 

             23     certainly is in the popular press.  And so if you're 

             24     not going to talk about it, you should define it and 

             25     say that you're not going to talk about it, and explain 
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              1     why.  Or, if you are going to talk about it, then 

              2     somewhere or another the phrase has to be dealt with 

              3     because it certainly is in the popular mind.  And along 

              4     with that phrase, of course, comes, you know, all kinds 

              5     of movies and books and things like that, and science 

              6     fiction. 

              7               So, I think it would be helpful to say, 

              8     what's science and what's science fiction in terms of 

              9     all of that. 

             10               The second point that I wanted to make is 

             11     that you talk here about identifying groups, collection 

             12     of data on race and ethnicity and I just want to say 

             13     that Ashkenazi Jews have been studied tremendously, in 

             14     part because it's a wonderful population for a 

             15     geneticist to study because there was a lot of -- in 

             16     marriage, and it's a relatively small population and so 

             17     you can trace genetic, you know, features and so on.  

             18     And, aside from that, Jews volunteer for all kinds of 

             19     studies. 

             20               But what that then leads to though, and 

             21     there's actually been a backlash in the Jewish 

             22     community to some extent is the worry that the Jewish 

             23     community would then be tainted in the minds at least 

             24     of some as a diseased community because you find out 

             25     that there are all of these various kinds of 
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              1     dispositions for this disease and that disease and so 

              2     on. 

              3               So, when you talk about that issue, you may 

              4     want to talk also about what on the one hand is 

              5     scientifically a golden population to study, but on the 

              6     other hand raises some of these sociological issues in 

              7     terms of people's -- I don't know, understanding of 

              8     themselves and of others. 

              9               And then the last thing I wanted to mention 

             10     was on the right not to know.  The one that I was just 

             11     talking about and that you were as well.  The right not 

             12     to know, especially in the -- I mean, the case, I 

             13     guess, that we're all thinking about is the VRCA1 gene 

             14     and 2 later, the breast cancer genes, you know, I think 

             15     the first issue is a little bit Bob raised and I think 

             16     he's absolutely right about that.  The part of the 

             17     problem at the beginning was that the initial study, 

             18     you know, sounded much too convinced of the connection 

             19     between the -- you know, between the allele and in 

             20     actual breast cancer, and the other real piece of it 

             21     was that, at least at that time, there was no research 

             22     as to whether a woman could do anything about it. 

             23               And so, I mean, I think that one of the 

             24     things you may want to explore is the right not to know 

             25     especially when there is nothing that could be done to 
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              1     do -- you know, to change the course of the disease to 

              2     begin with and then does that right change when later 

              3     research determines that there actually are some things 

              4     that could be done to either avoid the disease 

              5     altogether or to mitigate it. 

              6               And in that situation, so that's one point -- 

              7     and the other point I wanted to make on this issue is 

              8     that that situation raised a very interesting question 

              9     about interfamilial dynamics.  Let's say you have two 

             10     sisters, one of whom tests positive and the other one 

             11     tests negative.  Well, the one who tests positive is, 

             12     you know, is not happy, obviously, because that means 

             13     that there's an increased chance that she's going to 

             14     get breast cancer.  But the one who tests negative is 

             15     not free and clear either. 

             16               I mean, there's, you know, there's survivor 

             17     guilt very much like out of the Holocaust kinds of 

             18     things.  Right.  You know, how is it that I'm okay and 

             19     she's not.  So, I mean, I think you may want to at 

             20     least -- I don't think that since our job is not to 

             21     talk about everything on this issue, but, you know, but 

             22     simply to -- these are kinds of things I think that you 

             23     should at least identify as concerns although because 

             24     the human beings that are being involved in this that 

             25     have a stake in knowing or not knowing, include not 
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              1     only the subjects, but their family members. 

              2               DR. PELIAS:  If I could comment a little bit 

              3     further on that, one of the really serious issues that 

              4     we're dealing with in the world of genetics right now 

              5     is whether or not there may even be an obligation on 

              6     the part of investigators and medical professionals 

              7     when they find out that other families outside of the 

              8     immediate physician/patient relationship might be 

              9     affected, whether or not there might be an obligation 

             10     to step outside of the immediate relationship and to 

             11     inform other family members, at least maybe not to 

             12     clobber them with specific information if we have 

             13     specific information, but to suggest that perhaps they 

             14     might want to investigate their own situation a little 

             15     bit further. 

             16               MS. KORNETSKY:  I guess I'm in the minority, 

             17     but I like the first outline first -- best.  And I 

             18     guess the reason that I'm reacting that way is thinking 

             19     about the audience of this particular document which is 

             20     the IRB guidebook chapter which is, in all honesty, 

             21     predominantly used by IRB administrators and sections 

             22     get pulled once in a while and go to IRB members. 

             23               And I guess my concern was, and maybe this is 

             24     not really a concern is that I looked over the second 

             25     part and it's very, very technical, the terminology 
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              1     that's being used. 

              2               And so I guess, you know, perhaps if there's 

              3     a difference if an IRB has to get something and decide, 

              4     well, is this a predictive monogenic or is this, you 

              5     know, a prognostic complex, are there different issues? 

              6      If there aren't different issues, then I'm just 

              7     concerned about the complexity of it.  So that's my own 

              8     point of view. 

              9               I do like the idea of the first two things, 

             10     the exempt and the eligible or expedited review.  I 

             11     think that's very, very helpful to separate that out. 

             12               The last point that I have is -- I guess this 

             13     is more just about the particular group.  This whole 

             14     CLEA business in a hospital setting really comes up.  

             15     And I know that we worked very carefully with our 

             16     director of clinical labs to try and time resolve this. 

             17      And there is no resolution and I know even the 

             18     laboratory medicine people have lots of discussions and 

             19     I've been given information about that.  Is that 

             20     perspective from sort of the laboratory side brought 

             21     in?   

             22               I mean, because we've had to take a position 

             23     on certain things that we can't give results out 

             24     because it isn't replicated.  And sometimes the labs 

             25     will replicate things and sometimes they won't.  So is 
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              1     that -- how is that being addressed within the 

              2     workgroup? 

              3               DR. PELIAS:  It will be addressed in the 

              4     workgroup, let me put it that way.  I believe we're 

              5     obligated to acknowledge that these issues exist and we 

              6     have to put something into what we write to acknowledge 

              7     that there are problems here.  We can't solve all the 

              8     problems, but we will write it in. 

              9               One of my major concerns, and, Susan, thank 

             10     you very much for saying so, is that when we write this 

             11     up with the view to having it studied by people on 

             12     various IRBs, we are going to have to be very careful 

             13     not to be so technical with snips and ESTs and what not 

             14     that the people who are reading it and trying to use it 

             15     can't get anything out of it. 

             16               So I will go for simpler language rather than 

             17     a tremendous amount of technological language that 

             18     other folks aren't going to be able to understand. 

             19               Let's see, where are we?  Susan -- Bob. 

             20               DR. RICH:  Just to begin where we just left 

             21     off.  I tend to agree with Susan's view that less is 

             22     more in the sense of trying to really write a document 

             23     in this case that is useful for IRBs and not a document 

             24     that is a primer on concepts in molecular genetics.  

             25     That being said, I think one of the real challenges is 
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              1     going to be that we are trying to do this on rapidly 

              2     shifting ground at a time when there are other things 

              3     going on in the federal regulatory arena, some of which 

              4     are actually even in potential conflict with one 

              5     another.  So we've had substantial discussions about 

              6     HIPAA, for example and HIPAA will be relevant to all of 

              7     the issues that we deal with in terms of databases and 

              8     tissues and things. 

              9               On the other hand, one of the discussions we 

             10     have not yet had are the recently raised considerations 

             11     at NIH on data sharing and the requirements that in 

             12     order to get an NIH grant you actually have to be 

             13     explicit or the proposal you will have to be explicit 

             14     with regard to your intention of how you will make your 

             15     data available to any qualified investigator and how 

             16     you will be sharing it. 

             17               So, there will be moves in one direction on 

             18     increasing privacy and reducing access to data, and 

             19     moves on the other hand of making data as widely 

             20     available as possible.  But I think that because both 

             21     of these things are going on simultaneous with our 

             22     writing project, it's going to be a challenge to try to 

             23     come out with instructions to IRBs that will anticipate 

             24     in some sense where these controversies are likely to 

             25     come out.  But in actual fact, we probably won't know 
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              1     that for at least months and maybe longer than that. 

              2               One of the real challenges that I think -- 

              3     and it's been in a sense discussed around the table -- 

              4     is that the data that we'll be finding in genetics 

              5     either come from very large databases or very small 

              6     databases.  And the ethical challenges are different 

              7     when you're dealing with very large databases and when 

              8     you're dealing with very small databases. 

              9               I would say that in the very large databases 

             10     one of the things that we've not talked much about yet 

             11     is the notion that those very large databases are going 

             12     to be global bases, not necessarily in the United 

             13     States.  And, in fact, there are very good reasons for 

             14     that, because, as everyone knows, the defining 

             15     characteristic of the American populous is its 

             16     extraordinary heterogeneity which makes the challenge 

             17     of trying to identify complex diseases at the first 

             18     level, the genetic basis more difficult.  And that's 

             19     why there has been a great deal of attention to going 

             20     into large populations which are much more genetically 

             21     homogeneous as the first cut of trying to understand 

             22     genetic basis of complex diseases. 

             23               That being said, I think probably everyone at 

             24     this table is aware of recent controversies, for 

             25     example, in China, where there have been considerable 
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              1     questions raised as investigators go into these large 

              2     Chinese populations about just what kind of informed 

              3     consent processes were engaged in enrolling the data, 

              4     enrolling the subjects, or what kind of promises may 

              5     have been made with regard to medical care or other 

              6     kinds of things. 

              7               So one of the things that's going to be 

              8     difficult, I think, as we begin to need global data 

              9     will be an understanding of how those data are actually 

             10     obtained and validated from an ethical perspective 

             11     particularly when the data are based on populations 

             12     outside of the United States.  And I think we haven't 

             13     resolved all of that yet.  It eventually will come back 

             14     to American databases, I would say, because that's when 

             15     we'll be able to really understand is the genetic basis 

             16     really transcending across genetic heterogeneity of 

             17     population or is it defined within populations?  But 

             18     the first cut will be in populations that are as 

             19     homogenous as possible. 

             20               And that brings me to the second point which 

             21     is, in a sense they're very small databases and Elliot 

             22     already discussed -- I mean, the very small is the 

             23     pedigree analysis, obviously, and that's been the 

             24     traditional home for monogenic disease analysis for 

             25     many years.  But as we go beyond the individual family 
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              1     pedigree, we then go to small, but highly, well-defined 

              2     genetic pedigrees such as the Ashkenazi Jews.  I would 

              3     say even more so the one that put monogenic disease 

              4     analysis on the map in a sense are the old order Amish 

              5     where one really has a very small database of 

              6     extraordinary usefulness, but I think raising all of 

              7     the questions that Elliot has suggested with regard to 

              8     the Ashkenazi Jews. 

              9               MS. BORWHAT:  I just wanted to follow-up on a 

             10     comment that Jonathan made about the three options, and 

             11     the one being that the participant could okay specific 

             12     protocols provided they were contacted.  And I saw in 

             13     some of the documents that it was the obligation of the 

             14     participant to keep that information current so they 

             15     could be contacted.  And I wonder that we might want to 

             16     look and see how practical this is, how it's worked in 

             17     the past, and how good an option that might be.  It 

             18     might be very new to have much information on that, but 

             19     I think that's worthy of consideration. 

             20               I think related to that is the issue of not 

             21     informing participants of the results because the 

             22     results are preliminary and I think if we can maintain 

             23     the contact, I'm not sure related to what you said, 

             24     Elliot, that we couldn't at a time in the future 

             25     provide that information.  I mean, the study that you 
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              1     mentioned was treated very harshly in the press and 

              2     characterized as something similar to the syphilis 

              3     study.  And I think we would want to provide some 

              4     guidance to, you know, prevent that type of reaction to 

              5     any research being currently done. 

              6               DR. MORENO:  Can I just follow-up on 

              7     Margaret's good point?  I am not an expert on this, but 

              8     my understanding is that a reason that investigators 

              9     often prefer not to go back to individuals even if they 

             10     theoretically could is the way that the information  

             11     has been developed for study purposes is not thought to 

             12     provide any sort of clinical guidance and that it's 

             13     simply not definitive enough to bother people with. 

             14               I don't know how much validity that has from 

             15     case to case, but it's something that warrants more 

             16     discussion. 

             17               DR. KOSKI:  A quick comment on point.  The 

             18     Secretary's Advisory Committee on Genetic Testing has 

             19     obviously addressed this issue and already made the 

             20     point about information that's going to be conveyed for 

             21     clinical decision-making need to reach the appropriate 

             22     standards as we would for all laboratory testing and so 

             23     on, and I think that this ties right into that so that 

             24     our committee's work should not obviously be done in a 

             25     vacuum.  I know that it's not, but I just wanted to get 
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              1     that in to the record.  

              2               One other quick technical comment was the 

              3     fact that there is genetics research that in fact may 

              4     not even be human subjects research, not just exempt, 

              5     not just expeditable, but exact research that's done 

              6     totally on non-identifiable issues and all that are not 

              7     human subjects research.  It's basic research and we 

              8     need to make sure that that is also included in the 

              9     guidance.  

             10               DR. MORENO:  And just to follow-up on that 

             11     prior point, Greg, I've often heard that if the lab 

             12     isn't CLEA approved the assumption is that the 

             13     information doesn't go back.  Has the Secretary's group 

             14     commented on that?  Is that a standard of practice? 

             15               DR. KOSKI:  I think the Secretary's group has 

             16     commented on that.  It's not in regulation or anything 

             17     at this moment, but I think that would be my reading of 

             18     the intent that information that is going to be used 

             19     for clinical purposes would need to meet the 

             20     appropriate standard for all clinical laboratory 

             21     testing and this is one of the challenges of 

             22     laboratories that are doing testing that are not -- 

             23     there's not a large enough body of concern for the 

             24     particular disease that would be developed as a huge 

             25     laboratory enterprise and yet there could be a need for 
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              1     it.  So finding the appropriate mechanism for those 

              2     laboratories that would be doing the testing in a 

              3     research setting, but using it for clinical purposes is 

              4     a challenge that needs to be addressed. 

              5               MS. KORNETSKY:  I just want to add that the 

              6     definition of "using it for clinical purposes" also is 

              7     very murky. 

              8               DR. CHODOSH:  I had a little bit of concern 

              9     about this discussion and that is that I think that we 

             10     are underestimating the subject's ability to be a 

             11     participant in this kind of research.  That if they are 

             12     properly informed when they enter it, that this is 

             13     preliminary work, that it's not going to be definitive, 

             14     however you're in this and you should have access to 

             15     what comes out of it, and that you need to understand 

             16     in terms of what level it's at.  The individual needs 

             17     to understand that and it needs to be transmitted to 

             18     them properly.  And if they don't enter the study with 

             19     that understanding, and don't want to come out of it 

             20     with that understanding, they probably shouldn't be in 

             21     the study. 

             22               But I think that saying that we are going to 

             23     decide, you know, what a subject should know seems to 

             24     me a bit paternalistic, to say the least.  And I think 

             25     that we are ignoring the possibilities that people have 
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              1     the ability to understand preliminary results, et 

              2     cetera. 

              3               DR. PELIAS:  Thank you, Sandy.  Susan, are 

              4     you on point? 

              5               MS. KORNETSKY:  Yes. 

              6               DR. PELIAS:  You are and then we're going to 

              7     go on down the list. 

              8               MS. KORNETSKY:  Yes, I think one of the 

              9     issues, at least in this are and I know that the 

             10     workgroup will discuss it is that if an institution has 

             11     a CLEA license, I mean, it may not -- I agree with what 

             12     Sandy is saying, you know, but there are, at least I 

             13     have been informed that there are possibilities of an 

             14     institution losing their license if information being 

             15     used for clinical purposes isn't done in a CLEA lab.  

             16     So we've -- and they've showed me, they've cited, you 

             17     know, the chapter and verse of the CLEA regulations, 

             18     so, maybe it's a little bit differently at a university 

             19     where you have other labs, but they have been very 

             20     cautious of that.  And this is another area.  

             21               MS. MEYERS:  There's a subgroup of the 

             22     Secretary's Committee on Genetic Testing just based on 

             23     rare diseases.  And the problem is they call these 

             24     tests "home brews" because they are being done in 

             25     academic laboratories that are not CLEA certified.  And 
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              1     they have no way of ever becoming CLEA certified, 

              2     they're too small.  They're just not going to be able 

              3     to do it.  So it's not an institution that gets the 

              4     CLEA certification, it's the laboratory itself. 

              5               DR. PELIAS:  Thank you, Abbey. 

              6               We would like to move on now.  We have Adil, 

              7     then Alan, and then Kate.  

              8               DR. SHAMOO:  Thank you, Mary Kay.  This point 

              9     probably, Mary Kay, you know it better than anyone here 

             10     and that is, there is an emerging field of system 

             11     biology where the genetic components are strong or as 

             12     weak as any other one, and the disorders may not appear 

             13     at the cellular level and will appear at systems 

             14     levels.  And that will have the same phenomena as you 

             15     are trying to deal with.  And I was just putting that 

             16     for your consideration.  

             17               DR. PELIAS:  Thank you very much.  We will 

             18     probably get into that if we get through all the stuff 

             19     that we have right on the list right now.  

             20               Alan. 

             21               DR. FLEISCHMAN:  Yes, I just wanted to add to 

             22     the mix, the National Children's Study which is being 

             23     proposed and developed by the National Institute of 

             24     Child Health in collaboration with several other 

             25     agencies which will be the largest longitudinal cohort 
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              1     study ever attempted in the United States.  It plans to 

              2     take 100,000 pregnant women and follow them and their 

              3     offspring for 20 or 30 years.  The genetic component of 

              4     that study as it's being now planned will do serial 

              5     looks at the genome of those children to look at -- the 

              6     global question is, what are the effects on childhood 

              7     development of the environment at large.  

              8               So our discussions of pesticides yesterday, 

              9     discussions of what impacts on the genome, what social 

             10     and behavioral factors will impact on the development 

             11     of children over the long haul are all going to be 

             12     looked at in a comprehensive manner.  But apropos to 

             13     the genetics committee, if we do serial looks at genome 

             14     in order to look at how it changes over time in the 

             15     same identified subjects, we have a whole host of 

             16     interesting questions in terms of the research ethics 

             17     aspects of that. 

             18               As children get older and then become adults, 

             19     as we see changes in the genome, what does that mean 

             20     and who are we going to tell what about what?  We are 

             21     only studying one of a series of children within the 

             22     same family.  One can see a tremendous amount of 

             23     potential good genetics research that could spin off 

             24     from those studies.  So I just raise it because I think 

             25     they have an ethics committee.  For my sins I'm not 
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              1     that FACA to relate to that ethics committee.  And 

              2     they're thinking about some of these issues, but I 

              3     don't think they've gotten anywhere near to the depth 

              4     of need, particularly in the genetic area.  So as 

              5     you're doing this work, realize that there is a group 

              6     of colleagues who could dramatically benefit from the 

              7     wisdom of the committee. 

              8               DR. RICH:  On point to that, I find this 

              9     fascinating and one of the most interesting questions 

             10     will be as these infants are born, their mothers having 

             11     consented to the entry of their genetic information 

             12     into this database obviously over a course of 20 to 30 

             13     years, these people will be assuming their own majority 

             14     and their own responsibility for informing.  On the 

             15     other hand, the data by that time will have become an 

             16     invaluable and almost irretrievable part of a very 

             17     large database.  And I think the complexities of that 

             18     are going to be a challenge, to say the least. 

             19               DR. PELIAS:  Thank you, Bob. 

             20               Kate -- oh, Elliot. 

             21               DR. DORFF:  Plato thought that you knew 

             22     everything before you were born.  So the idea is you 

             23     have to get inter-utero, right --  

             24               [Laughter.]  

             25               DR. DORFF:  -- informed consent.  
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              1               [Laughter.]  

              2               MS. GOTTFRIED:  Well, it's opportune to 

              3     follow-up on Alan's comment because I just want to add 

              4     to that that I actually sit on the ethics workgroup of 

              5     this longitudinal NCS study.  And Alan is absolutely 

              6     right that there are numerous issues that have not been 

              7     contemplated and need to be.  One thought we've had in 

              8     talking with Alan about this is that we would bring in 

              9     an individual from NICHD to talk about the NCS study to 

             10     the committee if that's something that might be useful. 

             11      And we'll consider that. 

             12               The other point I wanted to make just in 

             13     terms of the outlines in front of you, it's not sort of 

             14     an either/or with respect to the outlines.  Certainly 

             15     we can meld them and this is pretty obvious, but we 

             16     will and we can meld the two.  The point of the second 

             17     one, in particular, I think was just that going back to 

             18     the 1993 outline much of it was good, but it wasn't -- 

             19     it didn't take into account obviously what we now know 

             20     ten years later.  And so we want it to be a 

             21     comprehensive approach.  But I think we do need to bear 

             22     in mind what Susan said in terms of it maybe being too 

             23     technical.  So we would want your input on that, but we 

             24     also want to make sure that we touch on all the issues 

             25     that need to be touched on. 
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              1               And, finally, just in terms of different 

              2     issues, the point that Elliot raised about, do you give 

              3     information if there's no know treatment, et cetera?  

              4     That's another issue that's come up in the Huntington's 

              5     context as well. 

              6               And in particular, something that Alan may 

              7     appreciate is also the issue of somebody who has tested 

              8     whether or not -- and Mary Kay and I have discussed 

              9     this -- about minor children and whether that 

             10     information ought to be conveyed.  And so we need to 

             11     take into account the issues with respect to people of 

             12     majority and people of "minority" age and what the 

             13     implications are.  And that's very controversial as I 

             14     understand it.  And I think probably the workgroup is 

             15     somewhat split on how to approach these issues.  So we 

             16     will need to look at that and also ask for your input 

             17     on that as well.  

             18               DR. FLEISCHMAN:  On point, Mary Kay.  My 

             19     understanding is that the screening issues in minors 

             20     has been fairly well agreed on in the genetics 

             21     community and in the pediatric community in terms of 

             22     standards.  Am I not correct on that? 

             23               DR. PELIAS:  We have worked this topic over 

             24     for the better part of ten years.  And generally 

             25     speaking where we are right now is that we have a 
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              1     consensus that you if want to test a child and you can 

              2     assure that the child will receive an immediate medical 

              3     benefit, then it's okay to investigate the genome and 

              4     generate genotype information on the child.  

              5               If on the other hand you can't guarantee an 

              6     immediate medical benefit, then the recommendation is 

              7     circumspection, step back and think about it, talk over 

              8     with the family the implications, the psychosocial 

              9     implications of generating this kind of information, 

             10     the possibility that if the child knows this 

             11     information it's going to have a negative effect on the 

             12     child's development and self-estimation.  And do a very 

             13     thorough genetic counsel -- job of counseling the 

             14     family so that they will understand both the negatives 

             15     and the positives of generating the information. 

             16               But then I think that many of us in the field 

             17     now including me say that once you've done this very 

             18     thorough job of counseling the family about 

             19     implications, then you've got to step back and let the 

             20     parents decide whether they want to pursue this testing 

             21     or not. 

             22               And we are -- at least a lot of us are 

             23     pulling away from the paternalistic attitude.  For 

             24     example, with Huntington's disease that you never test 

             25     a minor for that disease.  There are reasons why 
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              1     parents would want to know this information, very good 

              2     reasons why they would want to know the information 

              3     other than providing an immediate medical benefit.  So 

              4     that's, I think, where we stand now with the issue of 

              5     children. 

              6               DR. FLEISCHMAN:  And I think you would agree 

              7     that you need to add into that the assent of the 

              8     youngsters when appropriate, particularly as they get 

              9     older, and some of the work that's been done realizes 

             10     that some of our teenagers actually become mothers 

             11     before they have reached 18.  So that it may in fact be 

             12     appropriate for screening with assent in some problems. 

             13               DR. PELIAS:  That's correct.  And we bring up 

             14     again, the problem with emancipated minors and how much 

             15     they have in the way of rights.  Thank you. 

             16               CHAIRPERSON MARSHALL:  Anyone of our ex-

             17     officio or public members please feel free to step up 

             18     to the mike and we would love to hear from you. 

             19               And just remember to tell us who you are. 

             20               MR. COHEN:  Jeff Cohen, Director, Education 

             21     Division at OHRP.  A couple of things.  First of all, 

             22     very, very practical issues.  Has the working group and 

             23     NHRPAC interacted with the group that's preparing the 

             24     new guidebook?  There is a committee preparing the 

             25     guidebook. 
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              1               MS. GOTTFRIED:  Absolutely.  That's how we 

              2     got involved in this.  Because Susan Rose who is 

              3     overseeing that had asked us for and is inviting us to 

              4     give input because there --  

              5               MR. COHEN:  Because there is a time factor 

              6     involved because this is already going to an editor. 

              7               MS. GOTTFRIED:  Absolutely.  Well, from the 

              8     last we were told, it was not very far along.  But, in 

              9     fact, yes, I think we're ahead of the curve in terms of 

             10     where the other chapters are. 

             11               MR. COHEN:  And I would also like to 

             12     recommend that the other working groups also look at 

             13     the chapters appropriate for their working groups 

             14     because there will be chapters on informed consent and 

             15     chapters on social and behavioral sciences and so 

             16     forth.  And I think it's a very important way of 

             17     getting the guidebook to be a more effective tool. 

             18               MS. GOTTFRIED:  Yes, although I'm sure the 

             19     working groups are going to be delighted to accept more 

             20     work.  

             21               MR. COHEN:  Well, I think this --  

             22               MS. GOTTFRIED:  No, I'm joking.  Obviously 

             23     absolutely --  

             24               [Simultaneous conversation.] 

             25               MR. COHEN:  In terms of helping IRBS be the 
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              1     most effective use of --  

              2               MS. GOTTFRIED:  Yes. 

              3               MR. COHEN:  A couple points just in -- and 

              4     also, I do want to mention, because Bob Rich made a 

              5     point about this is evolving or a shifting field or 

              6     shifting playing field.  The guidebook is designed to 

              7     be a living document, unlike the last one that which 

              8     was done in '93 and done, this is designed to be a 

              9     living document and to be continually updated in both 

             10     the mechanics of it and the media that are going to be 

             11     used and so forth or hopefully will allow for that to 

             12     be a living document. 

             13               Two points.  One, I would suggest that a very 

             14     important point be included in the section and that has 

             15     to do with the expertise of the IRB.  This is one of 

             16     the major areas where many IRBs are limited in their 

             17     expertise and an important statement that the IRB must 

             18     either have that expertise on its membership or get 

             19     consultation before it makes reviews and approves 

             20     protocols involving genetics, and that's a very 

             21     important point that has to be made up front and very 

             22     strongly and I think to the benefit of both the IRBs 

             23     and the researchers. 

             24               Secondly, I want to reiterate Elliot's point 

             25     about communities.  Having just come from two weeks ago 
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              1     a workshop that we did for tribal colleges and 

              2     universities, the indian groups are very concerned 

              3     about genetics research.  This is a high priority 

              4     concern for them.  I think there definitely has to be a 

              5     section in there on communities and the impact of 

              6     genetics research on communities.  In fact, we heard an 

              7     excellent presentation on genetics research in Indian 

              8     communities from an American Indian genetics researcher 

              9     who I could put you in touch with if that would help. 

             10               DR. PELIAS:  By way of adding to that, both 

             11     the American Society of Human Genetics and the American 

             12     College of Medical Genetics are presently investigating 

             13     this question of communities and will probably have 

             14     papers out within a year on the issues that we're 

             15     considering with communities and genetics.  Thank you. 

             16               DR. SHAMOO:  Can I have a comment on that?  

             17     Just on that?  

             18               Five, six years ago there was a meeting of a 

             19     group of 20 to 25 people, ethicists, Indian 

             20     communities, other ethnic group sponsored by Center for 

             21     Mental Health Services, SAMSA.  And there is an 

             22     internal document that was supposed to be published 

             23     that's never been published, but internally is 

             24     available from SAMSA where they discussed all these 

             25     issues in a three-day conference and Paula Applebaum 
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              1     from Boston was a member of that group as well as, like 

              2     I said, there was two or three Indian Chiefs other 

              3     ethnic groups, even they had to my shocking, somebody 

              4     new with the Keldian in Detroit are.  That's a small 

              5     community of a quarter of a million population.  So I 

              6     just thought if you get it --  

              7               DR. PELIAS:  Adil, do you have more specific 

              8     information so that if we attempt to track that down we 

              9     can be specific that you could then send us? 

             10               DR. SHAMOO:  Yes, I could trace my own folder 

             11     on it because I'm a member of that group.  

             12               DR. PELIAS:  That would be great. 

             13               DR. SHAMOO:  And Paul Applebaum is another 

             14     source.  

             15               DR. PELIAS:  Okay.  Great. 

             16               DR. SHAMOO:  Sure. 

             17               MR. SCHATZ:  Good morning.  My name is Gerald 

             18     Schatz.  I'm a former member of the NICHD IRB.  I'm a 

             19     lawyer and an ethicist.  Yes, the two do go together 

             20     sometimes.  

             21               It is very helpful in doing the guide to 

             22     remember as the first set of authors did, that there's 

             23     lot of law out there, not just our own regulation.  In 

             24     this respect the NIH addressed the problem of CLEA in 

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              1     that said, "where a Privacy Act issue arises, the 

              2     subjects or the patient's right to obtain a record or a 

              3     report under the Privacy Act trumps the CLEA 

              4     regulation."  That is their interpretation. 

              5               Additionally we must be mindful, especially 

              6     in the cross-linkage studies, that there is a great 

              7     deal of state tort law about invasion of privacy. 

              8               DR. PELIAS:  Thank you very much.  

              9               MS. GOTTFRIED:  Mary Kay, just one thing to 

             10     add to that on point with respect to the state laws is 

             11     obviously, and this is something we'll have to address 

             12     in the chapter, I think, as well.  But there is 

             13     tremendous variability from state-to-state, both with 

             14     respect to minors and other aspects of, you know, 

             15     various laws, privacy included.  So we do need to be 

             16     mindful of that and address that. 

             17               DR. PELIAS:  I have a note here that we might 

             18     want to enter some information about the composition of 

             19     the working group in the record.  We have sort of 

             20     revised the composition of the working group in the 

             21     last couple of months and I've been very fortunate to 

             22     enlist the help of three colleagues who are in the 

             23     world of medical genetics and genetics research.  The 

             24     first I will mention is Dr. Rodney Howell who is at the 

             25     University of Miami as Chairman of Pediatrics there and 
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              1     has tremendous experience in the world of genetic 

              2     testing, particularly related to newborn screening also 

              3     with regard with related to cystic fibrosis and a 

              4     number of single gene disorders. 

              5               We have also enlisted the assistance of Dr. 

              6     Grody, Wayne Grody who is at UCLA who has been very 

              7     active in the world of CLEA testing and keeping us in 

              8     order with regard to what we're supposed to do in that 

              9     area.  Wayne will be working with us and also Dr. Steve 

             10     Warren who is at Emory and is going to be assisting us 

             11     in the information that we have to assemble on the 

             12     world of bioinformatics.  So we have some new blood in 

             13     the working group and we will be very grateful for 

             14     their input.  

             15               MS. KORNETSKY:  Mary Kay --  

             16               DR. PELIAS:  Yes.  

             17               MS. KORNETSKY:  -- a question on point and 

             18     forgive me, I don't remember the other working group.  

             19     Is there a member of the working group from industry or 

             20     a biotech company?  

             21               DR. PELIAS:  Yes, we do have at least two 

             22     folks on the working group.  Thank you.  

             23               DR. SHAMOO:  Is there a member of the group 

             24     in behavioral disorders, genetics of behavioral 

             25     disorders, mental illnesses? 
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              1               DR. PELIAS:  At this time, I don't think so. 

              2      I hear what you're saying.  

              3               DR. SHAMOO:  And there is quite a number -- 

              4     yeah, quite a number of those and --  

              5               DR. RICH:  I would say that Dr. Warren's 

              6     expertise, in particular, is in mental retardation, at 

              7     least.  So the genetic basis of mental retardation.  

              8     It's a little bit different, but it raises many of the 

              9     same issues. 

             10               DR. SHAMOO:  But behavioral issues are 

             11     broader, much, much broader issues. 

             12               DR. PELIAS:  We did have the assistance of a 

             13     colleague in psychiatric genetics, but he had rotated 

             14     office at work, so I assume you urge us to get another 

             15     person of that --  

             16               DR. SHAMOO:  Yeah, I would think so.  And 

             17     there is one at University of Virginia.  One of the 

             18     good people.  

             19               DR. PELIAS:  All right.  

             20               CHAIRPERSON MARSHALL:  Anything else in the 

             21     genetics arena that anyone would like to bring up, 

             22     committee members, ex-officios, folks who are our 

             23     public members?  

             24               MS. KORNETSKY:  I just want to say, Mary Kay, 

             25     that you've hit so many of the issues and I think it's 
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              1     going to be very welcome for the community and thank 

              2     you for thinking it all through so clearly. 

              3               DR. PELIAS:  I don't know that I've thought 

              4     it all through so clearly yet, but I know the pile of 

              5     things that I have to organize and come out from 

              6     underneath.  So thank you, Susan.  

              7               MS. GOTTFRIED:  We also owe some gratitude to 

              8     Dr. Collins who really encouraged us to take up the 

              9     handbook chapter as one of our priorities and so we are 

             10     glad that we can be of use in that respect. 

             11               CHAIRPERSON MARSHALL:  Well, we find 

             12     ourselves a little bit ahead of schedule which is a 

             13     good thing.  But I'm a little worried about moving 

             14     forward too quickly because we may have folks who are 

             15     coming for, you know, the part of the discussion that 

             16     begins in theory at 10:30, I believe.  So what we might 

             17     want to do, we have some extra time, obviously, is 

             18     break and then begin the discussion on bioterrorism and 

             19     research in the aftermath of bioterrorism a few minutes 

             20     early. 

             21               What do you think, Jonathan?  Does that sound 

             22     -- yeah, one of our speakers is not here yet. 

             23               So why don't we do that?  Why don't we take 

             24     until let's say five after ten and then we'll begin 

             25     just a few minutes early. 
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              1               Thank you.  And Mary Kay, thank you so much 

              2     for your leadership and great work.  

              3               [Applause.] 

              4               [Brief recess taken at 9:50 a.m.] 

              5               CHAIRPERSON MARSHALL:  Let's resume. 

              6               We are going to begin with Jonathan Moreno 

              7     who has kindly consented on the spot to give us an 

              8     overview of bioterrorism and research opportunities, I 

              9     suppose, that had been occasioned or that we have 

             10     become more thoughtful of after the events of September 

             11     11th.  So, Jonathan, thank you very much, and we're 

             12     just sort of turning the rest of the morning over to 

             13     you. 

             14               DR. MORENO:  Thank you, Mary Faith.  

             15               Apologies in advance to those of you who have 

             16     heard one or more portions of this talk before.  A pun 

             17     that I like to make in getting ready for this talk and 

             18     preparing people for it is that in my view the history 

             19     of human research ethics is not at all tangential to 

             20     this morning's topic. 

             21               That, in fact, in order to understand the 

             22     history of human research ethics, we really need to 

             23     understand what has not been, for the most part, an 

             24     element of the literature in bioethics which is the 

             25     military medical interest historically and the national 
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              1     security interest historically in experiments having to 

              2     do with preparation for nuclear, biological and 

              3     chemical attacks.  And so my -- there are long, medium, 

              4     and short versions of this talk, and this, you'll be 

              5     happy to know, is the short version. 

              6               I would like to start by noting that our 

              7     moral intuitions about these matters perhaps 

              8     unbeknownst to us probably have changed a bit since 

              9     September 11.  For example, exactly one week before 
             10     September 11, the New York Times had this story in 

             11     which a couple of investigative reporters got the 

             12     Defense Intelligence Agency and the CIA independently 

             13     to accede to the fact that the DIA was engaged in 

             14     attempts to reproduce an anthrax strain that has been 

             15     thought to be in Russian refrigerators since the 1980s, 

             16     but to which we have never been given access. 

             17               And the CIA indicated that it was going to 

             18     develop a replica of a bomblet that it is believed the 

             19     Soviet Union developed in the 1980s contrary to the 

             20     biological and toxin weapons convention of 1972 for the 

             21     dissemination of biological and chemical agents. 

             22               I, as somebody who is interested in this 

             23     stuff, was waiting for the human rights activists and 

             24     the lawyers to protest that this was a violation of the 

             25     biologic and toxin weapons convention and that I 
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              1     thought there would be quite interesting public debate 

              2     about that.  But, of course, that debate never 

              3     materialized because of the events of September 11th, 

              4     and my guess is, that some of us in this room, at 

              5     least, who might otherwise have been poorly disposed 

              6     toward these projects might not feel the same way now. 

              7               That all goes by way of the advertisement of 

              8     my book which -- what the hell, that's the only payment 

              9     I get is the ability to advertise my book.  Maybe I'll 

             10     show it to you again --  

             11               [Laughter.]  

             12               DR. MORENO:  -- just in case you missed it 

             13     the first time.  The story begins -- the book is called 

             14     "Undue Risk" which is -- and it was published by 

             15     Rutledge last year and it's a history of the use of 

             16     human subjects in atomic, biological and chemical 

             17     weapons experiments.  This is the most important person 

             18     that I'll be talking about today because he's the most 

             19     famous graduate of the University of Virginia Medical 

             20     School, this is Walter Reed. 

             21               Walter Reed actually plays a very important 

             22     role in the history of what we're talking about this 

             23     morning.  Not only because when he was called to Havana 

             24     in 1900 to deal with the yellow fever epidemic, as the 

             25     country's most eminent virologist and immunologist at 
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              1     the time, as an Army doctor, but also because as part 

              2     of his work in Havana, by order of the Surgeon General, 

              3     his job was to figure out the vector of the epidemic 

              4     which turned out to be a silver-backed female mosquito. 

              5      In the course of identifying the vector of yellow 

              6     fever, he, as well-known, engaged in a number of human 

              7     experiments. 

              8               Some of the experiments involved his own 

              9     commissioners, doctors, in his group, one of who, Jesse 

             10     Lazier [ph] in his early 30s, was a civilian doctor.  

             11     Another was a nurse named Clara Moss. 

             12               Clara Moss parenthetically is the only person 

             13     who has a stamp in her honor from both Cuba and the 

             14     United States. 

             15               I used to say that the next person will 

             16     surely be Illian Gonzalez, but everybody has forgotten 

             17     about him. 

             18               Not only did the commissioners themselves 

             19     self-experiment, a tradition, by the way, that is 

             20     virtually unheard of today.  And we can have another 

             21     conversation, perhaps, at a future meeting of NHRPAC 

             22     about why that is.  But also a number of Spanish 

             23     workers and soldiers, the American soldiers stationed 

             24     in Cuba, agreed to be subjects of the experiment 

             25     probably because of concerns about later Sir William, 
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              1     then Dr. Oceler's denunciation of another set of yellow 

              2     fever experiments being done by an Italian named 

              3     Sanarelli [ph] in Brazil. 

              4               The Surgeon General and Walter Reed developed 

              5     a consent form as we would today call it, in those days 

              6     they would have called it a contract or a release and 

              7     this is the Spanish version of the form that the 

              8     workers signed.  By the way, the American soldiers, 

              9     apparently, did not accept the money that the Spanish 

             10     workers were offered.  This is actually -- this is the 

             11     English translation of the form.  It's actually a 

             12     pretty good consent form, given what was known at the 

             13     time.  

             14               It says basically that you're in Cuba and so 

             15     you could get yellow fever and die whether in this 

             16     experiment or not.  But if you take the bite, we'll 

             17     give you $100 in American gold.  If you get sick we'll 

             18     give you $100 in American gold, and if you die, we'll 

             19     give it to your family.  Not a bad deal.  

             20               And it specified that they were volunteering 

             21     and so forth.  So not too bad as consent forms go and 

             22     certainly in plain English and plain Spanish, I'm told, 

             23     by people who can read Spanish.  And so it probably 

             24     would have passed muster. 

             25               None of the soldiers who were in the -- or 
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              1     the workers who were in the experiment died, by the 

              2     way.  For the next 40 years, I'd like to say, military 

              3     medicine and the whole area of human experimentation, 

              4     although occasionally controversial, was largely 

              5     inoculated, pun intended, by the both moral and medical 

              6     public health success of Walter Reed's experiments. 

              7               Walter Reed, himself, of course, became a 

              8     hero.  He died a few years later because of a doctor's 

              9     -- a fellow colleague's ill treatment.  But nonetheless 

             10     he became a hero, a kind of culture hero.  There was a 

             11     play about him called "Yellow Jack" which is the sort 

             12     of popular term, jargon term for yellow fever.  Also 

             13     became a movie.  He became a culture hero.  I'm sure 

             14     that the misconception that he actually took the bite 

             15     himself -- he didn't because he decided after Jesse 

             16     Lazier died that he was a little too old for that.  

             17     Probably have as something to do with the fact that 

             18     they're building his -- the Army hospital is named 

             19     after him.  It probably should be called the Jesse 

             20     Lazier Army Hospital. 

             21               In any case, of course, during and after the 

             22     second world war when it was learned that both the 

             23     Nazis and later on -- much later on that there had been 

             24     Japanese experiments involving human testing of 

             25     biological and chemical agents and delivery and 
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              1     disbursal methods of those agents, particularly by the 

              2     Japanese in Manchuria, guards really came to the public 

              3     consciousness less confidence in the self-direction of 

              4     military medicine, but not enough to be a fundamental 

              5     challenge. 

              6               The Nuremberg Code and the AMA policy that 

              7     was part of the Nuremberg Code developed actually 

              8     during the trial, but that's another story, resulted 

              9     from the trial of the Nazi doctors.  There was no 

             10     similar trial of the Nazi researchers even though -- 

             11     excuse me, of the Japanese researchers even though 

             12     their contributions to what is known about the methods 

             13     of disseminating biological and chemical weapons was 

             14     far greater than what the Germans did.  Hitler seems to 

             15     have not been a big fan of chemical and biological 

             16     agents.  He was gassed during World War I and so he 

             17     apparently didn't like the idea, but some of them were 

             18     done anyway in the camps.  But not nearly as much in 

             19     that area as did the Japanese for whom there was no 

             20     trial. 

             21               This is a disturbing familiar image to many 

             22     people of one of the experiments in the Dachau 

             23     Concentration Camp, a freezing or hypothermia 

             24     experiment.  This is the dock of the doctors' trial.  

             25     There were 23 defendants.  Only 19 of the defendants 
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              1     were medical doctors.  The other four were bureaucrats. 

              2      Interestingly of the seven who were hanged for war 

              3     crimes, four -- all four were the non-doctors and only 

              4     there were doctors.  So I'd like to say, if you're 

              5     going to commit crimes against humanity, it's probably 

              6     better to have an M.D.  

              7               [Laughter.]  

              8               DR. MORENO:  And there were various sorts of 

              9     experiments including experiments on battle field 

             10     injuries, experiments with early sulfa drugs to treat 

             11     those injuries.  They would create injuries and try to 

             12     treat them in various ways.  There were also, of 

             13     course, biological and chemical experiments. 

             14               The trial that was thought by the Army 

             15     lawyers to be an open and shut case took eight months 

             16     instead of a couple of months as they thought because 

             17     defense lawyers for the Nazi doctors had some very 

             18     interesting evidence to put on.  For example, they were 

             19     able to note that on June 3rd, 1945, "Life Magazine" 

             20     published this story called "Prison Malaria" in which 

             21     800 federal prisoners at penitentiaries in Georgia, 

             22     Illinois, and New Jersey were deliberately exposed to 

             23     malaria laden mosquitos.  You can see it in the young 

             24     man's stomach. 

             25               In cross-examination the defense lawyers 
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              1     said, "How come they were the only prisoners?"  If you 

              2     guys are so holy, how come you only used prisoners?  

              3     Well, the prosecution expert, Andrew Ivy, Dr. Ivy, the 

              4     AMA representative said, well, I guess because they're 

              5     more easily available than teachers and businessmen.  

              6               This is the rest of the article.  Obviously 

              7     this was not a secretive experiment in any sense.  This 

              8     is something that the prison officials are very proud 

              9     of and as you can see some of these guys got very sick. 

             10      They were treated with quinine, what was then being 

             11     developed for the treatment of malaria, atabrine, none 

             12     of them died.  And in at least one memoir of this 

             13     experience years later, the individual writing the 

             14     memoir said that this was the greatest thing he did in 

             15     his life, being part of this experiment because he was 

             16     part of a patriotic endeavor. 

             17               Well, the Nuremberg Code, if it applied to 

             18     anybody applied to prisoners, but prison experiments, 

             19     of course, did not stop, another story in the United 

             20     States, at least, until later in the 1970s and having 

             21     nothing to do with Nuremberg, but having more to do 

             22     with Tuskeegee and the Attica Prison riot and Mitford's 

             23     article comparing the prison experiments to the Nazi 

             24     experiments. 

             25               During the war there were also radiation 
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              1     experiments that were secret.  Perhaps the most famous 

              2     of them is that of the 17 plutonium injections of 

              3     hospitalized patients by the Manhattan Project trying 

              4     to figure out excretion rates for plutonium for the 

              5     sake of protecting the young lab workers.  They were 

              6     worried about plutonium as an internal emitter about 

              7     which they knew nothing.  There was also a kind of a 

              8     theory that maybe since plutonium is a bone seeker, it 

              9     could turn out to be a magic bullet for bone cancer in 

             10     which case they would both have gotten some important 

             11     national security information and maybe found a magic 

             12     bullet for cancer.  

             13               Unfortunately, about a third of the 17 people 

             14     who were given the plutonium without their information 

             15     or consent were misdiagnosed. 

             16               This is an example of some of the 

             17     communication that took place.  This is a letter or 

             18     rather a telegram to Wright Langham and Lou Hempelman 

             19     who were two of the people who were involved in 

             20     analyzing the data from the plutonium injections from 

             21     Dr. Fink at Rochester, University of Rochester was one 

             22     of the places where they were doing this.  And you can 

             23     see HP3 and HP4 referred to and then HP5, that's Human 

             24     Product 3, Human Product 4, and Human Product 5.  That 

             25     three Rochester subjects in the plutonium injections.  
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              1     Surely had this been known by the defense lawyers at 

              2     Nuremberg for the Nazi doctors, they would have had an 

              3     even more powerful case to make. 

              4               When the Atomic Energy Commission discovered 

              5     this, they were obviously rather concerned about it.  

              6     They decided to keep the plutonium injections secret.  

              7     They wrote two letters to professors who had been part 

              8     of the plutonium injection experiments during the war 

              9     who, of course, after the war wanted to do what all 

             10     professors want to do, which is publish their data.  

             11     And they said, okay, you can publish your data from 

             12     these injections.  By the way, nobody died from the 

             13     plutonium injections, I should add. 

             14               You can publish your data from the plutonium 

             15     injections, but these are the rules that you have had 

             16     to have followed in order to publish your data, did you 

             17     follow these rules?  And this is one letter that was 

             18     written by the general manager of the AEC, and this is 

             19     the second, and to my mind even more interesting 

             20     letter, same spirit but it includes the term informed 

             21     consent for the first time in English, that I know of. 

             22      Bob mentined the Amicus brief from the surgeons in 

             23     '57, the legal case, this I think actually had -- there 

             24     was no more thought given to the term informed consent 

             25     in '47 in this case than there was in '57 in that 
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              1     instance.  But this came from whom?  From MIT 

              2     engineers, administrators and lawyers.  And if you look 

              3     at it carefully you can see that the ethics 

              4     requirements are even greater than ours today and 

              5     probably unethical because the next of kin would also 

              6     have to give informed consent for somebody to be in an 

              7     experiment.  I don't think we even accept that today. 

              8               But the term "informed consent" comes up in 

              9     what context?  In a national security context. 

             10               This is the only document that shows that a 

             11     federal agency ever actually adopted the Nuremberg 

             12     Code.  And if I were to ask the people in the room, 

             13     what federal agency was this that actually adopted the 

             14     Nuremberg Code verbatim, most of you would probably be 

             15     surprise to know, unless you've heard me talk about 

             16     this before, that it's the Pentagon. 

             17               In 1953 the Pentagon adopted in top secret 

             18     the Nuremberg Code verbatim, word-for-word.  In fact, 

             19     if they had been in my class I would have to flunk them 

             20     because they plagiarized, they didn't cite it as the 

             21     Nuremberg Code.  And I can't go through the whole -- 

             22     the preface to it is very important for the purposes of 

             23     this session because it was developed in a vacuum -- in 

             24     a policy vacuum.  The DOD wanted to do a nuclear or 

             25     they called at the time "atomic biological and chemical 
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              1     weapons experiments" and it very carefully says, "for 

              2     defensive purposes."  They wanted to do these 

              3     experiments, they wanted to use human subjects, 

              4     soldiers, or perhaps people who were in Army or Navy 

              5     hospitals, but they didn't have any policy to cover 

              6     this, so the needed a policy. 

              7               They looked around, it's an interesting 

              8     story, fascinating story how they came up with this 

              9     policy.  The Army, the generals, the admirals and the 

             10     doctors were very opposed to this policy.  The lawyers 

             11     and the administrators and the political people in the 

             12     Pentagon said you had to have it.  Why?  Because we 

             13     just finished hanging seven Germans based on the 

             14     Nuremberg Code.  Actually, they were wrong about that. 

             15      They weren't hanged based on the Nuremberg Code.  The 

             16     Nuremberg Code came after the trial. 

             17               So this is the voluntary consent of the human 

             18     subjects is absolutely essential if the famous first 

             19     line of the Nuremberg Code, there it is along with all 

             20     the rest of it.  You can see this was a top secret 

             21     document.  Don't worry, you're not going to go to 

             22     Guantanamo because you saw this.  It was unclassified 

             23     in 1975. 

             24               You can ask yourself the question, how did 

             25     this get disseminated?  The answer is, not well.  And, 
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              1     in fact, here is for example a memorandum -- a cover 

              2     your butt memorandum from the Air Force Officer who was 

              3     in charge of the flash blindness studies that I briefly 

              4     mentioned yesterday. 

              5               He's told there's a policy, is what he is 

              6     saying here.  But he doesn't know what the hell it is. 

              7      And so he's like any good responsible bureaucrat he's 

              8     saying, I am not going to be responsible for going by a 

              9     policy that nobody has bothered to show me.  And I've 

             10     just written a letter to the higher ups to tell them 

             11     that I expect to see this policy because I don't know 

             12     what the hell I'm doing.  Meanwhile, he has had at 

             13     least two pilots become temporarily blinded by his 

             14     study.  So he's concerned. 

             15               Another problem is the fact that I mentioned 

             16     yesterday that I want to emphasize again today.  

             17     Everything turns into what you consider to be research. 

             18      The 200-plus-thousand men who were deployed at Desert 

             19     Rock, Nevada from '53 to '62 for the test shots, the 

             20     atomic test shots were not considered to be research 

             21     subjects for the most part.  And yet information was 

             22     gained about exposure to radiation from them in various 

             23     ways.  And this is just something -- I'm also on a 

             24     National Academy of Sciences panel on the dose 

             25     reconstruction of the atomic veterans exposures.  And 
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              1     this gives you a sense of where they were when at one 

              2     of the test shots, Shot Hood, 4:40 a.m., they were in 

              3     the trenches.  The bomb goes off at 4:55.  They do 

              4     double time, 2,000 marines in this case, to ground 

              5     zero.  They run around in ground zero for a couple of 

              6     minutes and then they go back to their landing zone 

              7     where they arrive by 7 a.m. 

              8               What were they doing there?  Well, they were 

              9     being trained.  They weren't human subjects.  And yet 

             10     the term "experiment" often appears in documents that 

             11     have been declassified, but not in medical experiment. 

             12               Ultimately the Nuremberg Code policy fails.  

             13     In many ways, and I'll simply summarize it by pointing 

             14     out, the Army Inspector General, himself determined in 

             15     1975 that there was a startling lack of consistency in 

             16     the interpretation of those regulations. 

             17               I'm not going to talk very much about Sidney 

             18     Gottlieb and the CIA except to say he also has a UVA 

             19     connection.  He died in the hospital about -- well, 

             20     when I was finishing my book, unbeknownst to me.  This 

             21     is one of the early MKULTRA documents that authorizes 

             22     the beginning of the LSD and other hallucinogenic 

             23     experiments.  You can see it's pretty heavily redacted, 

             24     still.  But it says enough to give us an idea what was 

             25     going on.  Gottlieb was in charge of the LSD 
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              1     experiments and also was the guy who developed the 

              2     botulin laced cigars that we tried to get in Fidel 

              3     Castro's mouth unsuccessfully. 

              4               This is Frank Olsen, the CIA Anthrax expert, 

              5     by the way.  He was an Anthrax expert during the second 

              6     World War.  Interestingly, he was assigned to Fort 

              7     Detrick, he was said to have been dosed with LSD and 

              8     the committed suicide -- because he was psychotic -- by 

              9     jumping out the 13th story of a hotel across from what 

             10     is now Penn Station.  This is his obituary.  I happen 

             11     to believe that he was -- in fact, that that was a 

             12     cover story, but we'll never entirely know the truth. 

             13               So the revelations of MKULTRA, the LSD 

             14     experiments influenced public support for new federal 

             15     requirements concerning human subjects research.  We 

             16     often forget that it wasn't only Tuskeegee and the 

             17     other -- we'll call civilian scandals -- it was also 

             18     the revelations of MKULTRA and the Army's LSD 

             19     experiments that led to these regulations. 

             20               And, incidentally, the relationship between 

             21     the -- what seemed to be the civilian experiments and 

             22     the military experiments turns out to be rather 

             23     complicated.  Can anybody tell me, for example, who 

             24     first provided the funding for the Hepatitis 

             25     experiments at Willow Brook?  
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              1               [No response.]  

              2               DR. MORENO:  1957, it was the Armed Forces 

              3     Epidemiologic Board.  So, although we think of sort of 

              4     the non -- the civilian pocket and the military pocket 

              5     to be distinct, in fact, there's a close and very 

              6     interesting relationship. 

              7               I'm not going to go through the rest of this. 

              8      There are a couple of nice images of one of my 

              9     favorite buildings, other than Mr. Jefferson's Rotunda, 

             10     also on the list of historic structures there is the 

             11     famous Eight Ball at Fort Detrick which you can still 

             12     go see.  It can't be torn down by law because it is on 

             13     the list of historic structures.  It's a million liter 

             14     cloud chamber that was used in the '50s and '60s to 

             15     conduct biological weapons experiments.  This is a 

             16     lovely plexiglass model of the Eight Ball that's on the 

             17     cover of my book.  You can see the portholes up there. 

             18      These are the dosimeters at the base of the eight 

             19     ball, checking the size and the nature and quantity of 

             20     the molecules.  What were they doing?  They were 

             21     inhaling Rick Valley Fever, Q Fever, Tularemia, 

             22     Venezuelan [inaudible] encephalitis, whatever happened 

             23     to be the agent of interest at the time.  Here are a 

             24     couple of the volunteers.  This is not a secret 

             25     experiment. 
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              1               These were Seventh Day Adventists, about 

              2     2,400 of them were used and volunteered between 1953 

              3     and 1972 with the enthusiastic cooperation of the SDA 

              4     church.  This is a copy of one of the pages of the 

              5     brochure that they disseminated -- the church 

              6     disseminated showing the -- they were called the "White 

              7     Coats."  This was part of a group called "Project White 

              8     Coat." 

              9               And I like the -- watching I Love Lucy in the 

             10     bottom picture on the old black and white TV, probably 

             11     the same one I watched. 

             12               There are reunions of the White Coats, like 

             13     the prisoners in the malaria experiment they are still 

             14     very proud of their participation.  Detrick will follow 

             15     -- Usamarit, I should say, will follow and monitor 

             16     their medical condition.  There is no validated 

             17     complaints relating to their exposures during the '50s 

             18     or '60s. 

             19               I am not going to run through all of the 

             20     Radiation Advisory Committee Findings, I've done that 

             21     before.  These are the recommendations.  I can show you 

             22     again later, if you like.  Essentially the conclusion 

             23     is that we are still waiting for the full 

             24     implementation of the recommendations for classified 

             25     research that were offered by -- in fact, accepted by 
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              1     the Clinton Administration which leads us to our 

              2     conversation today.  And so now I think we can move to 

              3     our guests. 

              4               CHAIRPERSON MARSHALL:  If Monica and John 

              5     could just come on up, we'd love to invite you both to 

              6     the table. 

              7               DR. MORENO:  So our first guest is Monica 

              8     Shoch-Spana.  Dr. Shoch-Spana is a senior fellow at the 

              9     Center for Civilian Biodefense Strategies at Johns 

             10     Hopkins University and we also welcome Dr. John 

             11     Livengood, Deputy Associate Director of Science or the 

             12     Centers for Disease Control and Prevention.  

             13               Dr. Shoch-Spana.  

             14               DR. SHOCH-SPANA:  Good morning.  I much 

             15     appreciate the invitation to present to the advisory 

             16     committee this morning and other individuals in the 

             17     audience.  

             18               I had a sneak peak at Dr. Livengood's 

             19     presentation, so I've tried to construct mine in such a 

             20     way so that it complements the information.  And I am 

             21     taking more the perspective of the needs of the 

             22     researcher in the aftermath of a bioterrorist incident. 

             23               And while that's being fired up, let me give 

             24     you an overview of the ideas I wanted to cover today.  

             25     First is just to review the urgency with which we 
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              1     should go about conducting research in the aftermath of 

              2     a bioterrorist incident.  The urgency is both of a 

              3     short-term and a long-term duration.  That does not 

              4     mean we put protections on the shelf.  What it means is 

              5     we need to look very carefully at our review mechanisms 

              6     such that we can provide full review of research so 

              7     that it can transpire in that particular context. 

              8               We also need to come back to issues of how to 

              9     define research in practice. 

             10               I want to talk about the timing of the impact 

             11     of research into the aftermath of a bioterrorist 

             12     incident and the different realms in which knowledge 

             13     can be put.  But there are certain imperatives in these 

             14     very different realms and I will go into that. 

             15               I want to talk very generally about whether 

             16     the current IRB universe in terms of it being a 

             17     practical regulatory structure, does it fit the needs 

             18     of biodefense in its current state? 

             19               I would like to illustrate some of those 

             20     generic observations with some concrete examples of our 

             21     experience at the Johns Hopkins Center for Civilian 

             22     Biodefense Studies.  They are very impressionistic, 

             23     anecdotal.  It's just us, but we think that they might 

             24     be reflective of some trends within the current IRB 

             25     structure.  And then a list of very, very preliminary 
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              1     recommendations or some thoughts on how the committee 

              2     should proceed. 

              3               [Simultaneous conversation.] 

              4               DR. SHOCH-SPANA:  This little machine, though 

              5     it is light, is very slow to wake up.  So let me just 

              6     jump in to talk about the exigency of research in the 

              7     aftermath of bioterrorism. 

              8               There were three compelling real reasons or 

              9     three compelling dimensions that speak to the urgency 

             10     of this type of generalizable knowledge.  The first is 

             11     the demonstrated vulnerability of U.S. civilians and 

             12     the global population to bioterrorism and other forms 

             13     of attack; and this was demonstrated last fall. 

             14               The second is that we have lived through a 

             15     bioterrorist incident that was incredibly disruptive, 

             16     even though there were few cases and few deaths.  But 

             17     in order to be proactive, we need to think about the 

             18     serious and growing dangers that bioweapons pose in 

             19     general.  That is, we can consider the fall of 2001 and 

             20     the problem with Anthrax dissemination as a prologue to 

             21     the problem.  That's why we need to think and act 

             22     proactively now. 

             23               And just very quickly the reasons why 

             24     bioweapons are a serious and growing danger, just to 

             25     recall things that have been covered and discussed very 
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              1     much in recent time is what they call the four Ds and 

              2     the V.  There is of course the destructive and 

              3     disruptive capacity of these weapons.  There's a whole 

              4     range of bioterrorist scenarios that cover hoaxes, what 

              5     we saw last fall which was a limited number of cases 

              6     and death, but incredible social disruption, and then 

              7     at the far end we have the potential for a catastrophic 

              8     outbreak of infectious disease and potentially a global 

              9     pandemic. 

             10               There's the dual use nature of these weapons. 

             11      The problem with bioweapons is that they have the 

             12     technology and the knowledge relevant to this type of 

             13     weapon has varied in legitimate uses such as beneficent 

             14     vaccine production.  It's very hard to control. 

             15               There's the issue of the desirability of 

             16     these weapons, the proven and growing demand for this 

             17     type of weapons capacity both among state actors and 

             18     non-state actors. 

             19               There's the fact that we're in the dawn of a 

             20     more potential bioweapons arsenal.  You have to 

             21     understand that we are now in the age of big biology.  

             22     And every leap in scientific knowledge of life 

             23     processes can be subverted.  We are looking at genomic 

             24     advances, enhanced computation power, and let us not 

             25     forget the entrepreneurial spirit of people in 
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              1     biotechnology.  So we are going to see incredible leaps 

              2     and bounds in our knowledge of biology which could 

              3     potentially be subverted to destructive ends.  And then 

              4     there's the issue of a global vulnerability to 

              5     infectious diseases should something be unleashed in 

              6     the population. 

              7               So we've got demonstrated vulnerability, a 

              8     growing problem with biological weapons at the third -- 

              9     and then thirdly we have an absence of relevant 

             10     knowledge to dealing with the aftermath of this type of 

             11     weapon. 

             12               And this is like something out of Star Trek. 

             13      Forgive me.   

             14               So that's so I can speak to the urgency of 

             15     this type of knowledge.   

             16               I did want to also just very simplistically 

             17     perhaps talk about the different realms in which 

             18     generalizable knowledge, just taking out the definition 

             19     of research, systematic investigation that contributes 

             20     to generalizable knowledge, there are three realms in 

             21     which knowledge of the aftermath of a bioterrorist 

             22     incident can have an effect.  Each of these realms has 

             23     different imperatives and also a different time cycle 

             24     embedded within it. 

             25               We have individuals such as political 
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              1     leaders, leaders in medicine and public health, public 

              2     health and safety institutions and the general public. 

              3      We have their interest in data, information, 

              4     knowledge, that can hance the immediate response to a 

              5     biological attack.  It's the type of feedback one would 

              6     need in trying to contain the medical and public health 

              7     effects of this type of weapon.  It's an immediate 

              8     need, for knowledge. 

              9               There is the realm of policy development 

             10     which can be -- can exist in a crisis context, in a 

             11     non-crisis context, but the temporal dimension of this 

             12     is tied to the policy decision-making cycles.  Okay.  

             13     Issues of budgets, issues of legislative sessions, and 

             14     more -- and different levels of government taking a 

             15     look at policy in terms of biodefense.  But it's a 

             16     different temporal dimension compared to emergency 

             17     response. 

             18               And then, thirdly, there's the realm of the 

             19     advancement of scientific knowledge which we could 

             20     think of as being the open-ended, iterative, 

             21     accumulation and advancement of scientific knowledge.  

             22               Now, these are not -- these realms are 

             23     connected to one another.  So it's a bit -- it's a 

             24     simplistic schematic, but I want you to think in terms 

             25     of the decision-making cycles that are inherent in 
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              1     these three different realms. 

              2               I think that it's probably easiest to imagine 

              3     the systematic investigation of the effects of medical 

              4     interventions as the type of research that we're 

              5     talking about.  But there's a wide range of potential 

              6     research scenarios in the aftermath of a bioterrorist 

              7     attack.  And these research emphases could incorporate 

              8     varying degrees of clinical, behavioral, social, and 

              9     political phenomena.  And the research subjects 

             10     themselves could range broadly and manifest different 

             11     thresholds and needs for protection. 

             12               I just wanted to throw up some concrete 

             13     examples of topics that have been discussed within the 

             14     biodefense community as research priorities so you get 

             15     a feel for the type of research ventures that have been 

             16     under way or are considered to be priorities.  

             17               We've talked about the efficacy of untested 

             18     medical regimens, I think Dr. Livengood can speak in 

             19     greater detail about that.  The mental health impacts 

             20     of bioterrorism, both of short- and long-term 

             21     durations.  Issues of effective strategies for leaders 

             22     and health officials in communicating with the public.  

             23               Let us recall that bioterrorism is an 

             24     instance in which we have the vagaries of infectious 

             25     disease mixed with a thinking enemy.  So we don't have 
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              1     baseline knowledge in which a great deal of it in which 

              2     to deal with this type of new phenomenon.  New -- 

              3     there's old and new aspects of this phenomenon, but in 

              4     terms of the higher-end effects of bioweapons we need 

              5     to think about this very seriously. 

              6               There's the issue of successful 

              7     organizational strategies in managing a biological 

              8     disaster.  Elements of community resiliency, this is a 

              9     priority for mental health professionals.  They want to 

             10     understand how it is that communities survive this 

             11     particular type of disaster.  And then also the social 

             12     and economic aftereffects of bioterrorism.  So that's a 

             13     range of potential topics that we're talking about. 

             14               Just some generic issues about the fit 

             15     between the current institutional review board process 

             16     and the priorities within biodefense.  I'm going to 

             17     illustrate these with some concrete examples of the 

             18     Johns Hopkins Center for Civilian Biodefense Studies 

             19     and our interaction with our local IRB, our 

             20     institutional review board. 

             21               Is the committee familiar with us?  Should I 

             22     give a few minutes --  

             23               DR. MORENO:  Give a little --  

             24               DR. SHOCH-SPANA:  Okay.  The Center was 

             25     founded in -- well, formally in September of 1998, 
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              1     although there were some meetings convened prior to 

              2     that time.  The founding director was D. A. Henderson 

              3     who is the current director of the Office of Public 

              4     Health Preparedness in Health and Human Services. 

              5               It was an enterprise or it is a joint 

              6     enterprise of the Schools of Medicine and Public 

              7     Health.  The mission of the Center is to prevent the 

              8     development and use of biological weapons, but should 

              9     prevention fail, we also want to arrest the human 

             10     suffering that is attendant with the effects of a 

             11     bioweapons, i.e., an epidemic. 

             12               Our objectives in carrying out that mission 

             13     are to raise awareness about the medical and public 

             14     health aspects of bioterrorism.   We needed to bring 

             15     medical and public health professionals to the table 

             16     because when the center was founded, that type of 

             17     expert knowledge was not adequately considered within 

             18     government programs to deal with the problem of 

             19     bioterrorism.  

             20               There was in the mid- to late-90s an 

             21     overemphasis on traditional first responders like fire 

             22     departments, search and rescue and police.  And there 

             23     wasn't enough of an effort to involve clinicians, 

             24     nurse, epidemiologists, infection control professionals 

             25     in this particular problem although their knowledge was 
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              1     most relevant to the health effects of an epidemic. 

              2               So we were attempting and continue to attempt 

              3     to raise awareness around bioweapons as a medical and 

              4     public health problem.  We also are interested in 

              5     building up the knowledge base related to biological 

              6     weapons response and prevention.  And we see ourselves 

              7     as trying to catalyze effective response systems to 

              8     deal with the after effects of a biological attack. 

              9               We are sort of -- I love this phrase -- "the 

             10     redheaded step child of the university" because we see 

             11     our constituents to include not only our peers in 

             12     medicine and public health, but policy makers.  We want 

             13     our knowledge to be relevant to the development of 

             14     national policy around prevention and response of -- 

             15     response to biological weapons.  So we may write for an 

             16     academic audience, or we may write to and speak to a 

             17     policy-driven audience as well. 

             18               So our academic peers have some difficulty 

             19     with us because we have this recognition of these 

             20     different cycles or these different realms with 

             21     different temporal dimensions and what effect our 

             22     knowledge production activities can have. 

             23               The IRB also looks at us as not your 

             24     traditional academic enterprise.  And we can come back 

             25     to that. 
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              1               Some of the generic issues that have been 

              2     raised about sort of the fit of the current IRB 

              3     structure is -- the problem of defining research versus 

              4     practice.  And we can discuss this.  I would rather -- 

              5     we can handle that in a question and answer session, 

              6     but the question of who and what activity gets 

              7     regulated, and the need to revisit -- need to revisit 

              8     definitions of research and practice.  Distinguishing 

              9     these does not mean removing protections for human 

             10     subjects, but we do need to go back to how it is we 

             11     have structured our review processes about protecting 

             12     human subjects. 

             13               The issue of benefits and risks.  There's the 

             14     preeminent moral status of the individual, of the 

             15     protections that have been put into place often times 

             16     in a reaction to biomedical, the reactions to problems 

             17     in the biomedical realm, certainly not exclusively, but 

             18     others have commented on the hegemony of the biomedical 

             19     model of IRB review.  And we can come back to that. 

             20               But there's also a larger trend.  So the 

             21     biomedical emphasis on the individual and then through 

             22     the IRB emphasis on protecting the individual.  That's 

             23     a more complicated issue but we can come back to that. 

             24               But I guess there's more -- that issue is 

             25     also tied up within, I guess, a larger cultural process 
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              1     in the United States of possibly a move toward zero 

              2     tolerance of individual risk in our highly litigious 

              3     society at the expense of any value placed on societal 

              4     benefits.  With regard to biological weapons, we are 

              5     looking at a population-wide impact.  We need to 

              6     revisit the question, what is at stake in the knowledge 

              7     that is produced and used regarding bioweapons 

              8     prevention and response. 

              9               In terms of the IRB review process, the 

             10     aspect that we've run into is the potentially 

             11     inflexibility of this review process in time-sensitive 

             12     contexts.  And some examples of that are, or issues 

             13     related to that is, the ephemeral nature of phenomena 

             14     being studied in the crisis context.   So there's a 

             15     need for -- felt among some researchers -- to get to 

             16     the field -- the research field as soon as possible 

             17     because of the transient nature of what is being 

             18     studied. 

             19               All we have to do is to think back to our own 

             20     personal states of mind and behaviors immediately post-

             21     911 and October 4th when we heard about the first 

             22     inhalational Anthrax death to recall that it is a 

             23     different social, political, economic, and 

             24     psychological environment.  So there's an ephemeral 

             25     nature to that crisis context. 
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              1               There's the issue of the research cycle as 

              2     it's currently constructed and there's an emphasis on 

              3     that third realm, the open-ended, iterative production 

              4     of scientific knowledge that perhaps IRB and -- I'm 

              5     just going to speak in gross, broad generalization, so 

              6     please forgive me -- but that our notion of research, 

              7     research protections is tied to that more lengthier 

              8     decision-making cycle and the sense of our knowledge 

              9     base in general, not as it's used in policy development 

             10     or in emergency response.  But we have to realize that 

             11     with this particular topic there are critical windows 

             12     of opportunity for change in the world that will be of 

             13     benefit to society, both in terms of emergency response 

             14     and in terms of policy development.  

             15               So we need to go back and think, is there 

             16     anything within the current structure of the IRB review 

             17     process that might impede the benefit of the knowledge 

             18     produced in the aftermath of a bioterrorist incident. 

             19               And then lastly there's these two -- and, 

             20     again, very impressionistic.  It's been our very 

             21     limited experience that at least our IRB is very -- 

             22     gets a little jittery when issues of bioweapons and 

             23     national security come before them.  So you can call it 

             24     sort of the -- in bioweapons you have to understand, 

             25     they are -- it is a taboo and has been a taboo subject 
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              1     in the academic setting.  So when we submit things to 

              2     the IRB, we have little red flags going up because we 

              3     are now moving into controversial waters.  We talk 

              4     about national security and we sit in a school of 

              5     public health and it really makes the institution as a 

              6     whole uncomfortable, but also the IRB. 

              7               But it makes all of us here today 

              8     uncomfortable.  We're in a new world.  There are risks 

              9     in our world related to bioweapons. 

             10               These generic issues come out of our 

             11     experiences -- and I'll just go through this quickly 

             12     because I would love to hear from Dr. Livengood myself. 

             13      But I wanted to bring examples of three -- oh, I have 

             14     plenty of time.  Okay.  There are three projects that 

             15     have been conducted or are currently being conducted 

             16     that sort of speak to these generic issues.  We have a 

             17     project we call the "Anthrax Chronicles."  And this is 

             18     an attempt to talk to public health, medical and 

             19     administrative experts who had direct involvement in 

             20     response to the anthrax dissemination crisis last fall. 

             21      In order to derive lessons learned that impinge on the 

             22     interactions between the realm of public health and 

             23     medicine.  We want to understand what went well.  What 

             24     didn't go so well in terms of the exchanges of 

             25     information across these two realms during that 
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              1     critical moment in responding to this bioterrorist 

              2     emergency. 

              3               And I've mentioned who the research subjects 

              4     are.  It is -- these are open-ended semistructured 

              5     interviews.  Most of them over the telephone, some in 

              6     person. 

              7               Some of the issues that came to the fore with 

              8     this particular project.  The Biodefense Center 

              9     originally approached this project as a form of 

             10     practice.  That is, we were speaking to peers in 

             11     medicine and public health about their experiences 

             12     during this crisis. 

             13               Again, just to speak to the unusual quality 

             14     of the biodefense center.  We're in an academic 

             15     institution, we try and effect national policy, and 

             16     during this crisis we went operational.  Okay.  People 

             17     were desperate for information about how you could -- 

             18     how you responded to this type of medical and public 

             19     health emergency.  They were calling us for basic 

             20     information, clinical management of inhalational 

             21     Anthrax, how you run a hospital in this type of 

             22     setting.  Calls from the general public about, do I go 

             23     buy a gas mask, or do I need to stockpile cipro. 

             24               So you have to understand, we were 

             25     transformed in this moment and became operational.  So 
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              1     I just want you to understand the blurring of the 

              2     boundaries that occurs.  During this type of -- in this 

              3     crisis context because it happened to us.  

              4               So when we originally approached this 

              5     project, we considered it practice.  That is, 

              6     practitioners talking to practitioners trying to 

              7     understand wht happened so that we could then help 

              8     precipitate guidance to our peers our peers in medicine 

              9     and public health and to also inform policy.  But then 

             10     we sort of stepped back and said, well, you know, this 

             11     reeks of research.  And we are systematically 

             12     collecting information.  Perhaps we need to go to the 

             13     IRB.  So we did.  And wht did we find when we went 

             14     there?  Well, people -- well, at Hopkins I think we all 

             15     realized --  

             16               [Laughter.]  

             17               DR. SHOCH-SPANA:  -- the pressures that have 

             18     been placed on the Hopkins institution as a whole and 

             19     in particular its IRB and its principal investigators 

             20     and so on.  Anyway so everyone is on high alert.  High 

             21     alert about IRB-related matters. 

             22               But what we encountered when we went through 

             23     the review process these are two things that came up, 

             24     sort of the issue of the balance between individual 

             25     protections and the societal benefits of this type of 
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              1     inquiry.  And the IRB, to its credit, gave due 

              2     diligence to the protection of research subjects.  You 

              3     will recall that the research subjects are medical, 

              4     public health, and administrative experts.  Okay.  

              5     People who held positions of authority and who were 

              6     responsible for protecting public health and safety. 

              7               The IRB was very concerned though about the 

              8     potential.  This is one risk.  Our priority risk was 

              9     the potential for some research subjects -- the 

             10     potential for the job loss due to sort of the 

             11     whistleblower effect.  Should someone, even though 

             12     holding a position of authority, say something that 

             13     indicated that there was an egregious error 

             14     particularly of the preventable kind that might have 

             15     had some impact.  Not just on the credibility of the 

             16     institution, but down the road someone could see it as 

             17     somehow affecting the morbidity and mortality rates 

             18     that transpired during this period.  So the IRB did 

             19     practice due diligence about making sure that we 

             20     thought through the potential risks to this highly 

             21     placed research subject population. 

             22               That emphasis though on protecting these very 

             23     well placed individuals in addition to recommendation 

             24     that we get a certificate of confidentiality so that we 

             25     wouldn't be compelled to turn over our raw data, 
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              1     perhaps indicates a tendency -- this is not passing 

              2     judgment.  I'm just trying to find some transfer 

              3     discussion that the tendency to elevate individual 

              4     protections above the population's benefit of public 

              5     health advances and improved public policy. 

              6               We must return to questions of relative risks 

              7     and benefit.  And so that's the Anthrax chronicles.  

              8               It took seven weeks, maybe this is speedy in 

              9     the world of the IRB.  But it took about seven weeks 

             10     with multiple phone calls and e-mail exchanges, a 

             11     little nudge here and there to get this expedited 

             12     review of the project. 

             13               So there was the delay in beginning research 

             14     into this timely topic.  Again, just to reference back 

             15     to the ephemeral nature of responses in the crisis 

             16     context and a delay in beginning research into a topic 

             17     with immediate relevance, immediate relevance to 

             18     national policy development.  We've just allocated $1.1 

             19     billion to state and local health departments in order 

             20     to improve response to bioterrorism incidents. 

             21               That's a lot of money with good directions 

             22     coming out of HHS.  But that's just so you understand 

             23     the context, the policy context for this type of 

             24     information. 

             25               One has to just sort of compare the 
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              1     constraints upon researchers of the academic kind to 

              2     researchers of the journalist kind and the incredible 

              3     impact that their generalizable knowledge has upon 

              4     policy development in the United States.  Again, we're 

              5     not advocating for reduced protections for human 

              6     subjects.  But we need to understand the -- again, 

              7     these different time cycles for impact of bioterrorism-

              8     related knowledge.  

              9               How are we doing on time?  Fine?  Okay. 

             10               Another project, this one is still going 

             11     through review.  It was first submitted in January, the 

             12     beginning of January.  We call it the "persephone 

             13     effect," but let me give you the more boring title.  

             14     Arresting biological weapons development self 

             15     governance for the bioscience community.  The purpose 

             16     of this project is to try and analyze and posit 

             17     possible new governance models for biological science 

             18     that would diminish the risk of beneficent science 

             19     being misused by others in order to further bioweapons 

             20     research or development. 

             21               Now, this is not per se research in to the 

             22     immediate aftermath of the bioterrorist incident.  I 

             23     bring this case study to you today because it speaks to 

             24     sort of the IRB discomfort with potentially 

             25     controversial issues in those that overlap with 
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              1     national security.  Basically we want to talk to 

              2     biological researchers about their own concerns about 

              3     the subversion of beneficent biological research to 

              4     destructive purposes.  There is black -- so-called 

              5     black science out there, that is, scientific knowledge 

              6     that is deliberately produced for the purpose of 

              7     improving bioweapons, okay.  So that's just -- the 

              8     commitment is to using technical expertise to build a 

              9     better bioweapons. 

             10               The persephone effect is about this gray area 

             11     that speaks to the dual-use nature of biotechnology and 

             12     the potential now applications of scientific knowledge 

             13     and biotechnology that has been produced for beneficent 

             14     purposes. 

             15               So we wanted to talk with scientists about 

             16     their own concerns about that, the persephone effect, 

             17     if you remember your Greek mythology, persephone was 

             18     picking flowers one day and stolen away and taken to 

             19     Haites and was allowed to return to earth on for part 

             20     of the year.  So we're talking about the capture of 

             21     good science for bad purposes.  So we're talking to 

             22     scientists about that and their own ideas about models 

             23     of governance for the scientific community. 

             24               Superficially, it looked like a pretty simple 

             25     project.  We're talking about the conversations with 
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              1     very highly placed individuals about their publicly 

              2     available research which we found by using just 

              3     google.com and the regular internet search engines, 

              4     tenured professors, heads of academies of thus and so. 

              5      So those are our research subjects.  

              6               The IRB, again, was exercising due diligence 

              7     about protecting research subjects.  Concerns over, for 

              8     instance, if we sort of fingered someone whose research 

              9     could potentially be misused, that perhaps the FBI 

             10     would be interested in scrutinizing their potentially 

             11     criminal acts related to controls over special agents 

             12     and such.  But there was concern over potential 

             13     scrutiny of this research subject population by figures 

             14     in law enforcement. 

             15               The potential loss of respect, credibility 

             16     and reputation in the field.  If someone was seen as an 

             17     unintentional perpetrator of bioterrorism, perhaps. 

             18               These are very high stakes inquiries and we, 

             19     again, wanted as much attention paid to the societal 

             20     benefits of this type of research as was given to 

             21     individual protections for the research subjects.  

             22     Again, a very highly placed population, again, 

             23     vulnerable to certain things.  And I've spoken to the 

             24     bioweapons taboo.  The title made a lot of people, we 

             25     heard, indirectly that the title seemed to be 
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              1     unsettling for members of the IRB, arresting bioweapons 

              2     development.  They thought we were actually going out 

              3     to investigate biological researchers about their own 

              4     perpetration of this type of bad or black science. 

              5               Interestingly, there was another -- there is 

              6     another research team out there in the world who is 

              7     doing the very same type of inquiry.  They, however, 

              8     don't come from a medical and public health 

              9     perspective.  They come from a political science 

             10     perspective.  It never crossed their minds.  In fact, 

             11     they were floored that we had gone through IRB.  It 

             12     never crossed their minds that their parallel inquiry 

             13     might need to be subjected to review by their local 

             14     IRB.  And this speaks to, again, just the generic 

             15     issues within the overall universe of IRB-related 

             16     matters, is the different approaches within various 

             17     professions about human subjects protection.  

             18               Now, I come from cultural anthropology and we 

             19     have our own ethical legacy about how it is one goes 

             20     about protecting our research subjects.  It does not 

             21     always overlap.  It does not overlap 100 percent with 

             22     what I see within my medical and public health 

             23     colleagues.  And I know that there are some -- there 

             24     are issues of whether social and -- you guys deal with 

             25     this more than I do, but I just want to point out that, 
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              1     again, we have that generic issue coming up in this 

              2     particular realm.  

              3               And then just lastly, one last case study 

              4     which is the people's role.  The people's role refers 

              5     to our interest of the biodefense center in helping 

              6     inform policy about the need to create a positive and 

              7     constructive role for the public in responding to 

              8     bioterrorism.  There is a tendency to sort of think of 

              9     the public as either a passive population who is just 

             10     going to do what it's told by authorities or a rock-

             11     throwing mob who is not going to do anything it's told 

             12     and it's going to use violence to acquire scarce 

             13     medical resources like antibiotics and vaccines.  So 

             14     these very simplistic stereotypical notions of what the 

             15     public is capable of doing in the aftermath of a 

             16     bioterrorist incident.  So we are interested in 

             17     speaking to the capacity for constructive reactions and 

             18     the need to take them in consideration in our response 

             19     systems not just to worry exclusively about negative 

             20     psychological and social impacts.  This is about 

             21     empowering the public, empowering the people to help 

             22     stop the effects of a bioweapons attack. 

             23               So to that end we led a rapid response 

             24     research team up to New York to study the local 

             25     humanitarian response to the World Trade Center tower 
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              1     attack.  We were interested in the way in which from a 

              2     manager's perspective volunteers were being organized 

              3     or were not being organized in such a way to enhance 

              4     the emergency response to this problem. 

              5               The subjects in that case were more 

              6     individuals at the managerial level.  Because we were 

              7     allowed to do observation, there were indirect -- sort 

              8     of the volunteers who were being organized by these 

              9     managers, but that was strictly in an observational 

             10     mode.  We had an emergency expedited review.  And I use 

             11     the word "emergency," but it was given an expedited as 

             12     in timely review.  And that was a successful 

             13     interaction with the IRB.  

             14               In subsequent interactions with the IRB, 

             15     we've talked about the generic need.  No one expected 

             16     911 and the need for us to go so quickly to the field 

             17     to study a phenomenon.  We just didn't anticipate that. 

             18               But now that we know that that's altogether 

             19     possible, that we could face another attack, that we 

             20     wanted to take proactive steps with the IRB so that 

             21     they understood that we wanted that capacity to respond 

             22     rapidly from a research perspective.  So we've had 

             23     conversations with them and we've talked about several 

             24     solutions, one of which is if it is more in the realm 

             25     of practice, not systematic, but more practitioner-to-
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              1     practitioner gathering of information.  And, again, 

              2     this is sort of vague. 

              3               There's been no actions on this, it's just 

              4     sort of preliminary conversations.  There's that, 

              5     talked about that, what constitutes research and what 

              6     needs to be regulated.  The issue of potentially having 

              7     the IRB review a generic proposal where we talk about 

              8     the types of bioterrorist incidents we would like to 

              9     respond to rapidly, the types of research subjects we 

             10     anticipate encountering, the types of research 

             11     methodologies and so on.  

             12               I'm very sort of everything in the kitchen 

             13     sink, everything that we could anticipate.  There's 

             14     that possibility and then also they're agreeing to 

             15     allow for an emergency -- again, an emergency expedited 

             16     review of a project. 

             17               Now, these are the options that we've talked 

             18     about.  But interestingly we find that -- and, again, 

             19     we typically go through the school of public health 

             20     IRB.  There is not a whole lot of familiarity with 

             21     rapid response teams.  And I draw a comparison to the 

             22     University of Delaware which has the Delaware Disaster 

             23     Research Center where their IRB works with the DRC in 

             24     both emergency reviews and then these more sort of 

             25     generic, on-the-shelf approvals that can get activated 
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              1     when a disaster goes down. 

              2               Our IRB is not familiar with that type of 

              3     concept.  We've had to engage in a lot of education 

              4     about that.  I don't know about other IRBs, but that's 

              5     something that's come up with ours.  So just to 

              6     conclude and thank you for your time today. 

              7               We need to clarify realms of research and 

              8     practice and applicable protections. 

              9               The need to recognize the qualitatively 

             10     different realms in which bioterrorism-related research 

             11     can have an impact. 

             12               Okay.  Emergency response policy development 

             13     and the advancement of scientific knowledge.  

             14               We need to readdress our social approaches 

             15     and our institutional approaches to balancing 

             16     individual protections and societal gains.  Okay. 

             17               And, again, that's in the context of this 

             18     increasing tendency towards zero tolerance of risks.  

             19     And it's just not in the IRB realm.  Okay.  It's out in 

             20     our culture.  And the need to articulate, it's 

             21     incumbent upon researchers in biodefense to articulate 

             22     very well the societal benefits of their ventures.  

             23               We need our review institutions to think 

             24     about the balance of these two things and the way in 

             25     which we allow for a good balance. 
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              1               And lastly, to consider guidance to local 

              2     IRBs on the time sensitive nature of research in the 

              3     aftermath of a bioterrorist incident.  Speaking to 

              4     things such as rapid response, the needs of rapid 

              5     response research and how to facilitate that.  And 

              6     that's just one concrete example.  

              7               Thank you very much.  

              8               [Applause.]  

              9               DR. MORENO:  Thank you very much.  

             10               Dr. Livengood.  

             11               DR. LIVENGOOD:  Thank you.  I'm glad to be 

             12     here this morning. 

             13               My presentation is going to be somewhat of a 

             14     different focus, because, after all, I work for the 

             15     Centers for Disease Control and Prevention, the 

             16     nation's public health agency.  I am very happy and 

             17     proud to be a public health practitioner where I've 

             18     spent basically my entire career since I finished my 

             19     pediatrics training.  And where I also supervise, as 

             20     part of my functions, the Human Research Protection 

             21     Program at CDC.  

             22               So very much the types of things that I'm 

             23     going to talk about I think meld very well with what 

             24     was covered previously, but try to illustrate it in 

             25     terms of the practical examples that we have recently 
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              1     or are currently facing in trying to address dealing 

              2     with some of these issues in the potential context of 

              3     bioterrorism.  

              4               As soon as they get the things up we'll 

              5     start. 

              6               What I'm going to talk a little bit, just a 

              7     little bit of context because, after all, I think 

              8     everyone here realizes what the context is, these 

              9     things changed recently and things are different and 

             10     probably will never go back to the way they were 

             11     previously. 

             12               I'm going to provide you a little bit of 

             13     background on some of the agents, just for familiarity. 

             14      I'm not an expert on Anthrax.  I am somewhat more of 

             15     an expert on vaccines, that being my particular 

             16     background.  But I'm not from the part of the Agency 

             17     that has the technical knowledge about these.  I'm 

             18     going to try to be talking about the human subjects 

             19     issues as they presented themselves to us at CDC. 

             20               And I think the issues that I'm most going to 

             21     spend my time on are two.  One of which was already 

             22     quite some covered, so I'll try to be a little briefer 

             23     on that part, and that has to do about whether what 

             24     you're doing is research or it is not research, it is 

             25     practice.  It is something you are doing.  And that's a 
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              1     very hard concept in many ways in some of the 

              2     permutations such as we faced recently. 

              3               The second one I'd like to talk about a 

              4     little bit as well is the process by which you can 

              5     obtain voluntary informed consent in the middle of an 

              6     emergency.  It's almost a contradiction in terms to be 

              7     in that type of sitting to have subjects who you know 

              8     are participants who are being torn by a lot of 

              9     different conflicts and, you know, to be in a position 

             10     of showing them an eight-page consent form written at 

             11     the 12-plus-grade reading level because lots of people 

             12     have been involved in drafting it and to think that 

             13     that is, in fact, obtaining informed consent from 

             14     people because you may be complying with the legalistic 

             15     regulations on these. 

             16               I'm going to talk a little bit about the 

             17     implications of some of these things, in particular 

             18     with the several examples.  The two main examples, 

             19     although I do have a third one I'll talk a little bit 

             20     about if we don't run on too much are anthrax and small 

             21     pox.  I think those are the two things most in the 

             22     news, most current in terms of people's thinking on 

             23     this issue and we'll be glad to deal with that as well. 

             24               I'm going to try to spend a brief period of 

             25     time talking about some of the lessons I think we've 
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              1     learned.  And if some of you read Monica's paper in 

              2     advance, let me tell you, the lessons learned are out 

              3     there.  They're pretty broad, but they're important 

              4     because you run up against them all the time.  And then 

              5     I'm going to end up a little bit with just a summary at 

              6     the end where hopefully can lead into some discussions 

              7     and answer questions from the group here.  And that 

              8     might build on some of the examples as well. 

              9               Okay.  Going on with the context.  I mean, 

             10     after September 11th lots of things changed.  I mean, 

             11     the world was different for us.  Preparedness which had 

             12     been something CDC had been funded somewhat to do, but 

             13     it became reinvigorated.  Suddenly it was much more 

             14     important to be prepared, to know what the responses 

             15     would be.  A lot more detail took what had been an 

             16     activity, but activity more at the planning level of 

             17     how do we ship emergency supplies here or there, very 

             18     much at the logistical level and not so much at the 

             19     scientific or human subjects level.  

             20               And then once the anthrax activities happened 

             21     shortly thereafter, bioterrorism became a real world 

             22     event again.  Because, after all, this was the second 

             23     bioterrorism event in the United States which I mention 

             24     for both personal reasons and for background reasons as 

             25     well. 
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              1               And I think it was quite clear you said 

              2     earlier, the impact went way beyond the unfortunate 

              3     people who became sick or died due to anthrax or even 

              4     the thousands of people who took antimicrobial 

              5     prophylaxes during that time.  The effect was 

              6     incredibly widespread.  I mean, many more people, many 

              7     more children died during this time interval from not 

              8     wearing their bicycle helmets.  I mean, there's just -- 

              9     but that's not the story, anthrax is the story.  So to 

             10     some extent I think we need to deal with that. 

             11               Okay.  The previous bioterror attack, since I 

             12     mentioned that.  Many of you may remember that 

             13     followers of the Bagwan Sri Rajniche [ph] intentionally 

             14     poisoned salad bars in Dows, Oregon in 1984.  They were 

             15     doing this to try to create terror in the community but 

             16     also if they could incapacitate a large enough 

             17     proportion of the county voters, most of whom resided 

             18     in the Dows, they could vote and take over the county 

             19     government.  This was a dry-run, if you will, during 

             20     September for what was anticipated to be an attempt to 

             21     take over the county government because the county 

             22     government had been very hostile to them. 

             23               I know because I was the epidemic 

             24     intelligence surface officer assigned to Oregon in 

             25     1983-85, and although I was out of the country when 
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              1     this happened, it's somewhat of a thing, and it has 

              2     been published in JAMA and some of the other places.  

              3     Because until recently it was the only documented 

              4     attempt ever to have a bioterrorist. 

              5               Some of the lessons learned from the talks I 

              6     gave after that are the same lessons we are now 

              7     relearning again, by the way.  And you've already heard 

              8     some of them referred to. 

              9               Let me go back one, I'm sorry.  Can you go 

             10     back two, please? 

             11               Some of the funding for -- back one more, 

             12     please.  Thanks. 

             13               The funding for -- that come in primarily 

             14     went towards building a national pharmaceutical 

             15     stockpile.  There's a lot of different antibiotics and 

             16     things that -- it was already stressed, even during 

             17     this interval, but has been subsequently greatly 

             18     expanded.  A laboratory response network was 

             19     established whereby many state labs had added reagents 

             20     and added a detection capacity for bioterrorist agents, 

             21     and they played a role in this detection of this 

             22     outbreak.  State and local bioterrorism plans were 

             23     developed, but funds were not made available to 

             24     actually implement any of those until the cooperative 

             25     agreement funds that are now in the process of being 
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              1     reviewed at CDC. 

              2               And they developed a series, I believe, of 

              3     eight, what they called, "push packs" which were huge 

              4     collections of supplies and materials that might be 

              5     needed in a bioterrorist thing and they were 

              6     distributed -- "predeployed," I think, is the word 

              7     around the country.  

              8               But there was relatively limited staffing 

              9     provided for people so things that are in fact very 

             10     resource intensive in terms of human resources such as 

             11     writing draft consent forms, getting IRB approval for 

             12     things, talking with the FDA about what would need to 

             13     be done for various investigational new drug or new 

             14     device exemptions were not actually being done in 

             15     advance.  Though were being done, but not in a complete 

             16     way. 

             17               I've got to learn to pause each time after 

             18     it. 

             19               I want to talk briefly, and very briefly just 

             20     about the agents and the interventions because as some 

             21     of these things come up, it might be helpful to have -- 

             22     back one, please. 

             23               First anthrax.  Anthrax is a bacteria.  That 

             24     means certain things about it in terms of its 

             25     prevention and control.  The disease takes several 
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              1     forms from relatively benign forms such as cutaneous 

              2     anthrax to relatively more severe or deadly forms such 

              3     as inhalational anthrax.  The anthrax bacterium itself 

              4     naturally occurs in environment, although certainly one 

              5     wouldn't expect a background detection of anthrax in a 

              6     Florida office or a Senate thing, there are places in 

              7     the United States where you do find it in the soil and 

              8     there are naturally occurring anthrax cases in the 

              9     United States. 

             10               And it's not transmissible from person to 

             11     person.  It is more similar in some ways to a chemical 

             12     agent than an actual infectious agent that transmits 

             13     from person to person.  You're either exposed or you're 

             14     not exposed generally at that time. 

             15               Small pox is very much different in that it's 

             16     a virus.  There is no natural small pox anywhere in the 

             17     world.  Small pox is the only disease humans have ever 

             18     intentionally eradicated from the face of the earth and 

             19     it remains a great public health irony that we spend so 

             20     much time preparing about and talking about new vaccine 

             21     development, talking about a lot of expense put into 

             22     the only thing that in fact we supposedly have already 

             23     eliminated from the face of the earth.  It is 

             24     transmissible from person to person.  That's how it's 

             25     transmitted.  That's the very nature of the thing.  So 
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              1     it has a lot of attributes that would make it very 

              2     different from what we actually observed in terms of 

              3     the anthrax.  

              4               In terms of treatment and prevention you've 

              5     got various modes you could use.  Antibiotics are quite 

              6     good for both the treatment and the prevention, a 

              7     preventive prophylaxis to anthrax.  You have antiviral 

              8     agents which are probably not as well documented at 

              9     this point, but certainly are under investigation for 

             10     potential treatment of small pox or for use, perhaps, 

             11     as opposed to exposure prophylaxis. 

             12               You have vaccines for both of these diseases, 

             13     both of which have certain considerations about them.  

             14     Vaccines for pre-exposure, that is something you would 

             15     give to somebody before they were exposed to prevent 

             16     them from contracting disease should they come down 

             17     with it, as well as vaccines you can give after 

             18     exposure to moderate or reduce the risk of disease. 

             19               There's issues around the detection and 

             20     diagnosis of these things.  These reagents are not in 

             21     common use.  CDC frequently in this situation produces 

             22     reagents which they ship around the United States.  But 

             23     clearly until recently it was thought that there would 

             24     never be any market for an actual test kit that could 

             25     detect anthrax in the regular hospital laboratory, or 
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              1     could detect anthrax spores in the environment. 

              2               Both of these have different issues around 

              3     isolation, doing things with buildings to prevent 

              4     subsequent exposure or even moving on to maybe the old 

              5     line public health intervention of considering 

              6     quarantine of people who were exposed or have these 

              7     diseases that play a role as well. 

              8               A point that was made previously and I would 

              9     like to reiterate here is the information on the 

             10     natural disease was actually of limited applicability 

             11     in this setting.  One of the things that came up in 

             12     writing the anthrax consent form, as we had to explain 

             13     so many things that we did not know, we don't know 

             14     this, we don't know that, and, you know, we got 

             15     questions saying, well, why don't you know that.  It's 

             16     because this had never happened before.  This is not 

             17     how natural anthrax was transmitted in the United 

             18     States.  This was not the natural form of the bacteria. 

             19               So this was very much a different route of 

             20     exposure in doses that frankly were not even 

             21     anticipated in the military in terms of protection.  

             22     The staff members in Senator Daschle's office were 

             23     exposed to huge numbers of spores, beyond that which we 

             24     had ever even seen modeled in military battlefield 

             25     exposures.  This was a completely different situation 
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              1     in many cases than what we anticipated.  And, for many 

              2     of these things, you know --  

              3               DR. R. LEVINE:  You're talking about 

              4     developing a consent form.  What are you having -- what 

              5     aspect of your studies is this?  Is this a vaccine 

              6     trial or what?  

              7               DR. LIVENGOOD:  Where we'll end up with this 

              8     is the consent form that was actually used in making 

              9     the vaccine available to people who had been exposed 

             10     and the late period post-exposure.  That's where we'll 

             11     end up.  Although there is a little bit, as you know, 

             12     about research that's ongoing in this area as well. 

             13               For small pox and to some extent for anthrax, 

             14     the information that's available is dated, it's not 

             15     current.  I mean, we talk about what the death rate 

             16     from small pox would be, but do we really know what it 

             17     would be in a modern hospital setting with different 

             18     things and other impacts. 

             19               And the prevention or the treatments in this 

             20     case were limited.  Some cases, actual physical 

             21     availability.  Anthrax vaccine had had regulatory 

             22     problems, was not actually available outside of the 

             23     military sector at the time that this procedure began. 

             24     And they all had regulatory limitations, and by that I 

             25     mean, limitations, unlicensed uses, use of coverage 
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              1     under FDA regulations that also is a source of a 

              2     challenge that we go over. 

              3               Human protection issues.  Again, we've talked 

              4     whether it's research or not research.  In some 

              5     settings, clearly we want to do research and some 

              6     settings we are clearly not interested in doing 

              7     research at all.  Some settings we actually have two 

              8     desires we might want to do.  And I'll try to give a 

              9     brief illustration of that.  But generalizable 

             10     knowledge is what we're talking about here when we're 

             11     using the term "research" because we're trying to deal 

             12     with the context of being a federal agency and subject 

             13     to 45 C.F.R. 46 and the subparts. 

             14               But how does that differ from when you're in 

             15     an emergency response situation where you're trying to 

             16     crisis -- respond to a crisis, per se, right there but 

             17     the desire is not in any way, perhaps to develop 

             18     generalizable knowledge?  It is possible that 

             19     subsequently generalizable knowledge might be derived 

             20     from the information that happened during this time 

             21     interval, but that's not the focus of actual thing. 

             22               The second issue I mentioned before in the 

             23     informed consent process how do you inform people and 

             24     obtain consent in this type of setting?  And how can 

             25     you deal with the issue of trying to obtain voluntary 
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              1     informed consent when in fact somebody's choice to or 

              2     not take a vaccine such as in the case of small pox 

              3     might also impact on the decision of whether or not 

              4     they're going to be allowed to go home, or whether 

              5     they're going to get an all-expense-paid holiday 

              6     courtesy of the federal government in some beautiful 

              7     location yet to be specified on the outskirts of town? 

              8               I mean, I think that those types of concerns 

              9     have to be brought to people's attention, but it is 

             10     very different from the way -- and particularly most 

             11     IRBs -- would look at a consent form.  And, you know, 

             12     you're not -- you don't suffer any loss of rights or 

             13     benefits to which you might otherwise be entitled, but 

             14     you may not go home if you say no.  Actually, you may 

             15     not go home if you say yes too in some settings with 

             16     small pox.  So it is fairly complicated. 

             17               What do we do in this setting for treatment 

             18     of adverse events?  I mean, no vaccine, as I used to 

             19     say, in many a talk is perfectly safe or perfectly 

             20     effective.  No antibiotic is perfectly safe.  Moreover, 

             21     what do you do in terms of treating people for 

             22     potential adverse events that they might have because 

             23     of this or compensation should they have lingering 

             24     events or be unable to work or some of those issues?  

             25     That was quite a big concern as we went forward in 
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              1     this. 

              2               And then a whole series of regulatory 

              3     concerns which I think we will cover as well. 

              4               With the implications for research, by 

              5     "research" here I really mean the research definition 

              6     which means that this will be subject to 45 C.F.R. 46 

              7     and the provisions of that.  Why would that be an issue 

              8     for us?  Well, when you're looking at something like an 

              9     emergency response where I do not know today where the 

             10     vaccine program will be established, will it be in a 

             11     school, will it be in a hospital, will it be in a local 

             12     health department, you have a lot of issues around 

             13     performance sites.  We don't know where those sites 

             14     are.  We don't know where they'll be. 

             15               How will we get local IRB review in all these 

             16     sites overnight before we do things? 

             17               And then there's the issue of assurances and 

             18     compliance which since most of the settings in the 

             19     public health do not have pre-existing assurances at 

             20     this time, at the local level.  That we would have to 

             21     also get assurances of compliance.  And, also, too, in 

             22     many of these things there are required elements of 

             23     consent, one of which would be to tell people it's 

             24     research.  But if it's your supposition that what 

             25     you're doing is emergency response and it is not 
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              1     research, then you get a consent form where you have to 

              2     include the words "you are free to participate or not 

              3     in this research."  You must use the word there.  

              4               There were a lot of implications separate 

              5     from the research, non-research determination here 

              6     because these products were subject to FDA regulation. 

              7      And as I believe most of you know, clearly it makes no 

              8     difference whether it's research or not if you're using 

              9     an FDA-regulated article in a way subject to regulation 

             10     you are subject to the regulations and it doesn't make 

             11     any difference what your intent or your purpose is. 

             12               So we attempted to conduct this emergency 

             13     response and be responsive to the FDA regulatory 

             14     requirements.  

             15               One of the questions here would be how to 

             16     make a determination that is appropriate to the 

             17     situation when the goal of this emergency response is 

             18     to make available a treatment or a prevention to people 

             19     that for whatever reason is not otherwise available or 

             20     licensed for that in the United States. 

             21               Some of the implications for the consent 

             22     process.  I have already talked a bit about the 

             23     voluntary nature of this.  And it's very difficult 

             24     because in public health a lot of what we deal with is 

             25     a balance between both the individual rights and the 
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              1     rights of the community and the population as a whole. 

              2      We very much see ourselves as caring for the 

              3     population as if the entire population were our 

              4     patient.  Singular, not plural, not our "patients" our 

              5     patient.  So we want to do things which sometimes are 

              6     intrusive to individuals, but it's for the benefit of 

              7     the population as a whole.  You can see this, for 

              8     example, in issues around treatment of tuberculosis.  

              9     Somebody might be quarantined for a couple weeks until 

             10     they get their tuberculosis treatment.  I've often told 

             11     people, I believe it's probably intrinsically intrusive 

             12     for you to be in the STD clinic and somebody asks you 

             13     who all you've had sex with while you're there getting 

             14     treatment. 

             15               There are thing public health routinely does 

             16     that are intrusive to the individual, but are designed 

             17     to protect the community.  

             18               Information.  How do you present information 

             19     to people when you're in the context of trying to make 

             20     a recommendation or trying to give them the information 

             21     for a choice when there's an absence of definitive 

             22     data.  I cannot tell you, and we condemned this very 

             23     much with this anthrax availability consent form, I 

             24     can't tell you whether you're truly at risk, I can't 

             25     tell you whether this is going to be in benefit, all I 
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              1     can tell you is I'm making it available to you and if 

              2     you want to take it, you can. 

              3               That didn't go over very will with the 

              4     participants.  Why you, you're the government, you're 

              5     the experts in this, you should tell me what I need to 

              6     do.  And to not be able to make a recommendation 

              7     because there weren't clear data underlying what we 

              8     would hope would be a recommendation based on evidence 

              9     was very difficult. 

             10               And then trying to convey the information in 

             11     the context of an emergency setting or a brouhaha, it 

             12     was just -- it was very, very difficult.  

             13               Then issues around documentation of consent. 

             14      We still face those to this day in trying to decide is 

             15     a signature anywhere?  Could you waive documentation?  

             16     After all, the person did listen to the information and 

             17     is still standing there in the line and gives you their 

             18     shoulder to give the shot.  What are some of the issues 

             19     around documentation?  

             20               And I'm willing and continue to think about 

             21     this in great detail, what options or alternative 

             22     methods could we use?  And we're trying to explore some 

             23     of those as well. 

             24               Implications of the adverse events, I mean, 

             25     costs of treatment of adverse events.  If we were a 
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              1     sponsor trying to do this study to get this vaccine 

              2     licensed for this indication in the United States, your 

              3     IRB probably would require us to pay for any medical 

              4     treatment that would occur for these adverse events.  I 

              5     believe that's pretty close to being standard practice. 

              6      However, we're the federal government; and, two, we're 

              7     not trying to do this to produce a profit; and, three, 

              8     we apparently have very limited legal options available 

              9     to us to do this.  So, I me, when we're giving an 

             10     intervention that has a known risk, I think that's one 

             11     option.  That's one situation. 

             12               When we're dealing with events that may occur 

             13     to people because they're exposed or because it's an 

             14     emergency setting and they may have no or an uncertain 

             15     relationship to the intervention we're giving, or when 

             16     we're giving intervention with unknown risks.  And you 

             17     may say, well, that would never happen, but consider 

             18     the small pox vaccine from adventist Pasteur recently 

             19     discovered, last licensed 50 years ago, not in the 

             20     United States, and the discussion is underway at high 

             21     levels in the department that we might need to use that 

             22     or we might need to use the new vaccine that's just 

             23     about to be produced which has not yet gone into the 

             24     first person anywhere in the world.  I mean, there are 

             25     going to be concerns as to how we should deal with 
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              1     this. 

              2               Connecticut, one of the sites of the anthrax 

              3     availability program, the Attorney General of 

              4     Connecticut called me and said, "The United States 

              5     Government should waive sovereign immunity."  Since 

              6     we're the U.S. Government we can't be sued unless we 

              7     can say you can sue us. 

              8               And that certainly was acceptable to me, but 

              9     that takes an act of the United States Congress.  I 

             10     can't sign.  That's not one of my duties at CVC to --  

             11               [Laughter.]  

             12               DR. LIVENGOOD:  -- authorize waiver of 

             13     sovereign immunity. 

             14               And then also related to that is 

             15     compensation.  Because I think we are dealing with 

             16     things that might potentially have issues around 

             17     compensation, but we don't have an approach in the U.S. 

             18     Government that's standard for this.  And the standard 

             19     approach is just saying, you know, you or your 

             20     insurance company will be responsible for this probably 

             21     is not adequate in this setting.  Because, again, we 

             22     are using these in situations where they're truly isn't 

             23     voluntary informed consent in some of the usual 

             24     standards. 

             25               Some of the regulatory issues, use of 
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              1     unlicensed products.  Some of the products potentially 

              2     that could be used here are not licensed for use in the 

              3     United States.  Some of them are not licensed for use 

              4     anywhere when we are into off-label use of licensed 

              5     products.  And here where it's you as a physician could 

              6     see somebody in your practice and as part of the 

              7     practice of medicine use a licensed medication for 

              8     whatever indication you wanted, we are not permitted as 

              9     public health agency to ship products across state 

             10     lines to be given for an off-label use.  Just to point 

             11     out, ciprofloxacin, doxycycline are licensed -- are 

             12     labeled for use for anthrax.  Cipro has never been 

             13     tested in children.  Doxycycline is contraindicated in 

             14     children.  We shipped ampicillin to give to the 

             15     children based on the reasoning that penicillin will 

             16     kill anthrax, but that was an off-label use of a 

             17     medication shipped across state lines and represents a 

             18     technical violation in what needs to be done. 

             19               Use of unlicensed laboratory tests.  The 

             20     detection of the Florida case was made based on use of 

             21     one of these lab reagent tests that we had shipped to 

             22     Florida to be conducted for surveillance.  Normally we 

             23     say that's okay, because we're not diagnosing patients. 

             24      But it isn't really a stretch to see that detecting 

             25     anthrax in various settings doesn't have implications 
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              1     for whether the people who worked in that setting say 

              2     it's an environmental thing.  We're exposed so they get 

              3     the ciprofloxacin so there are potential treatment 

              4     outcomes that are related to use of these tests even in 

              5     unusual ways.  The tests -- I mean, were completely 

              6     unevaluated prior to this time for the detection of 

              7     environmental samples.  We had always thought they 

              8     would be used on samples from humans, and then suddenly 

              9     we began doing environmental samples.  

             10               And I guess the question here, I'd say, is 

             11     the IND and the ID mechanism optimal in this situation? 

             12      I mean, we're taking an available mechanism and we're 

             13     making ourselves try to fit into it, but to me it feels 

             14     very much that we're trying to round off a little bit 

             15     the edges of this square peg and fit it right into the 

             16     round hole.  And it leaves both the federal government 

             17     and the participants, I think, in an unsatisfactory 

             18     situation. 

             19               A little bit anthrax, briefly.  The initial 

             20     case was detected through the surveillance system at 

             21     the Florida State lab which was using reagents we had 

             22     supplied to them as part of the laboratory response 

             23     network.  And it was confirmed at CDC in our labs.  

             24     When we run our own tests in our own labs, we're not 

             25     covered by FDA regulations.  So frequently we do try to 
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              1     gear up and run confirmatory tests personally at CDC. 

              2               With the contaminated letters in the Senate 

              3     we got into prophylaxis of exposed persons and we 

              4     started dealing with issues that there were children 

              5     there in the Senate office at the time and we didn't 

              6     really have correct things present for that.  We began 

              7     detecting of exposure by screening persons and 

              8     discovered in fact that there was a very high exposure 

              9     level among persons.  We began detecting exposure among 

             10     the environment and when we moved on to the post office 

             11     we used the screening method not so much to try to 

             12     detect whether an individual person had been exposed, 

             13     but was there any exposure in that area so a larger 

             14     group of people who had been exposed at that area could 

             15     be given prophylaxis. 

             16               We ended up very much later, as I was 

             17     alluding to, to the use of the vaccine or prolonged 

             18     antibiotics based on very limited information. 

             19               In a research study previously involving 

             20     monkeys not given such finely milled doses of these, 

             21     but one of the monkeys had viable anthrax spore 

             22     detected in the lungs at 97 days post-exposure.  That 

             23     turned out to be very discomforting to us.  One because 

             24     they were wet mound preps and not as easily inhaled as 

             25     what the people had seen.  We were giving 60 days of 
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              1     antibiotics based on somewhat limited information. 

              2               So we decided very late in the process we 

              3     would offer people the opportunity to continue on 

              4     antibiotics for another 40 days for which there is no 

              5     licensed indication in any antibiotic for 100 days post 

              6     exposure to treatment and the anthrax vaccine to 

              7     potentially build immunity. 

              8               There's fair evidence that three doses of 

              9     vaccine will produce an antibody response in you.  Will 

             10     that protect you?  That's not really known because 

             11     anthrax vaccine is not really licensed for post-

             12     exposure use at all.  And at the time we were doing 

             13     this the licensed product was unavailable and in fact 

             14     all licensed product -- all license had been suspended 

             15     by the Food and Drug Administration for production of 

             16     this pending regulatory compliance by the manufacturer. 

             17               This was a very regulatory, complicated 

             18     environment to try to get information to people.  

             19               What were some of the uncertainties?  We 

             20     didn't know exactly how much anthrax everybody had been 

             21     exposed to.  I mean, we had a perception that the 

             22     people standing next to the clerk in the Senate office 

             23     who opened the envelope were exposed to a large amount. 

             24      But how much was the postal worker who walked past 

             25     that machine sometime after lunch on the day that that 
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              1     letter went through, how many, how much, so we didn't 

              2     know what degree of exposure was or what the potential 

              3     impact would be. 

              4               Therefore it was nearly impossible for us to 

              5     tell any individual whether they would have any 

              6     potential benefit from taking the vaccine.  And we 

              7     debated this back and forth, because as you can imagine 

              8     writing a form that somebody signs that says we don't 

              9     know if this will give you any benefit or not, and by 

             10     the way, here are the known risks of anthrax vaccine.  

             11     It's very hard to do that. 

             12               What should be the choice or duration of 

             13     treatment?  We talked a little bit about 60 days, we're 

             14     now up to 100 days.  Antibodies are not benign to take. 

             15      A great number of the people had gastrointestinal side 

             16     effects from this.  The availability of the vaccine was 

             17     complicated.  As we said, it wasn't really available.  

             18     When, if you were going to give it post exposure, you 

             19     should do it early on.  It became available, so we 

             20     offered it 60 days after that.  Certainly not a 

             21     strategy anyone would picked a priori.  

             22               And how to best inform or guide exposed 

             23     persons.  And that was a conundrum -- I think you can 

             24     tell by the reaction in the press -- we freely 

             25     acknowledge we had to make success in this.  We seemed 
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              1     to do fairly well and make some people satisfied who 

              2     tended to be highly educated workers at the Senate who 

              3     the Senate physician told them it was his opinion they 

              4     should take it.  And we seemed to do very poor with the 

              5     postal workers who felt that we should tell them one 

              6     way or the other.  And when it came right down to it, 

              7     they didn't really believe us anyhow.  But the 

              8     situation was very complicated and the reactions were 

              9     totally different across these two populations.  

             10               Briefly on small pox, you know, as we said, 

             11     it's gone.  But apparently not forgotten.  We spend a 

             12     lot of time talking about it.  How can you talk about 

             13     the risks and benefits of vaccination when the benefit 

             14     can only possibly come if there is still small pox and 

             15     if it's used in an event where you become exposed.  

             16     Would you even consider, as some people have suggested, 

             17     a universal vaccination program where we have no 

             18     documented evidence there is even this agent in the 

             19     world that would be used in this. 

             20               How do you balance risks and benefits to the 

             21     population?  Vaccine formulation issues.  We have a 

             22     vaccine that was licensed previously, but it's past its 

             23     expiration date.  The diluent has gone bad and we're 

             24     having unlicensed diluent that we're using in it.  We 

             25     have conducted research that has said we can dilute it 
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              1     one to five with additional diluent and make more 

              2     doses.  But we're in this thing. 

              3               The vaccine here we do know a bit more about 

              4     because we know it is effective in preventing small pox 

              5     when you give it post -- pre-exposure and early post-

              6     exposure.  So we have some more information here than 

              7     we do in others, but then what should the strategy be 

              8     if we were going to do that. 

              9               Next. 

             10               What are some of the uncertainties?  You 

             11     know, the government has let a contract to produce 

             12     millions of doses of new vaccine through a new method 

             13     that has never been licensed or tested, or right now 

             14     for the most part evaluated in persons.  What's the 

             15     risk of exposure to the agents as I've talked about?  

             16     What should be our optimal strategy post-event? 

             17               I mean, public health people we would like to 

             18     go find the people directly surrounding the person and 

             19     vaccinate them.  But it's not a realistic strategy in 

             20     the middle of what may be a panic situation.  And it's 

             21     not immediate panic, one that would gradually build in 

             22     demand for the vaccine, over that time.  So we may need 

             23     to have simultaneous types of measures. 

             24               If we went with universal pre-event 

             25     vaccination, what would the tolerance for adverse 
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              1     events be?  Small pox vaccine is not benign.  The 

              2     literature describes the death rate of about one in a 

              3     million doses, one in 100,000 for encephalitis.  I 

              4     mean, you're talking about people who would die during 

              5     the vaccination effort because of vaccine when we don't 

              6     know that there's a risk.  So how would that be 

              7     tolerated in the United States? 

              8               People say, well, just go ahead and do 

              9     voluntary.  But I don't think just making it 

             10     voluntarily available to people covers all the 

             11     contingencies and all the considerations you would need 

             12     there. 

             13               And what impact is an old immunization 

             14     program person -- what impact would trying to do 

             15     something like this, and the resultant brouhaha have on 

             16     our other essential vaccination programs that we have 

             17     right now?  That's one that bothers me. 

             18               And at some point, I mean, if we do get into 

             19     a small pox thing, we will have some sort of consent 

             20     form, but we have some untried adjunct therapies, 

             21     vaccinia, immune globulin that we might be trying to 

             22     use, there's going to be other investigational products 

             23     used in combination with the vaccine should we ever 

             24     need to do that.  

             25               What are some of the lessons learned?  I 
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              1     think the first is the obvious, it's very difficult to 

              2     work in this environment.  Communication is vital at 

              3     all stages.  You need two levels of communication.  You 

              4     need to be as cognizant of the general public as you do 

              5     the exposed persons.  Because there's just tremendous 

              6     interest in this.  And the second one, I guess is also, 

              7     long, complex consent forms are not ideal in this 

              8     setting.  We need to find other ways.  We don't really 

              9     have terminology to say it's not research, but it's 

             10     investigational.  We lost the average person a long -- 

             11     right at the beginning of those forms and that process 

             12     there. 

             13               And we need to have some clarity of 

             14     recommendations when we offer things to people.  We 

             15     need to tell them why we think they should do it or 

             16     not.  It just seems to me it's impossible to truly 

             17     leave it completely open to a person, particularly when 

             18     there might be other impacts on them. 

             19               So what has happened here, you know, the 

             20     world has changed.  The bioterrorist threat is now 

             21     officially here to stay.  Most of our colleagues who 

             22     went around saying, it's not a matter of if, it's just 

             23     a matter of when, now will have to find something else 

             24     to say, you know, because it's already happened. 

             25               I think we have really worked enhanced 
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              1     preparedness and response efforts.  And we clearly need 

              2     more research.  Whereas, I don't think the emergency 

              3     response things are research.  I think there is a need 

              4     for research in this area.  And some of it that's gone 

              5     on has been very good so far, the small pox dilution 

              6     study clearly research, has a lot of implications, but 

              7     it's research, its desire is generalizable knowledge.  

              8     We're conducting a clinical trial of anthrax to change 

              9     doses and routes of administration.  These are research 

             10     things. 

             11               We'll be conducting new vaccine development. 

             12      Clearly that is a research effort to develop new 

             13     vaccines and to develop the safety and efficacy profile 

             14     that you would need, preferably to get licensure.  And 

             15     lots of applied research around how you deliver these 

             16     things, what are people's perceptions, what's the best 

             17     way to communicate with people that will be needed? 

             18               Emergency response or this type of 

             19     availability program doesn't fit well in the research 

             20     mode.  It was confusing to people to get a consent 

             21     form.  It had too many research trappings to then tell 

             22     them it's not research, but it sort of looked like it. 

             23      People were very confused. 

             24               And I think there is room here for some 

             25     harmonization and some better working interplay between 
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              1     the 45 C.F.R. 46 and the FDA regulations. 

              2               I mean, how do you adequately protect 

              3     subjects in this setting?  I mean, simply saying that 

              4     this set of rules or this set of regulations applies 

              5     probably is not adequate here to really assure, because 

              6     you need to still protect people, you need to still 

              7     provide them the information, but the framework maybe 

              8     needs some adjusting.  

              9               How to best give them the information to make 

             10     this choice and how to pay for the injuries or 

             11     compensation that may come from these.  Because right 

             12     now that's an issue of a lot of difficulty for this. 

             13               And I'm going to stop there, but I certainly 

             14     would appreciate any comments for NHRPAC or anything 

             15     about the role NHRPAC may play in this.  

             16               [Applause.]  

             17               DR. MORENO:  Thank you.  Those were two 

             18     thorough, excellent and very complimentary 

             19     presentations. 

             20               I have Alan, Adil, Bob, Felice, Susan, Sandy, 

             21     Margaret.   

             22               DR. LIVENGOOD:  Just start at the one end and 

             23     go around.  

             24               DR. MORENO:  Bob.  Who doesn't want to talk, 

             25     maybe that's the way to do.  
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              1               DR. SHAMOO:  Take my name off.  

              2               DR. MORENO:  Oh, good.  Fine.  Thank you very 

              3     much.  That makes things easier.  Okay.  And I saw 

              4     another hand.  Okay.  We'll get there.  I'm sure 

              5     everybody will get a chance.  Alan. 

              6               DR. FLEISCHMAN:  Let me start because John 

              7     had the second comment with John.  First of all, thank 

              8     you.  Thank you for sharing the information, but more 

              9     importantly thank you for those months in which you had 

             10     to worry about these issues.  You're final comment 

             11     about informing and playing more of a clinician's role 

             12     than a researcher's role, I think is critical one.  And 

             13     many of us who observed the lack of having a nation's 

             14     doctor in the informing were concerned when Dr. 

             15     Copeland and Dr. Satcher and others were not doing what 

             16     clinicians do every day at the bedside.  And that is 

             17     take uncertainty and make recommendations to patients. 

             18      And I think we saw that response. 

             19               And I think your conclusion that this may 

             20     have some trappings of research because you want to 

             21     learn from what you're doing doesn't mean that it ought 

             22     to have all of the regulatory structures of research in 

             23     some of our dealings.  So, you know, I think we need to 

             24     learn from that going forward and do what we can 

             25     prospectively to assure that you have the flexibility 
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              1     that you need within a complex governmental structure. 

              2               That business of moving drugs across state 

              3     lines without a -- that really was -- that one was 

              4     truly amazing to me.  I would never had dreamt that 

              5     that would preclude your activities. 

              6               But, to Monica, I had a few responses.  One, 

              7     all of us around this table are sympathetic to the 

              8     unique circumstances of the Johns Hopkins University in 

              9     the fall of 2001.  

             10               [Laughter.]  

             11               DR. FLEISCHMAN:  And I think you know that 

             12     Dr. Miller started our two days with a presentation and 

             13     he's going to solve all of your problems by the end of 

             14     2002. 

             15               We also appreciate the distinction you've 

             16     made between the academic medical center, the school of 

             17     public health and investigative journalism and even 

             18     political science investigation and we're interested in 

             19     that in looking at some of those distinctions.  But in 

             20     my opinion there's nothing inherent in the common rule 

             21     or an IRB process that mandates inefficiency and 

             22     insensitivity to the science or the investigator.  And 

             23     I think that's an important thing that at least some of 

             24     us are aware of.  You know, most of us think that most 

             25     research subjects are educable, rapidly.  And almost 
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              1     all of us think that most IRB members are educable, 

              2     rapidly. 

              3               At the New York Academy of Medicine, by the 

              4     afternoon of September 11th, we understood that there 

              5     was a research urgency.  And the IRB, as well as the 

              6     administration of the institution convened with its 

              7     investigators to answer the question, how could we 

              8     facilitate good research which would be ethically done? 

              9      And we did.  And I think we are very proud of our 

             10     contributions in that regard.  So if you would like to 

             11     move the Center to New York, we would be happy to talk. 

             12               [Laughter.] 

             13               DR. FLEISCHMAN:  Since one of our major 

             14     researchers we did extract from your School of Public 

             15     Health as you well know. 

             16               But I think that is an important issue that 

             17     the academic community has to demand of the deans and 

             18     the leaders within academe to understand the importance 

             19     of what you're doing.  And the other thought that we've 

             20     had, and we've already begun to work on, we have two 

             21     approved protocols with a great deal of specificity 

             22     with approved informed consent processes for the next 

             23     event.  We've gone down that route knowing that we want 

             24     to do some intervention work within the first hours of 

             25     an event. 
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              1               So we've actually already talked about those 

              2     protocols and we are in the process of getting, you 

              3     know, all the "t"s  cross and "i"s dotted.  And I think 

              4     other IRBs can do that kind of work, prospectively, not 

              5     just putting on the shelf kind of, you know, anything 

              6     you might ever think of.  But actually specific 

              7     protocols which you have thought about.  So I think 

              8     there's a lot that can be done in that regard and 

              9     should be done, but it isn't inherent in the process to 

             10     do bad work.  

             11               DR. R. LEVINE:  Thank you.  I have three 

             12     comments, two of which are related to what Alan just 

             13     said. 

             14               My first comment would be to second the 

             15     thanks to both of you.  In response to Dr. Schoch-

             16     Spana's presentation, the idea of the IRB finding a way 

             17     to accommodate a rapid response can be found in the 

             18     reports of the National Commission for the Protection 

             19     of Human Research Subjects. 

             20               The National Commission recommended that 

             21     expedited review be made available by the IRB or to the 

             22     IRB based upon the particular experience of a 

             23     particular IRB.  The National Commission in retrospect 

             24     very foolishly added a set of procedures to its 

             25     recommendation, the set of procedures that were being 
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              1     considered for expedited review by the clinical center 

              2     at NIH, and then they were kind of frozen chiseling the 
              3     stone of the Federal Register and that became 

              4     everything that was eligible for expedited review for 

              5     many years thereafter.  It had nothing whatever to do 

              6     with the expertise of a particular IRB.  And then 

              7     recently there was some loosening up of the expedited 

              8     review procedures, but it's still a uniform, nationwide 

              9     policy.  

             10               And from what I hear from you it would have 

             11     been well within the intent of the National Commission 

             12     to say that places like Delaware and Johns Hopkins with 

             13     their experience could be able to give an expedited 

             14     review in response to your need to engineer a rapid 

             15     response.  In saying that, I would say that as of this 

             16     month, this would not at all be appropriate at Yale 

             17     University because we have never reviewed such a thing. 

             18               But after we reviewed one or two, perhaps we 

             19     would be able to consider expedited review appropriate 

             20     there.  Another point I want to make elaborates on 

             21     John's observations of the anthrax and cipro study. 

             22               A little bit of the history that you may have 

             23     left out in the interest of time was that an initial 

             24     response in the Senate was by the White House 

             25     physicians.  And they moved right in thinking they were 
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              1     doing something good for people and used the general 

              2     license -- you know, unwritten license to use 

              3     investigational products under sort of a compassionate 

              4     use concept.  What happened then is that postal workers 

              5     said, "What about us?"  And the motivation was 

              6     precisely the same.  CDC, well, let's do the same good 

              7     thing for the postal workers and then somebody said, 

              8     "Whoa, this is an off-label use" and all of a sudden 

              9     the consent form and procedures became enormously more 

             10     complicated. 

             11               And what happened as an effort to do good for 

             12     postal workers in response to the postal workers' 

             13     wishes ended up having only 2 percent of the postal 

             14     workers were willing to accept this thing after it had 

             15     the consent form buffed up to meet regulatory 

             16     expectations.  I'm part of the committee that 

             17     recommended that you pull back on some of these 

             18     warnings and anxious statements of uncertainty. 

             19               The final comment.  I think, though, that 

             20     what we're hearing about has a lot in common with what 

             21     we talked about yesterday, and that is how using a 

             22     uniform algorithm for consent discussion or consent 

             23     form actually accomplishes the opposite of what we all 

             24     together want to accomplish.  Although yesterday we 

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              1     sciences.  

              2               My last comment has to do with what appears 

              3     to be an unwillingness of some agencies to get 

              4     prepared; for example, the Department of Defense.  

              5     During the early days of the -- and I'm not saying it's 

              6     the whole agency, but the particular individuals who 

              7     seem to be given responsibility from time-to-time.  

              8               During the early days of the Persian Gulf 

              9     experience, I was called by DOD and asked if I would be 

             10     their consultant on whether or not the drugs being used 

             11     in the Persian Gulf were investigational, and to 

             12     respond to the allegations that had been made, 

             13     actually, in a law suit that DOD plus FDA were using 

             14     troops in the Persian Gulf as guinea pigs.  I said, 

             15     "All right, I'll do that.  What's the name of the 

             16     drugs?"  They said, "Oh, we can't tell you, they're 

             17     secret." 

             18               I said, "Well, is it fair to assume that 
             19     they're the same ones that were mentioned in the New 

             20     York Times this morning?"  

             21               [Laughter.]  

             22               DR. R. LEVINE:  And they said, "Yes, that's a 

             23     fair assumption."  I said, "All right."  But I said, 

             24     "First, this experience is going to end, you know.  And 

             25     what you have to do immediately is get ready for the 
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              1     next Persian Gulf."  There is going to be another 

              2     crisis somewhere down the line.  "Oh, absolutely" they 

              3     say. 

              4               Well, as soon as the judge kicked that case 

              5     out of court on grounds that it wasn't research, which 

              6     was remarkably perceptive of the court, my contacts in 

              7     DOD vanished.  And I called once or twice and said, 

              8     "Well, what about getting ready for the next one?"  

              9     They said, "Well, you know, don't call me, we'll call 

             10     you."  And they haven't. 

             11               I think we have to also motivate the people 

             12     in the agencies that are called upon to respond to 

             13     these crises and emergencies to develop what you call 

             14     some long-range planning attitudes.  Thank you. 

             15               DR. MORENO:  For the second time, I would 

             16     like to collect comments and ask Monica and John to 

             17     respond collectively, if they would, at the end.  

             18     Because we've got, all of a sudden, a lot of people. 

             19               Is your response right on point?  Then why 

             20     don't you go ahead.  Because I do want to let our ex-

             21     officio members be part of this. 

             22               MS. BOLL:  Hi, I'm Patty Boll with the 

             23     Department of Defense.  And real short, we finally are. 

             24               [Laughter.]  

             25               DR. MORENO:  That was wonderful comment from 
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              1     you, Patty.  From the point of view of the moderator. 

              2               Let's try to follow the DOD's example.  

              3     Felice. 

              4               DR. F. LEVINE:  I guess my comment is as much 

              5     to all of us.  I thought both presentations were 

              6     extraordinarily important.  Actually all three, 

              7     Jonathan.  I think I've heard your short version 

              8     before.  But each time I do I --  

              9               DR. MORENO:  I make up something new every 

             10     time. 

             11               DR. F. LEVINE:  Ah-ha.  Well, I find it very 

             12     riveting. 

             13               I think that both of you emphasized that the 

             14     world has changed.  You know, sometimes when those of 

             15     us who are involved in global change research and 

             16     transnational studies in the last decade and a half 

             17     wondered whether we're just reinventing the wheel.  And 

             18     500 years ago, of course, others were saying the world 

             19     is rapidly changing, so is it or isn't it?  But clearly 

             20     something quite different has occurred.  It has created 

             21     not only the kinds of challenges the two of you 

             22     discuss, but actually challenges for human research 

             23     protection around the world with many other forms of 

             24     research that are not going on both in the health area, 

             25     in the biomedical arena, in the emergency relief area, 
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              1     and of course in both the social and political, and 

              2     economic dimensions of those studies. 

              3               And I made mention in October that I had been 

              4     invited last June -- and I only say this again because 

              5     it was all before 911 -- to participate in a conference 

              6     that the committee on populations for the National 

              7     Research Council was holding on humanitarian 

              8     emergencies.  And I was invited to speak on human 

              9     subjects issues and I thought at that moment that I was 

             10     going to go and that I was going to address disaster 

             11     research and how disaster researchers have addressed 

             12     that issue in the context of human subjects protection 

             13     as this committee was turning to that. 

             14               Of course, then about six weeks before which 

             15     was still before 911 I looked through the papers to 

             16     think about what in the heck I was going to start 

             17     preparing about only to learn that the focus of this 

             18     work was on refugee status in forced migration.  And it 

             19     seems to me in this arena where we do have some models, 

             20     you made mention of the Delaware Center of Disaster 

             21     Research of the kinds of considerations that you made 

             22     -- each of you -- I thought very important and 

             23     compelling ones between the difference actually between 

             24     practice and research.  You knew that you needed to 

             25     step back at a very important point of time and say 
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              1     that there was some difference between just answering 

              2     those inquiries, talking to those medical doctors to 

              3     build information.  And there was a point at which you 

              4     really made a transition to really developing research 

              5     at a research protocol. 

              6               And it seems to me it's really a very 

              7     important challenge in this mix of areas, these:  

              8     bioterrorism, disaster research, humanitarian 

              9     emergencies -- I think there's no other committee 

             10     better situated than ours to offer some to the IRB 

             11     process.  There's no committee that really has engaged 

             12     with us. 

             13               So I hope that what we've -- you know, I 

             14     know, Alan, you've been working on this and developing 

             15     some working papers and that we can figure out a way of 

             16     engaging and giving some input to an area where I think 

             17     we've got many lessons learned and something that we 

             18     could say that would really inform the process and 

             19     contribute to national awareness and anticipation on 

             20     these issues.  I hope we do.  

             21               Thank you.  

             22               DR. MORENO:  Susan. 

             23               MS. KORNETSKY:  My question is really for 

             24     John, but I'll just start by saying that Monica spoke 

             25     about the trials and tribulations of working with an 
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              1     IRB in this type of situation.  And her IRB was very 

              2     unfamiliar with the type of issue and I think most are. 

              3               Certainly the CDC has not had to work with 

              4     anything with bioterrorism but has had more experience 

              5     thinking about disease outbreaks, requiring fast 

              6     turnaround time, research versus investigation, public 

              7     health surveillance, and the idea of sort of risk 

              8     analysis for the public health versus, you know, the 

              9     benefit. 

             10               I guess my question is, in taking aside sort 

             11     of the regulatory issues that you had to deal with, how 

             12     did the CDC IRB sort of react to the things that you 

             13     were doing?  And is there anything that we can learn 

             14     from that because I can't think of another IRB who 

             15     would have thought about some of these issues more than 

             16     that. 

             17               DR. MORENO:  Why don't you make note of that 

             18     and hold it until the end.  

             19               Sandy. 

             20               DR. CHODOSH:  John, you mentioned that 

             21     there's no way that the government can compensate for 

             22     adverse events.  However, the VA does that.  The VA 

             23     takes care of all subjects whether they're veterans or 

             24     not, if they're in a VA-approved study.  So there is a 

             25     mechanism there somewhere in the government to 
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              1     accomplish that.  

              2               And I may be wrong about this, but it seems 

              3     to me that vaccine producers, and you should know this, 

              4     some of the drug companies will not develop a vaccine 

              5     unless there is some protection against liability by 

              6     the government.  Am I wrong about that?  I think that's 

              7     correct.  So there are some mechanisms that can be used 

              8     and perhaps should be looked into ahead of time.  

              9               My other concern is -- and I'm sure that 

             10     neither one of you really meant it to come across that 

             11     way, but it just hit me that way, and that is the talk 

             12     about we have to sometimes put aside individual rights 

             13     and benefits for the public good. 

             14               I immediately said, we're back to Nazi 

             15     Germany.  We have to be very careful when we tread down 

             16     that road.  And it all makes good scientific sense, but 

             17     I'm not sure that it makes good moral sense or good 

             18     ethical sense.  And I'm sure that you didn't mean that. 

             19      But it sounds like that.  And if that becomes in the 

             20     hands of a political group that decides that, yes, we 

             21     must do this for our good, for the public good, then 

             22     indeed individual rights go down the tube again. 

             23               So I just make a plea for that.  

             24               DR. MORENO:  Bob, did you --  

             25               DR. R. LEVINE:  Just a very quick 
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              1     clarification.  In the regulations there are separate 

              2     statements about provision of medical therapy for 

              3     research induced injury which the VA does offer and 

              4     compensation for disability which is like the workers' 

              5     compensation which no U.S. agency provides.  And it's 

              6     been recommended by every prestigious national 

              7     deliberative body since the mid-1970s. 

              8               DR. MORENO:  Abbey's turn. 

              9               MS. MEYERS:  Thank you.  I really appreciated 

             10     the presentations very much, especially the work that 

             11     CDC is doing because it's always had this leadership in 

             12     this whole field of public health emergencies.  But I'm 

             13     really worried about the amount of attention and 

             14     funding that's going to be diverted for the 

             15     bioterrorism diseases.  You know, the rest of the 

             16     field, for example, there are some very good scientists 

             17     who have very good diseases and they have a very hard 

             18     time getting funded for diseases that are not reserved, 

             19     you know, money isn't reserved; some Congressman has 

             20     put it aside and earmarked it or whatever.  And so 

             21     after years of a huge chunk going off to AIDs and then 

             22     a huge chunk going to the genome project, we are now 

             23     going to have a huge chunk for the bioterrorism 

             24     diseases.  

             25               And the bioterrorism diseases are basically 
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              1     third-world diseases that we should have been studying 

              2     all along.  You know, it's not just the two that you 

              3     mentioned.  We know that there are a lot of -- there's 

              4     a lot of talk about the bleeding disorders like lasa 

              5     [ph] fever and all of them that are potential.  But we 

              6     should have been doing it all along. 

              7               The reality is that if these things are 

              8     really studied and you come up with vaccines, you're 

              9     not going to get them manufactured because the industry 

             10     is not even manufacturing the mumps vaccine at this 

             11     point.  You know that we have these shortages of 

             12     childhood vaccines where the liability has been taken 

             13     care of.  There's a Child Vaccine Compensation Act 

             14     which puts a little tax on each vaccine and so anybody 

             15     who is harmed by the vaccines could collect for their 

             16     lifetime from that federal pool of money.  And, yet, we 

             17     don't have companies making enough of the vaccines.  

             18     They've had manufacturing problems and there's a 

             19     terrible shortage and CDC is rationing the vaccines to 

             20     pediatricians. 

             21               So we have a very big problem aside from 

             22     that.  But, again, I feel that it is not right to put 

             23     aside a large chunk of money to study these diseases 

             24     and to take away from the rest of the field by doing 

             25     that. 
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              1               DR. MORENO:  Greg. 

              2               DR. KOSKI:  Just a couple of points.  Bob 

              3     talked about the -- using the opportunities for 

              4     expedited review in order to facilitate some of these 

              5     processes in certain situations.  It's obviously a 

              6     great suggestion, the trouble is, it presumes a certain 

              7     robustness to the process that in fact, if you read 

              8     "Time Magazine" last week and all, it's not clear to 

              9     the vast majority of the public that in fact the 

             10     current process for protection of human subjects is at 

             11     the point that, you know, they can have confidence that 

             12     it in fact is going to be done and indeed when we have 

             13     instances where the expedited review process is not 

             14     used in an appropriate way, but in fact to circumvent a 

             15     process that's intended for -- that undermines 

             16     confidence. 

             17               Part of the problem with the postal workers, 

             18     of course, is that when we find ourselves in that 

             19     situation where the postal workers adamantly see 

             20     research as using them as guinea pigs, then in fact, 

             21     you know, we're at a situation where again we have sort 

             22     of shot ourselves in the foot by allowing a situation 

             23     to develop whereby they see the research participation 

             24     not as something that would be an opportunity, but in 

             25     fact would be something that's undesirable. 
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              1               And while you stated, Bob, that, you know, 

              2     the process that they went through resulted in postal 

              3     workers only 2 percent of them who were eligible to 

              4     take the vaccine to actually take it.  While that 

              5     presumes that there would have been some advantage to 

              6     them in taking the vaccine, but in reality the analyses 

              7     that have been done suggests that it made no difference 

              8     whether or not anybody took the vaccine, or for that 

              9     matter, whether or not anybody even took an additional 

             10     course of antibiotics that the frequency of actual 

             11     occurrence was so small that we don't know. 

             12               I guess my biggest concern in this is that 

             13     the situation that existed, you know, back when people 

             14     were about to come off the course of recommending 

             15     antibiotics was one that was ideally suited to 

             16     conducting a well-designed, meaningful research study 

             17     to find out whether or not there would be efficacy in 

             18     giving additional vaccine, or additional antibiotics 

             19     with or without the additional vaccine.  And, indeed, 

             20     we in a sense squandered the opportunity to get 

             21     meaningful data that would guide us in the future where 

             22     we could actually make recommendations as to whether or 

             23     not something was going to be safe and effective 

             24     because of, in a sense, a fear that conducting research 

             25     would be something that would be unacceptable to the 
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              1     American people.  And that is, I think, a very damning 

              2     situation to be in and one that I hope, you know, as we 

              3     look at these processes we can begin to move toward a 

              4     more functional environment.  

              5               I don't want to see us get constrained also 

              6     in these discussions into using, trying to force these 

              7     activities into existing models.  I think we need to 

              8     really think beyond that and recognize that in a 

              9     situation such as a large scale release of small pox or 

             10     something that's a situation that we haven't seen 

             11     before and there may need to be, in the sense of 

             12     preparedness, much greater thought given to an 

             13     appropriate, say, declaration by the president of a 

             14     national public health emergency under which specific 

             15     new procedures that could be developed in advance of 

             16     the crisis could be actually set up.  So that people 

             17     know and it can be discussed with the American people 

             18     and they'll be prepared. 

             19               So that let's not shoehorn everything into 

             20     this model and say, how do we get our base to move 

             21     faster.  Let's think about how the process really ought 

             22     to work in a prospective way. 

             23               DR. MORENO:  Elliot, I'm knocking you off the 

             24     list because we're a little late here.  But I want to 

             25     give Monica and John a chance to respond and then open 
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              1     it up to the floor.  

              2               DR. LIVENGOOD:  Yes, I'll try to be fairly 

              3     brief.  I think you're quite right in how you pointed 

              4     out that the CBC IRB had some unique experiences in a 

              5     wide range of even members who have unique experiences 

              6     that wouldn't necessarily be share with others.  

              7               We had previously also looked at anthrax 

              8     protocols for emergency use under INDs under various 

              9     scenarios.  This particular one as sort of Greg 

             10     implied, the decision made so late, the availability of 

             11     the vaccine and no prior conception that we would ever 

             12     use that really did strain both, I think it's fair to 

             13     say, Greg and my time as well as others in the 

             14     department as this was debated at very high levels.  

             15     And the IRB met in emergency session starting about 

             16     7:30 on the Wednesday night before the program started 

             17     on Thursday. 

             18               So, really, I think the process can work.  We 

             19     had to convene emergencies, we had tremendous number of 

             20     people working on this, both at CDC and elsewhere.  It 

             21     was very difficult though when you go to local cites 

             22     and you're saying, please don't send this to your IBR. 

             23      Or even one of the states that did do it, then working 

             24     with that IRB for all night the next night as you try 

             25     to explain why it's not research and what the FDA 
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              1     regulations say and why you chose this particular 

              2     wording which was developed by a committee to try to 

              3     adequately represent the murky science around there. 

              4               Even in the setting where I agree we're 

              5     somewhat specially constituted and experienced in this 

              6     type of thing, it was very difficult. 

              7               One of the things we have done is make a 

              8     uniform application to FDA to not to waive local IRB 

              9     review if we ever get into any of these emergency 

             10     responses again for that issue. 

             11               I wanted to mention just briefly the 

             12     Department of Defense also compensates for its 

             13     participants in research in terms of treatment for 

             14     adverse events.  We very much would like to do that.  

             15     We do not have a clinical facility at CDC.  So that's 

             16     one major impediment to us.  When we try to tell our 

             17     grantees that we would like them to treat medical 

             18     injuries we can't blanket authorize that in advance 

             19     because that's an illegal procurement in the federal 

             20     grant system.  We could authorize them to buy 

             21     insurance, but in the middle of the anthrax clinical 

             22     trial we've been unable to find anybody who would 

             23     provide insurance --  

             24               [Laughter.]  

             25               DR. LIVENGOOD:  Yeah, we're asking an 
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              1     insurance company to insure against anthrax vaccine 

              2     after all that's happened.  I mean, that's not the most 

              3     surprising result. 

              4               It is a little difficult, for example, in our 

              5     anthrax clinical trial where Walter Reed is one of the 

              6     sites that will provide medical care for the 

              7     participants at that site should they be.  And with 

              8     anthrax vaccine, although I believe it is a safe and 

              9     effective vaccine, there are people who will get a big 

             10     swollen arm and have to go back to the emergency room 

             11     and might need a course of antibiotics, may need to be 

             12     off from work for several days. 

             13               I mean, those are known things.  Those are 

             14     not saying that there's anything particularly wrong 

             15     with that.  That will happen to people.  And I think I 

             16     agree with your point that it's really unfortunate that 

             17     we tell that person, well, you know, if your insurance 

             18     won't pay, which most of them wouldn't for that, you'll 

             19     have to pay.  There needs to be some way around that. 

             20               DR. MORENO:  Monica.  

             21               DR. SHOCH-SPANA:  Thanks to Dr. Fleischman 

             22     and Robert Levine for helping dealing with our Hopkins' 

             23     specific woes.  

             24               [Laughter.]  

             25               DR. SHOCH-SPANA:  And then to Ms. Levine's 
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              1     remarks that it would -- guidance on dealing with 

              2     disaster and crisis context related research would be 

              3     heartily welcomed as a practitioner -- I mean, as a 

              4     researcher in the field.  Thank you very much. 

              5               On the issue of -- and going over my remarks 

              6     and listening to myself, even before I come here and 

              7     present them, I did, and I continue to worry about this 

              8     juxtaposition between, you know, individual sacrifices 

              9     and the public good.  I mean, once you get into that 

             10     dichotomy, you lose sleep and rightly so.  And so thank 

             11     you very much for bringing that to my attention.  It 

             12     does bother me when I use that type of language.  We do 

             13     need better language to discuss those tensions.  And we 

             14     can't juxtapose a theoretical individual subject with a 

             15     theoretical public good.  Because we do then get into 

             16     the political situation that you mentioned.  We need to 

             17     be very specific about what the particular tradeoffs 

             18     are and be attentive to those. 

             19               I think we're at a moment where we as a 

             20     nation do need to foster open conversation at local and 

             21     national levels about our strategies for dealing with 

             22     the effects of a bioterrorist attack.  That we need to 

             23     improve our research review process, but as a nation we 

             24     need to talk about those interventions that governments 

             25     -- our government and other institutions will take in 
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              1     order to stop the effects of a biological attack. 

              2               For instance, we need an open publicly 

              3     informed debate about national vaccination -- small pox 

              4     vaccination strategy.  We need to have that to be an 

              5     open process.  And the decision-making around the 

              6     policy options needs to be participatory.  And so there 

              7     needs to be right now those ongoing debates about 

              8     specific medical and public health management of this 

              9     problem.  And I know members of this committee are 

             10     doing that as well. 

             11               We do have a moment also to act to be 

             12     proactive about what type of research review processes 

             13     we really want.  Now is the time to envision those 

             14     ideal review processes and then build them as opposed 

             15     to acting in a reactive fashion.  Thanks. 

             16               DR. MORENO:  A very short sentence. 

             17               DR. DORFF:  Just a reminder of Alan's point 

             18     in October.  Part of those processes have to be how do 

             19     you guarantee that research properly approved by 50 

             20     IRBs from all over the country don't end up sending 50 

             21     teams of researchers to the World Trade Center to 

             22     interview the exact same people.  

             23               DR. MORENO:  Okay.  I'm going to give John 

             24     Mather a chance to tell us if the VA will cover 

             25     everybody or not.  Yes or no?  
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              1               [Laughter.]  

              2               DR. MATHER:  Maybe.  There is a statutory 

              3     requirement for us to take care of any individual that 

              4     has been enrolled in a research protocol that's been 

              5     conducted in the VA.  There's one caveat though and 

              6     that is that participant must be shown and has shown 

              7     that they are compliant with the protocol.  More 

              8     especially we are not talking about a long-term 

              9     disability benefit.  We are talking about perpetual 

             10     medical care.  If you're a veteran you may get 

             11     disability, but if you're a non-veteran, you will not 

             12     necessarily get anything other than cash payment. 

             13               Jon, could I just go on a little different 

             14     tag --  

             15               DR. MORENO:  No.  

             16               DR. MATHER:  -- very briefly? 

             17               DR. MORENO:  No.  No. 

             18               DR. MATHER:  Because I think it's --  

             19               [Laughter.]  

             20               DR. MATHER:  -- preparedness. 

             21               DR. MORENO:  Go ahead, John.  Go ahead.  

             22               DR. MATHER:  Well, the VA has a great concern 

             23     about it being a health care system with 170 VA medical 

             24     centers and 600 community outpatient clinics.  And here 

             25     is a system of health care that classically is a 
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              1     national resource that could be used in this particular 

              2     arena.  And I'm aware of an Office of Security and 

              3     Preparedness being prepared to come into existence.  It 

              4     will be working closely with DOD.  So, I just want to 

              5     give you a sense that there's another agency in this 

              6     that has a very significant health care system can 

              7     apply itself and indeed has an office, the Public 

              8     Health Environmental Medicine that works closely with 

              9     CDC as John well knows.  So there's another side to 

             10     this that I think is important to just put on the 

             11     table. 

             12               DR. MORENO:  That was a worthwhile extra 

             13     sentence. 

             14               Thanks again to our guests.  Mary Faith.  

             15               [Applause.] 

             16               CHAIRPERSON MARSHALL:  Thank you very much.  

             17     Those were just superb presentations beginning with 

             18     Jonathan and Monica and John as well. 

             19               I think we need to, you know, consider, to 

             20     answer your last question, where NHRPAC goes and what 

             21     NHRPAC does with this and sort of look to the agencies 

             22     that are involved in terms of their needs and 

             23     perceptions as to the most appropriate questions and so 

             24     forth.  So I imagine we will be going down that road in 

             25     the interim, perhaps between now and the next meeting. 
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              1               We need to go to lunch so that we can come 

              2     back and work on time and expeditiously because people 

              3     need to catch planes and so forth this afternoon. 

              4               Kate has asked me to ask whether anyone has 

              5     seen or accidentally picked up a motorola phone 

              6     recharger?  Hers has taken a walk.  We will see you 

              7     back here at 1:30.  

              8               And, thank you, again, a great panel.  

              9               [Applause.]  

             10               [Whereupon at 12:39 p.m., the meeting was 

             11     recessed to be reconvened this same day at 1:30 p.m.] 

             12 

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              1                A F T E R N O O N   S E S S I O N 

              2                                    [Time noted:  1:36 p.m.] 

              3               CHAIRPERSON MARSHALL:  We are going to go 

              4     ahead and begin so that we can try and end on time so 

              5     that people can make their planes, et cetera. 

              6               We are putting Jonathan to work today.  That 

              7     is your day, Jonathan. 

              8               DR. MORENO:  And I love it. 

              9               CHAIRPERSON MARSHALL:  He's going to segue 

             10     into the workgroup on decisional incapacity or decision 

             11     capacity, actually, not "incapacity."  Sorry about 

             12     that. 

             13               DR. MORENO:  Incapacity, you're incapable. 

             14               CHAIRPERSON MARSHALL:  I'm incapable we knew 

             15     that was a because --  

             16               DR. MORENO:  I'm going to begin by saying 

             17     again several things that I said before about this 

             18     effort.  First, there's a long complex history to this 

             19     problem.  I hope we -- I think the workgroup certainly 

             20     has appreciated it, I hope that the rest of us 

             21     appreciate that we can deal a priori with all the 

             22     issues and cases that are going to come up in the 

             23     coming years.  We're going to have to continually 

             24     revisit this.  This is an iterative process. 

             25               Secondly, this unlike the NBC report is 
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              1     dealing with -- we are dealing with all those who are 

              2     lacking decisional capacity regardless of the reason or 

              3     the source or etiology of their lack of capacity.  But 

              4     not including emergency research which is covered by a 

              5     waiver and not including kids.  

              6               Thirdly, as you all note, from the document, 

              7     unlike the NBC report, we have incorporated a 

              8     tripartite risk scheme which is perhaps the single most 

              9     innovative part of this report at the federal level, 

             10     although as Alan Fleischman who I am sure will remind 

             11     me, our group in New York some years ago did the same 

             12     thing.  I also want to point out by way of introducing 

             13     the report that -- and remind people that the 

             14     providence of this report or the impetus of this 

             15     report, I should say is the fact that DHHS responded to 

             16     the NBC report and asked OHRP to come to grips with 

             17     several issues with which they were not on all fours 

             18     with the NBC report. 

             19               But at the same time, there were seven or 

             20     eight recommendations from NBC that the DHHS group 

             21     found unobjectionable, found acceptable, and there were 

             22     a number of others that weren't relevant to them 

             23     because they had to do with admonitions that the NBC 

             24     gave to state law, for example, around who counts as a 

             25     legally authorized representative for research 
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              1     purposes.  And then there are one or two 

              2     recommendations to the NIH for further research on some 

              3     of these topics.  That also did not require further 

              4     comment with respect to DHHS perhaps implement 

              5     guidelines or regulations. 

              6               So we are specifically focusing on one, 10, 

              7     11, and 12, for those of you who are keeping score, of 

              8     the NBC recommendations.  Excuse me, two, 10, 11 and 

              9     12.  Somebody is keeping score, fortunately for me. 

             10               And in the introduction we specify, and I 

             11     don't know how to be more emphatic about this, that 

             12     none of the rest of this is acceptable to the workgroup 

             13     unless the NBC recommendations, one, three, four, five, 

             14     seven, eight, nine, and 17 are taken as part of the 

             15     package.  And I have not committed to memory, even 

             16     though I helped to write them, each of these 

             17     recommendations.  But anybody is free to go on the web 

             18     and see what they are.  We can talk about them -- 

             19     necessary, but those did not seem to be objectionable 

             20     to the DHHS group that received them. 

             21               So let me move to the recommendations.  And I 

             22     suppose that what we are going to be looking for today 

             23     is a motion to accept these recommendations but with 

             24     the proviso that there are a number of issues, as 

             25     you'll see at the end of this document, and probably 
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              1     others as well, to which the workgroup appreciates it 

              2     will need to return in order to flesh out these 

              3     recommendations.  

              4               So let me simply start with recommendation 

              5     one.  This starts -- the language here is very 

              6     familiar.  It actually rides the language of the 

              7     pediatric regulations to a very great extent.  And I'll 

              8     not rehearse the intimate relationship that Bob Levine 

              9     could do better than I of the way the National 

             10     Commission thought through the Pediatric regs and the 

             11     so-called -- or their pediatric proposals and the so-

             12     called Institutionalized as Mentally Infirmed Report 

             13     which did not ever become regulation.  

             14               So in a certain sense we are -- we are 

             15     bringing forward the work that was done 23 years ago by 

             16     the National Commission. 

             17               We believe that research may be conducted or 

             18     funded that does not involve greater or minimal risk if 

             19     the subject -- and you notice that there is a footnote 

             20     here about the disagreement about what term should be 

             21     used to describe people who are in research as subjects 

             22     or participants or volunteers.  We use the language of 

             23     "subject" in this document because it's still the 

             24     language that's in the regulations.  We can debate 

             25     about that, but it didn't seem to us to be critical to 
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              1     the spirit of the report. 

              2               If the subject has given informed consent or 

              3     if a legally authorized representative has given 

              4     permission for a subject who lacks decision-making 

              5     capacity.  Now, I'm going to open this up for 

              6     discussion in a moment.  But let me just point out that 

              7     what we've tried to do here is preserve what many 

              8     critics of the NBC report felt was a problem, namely 

              9     that the -- what seemed to them, although I don't 

             10     agree, what seemed to them was a presumption that 

             11     people who have mental disorders lack decision-making 

             12     capacity sort of a priori. 

             13               Here you see this is written in such a way 

             14     that that presumption is not made.  And so that the 

             15     capacity of the individual has to be presumably 

             16     assessed.  So, I'm going to leave this up now for 

             17     discussion.  Adil. 

             18               DR. SHAMOO:  For information, I think the NBC 

             19     report with all due fairness to them, they mention that 

             20     not in the same recommendation, but prior to that in 

             21     the introduction there is no assumption that mentally 

             22     ill means incapable, decisionally impaired, in terms of 

             23     informed consent.  They make that very clear.  So those 

             24     who misunderstood it, either did not read the whole 

             25     report or I don't know what else they did.  
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              1               DR. MORENO:  You say that because among some 

              2     people particularly in the psychiatric community there 

              3     was a concern that there is a stigmatization of people 

              4     who have mental disorders.  But, again, we're moving 

              5     beyond the scope of people with mental disorders to the 

              6      -- capacity in general.  Alan. 

              7               DR. FLEISCHMAN:  I'm not going to debate 

              8     that.  I have one question about what would the product 

              9     of this workgroup look like if we were to approve it 

             10     today?  Is what we're looking at the product? 

             11               DR. MORENO:  Yes.  This would be this 

             12     document unless people want to table it or work on it 

             13     electronically with various emendations.  This would be 

             14     the product of the workgroup. 

             15               DR. FLEISCHMAN:  I guess -- and we can talk 

             16     about this later, but I think it will be more helpful 

             17     to people reading it if those NBC recommendations were, 

             18     you know, attached somehow or somewhere nearby. 

             19               DR. MORENO:  They will be appendized. 

             20               DR. FLEISCHMAN:  Do you know what I mean?  

             21     Because I like this a lot and I don't have much problem 

             22     with any of it.  But, I think, you know, it needs a 

             23     little context. 

             24               DR. MORENO:  No problem.  

             25               DR. FLEISCHMAN:  Now, I do have a question.  
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              1     And that is, the clarification of the "legally 

              2     authorized representative," and how does the workgroup 

              3     perceive that playing out in the provinces? 

              4               DR. MORENO:  Right.  This, Alan, is, of 

              5     course, one of the matters that at the end of the 

              6     document we indicate is probably going to be a topic 

              7     for further discussion.  Number five, and one of the 

              8     difficulties here as you well know is that that is a 

              9     state matter.  And so, like NBC, the best any group can 

             10     do is offer advice to state legislatures on this 

             11     question.  And I don't really know how else to handle 

             12     it.  But I'll be open to suggestions.  

             13               DR. FLEISCHMAN:  Well, my hope would be that 

             14     the workgroup would think about what would constitute a 

             15     reasonable surrogate.  And whether we could try to move 

             16     the discussion in the direction of recommending, if 

             17     there are natural surrogates who would have the 

             18     capacity to consent to clinical judgments. 

             19               My problem here really just is this business 

             20     of lawyers interpreting this very narrowly as someone 

             21     appointed as a legal guardian.  Even though most of 

             22     know there are others who are legally authorized to 

             23     make choices, it just seems to me that we would be 

             24     better off saying, what do we mean by that?  How do we 

             25     think we would be most helpful to the community?  
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              1               DR. MORENO:  That's fine, thank you.  

              2               I have Greg and Bob and Felice and Elliot. 

              3               DR. KOSKI:  A quick technical point, Alan -- 

              4     Jonathan. 

              5               I would ask that you consider framing this 

              6     particular working group not specifically in the 

              7     context of the NBC recommendations, but rather the HHS 

              8     working group -- interagency working group response to 

              9     that.  We don't want to loop back to the original 

             10     thing.  There's already 18 months of work that's gone 

             11     into the process at this point.  So if you could do 

             12     that since there is in that working group report 

             13     discussion of each of the issues and so on. 

             14               The other quick technical point is that I 

             15     don't see Glen Dew out there, but I believe in fact our 

             16     office has already sent as recommended by the HHS 

             17     working group a letter to the State Attorneys General 

             18     to sensitize them to the issues so they can at least 

             19     start thinking about it.  And if this committee were to 

             20     offer further advice on who should be a legally 

             21     authorized representative they may be receptive to 

             22     that.  

             23               DR. SHAMOO:  And just on that point.  I think 

             24     we need to look at the Maryland Attorney General's 

             25     Office, they have a Maryland Health Care Act.  They 
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              1     have what constitutes legally authorized and surrogate 

              2     and the have a tree.  And as a matter of fact, the 

              3     group that was one of the diverse group of research, 

              4     there was one thing they agreed on, that tree was good. 

              5      There was no discussion sort of disagreement on that 

              6     one when we were discussing decisionally impaired.  So 

              7     I would recommend that we see that as a good tree.  

              8               DR. MORENO:  Bob. 

              9               DR. R. LEVINE:  Thank you.  I have four 

             10     comments.  The first is that you departed greatly from 

             11     the NBC report by reinstating the minor increase above 

             12     minimal risk category.  I want to applaud that with 

             13     great enthusiasm.  

             14               Secondly, in that same recommendation, number 

             15     three, (b) --  

             16               DR. MORENO:  We're just on one right now. 

             17               DR. R. LEVINE:  I beg your pardon.  Then I've 

             18     only got --  

             19               DR. MORENO:  But I'll take your applause for 

             20     the time being.  

             21               [Laughter.]  

             22               DR. R. LEVINE:  Right.   

             23               DR. MORENO:  We'll come back to you for the 

             24     rest. 

             25               DR. R. LEVINE:  Well, then I'll come -- 
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              1     before recommendation number one, I'm concerned about 

              2     the definition of the category of people to which this 

              3     applies.  All persons involved in research who have a 

              4     condition or a disorder that disposes them to impaired 

              5     decision-making that includes a very much larger set of 

              6     people than I think we should be interested with here. 

              7      That would, for example, include people high fevers.  

              8     I don't think I need to -- I think you really want to 

              9     narrow this down to the people you are really 

             10     interested in.  And I'll reserve my most serious 

             11     criticism to when we get to number two. 

             12               DR. MORENO:  I think I can speak for the 

             13     workgroup when I say that we precisely did not want to 

             14     narrow it down to another group.  But you can make a 

             15     judgment about that as you will. 

             16               DR. R. LEVINE:  So you want all people with 

             17     high fevers to go through all these four 

             18     recommendations?  

             19               DR. MORENO:  Well, it will very much depend 

             20     on what the risk level is and what kind of study is 

             21     being proposed. 

             22               DR. R. LEVINE:  Well, I will resist then.  I 

             23     think it's an overly broad application. 

             24               DR. MORENO:  Understood.  

             25               DR. RICH:  To that point. 
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              1               DR. MORENO:  Yes. 

              2               DR. RICH:  The difficulty it seem to me is 

              3     the word "disposes them toward."  I mean, because being 

              4     disposed toward impaired decision-making is an 

              5     exceedingly broad motion.  I mean, there are many, many 

              6     things that may dispose you toward that that cannot be 

              7     demonstrably associated with impaired decision-making. 

              8      And to associate myself with Bob's point of view, I 

              9     think that that would be the word that would trouble me 

             10     a great deal because I think one here wants to be 

             11     concerned with people who have demonstrably impaired 

             12     decision-making and not a disposition toward that. 

             13               DR. MORENO:  Greg, did you want to --  

             14               DR. R. LEVINE:  I mean, this could be anybody 

             15     with a history of depression.   

             16               DR. RICH:  Or alcoholism or lots of things.  

             17               DR. R. LEVINE:  Or social drinking.   

             18               DR. RICH:  Yes.  

             19               [Laughter.]  

             20               DR. MORENO:  All right.  Let's try not talk 

             21     about ourselves.  

             22               [Laughter.]  

             23               DR. MORENO:  I respect your confidentiality, 

             24     even if you don't. 

             25               Let's go back in order, Felice and then 
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              1     Elliot and them Mary Faith and then Adil. 

              2               DR. F. LEVINE:  I only had a modest point 

              3     until Bob just made his point which I'm hoping maybe we 

              4     can go back and bracket and discuss that because it 

              5     slipped by me until you made the point.  And I think 

              6     it's an important one for us to reflect on.  But, I 

              7     think it's a friendly amendment and that is that I feel 

              8     that in general in our report we might not want to 

              9     address the issue of funding just because of the 

             10     practice of the human subjects protection system isn't 

             11     making the allocated funding decisions, so it's 

             12     conducted or funded where it's as if in this working 

             13     paper for the first time NHRPAC would be speaking to 

             14     funding decisions.  So I just would sort of edit out 

             15     the "or funded" part of this throughout.  That's in 

             16     number one, so I raise it.  

             17               DR. MORENO:  It just tracks the 45 C.F.R. 46. 

             18               DR. RICH:  Okay.  Well, I don't know why --  

             19               DR. KOSKI:  45 C.F.R. 46 speaks to supported, 

             20     not funded.  

             21               DR. F. LEVINE:  It made it sound as if it was 

             22     advice on external funding and, you know, sort of 

             23     federal funding.  I just think we should sort of avoid 

             24     that role.   

             25               DR. MORENO:  Thank you.  
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              1               DR. R. LEVINE:  A point on that point.  Do I 

              2     infer then that you don't means this to apply to FDA-

              3     regulated research? 

              4               DR. MORENO:  Due to the extent that the FDA 

              5     requires that the investigators have complied with 45 

              6     C.F.R. 46, that's out of our hands.  

              7               DR. R. LEVINE:  But they don't do that.  They 

              8     have their very similar-looking regulations which are 

              9     not concerned with funding at all.  

             10               DR. KOSKI:  Let me just sort of cut that one 

             11     off because I think clearly the department's intent 

             12     here would be to move toward a uniform standard for 

             13     dealing with this.  

             14               DR. R. LEVINE:  Whatever the department's 

             15     intent, I would rather this commission -- this 

             16     committee said what it intended -- what we intend.  We, 

             17     I trust, don't intend to limit these recommendations to 

             18     federally regulated research that's connected with 

             19     funding the research.  

             20               [Simultaneous conversation.]  

             21               DR. F. LEVINE:  That's why I made my point. 

             22               DR. R. LEVINE:  Yes, I'm agreeing with you.  

             23               DR. F. LEVINE:  I knew you were. 

             24               DR. MORENO:  We'll do a universal 

             25     substitution of "funded" with "supported", Bob.  
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              1               DR. F. LEVINE:  We don't want it --  

              2               DR. R. LEVINE:  It's not supported either.  

              3     In the FDA's case it's required.  

              4               DR. F. LEVINE:  Yes, it's federally 

              5     regulated.  

              6               DR. SHAMOO:  I don't think there is a 

              7     difference between -- I mean, it's just a matter of 

              8     choosing the right words to mean the same thing.  All 

              9     of you have the same goal.  That is, regardless of what 

             10     research is, whether it's FDA or NIH-funded, the one 

             11     which Abbey is saying the word "regulated" that's the 

             12     intent, and I don't see the argument back and forth 

             13     continuous.  

             14               DR. MORENO:  Then write what you intend to 

             15     say. 

             16               DR. KOSKI:  I think the department would 

             17     welcome the committee's recommendation on the scope of 

             18     the applicability of this set of recommendations. 

             19               DR. MORENO:  We'll just say "conducted"; 

             20     how's that? 

             21               All right.  Elliot. 

             22               DR. DORFF:  Just a very simple question.  The 

             23     role of children in this, in particular teenagers.  

             24               DR. MORENO:  Irrelevant.  

             25               DR. DORFF:  Well, it's not defined anywhere 
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              1     here.  Right?  In other words --  

              2               DR. MORENO:  We're not talking about -- 

              3     right, we're not talking about children.  We're not 

              4     talking about legal minors.   

              5               [Simultaneous conversation.]  

              6               DR. DORFF:  Well, I think you need to say 

              7     that. 

              8               MS. GOTTFRIED:  We should just state that it 

              9     only applies to adults.  

             10               DR. MORENO:  Thank you.  

             11               Mary Faith.  

             12               CHAIRPERSON MARSHALL:  I guess this is more 

             13     general, Jonathan, but I would think that at some point 

             14     perhaps we could outline a couple of caveats, and those 

             15     would be that these were recommendations obtained in 

             16     the context of all efforts having been made to optimize 

             17     or enhance decisional capacity and that regardless of 

             18     the level of capacity that the individual, the research 

             19     subject participates in decision-making to the -- you 

             20     know, highest degree possible and that those are 

             21     understood background conditions that obtain 

             22     throughout. 

             23               DR. MORENO:  I think that once we have the 

             24     recommended appendix of the NBC recommendations that 

             25     we're also presuming will cover that, but if they're 
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              1     not we'll --  

              2               CHAIRPERSON MARSHALL:  Yes, I would think if 

              3     we could specifically articulate those background 

              4     conditions.  

              5               DR. MORENO:  Right.  Thank you.  

              6               PARTICIPANT:   [Off mic.]  

              7               CHAIRPERSON MARSHALL:  I'm just trying to get 

              8     the sentiment across that we need to -- you know, that 

              9     --  

             10               [Simultaneous conversation.]  

             11               CHAIRPERSON MARSHALL:  -- level of their 

             12     capacity they're involved in decision-making and that 

             13     we do all we can to enhance that.  

             14               DR. MORENO:  All right.  Adil, you want to -- 

             15     you're on the list.  Are you off the list? 

             16               DR. SHAMOO:  Mary Faith just made that 

             17     comment. 

             18               DR. MORENO:  All right.  Mary Kay. 

             19               DR. PELIAS:  In line one I don't think you 

             20     need to say "conducted" either.  You can just say, we 

             21     believe that research that does not involve greater 

             22     than minimal risk.  You don't need either "conducted" 

             23     or "funded". 

             24               And one question, are we going to entertain 

             25     any discussion about subjects and participants, or is 
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              1     that done with for now? 

              2               DR. MORENO:  It's your ball.  You can do 

              3     that.  

              4               PARTICIPANT:   [Off mic.]  

              5               DR. PELIAS:  Or an adverb. 

              6               [Simultaneous conversation.]  

              7               DR. SHAMOO:  I'm glad I didn't write this 

              8     one. 

              9               DR. PELIAS:  My concern with the question of 

             10     "subject" and "participant" is that I find in research 

             11     with human subjects what I call a fiduciary imbalance. 

             12     The subject is not on an equal level with the 

             13     researcher most of the time.  And the researcher does 

             14     have a heightened obligation to make sure that 

             15     something doesn't happen to the subject or participant. 

             16      And I like bringing in the idea of something of a 

             17     fiduciary imbalance, but it would have to be done with 

             18     rewriting this footnote.  

             19               That's all. 

             20               DR. MORENO:  I hear you. 

             21               Sandy.  Then we'll come back to this 

             22     disposition issue.  

             23               DR. CHODOSH:  Actually, I'm going back to 

             24     Bob's statement about acute and chronic impairment.  

             25     And I think that probably the working group should 
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              1     address those two separate categories as two different 

              2     things.  But nevertheless, they both have impaired 

              3     ability and it may well be that we need to deal with 

              4     them differently.  But I think that they need to be 

              5     addressed because it's something that comes up very 

              6     frequently in our IRB discussions.  

              7               It has to do with whether we're discussing 

              8     whether someone with a high fever and there are many 

              9     other situations like that where the person is 

             10     temporarily impaired, nevertheless important to obtain 

             11     consent if possible or need to have a mechanism of 

             12     knowing how to proceed with that situation.  We 

             13     certainly would not want to impede research in that 

             14     area, but I think that we shouldn't just say, you know, 

             15     that doesn't -- we're not talking about them.  I think 

             16     we have to talk about them, but talk about them 

             17     separately.  

             18               DR. MORENO:  Bob and then Adil.  

             19               DR. R. LEVINE:  Let me clarify that point.  

             20     What I object to is not having special procedural 

             21     protections.  And even substantive protections for 

             22     people who actually have or look like they might have 

             23     impaired decision-making capacity.  I'm concerned with 

             24     the language that says, "conditions or disorders that 

             25     dispose them."  And I would not want to see this whole 
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              1     apparatus trotted out for every patient that has a high 

              2     fever or for every patient that has a stroke.  I want 

              3     there to be a different threshold where you define a 

              4     population of people who it's a serious concern.  

              5               Well, no, you've got to -- in order to invoke 

              6     the procedural protections you have to be able to 

              7     locate a population who might have it, but might not 

              8     have it.  And then the first thing you do is to 

              9     determine whether or not they do have it, and then all 

             10     the rest gets triggered.  But you don't want to be 

             11     looking at everybody with a stroke.  

             12               DR. MORENO:  Can I just observe, this has 

             13     been one of the traditional problems with getting off 

             14     center with this topic.  Kids or kids or not, pregnant 

             15     women, and fetuses, or pregnant women and fetuses are 

             16     not, prisoners or prisoners are not.  But this 

             17     population is -- the problem of definition has been the 

             18     traditional stumbling block. 

             19               Adil. 

             20               DR. SHAMOO:  However, I think there is a 

             21     consensus the word "disposes" is too general.  I agree 

             22     with Bob and that was not the intent, I think, of the 

             23     workgroup discussion.  However, intermittent decisional 

             24     capacity or incapacity is the same whether you have 

             25     high fever and you are impaired, or you are depressed 
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              1     and in a psychotic episode.  During that period when 

              2     you are decisionally incapable you don't give them an 

              3     informed consent to sign. 

              4               However, when they have a clear, three, four, 

              5     five, six days or a week or a month and you give them 

              6     the informed consent that that will be okay.  This is 

              7     what this means, whether we have written it to mean 

              8     that or not, that was the discussion.  And even with 

              9     schizophrenia probably a third of them are capable of 

             10     signing informed consent and we have agreed to that for 

             11     the past five, six, seven, eight years.  I think it's a 

             12     red herring raising it all over again.  No one should 

             13     tell mentally ill patients that they are all the time 

             14     decisionally impaired.  That is inhumane and unethical 

             15     and we are not doing that. 

             16               DR. MORENO:  I'm tempted to jump into the 

             17     foray here and suggest another word which will, of 

             18     course, shift away from the concern about capacity 

             19     assessment.  And the word that I have in mind is 

             20     something like, "that renders them incapable."   

             21               PARTICIPANT:  [Off mic.]  That predisposes 

             22     them --  

             23               DR. MORENO:  It does.   

             24               PARTICIPANT:   -- they have been so rendered. 

             25               DR. MORENO:  Yes.  And we are in between 
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              1     [indiscernible] and should this here.  Either we have a 

              2     framework that requires this assessment and therefore 

              3     of whom and under what circumstances and by whom.  Or 

              4     we presume that there has been an adequate assessment 

              5     and then develop the framework for those who haven't 

              6     gotten over the threshold capacity.  

              7               DR. SHAMOO:  Jonathan, again, NBC dealt with 

              8     that.  That is, if you are dealing with a group of high 

              9     fevers, you don't worry about it.  Most likelihood they 

             10     are not continuously and decisionally impaired.  If you 

             11     deal with schizophrenia patient, most likelihood you 

             12     will have a certain percentage with decisional 

             13     incapacity and therefore for that group you have 

             14     greater built-in safeguards than those who are on high 

             15     fever. 

             16               DR. MORENO:  Renders them chronically --  

             17               DR. SHAMOO:  Exactly.  

             18               DR. MORENO:  -- incapable.  

             19               [Chorus of no.] 

             20               DR. MORENO:  Gone too far.  See. 

             21               DR. F. LEVINE:  Jonathan, I don't know if 

             22     this will help, but --  

             23               DR. MORENO:  Go ahead.  

             24               DR. F. LEVINE:  -- "should apply to all 

             25     persons involved in research when they have a condition 
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              1     or disorder that impairs decision-making capacity."  

              2               DR. R. LEVINE:  It allows more wiggle room. 

              3               DR. RICH:  Well, does one even need 

              4     "condition" or "disorder"?  Can you simply --  

              5               DR. F. LEVINE:  Well, at least it is not 

              6     disposing and it is when, it's only under those 

              7     circumstances when. 

              8               DR. RICH:  Can one simply say, "to all 

              9     persons involved in research who have impaired 

             10     decision-making capacity"?  

             11               DR. MORENO:  That is not exactly what Felice 

             12     --  

             13               DR. RICH:  No, I'm asking whether that 

             14     alternative which is simplifying language --  

             15               DR. MORENO:  Does this avoid the high fever 

             16     problem?  

             17               DR. RICH:  Well, I think it -- I mean, the 

             18     onus then is that what you're looking at is the 

             19     capacity and not the condition or the disorder or the 

             20     predisposition to it.  You're really focused on the 

             21     impaired decision-making capacity.  

             22               DR. MORENO:  Right.  Okay.  We like that.  I 

             23     like that. 

             24               DR. CHODOSH:  Perhaps what needs to be done 

             25     is some guidance about the fact of determining that and 
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              1     then proceeding.  In other words, it should be a 

              2     determination of the capacity.  And I'm not thinking 

              3     about testing necessarily, but, you know that there are 

              4     certain circumstances where one can expect there might 

              5     be impaired capacity.  And in those situations it 

              6     should be assessed before obtaining --  

              7               DR. MORENO:  Well, I want to hear some 

              8     comments about this.  Susan. 

              9               MS. KORNETSKY:  Yes, I think that if you took 

             10     those few statements that Robert just said and put that 

             11     in the introduction in saying that this is what it is 

             12     supposed to be, that that will help clarify how the 

             13     words are.  That this is what the concentration is on 

             14     when they have the incapacity.  And I think it just 

             15     needs to be stated here.  

             16               DR. MORENO:  And this is -- how does this 

             17     interpolate with the process of assessing capacities? 

             18               DR. SHAMOO:  Jonathan, this is a whole 

             19     different issue.  And, again, NBC dealt with it and we 

             20     have dealt with it by deferring it because it's a 

             21     sticky point. 

             22               DR. MORENO:  Exactly. 

             23               DR. SHAMOO:  He said "independent capacity 

             24     assessment" that's one of the outstanding major issues. 

             25      I don't think you could insert it in every single 
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              1     paragraph we are writing.  You have to assume in this 

              2     first part -- I'm defending Jonathan's writing -- in 

              3     this first part that they have decisional incapacity 

              4     and during that what will happen in terms of these 

              5     categories of research and informed consent.  That's 

              6     really what this is.  

              7               DR. MORENO:  This is a chicken and egg 

              8     problem, in effect.  Elliot. 

              9               DR. DORFF:  I just wanted to recapture 

             10     Sandy's point though which is that -- and I think Bob 

             11     Rich's revising of this is right.  All persons involved 

             12     in research who have impaired decision-making capacity. 

             13      But then maybe a sentence after that, something like 

             14     this impairment may be temporary or permanent.  And 

             15     then talk about what happens if it's temporary and what 

             16     happens if it's permanent. 

             17               DR. SHAMOO:  That's difficult, how long and 

             18     how --  

             19               DR. CHODOSH:  You're really talking about 

             20     when you obtain consent.  You know, someone can give 

             21     you consent for an Alzheimer study, apparently a couple 

             22     years before they have Alzheimer's with the idea that 

             23     there's a point at which they will become impaired.  

             24     And so it's at the time that consent is obtained.  And 

             25     once you obtain the consent unless a legal 
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              1     representative pulls you out of it, you know, you 

              2     essentially have done it. 

              3               DR. MORENO:  Greg and then Mary Faith.  

              4               DR. KOSKI:  I find the language that Bob 

              5     recommended to be attractive because having an impaired 

              6     ability to do something doesn't mean that you have no 

              7     capability of doing something.  I may have, you know, 

              8     an impaired ability to walk, but it doesn't mean I 

              9     can't walk at all.  And so I think the goal here is to 

             10     try and determine when it is possible for someone to 

             11     make a legitimate decision for one's self and when it's 

             12     not and afford special protections in those instances 

             13     where it's deemed that that's not possible.  So I'd 

             14     find some attractiveness of the language of impairment 

             15     as opposed to incapability. 

             16               DR. MORENO:  Right.  Mary Faith. 

             17               CHAIRPERSON MARSHALL:  I think we should be 

             18     mindful that what we say here reflects sort of the 

             19     paradigm shift, if you will, in how we can see about 

             20     informed consent.  And what I'm hearing sort of 

             21     reflected in the discussion, it may not be intended, is 

             22     the event model rather than the process mode, decision-

             23     making, ongoing conversation.  And we are really 

             24     talking about functional criteria for decision-making 

             25     and they may wax and wane or they may stay the same.  
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              1     And I think that's why the language is that, you know, 

              2     the requirement for continuing to enhance or optimize 

              3     decisional capacity involving the individual to the 

              4     degree possible in decision-making is important as 

              5     well, in an ongoing way. 

              6               DR. R. LEVINE:  I think Mary Faith has just 

              7     made a very important point.  But I think to assume 

              8     that the consent process is, you know, that the horizon 

              9     for being able to say something final is way out there. 

             10      We have to also acknowledge that there's a goodly 

             11     number of people who are crafting the so-called 

             12     research living wills.  And the -- I think the most 

             13     thoughtful among these people are those who designate 

             14     somebody holding a durable power of attorney to speak 

             15     for them.  And when specific contingencies come up that 

             16     couldn't be specified in the original document.  

             17               But still, I also sympathize with Sandy that 

             18     at the time you do something of that sort, you need an 

             19     individual who has the capacity to make that decision. 

             20      And it probably is a good idea to be dealing with 

             21     somebody who looks likely to retain that capacity at 

             22     least for a reasonable amount of time. 

             23               One thing that's missing from the NBC report 

             24     and or may not be in what we haven't seen here is the 

             25     idea that is developed so well in the report of the 
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              1     president's commission.  There's one we haven't heard 

              2     mentioned this time yet.  Where they talk about 

              3     capacity being evaluated along a sliding scale 

              4     depending upon just what's at stake.  So you would be 

              5     less rigorous about imposing a high standard of 

              6     capacity if all you're doing is asking somebody to 

              7     respond to an interview than you would be if you were 

              8     asking somebody to decide to participate in a 

              9     randomized clinical trial.  Where is it? 

             10               I haven't noticed it in here --  

             11               [Simultaneous conversation.]  

             12               DR. SHAMOO:  That kind of discussion we said 

             13     commensurate with risk.  We said that in the working 

             14     group.  I don't know if it's reflected by words here, 

             15     but by deed that was the intent of the working group. 

             16               DR. R. LEVINE:  I meant to accommodate that 

             17     possibility when I limited my remarks only to what's on 

             18     these three pages.  It might be in one of these other 

             19     recommendations.  

             20               DR. MORENO:  All right.  Well, let's see if 

             21     we have any more discussion about either the first 

             22     paragraph after "recommendation" or the first 

             23     recommendation?  I've taken careful notes, I want you 

             24     to know, which I can't read, but they're very careful. 

             25               DR. R. LEVINE:  Could I say something about 
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              1     number two? 

              2               DR. MORENO:  Number two is now on the floor. 

              3      I haven't read it.  Do you want to have a silent 

              4     meditation on two?  I'll read it for you since that's 

              5     the ritual. 

              6               "The workgroup also concludes that 

              7               research may be conducted that 

              8               involves greater than minimal risk 

              9               but presents the prospect of direct 

             10               benefit to subjects if:  (a) the 

             11               risk is justified by the intended 

             12               benefit to the subjects; (b) the 

             13               relation of the anticipated benefit 

             14               to the risk is at least as 

             15               favorable to the subjects as that 

             16               presented by available alternative 

             17               approaches; and (c) adequate 

             18               provisions are made for obtaining 

             19               the informed consent of the 

             20               subject, or a legally authorized 

             21               representative gives permission for 

             22               a subject who lacks decision-making 

             23               capacity." 

             24               Bob. 

             25               DR. R. LEVINE:  This is what I found to be 
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              1     the most unacceptable component of the NBC report.  

              2     What it succeeds in doing is recreates the foolishness 

              3     of therapeutic research. 

              4               When I confronted NBC with this I asked them, 

              5     would you say that a placebo controlled trial is 

              6     therapeutic or beneficial or non-beneficial?  And I got 

              7     an even split in the responses.  What all the rest of 

              8     the regulations have to do with and what Alan's group 

              9     so clearly presented yesterday is that what we are 

             10     evaluating is each component of the research.  If one 

             11     procedure or intervention holds out the prospect of 

             12     direct benefit, then we justify it in these terms.  If 

             13     another component does not hold out such a prospect 

             14     then we evaluate it in terms of whether it meets the 

             15     minimal risk threshold.  

             16               But to put it all together about risk -- 

             17     research maybe conducted that involves greater than 

             18     minimal risk but the prospect of direct benefit 

             19     recreates what I call the fallacy of the package deal. 

             20      Jonathan has heard that so often he recites it before 

             21     I do. 

             22               You don't want to do this.  If anybody here 

             23     needs convincing of this, I will give you examples of 

             24     package deals that have been approved by IRBs and 

             25     funded by the federal government.  
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              1               For example, putting catheters in coronary 

              2     arteries in order to administer placebos.  I'm not 

              3     saying that can't be justified ethically, but it should 

              4     not be justified in terms of the prospect of direct 

              5     benefit, if you were evaluating the whole protocol as a 

              6     package. 

              7               DR. RICH:  I think the last phrase, though, 

              8     buys out of that problem, Bob, and that is to the 

              9     subjects.  And the point that I'm making is that the 

             10     word is plural.  So if one says, "to the subjects" 

             11     plural, then one says, is the intent of the study as 

             12     opposed to the -- in other words, is there intended 

             13     benefit in the study as opposed to is there intended 

             14     benefit to the individual? 

             15               DR. R. LEVINE:  Let me finish then.  In the  

             16     protocol I'm talking about, there was an evaluation of 

             17     thrombolytic treatments of myocardial infarction.  It 

             18     was classified as therapeutic research because the 

             19     thrombolytic therapy itself held out the prospect of 

             20     direct benefit.  But that meant you accepted the whole 

             21     package.  And the coronary artery catheterization in 

             22     order to give a placebo was swept up into the -- under 

             23     the rubric of therapeutic research and justified 

             24     accordingly. 

             25               So what I'm saying is that you do not 
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              1     evaluate the entire protocol.  You evaluate each 

              2     component.  And you might say, yes, we really like the 

              3     idea of evaluating thrombolytic therapy and we think 

              4     that the prospect of direct benefit justifies the risks 

              5     involved.  On the other hand, we don't like the idea of 

              6     sticking a catheter in the coronary artery for no 

              7     purpose other than to give a placebo. 

              8               If you look at the component analysis it 

              9     gives you the possibility of making more nuanced 

             10     approvals or disapprovals of particular protocols. 

             11               Another example was the National Gallstone 

             12     Project where they approved doing liver biopsies on the 

             13     placebo controlled group for no purpose other than 

             14     maintaining the double blind.  I can go on and on with 

             15     these things. 

             16               You need to have some vocabulary that allows 

             17     you to evaluate specific components of research 

             18     protocols. 

             19               The other thing is that everybody else seems 

             20     to have recognized this, after 25 years we finally got 

             21     therapeutic research out of the so-called subpart B.  

             22     Even the World Medical Association has tried to get rid 

             23     of it.  Let's not lead a regressive move in this 

             24     regard. 

             25               DR. MORENO:  Anyone else?   
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              1               DR. SHAMOO:  Yeah, I didn't hear them, but I 

              2     want to make my comment anyway.  And that is --  

              3               DR. R. LEVINE:  [Off mic.]  

              4               DR. SHAMOO:  -- I won't quote you, Bob, 

              5     anymore. 

              6               Someone who is a few years older than me said 

              7     -- no -- this is borrowed from the regs for pediatrics 

              8     and that's why we try to maintain that language.  

              9     That's one thing.  

             10               Second, there are linguistic use, it doesn't 

             11     mean what a language expert will tell us to mean.  It's 

             12     an accepted after using it for, what, 20, 30 years now 

             13     and therapeutic versus nontherapeutic even though I 

             14     agree with Bob in his absolute interpretation of those 

             15     two words.  However, now it's accepted what they mean 

             16     by "therapeutic" it means there is some benefit to the 

             17     group at large and maybe direct medical benefit not 

             18     every single piece of the protocol is direct medical 

             19     benefit.  The compilation of those procedures they  may 

             20     be benefit to the individual.  It's an accepted now and 

             21     that's the way we go.  We are not going to change the 

             22     language every few years just because Bob keeps 

             23     insisting on it.  

             24               DR. R. LEVINE:  Let me repeat what you 

             25     missed.  The regulations on research involving children 
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              1     were the first regulations in the United States to 

              2     explicitly repudiate the distinction between 

              3     therapeutic and non-therapeutic research.  It uses the 

              4     language that Alan Fleischman and his group faithfully 

              5     copied and presented to us yesterday.  It says, 

              6     "interventions or procedures that hold out the prospect 

              7     of direct benefit." 

              8               It does not say "research that holds out the 

              9     prospect of the direct benefit." 

             10               Now, people who only read the pediatric 

             11     regulations superficially read the subtitles that were 

             12     written after the national commission signed off on it. 

             13      The subtitles have it all wrong.  But the actual text 

             14     of the regulations calls for a component analysis.  

             15     Thank you. 

             16               CHAIRPERSON MARSHALL:  I just want to caution 

             17     us not to have ad hominem in our remarks and to stick 

             18     to the content of the recommendations. 

             19               DR. R. LEVINE:  [Off mic.]  

             20               CHAIRPERSON MARSHALL:  No. 

             21               DR. MORENO:  Just in case.  If we -- the 

             22     language interventions of procedures, Bob, will that 

             23     care of this concern here? 

             24               DR. R. LEVINE:  If you just copied what Alan 

             25     gave us yesterday. 
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              1               DR. MORENO:  Done. 

              2               DR. R. LEVINE:  Thank you.  

              3               DR. MORENO:  Alan, would you rewrite this, 

              4     please?  Another job for you. 

              5               All right.  Any other comments on number two? 

              6               DR. SHAMOO:  Is the assumption all these, 

              7     (a), (b), and (c) has to be satisfied? 

              8               DR. MORENO:  Yes. 

              9               DR. SHAMOO:  I think somewhere should be the 

             10     word "and" at the very -- after (b) then. 

             11               DR. MORENO:  Well, the colon is supposed to 

             12     function that way, but we'll do that. 

             13               DR. MORENO:  Anything else? 

             14               [No response.]  

             15               DR. MORENO:  Okay.  We're going to move to 

             16     number three and things get even more fun. 

             17               "We also conclude that research 

             18               involving a minor increase over 

             19               minimum risk that does not" 

             20     and then we will substitute the preferred language to 

             21     the whoever we're talking about -- 

             22               "but is likely to yield a 

             23               generalizable knowledge about these 

             24               individuals" 

             25     and now we have another caution here about the use of 
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              1     the word "condition" which is footnoted -- 

              2               "or disorder may be conducted if:  

              3               (a) the" -- 

              4               ah, I knew we did something right -- 

              5               "the intervention or procedure 

              6               presents experiences to subjects 

              7               that are reasonably commensurate 

              8               with those inherent in their actual 

              9               or expected medical, dental, 

             10               psychological, social, or 

             11               educational situations."  

             12               Now, we went around the block a few times in 

             13     the workgroup to try to figure out if there were more 

             14     dimensions of human experience that need to be added to 

             15     this list and we decided that ultimately this list is 

             16     about as good as we can get without being even more 

             17     redundant than this list.  

             18               And then we just have this historical note 

             19     about the use of the word "inherent" which some people 

             20     thought we ought to have in there.  And with help from 

             21     Al Johnson in helping us understand the role of the 

             22     word "inherent" in the National Commission statement. 

             23               "(b)  the intervention or procedure 

             24               is likely to yield generalizable 

             25               knowledge about the subject's 
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              1               disorder or condition which is of" 

              2               --  uh-oh --  

              3               "vital importance" --  

              4               We'll come back to that, I'm sure -- 

              5               "for the understanding or 

              6               amelioration of the subject's 

              7               disorder or condition."  

              8               "(c)  adequate provisions are made" 

              9               and these are all with an "and" between them 

             10     --  

             11               "adequate provisions are made to 

             12               solicit the informed consent of the 

             13               subject or for a subject who lacks 

             14               decision-making capacity, a legally 

             15               authorized representative is given 

             16               permission." 

             17               Comments?  Bob. 

             18               DR. R. LEVINE:  Let me just repeat what I 

             19     said out of place before and that is, I'm really happy 

             20     to see that you've linked the analysis to the 

             21     intervention or procedure at least in number -- in the 

             22     (a) and (b). 

             23               The other thing I wanted to flag is something 

             24     I think you've already flagged by saying, "uh-oh."  I 

             25     want to recall the discussion we had yesterday about 
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              1     vital importance.  Everything that was said yesterday 

              2     against vital importance is -- ought to be -- we ought 

              3     to think about this, it was vitally important as Felice 

              4     puts it, yes.  Thank you.  

              5               DR. MORENO:  Thank you.  Adil. 

              6               DR. SHAMOO:  I have a couple comments on 

              7     this.  The footnotes could be construed to be 

              8     disingenuous because it says the term "condition" may 

              9     be too broad or too narrow.  I can understand too 

             10     broad, but trying to put those out equivalent or too 

             11     narrow, condition how could it be too narrow?  One is 

             12     talking about cosmos and one is talking about the 

             13     earth.  And you're saying, "condition" be anything, 

             14     literally.  Like I said, the dictionary definition of 

             15     "condition" is state of being and it could be height, 

             16     weight, race, gender, anything.  So that's only to make 

             17     the two are equivalent and therefore the workgroup took 

             18     a happy medium between the two positions for the 

             19     definition of "condition."  And I think that footnote 

             20     should be corrected.  That's one. 

             21               Second, everything we discuss and everything 

             22     I said, when we were discussing the pediatrics, about 

             23     the condition and how the pediatric regs and the 

             24     National Commission's comment that there was 

             25     specificity to those research related to the condition 
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              1     should be copied verbatim into this paragraph because 

              2     that is supposed to be there as equivalency.   

              3               DR. MORENO:  Which paragraph, Adil, just so I 

              4     make sure? 

              5               DR. SHAMOO:  Wherever we mention the word 

              6     "condition" we should reinsert the narrowness.  

              7     Remember the National Commission required this is a 

              8     specific ethical consideration that this is not meant 

              9     to be so broad to include anything, et cetera. 

             10               DR. MORENO:  All right.  

             11               DR. R. LEVINE:  Adil, if I recall correctly 

             12     what you read in order to help us understand what the 

             13     Commission intended was the quotation of its chairman 

             14     that was written by a journalist.  And I don't see 

             15     that.  I happened to be there when the Commission 

             16     expressed its intent and it was very clear that they 

             17     did intend to include condition because they wanted to 

             18     relativeize this to something more than simply 

             19     disorders. 

             20               DR. MORENO:  Felice. 

             21               DR. F. LEVINE:  Well, I'm --  

             22               DR. SHAMOO:  Can I ask for a moment?  What 

             23     the chairman said was part of the National Commission's 

             24     report.  I mean, transcript, not the journalist.  What 

             25     I read about Ken Ryan.  Okay.  
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              1               DR. R. LEVINE:  There were some remarkable 

              2     things in that transcript.  For example, it quoted 

              3     Donald Sullivan as illustrating autonomy by saying, "I 

              4     move your arm."  There are typos in transcripts.  I am 

              5     telling you what the content was of the discussion that 

              6     led into the crafting of that passage. 

              7               DR. SHAMOO:  Well, all I could go is by the 

              8     --  

              9               DR. MORENO:  Felice. 

             10               CHAIRPERSON MARSHALL:  You don't want me to 

             11     come out there and referee gentlemen, it will be 

             12     painful. 

             13               DR. MORENO:  Felice. 

             14               DR. F. LEVINE:  I'm hoping that when this 

             15     migrates from what was perhaps difference in view 

             16     within the working group that maybe we could reach a 

             17     meeting of the minds in NHRPAC so that it is -- that we 

             18     don't have to have an either/or.  And I'd like it to 

             19     have the same fit as we have in the children's working 

             20     group and that is that we did -- we were able to see 

             21     condition as broader so that if it's of benefit in 

             22     advancing knowledge about that condition, the 

             23     generalizable knowledge about the condition that it 

             24     might be conducted.  So I would like us, ultimately as 

             25     NHRPAC to resolve the footnote and also have a fit 
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              1     between our other uses of condition, most in particular 

              2     with the children's working group where we did not have 

              3     that internal ambiguity in that working group.  

              4               DR. MORENO:  Elliot. 

              5               DR. DORFF:  I just have two editorial things. 

              6      Of vital importance, I think just as significant for 

              7     the understanding of amelioration of the subject's 

              8     disorder or condition, or just "important" if you want 

              9     that.  But I think "significant" is a little bit nicer. 

             10               And (c) is not -- this is my mother the 

             11     English teacher speaking -- (c) is not a sentence.  You 

             12     need -- these are -- you have, "adequate positions are 

             13     made to solicit the informed consent of the subject or, 

             14     for a subject who lacks decision-making capacity a 

             15     legally authorized representative." 

             16               DR. MORENO:  I'm not sure we need the comma 

             17     there, but I'll check with the grammarians. 

             18               DR. DORFF:  All right.   

             19               DR. MORENO:  I appreciate it. 

             20               Other comments?   

             21               [No response.]  

             22               DR. MORENO:  All right.  So what I take from 

             23     this is that we need to rethink vital importance along 

             24     the lines of our discussion yesterday.  I am going to 

             25     make an effort to revisit the problem of condition or 
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              1     disorder.  But I'm not entirely sure exactly how that 

              2     is going to work out.  So I'm still interested in 

              3     recommendations on that.  

              4               Susan. 

              5               MS. KORNETSKY:  Jon, I think yesterday -- I 

              6     mean, my own view on this is that we somehow came to 

              7     some agreement on some language that Alan was going to 

              8     try for vital importance and condition and if it means 

              9     the same thing for children as we're trying to get 

             10     across for this, then I would say I'm not -- you know, 

             11     maybe we should talk -- 

             12               DR. MORENO:  Alan and I will talk. 

             13               MS. KORNETSKY:  -- Alan and talk and use the 

             14     same stuff.  

             15               DR. MORENO:  We'll work on it. 

             16               DR. DORFF:  Can I just mention that basically 

             17     the idea was that research -- research is not always of 

             18     vital importance.  I think I said 2 percent of research 

             19     is probably of vital importance.  But nevertheless, 

             20     that doesn't mean it shouldn't happen.  Because the 

             21     vitally important research will not happen unless 

             22     somewhat less vitally important research happens along 

             23     the way.  And that's just the way that human knowledge 

             24     gets expanded.  

             25               And so consequently what you need is 
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              1     significant.  Right.  In other words, this is not a 

              2     fishing trip.  Right.   

              3               DR. RICH:  You don't need an adjective there 

              4     at all. 

              5               DR. DORFF:  All right.  So just as important. 

              6               DR. RICH:  It's either important or it's not. 

              7               DR. DORFF:  Or significant.  

              8               DR. RICH:  Significant importance to me is -- 

              9               DR. DORFF:  No, no, no.  No, what I was 

             10     saying is -- I wasn't saying that.  What I was saying, 

             11     which is of significance for the understanding or 

             12     amelioration of the subject's disorder or condition.  

             13     That's what I was arguing for. 

             14               DR. MORENO:  I think we're going for 

             15     important here, but Alan and I will talk more about 

             16     this.  

             17               PARTICIPANT:  [Off mic.]  You could also use 

             18     the word "meaningful."  

             19               DR. DORFF:  Yes, that's another possibility. 

             20               DR. MORENO:  That's a very sensitive word. 

             21               DR. FLEISCHMAN:  In the children's 

             22     regulations we are, quote, "stuck with" a certain 

             23     language that we need to interpret.  Here we are not 

             24     "stuck with" that language, so we can then --  

             25               DR. MORENO:  Be a little more creative. 
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              1               DR. FLEISCHMAN:  -- use language with more 

              2     creativity.  However, I would like to point out that in 

              3     our conversations yesterday Adil and I made quite clear 

              4     that we were disagreeing about the definition of 

              5     "condition."  And I would lay on the table that I 

              6     continue to disagree with Adil's definition of 

              7     "condition," and I think we reached consensus, although 

              8     not unanimity yesterday, that "condition" would be 

              9     fairly broadly viewed. 

             10               DR. MORENO:  And, again, in this case it may 

             11     not be possible to reach unanimity, but at least we can 

             12     harmonize our use of the language within the NHRPAC. 

             13               Abbey, Felice. 

             14               MS. MEYERS:  I think I said yesterday that 

             15     the reasoning that was used when those words were put 

             16     into the Orphan Drug Act was that a disorder is a 

             17     syndrome or a disease, but a condition could be from a 

             18     trauma.  It doesn't necessarily mean that it's a 

             19     diagnosable disease.  It could be a broken leg.  And so 

             20     I would feel that the word "condition" should be there. 

             21      I think the wording is right on this.  

             22               DR. MORENO:  Thank you.  Felice. 

             23               DR. F. LEVINE:  I think I was making the 

             24     point that as we rewrite, as I've done with other of 

             25     the social behavioral science working group documents 
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              1     from it being a working group document to a NHRPAC 

              2     document that the difference in view in the working 

              3     group becomes, in a way, moot, because if NHRPAC 

              4     reaches a consensus which we think we did, then we can 

              5     just say, NHRPAC conceives of condition as, and 

              6     whatever language --  

              7               DR. MORENO:  Well taken.  Right.  

              8               Anyone else on anything in 3(a), (b) and (c)? 

              9               [No response.]  

             10               DR. MORENO:  All right.  I'm going to read 

             11     four then. 

             12               "The workgroup recommends that 

             13               research not otherwise approvable, 

             14               which presents an opportunity to 

             15               understand, prevent, or alleviate a 

             16               serious problem affecting the 

             17               health or welfare of persons with a 

             18               condition or disorder that may 

             19               affect decision" --  

             20               excuse me --  

             21               "affect the capacity --  

             22               "affect capacity --  

             23               I'm worried about Elliot here. 

             24               "to give informed consent may be 

             25               conducted if the Secretary" --  
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              1               and the rest of this will certainly be as 

              2     familiar as the previous portion to those of you who 

              3     have been reading the regs. 

              4               "-- after consultation with a panel 

              5               that includes both experts in 

              6               pertinent disciplines" --  

              7               and I have added a few here -- 

              8               "e. g., medicine, psychiatry, 

              9               neurology, ethics law, and persons 

             10               knowledge about the experience of 

             11               the population with the disorder or 

             12               condition" --  

             13               and here I've written, "e.g., or the 

             14     workgroup that wrote --  

             15               "e.g. groups that represent the 

             16               problems and interests of the 

             17               population, and following 

             18               opportunity for public review and 

             19               comment has determined that: 

             20               (a)  The research presents an 

             21               opportunity to understand, prevent 

             22               or alleviate a serious problem 

             23               affecting the health or welfare of 

             24               persons with a condition or 

             25               disorder that may affect capacity 
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              1               to give informed consent; 

              2               (b) The research will be conducted 

              3               in accordance with sound ethical 

              4               principles;" 

              5               I don't think anybody is going to object to 

              6     that. 

              7               (c)  Adequate provisions are made 

              8               to solicit the informed consent of 

              9               the subject or for a subject who 

             10               lacks decision-making capacity, a 

             11               legally authorized representative 

             12               has given permission."  

             13               DR. DORFF:  Period. 

             14               DR. MORENO:  All right.  No, LARs, give 

             15     permission, not consent.  

             16               DR. DORFF:  [Off mic.] -- you solicit the 

             17     informed consent of the subject or a legally authorized 

             18     representative --  

             19               DR. MORENO:  Representatives give permission 

             20     not consent.  Only the individual can give consent. 

             21               DR. DORFF:  I see.  Okay.   

             22               DR. MORENO:  All right.  Bob and then Alan. 

             23               DR. R. LEVINE:  I think that our discussion 

             24     of "condition" -- which is repeated here -- a few 

             25     minutes ago was too abrupt.  I want to make it clear 
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              1     that the Commission's choice of the term "condition" 

              2     was not capricious or meant to be overly broad.  In 

              3     particular, in studying in the recommendations on 

              4     research involving children, some research is justified 

              5     in relation to a condition that is not a disorder. 

              6               For example, there are separate passages on 

              7     those who are wards.  These is separate -- there was 

              8     commentary on children who were orphans.  Being an 

              9     orphan is a condition which is not a disorder. 

             10               With regard to what the Commission called 

             11     "mentally infirm" it made a difference to the 

             12     Commission whether they were institutionalized or not. 

             13      It would be legitimate to select people with mental 

             14     impairment or incapacity -- decisional incapacity, for 

             15     participation in the study on the effects of 

             16     institutionalization on these people and to establish 

             17     it as your eligibility criteria that you had to be in 

             18     an institution.  

             19               So the term "condition" is there for a 

             20     meaningful purpose. 

             21               Thank you.  

             22               DR. MORENO:  Thank you.  Alan and then 

             23     Elliot. 

             24               DR. FLEISCHMAN:  Harking back to some of the 

             25     problems we've had with the 407 in the children's 
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              1     regulations, perhaps we ought to include in number four 

              2     that the local IRB would wish to approve the protocol, 

              3     but it is not permissible under the prior three 

              4     statements and that they in a sense are advocating --  

              5               DR. MORENO:  That's interesting.  

              6               DR. FLEISCHMAN:  -- approval.  I think that 

              7     in the 407 committee report that has circulated 

              8     previously there is some conversation about that and it 

              9     seems to me to be a very reasonable approach to that -- 

             10     you know, to that -- excuse me, elevation to the 

             11     Secretary level. 

             12               DR. MORENO:  That's interesting.  Anybody 

             13     want to speak to that? 

             14               DR. SHAMOO:  Would you please repeat it 

             15     because I didn't -- I did not get it.  

             16               DR. MORENO:  Before it gets kicked up to the 

             17     Secretary local IRB should express its wish to approve, 

             18     but can't -- but can't approve.  

             19               DR. FLEISCHMAN:  The children's regulations 

             20     has this an approach for very important work that 

             21     cannot otherwise be permitted by an IRB.  What I think 

             22     has been observed in some of the 407 committee work is 

             23     that the IRBS have not voiced their idea about this.  

             24     So the local IRB says, we can't approve it, and we 

             25     punt. 
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              1               I think it would be --  

              2               CHAIRPERSON MARSHALL:  Wait --  

              3               DR. FLEISCHMAN:  No? 

              4               CHAIRPERSON MARSHALL:  Just to clarify.  It 

              5     doesn't say we can't -- well, it says, we're sending 

              6     this to the OHRP because we have made the determination 

              7     that it could be approved under 407.  And that here is 

              8     why it can't be approved on all the other things, so we 

              9     are asking you.  

             10               DR. FLEISCHMAN:  No, but my argument is that 

             11     there should be a "should" -- not "could."  

             12               CHAIRPERSON MARSHALL:  Yes.  I'm not taking 

             13     issue with that. 

             14               DR. FLEISCHMAN:  Okay.  

             15               CHAIRPERSON MARSHALL:  I just wanted to 

             16     clarify the process that exists.  Sorry.  

             17               DR. FLEISCHMAN:  Okay.  I'm just suggesting 

             18     that it seems to me that if there's an investigator in 

             19     a local institution and the local IRB has reviewed it 

             20     and says that this could be approved, I think it would 

             21     be helpful and maybe even decrease the numbers of 

             22     protocols that move in this direction that the IRB 

             23     would have to say, it should be approved.  We believe 

             24     it's a good thing.  It just cannot be approved except 

             25     through this mechanism.  
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              1               DR. MORENO:  Alan, is there a danger that 

              2     that could short circuit the review process in the 

              3     sense that it should be approved if this "UBER" [ph] 

              4     IRB that the Secretary is going to appoint approves it? 

              5               There seems to be some lack of fit there.  It 

              6     should be reviewed, not that it should be approved; 

              7     right?  

              8               DR. FLEISCHMAN:  Yes.  It's a recommendation 

              9     that the UBER IRB take seriously this proposal because 

             10     the local IRB would have wished to have approved it if 

             11     it could have.  

             12               DR. MORENO:  Right.  

             13               DR. FLEISCHMAN:  The reason why I'm 

             14     suggesting is because my anecdotal or perhaps 

             15     idiosyncratic belief is that there are an increasing 

             16     number of proposals being sent for 407 review based in 

             17     kind of a conservative interpretation of what's 

             18     permitted among IRB reviews.  So at least the IRB would 

             19     have had to do the hard work of thinking through these 

             20     standards and saying, yes, I think it reaches this 

             21     level of importance, but we do believe we do not have 

             22     the authority locally to approve it. 

             23               So I'm just throwing it on the table as 

             24     something I think would be helpful on the children's 

             25     side, and I think would be helpful here. 
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              1               DR. MORENO:  Okay.  Other comments?  Did you 

              2     want to -- okay been said.   

              3               Okay.  Elliot and then --  

              4               DR. DORFF:  I don't want to endorse that.  

              5     And in particular I think what that would do is that it 

              6     would prevent the possibility of, you know, researchers 

              7     trying to trump the local IRB.  In other words, the IRB 

              8     said, no, but I'm going to try to appeal it to a higher 

              9     court, as it were.  

             10               DR. MORENO:  Well taken. 

             11               DR. SHAMOO:  That's not usually what will 

             12     happen.  The local investigator cannot trump 407.  What 

             13     they will do, they will push it to 406 and that's why 

             14     you told us yesterday there's only two cases that has 

             15     ever gone to this Secretary that is prior to recent 

             16     times.  And so I have trouble with your argument.  From 

             17     one side you want to give the IRB all the leeways, at 

             18     the same time what you are doing now, you want to take 

             19     them a step further and you want them to overstep their 

             20     mandate, their federal regs mandate.  There is no 

             21     mandate in the regs to say they should or should not 

             22     recommend. 

             23               And why should they recommend?  Either way, 

             24     that is outside their purview basically.  

             25               DR. MORENO:  Greg. 
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              1               DR. KOSKI:  I think it's essentially implicit 

              2     in the regulations as written that the IRB will go 

              3     through the process and -- I mean, it would be, in my 

              4     mind, somewhat foolish to take research that would be 

              5     disapproved by the IRB and send it for 407 approval.  

              6     So that in the process -- I think there's an implicit 

              7     assumption that they've reviewed this and they do not 

              8     believe that it can be approved under the others, but 

              9     if they didn't think that it should be approved, then 

             10     in fact it would never go.  All Alan is doing is 

             11     saying, rather than having that be an implicit 

             12     assumption making it an explicit designation in the 

             13     exercise of the covalent of a 407 protection may not be 

             14     a bad idea business it lays out there for everyone to 

             15     see exactly what the thinking of the local IRB might 

             16     be. 

             17               DR. MORENO:  Greg, who actually has the 

             18     authority -- doesn't the investigator on his or her own 

             19     have the authority to take it up?  No? 

             20               DR. KOSKI:  It has to go through the IRB. 

             21               CHAIRPERSON MARSHALL:  Can I say something to 

             22     this point? 

             23               DR. MORENO:  Sure.  

             24               CHAIRPERSON MARSHALL:  I just send -- Greg 

             25     and I have been sending notes back and forth like we 
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              1     were in school, we are in a sense, but I just wanted to 

              2     say that we will put on the agenda for the next meeting 

              3     an update from the OHRP on the current 407 process 

              4     which does live again.  And I think that would be 

              5     helpful for all of us and the research community to 

              6     understand how that's working these days. 

              7               Jeff, do you want to add something?  Just 

              8     step up to the microphone and just identify yourself 

              9     for the transcript. 

             10               MR. COHEN:  My name is Jeff Cohen from OHRP. 

             11      407 does state -- 407(a) does specifically states that 

             12     the IRB finds that research presents a reasonable 

             13     opportunity to further the understanding, et cetera, et 

             14     cetera.  So it does require that the IRB thinks this is 

             15     good stuff.  

             16               DR. MORENO:  Does it?  

             17               MR. COHEN:  That's what it explicitly says in 

             18     407.   

             19               DR. MORENO:  Okay.  We're cooking. 

             20               MR. COHEN:  Okay.  407(a) it says: 

             21               "The IRB finds that the research 

             22               presents a reasonable opportunity 

             23               to further the understanding, 

             24               prevention or alleviation of a 

             25               serious problem affecting the 
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              1               health or welfare of children." 

              2               DR. MORENO:  Hm -- I must have redacted my 

              3     Bible somehow.  Thank you.  

              4               Abbey. 

              5               MS. MEYERS:  Yesterday I had mentioned that a 

              6     lot of what's written in the regs are for people who 

              7     aren't sick or are minimally sick.  And what it looks 

              8     like to me is that any kind of drug research, clinical 

              9     research on a new drug would have to go through this 

             10     number four because it might -- it represents more than 

             11     minimal risk.  And something like Clozaril would have 

             12     never been approved for schizophrenia, you know, for a 

             13     clinical trial.  I don't understand this because it 

             14     really doesn't address -- number four, does not address 

             15     the question of people who are very sick and are 

             16     willing to take more of a risk and it also puts all of 

             17     the work into Greg's office and he doesn't have the 

             18     manpower to look at several hundred protocols. 

             19               DR. MORENO:  I think number two is intended 

             20     to do what you suggest.  Bob. 

             21               DR. R. LEVINE:  Yes, this is what I was 

             22     talking about a few minutes ago.  The procedures or 

             23     interventions that hold out the prospect of direct 

             24     benefit are not to be evaluated according to the 

             25     standards of minimal risk or minor increase.  Clozaril 
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              1     would be one such intervention.  They're to be 

              2     evaluated much more like procedures are evaluated for 

              3     prescription in the practice of medicine in terms of 

              4     the risk benefit balance for the individuals involved. 

              5               So this is one of the reasons that I insist 

              6     that we get rid of this business of beneficial 

              7     therapeutic or non-therapeutic research, it's the 

              8     specific intervention that has to be evaluated.  And if 

              9     it holds out the prospect of benefit, then we don't 

             10     think minimal or anything like that. 

             11               DR. MORENO:  Well taken. 

             12               Elliot had his hand up a long time ago.  

             13               DR. DORFF:  Yes, my question is just it's a 

             14     number four and it's on a different issue.  Alleving 

             15     the serious problem affecting the health or welfare of 

             16     persons with a condition or disorder that may affect 

             17     capacity -- may be conducted and so on.  Is this only 

             18     going to be for the condition that leads to the 

             19     incapacity to give informed consent?  Or do you want it 

             20     to be broader than that?  

             21               So like, for example, if you had a 

             22     schizophrenic person who also had kidney disease, could 

             23     that person be part of a study of some kind of kidney 

             24     drug?  

             25               DR. MORENO:  One of the NBC recommendations 
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              1     that we want to accept is that if there's an 

              2     opportunity to do this with a population that has 

              3     decision-making capacity, you should do it with them 

              4     and not with others. 

              5               Thank you for putting that --  

              6               DR. SHAMOO:  Yes, as a matter of fact, in 

              7     answer to Abbey, remember, these are for global people 

              8     who we have decided that they are decisionally 

              9     impaired.  And, therefore, even according to the common 

             10     rule or any other code of ethics, we have a greater 

             11     responsibility of raising the ethical bar for their 

             12     protection.  The rule gives us that right to have 

             13     greater protection because they are vulnerable.  They 

             14     could be exploited, and that is why we are dealing with 

             15     this. 

             16               If somebody has a serious disease and he's 

             17     competent, this doesn't -- it doesn't have to follow 

             18     that and they could volunteer and sign informed 

             19     consent.  There is no problem.  So your examples are 

             20     fine.  But these are for a group of people who are 

             21     decisionally impaired in the society basically or the 

             22     surrogate, or whoever it is, is making those decisions 

             23     for them.  And we have a greater responsibility. 

             24               MS. MEYERS:  Where is the clinical trial on a 

             25     risky drug fall under this draft?  
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              1               DR. R. LEVINE:  It doesn't.  

              2               [Simultaneous conversation.] [Off mic.] 

              3               DR. R. LEVINE:  [Off mic.]  No, it's number 

              4     two, it's not any of these numbers.  You don't apply 

              5     minimal, minor increase or anything like that if the 

              6     intervention or procedure holds out a prospect.   

              7               DR. MORENO:  Bob.  Microphone. 

              8               MS. MEYERS:  What does number four cover?  

              9     Give me an example of what Number four would cover? 

             10               DR. R. LEVINE:  Let me finish what I was 

             11     saying.   

             12               DR. MORENO:  Go ahead.  

             13               DR. R. LEVINE:  The prospect -- I was not 

             14     referring to number two as it is written here, but 

             15     number two as it will be rewritten after they sort out 

             16     the --  

             17               DR. MORENO:  Right.  

             18               DR. R. LEVINE:  -- intervention or procedural 

             19     language.  And then this 2(a) will no longer be located 

             20     there.   

             21               DR. MORENO:  Right.  In answer, Abbey, to 

             22     your question, you know, I learned a long time ago in 

             23     graduate school that we're prisoners of our examples.  

             24     But I think what we're thinking about here is some 

             25     potential great breakthrough.  You know, Interleukin 
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              1     for schizophrenia, I mean, pull something totally out 

              2     of the air -- that has, for various reasons, given 

              3     people some hope, but doesn't -- requires a national 

              4     conversation and very public and transparent discussion 

              5     before you put people in that position. 

              6               MS. MEYERS:  [Off mic.]  If it's a drug study 

              7     -- drug company -- discretion of their --  

              8               DR. MORENO:  That's not our problem.  And, by 

              9     the way, they might.  I mean, if they're going to make 

             10     a billion dollars a year.  Bob. 

             11               DR. R. LEVINE:  Interleukin two for 

             12     schizophrenia probably would not be in this category.  

             13     Because, by the time you were ready to start the trials 

             14     of interleukin you should have already developed some 

             15     information that would support a statement that it held 

             16     out the prospect of direct benefit.  What they were 

             17     talking about in the what we're now calling 407 

             18     category was a breakthrough in the basic understanding 

             19     of a disorder.  So, for example, to follow your 

             20     analogy, a promising lead that says you might find 

             21     interleukin two receptors in patients with Alzheimer's 

             22     disease that would be a 407 thing.  And once you found 

             23     them, then you do a little preliminary work and you're 

             24     moving back into hold out the prospect of direct 

             25     benefit research.  
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              1               DR. MORENO:  Thank you.  

              2               Sandy, you wanted to say something a long 

              3     time ago. 

              4               DR. CHODOSH:  [Off mic.]  Yes, very brief.  I 

              5     just want to be really sure that the -- thank you, that 

              6     in four you put the "and"s in.   

              7               DR. MORENO:  The "and"s are going in.  

              8               DR. CHODOSH:  Because if one were to stop at 

              9     (a), one could have Tuskeegee.   

             10               DR. MORENO:  No Tuskeegees allowed. 

             11               DR. SHAMOO:  You said that before.  

             12               DR. CHODOSH:  But we did it for the others, 

             13     but it's more important here.  

             14               DR. MORENO:  Thank you.  

             15               DR. SHAMOO:  Yeah, I agree.  

             16               DR. MORENO:  Mary Faith.  

             17               CHAIRPERSON MARSHALL:  No.  

             18               DR. MORENO:  All right.  Any other comments 

             19     on any of this from the members of the committee?  If 

             20     not -- yes, Alan.  

             21               DR. FLEISCHMAN:  Are we going to talk about 

             22     the future work list? 

             23               DR. MORENO:  Well, I would like to do that.  

             24     I'm getting -- yes, all right.  Let's talk about the 

             25     future work list.  Anybody want to add some work to 
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              1     this, obviously we're going to go back and revise this 

              2     document in light of this very helpful discussion.  But 

              3     we're also talking about work that is implicated by 

              4     this topic on this list.  And there may be other topics 

              5     as well.  Keep in mind that we want to finish this in 

              6     the 21st Century if we can.  And I'm not going to be 

              7     around that much longer. 

              8               DR. SHAMOO:  Can I? 

              9               DR. MORENO:  Yes.  

             10               DR. SHAMOO:  In the future list, I think we 

             11     need to elevate to number one the independent capacity 

             12     assessment.  Because it is so intertwined with the rest 

             13     of the document.  So we need to deal with that first 

             14     before we go on advance directives or placebo.  Because 

             15     those almost stand on their own. 

             16               DR. MORENO:  I would have thought in the 

             17     capacity assessment and the legally authorized 

             18     representative problem.  

             19               DR. SHAMOO:  Yeah, I agree.  I agree.   

             20               DR. MORENO:  Okay.  Anybody else?  Alan and 

             21     then -- well, go ahead, Sandy. 

             22               DR. CHODOSH:  Just logical, however, and Greg 

             23     can speak to this, knowing what's number and that 

             24     current number one will take in order to enact.  We 

             25     don't have a mechanism for this, I don't think.  This 
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              1     is establishing a new special standing panel.  How long 

              2     does that take?  And if so, that should be started 

              3     while we're doing the other things.   

              4               DR. MORENO:  Well --  

              5               DR. CHODOSH:  Because there's no sense in 

              6     getting this whole process in place and not having 

              7     that. 

              8               DR. MORENO:  Well, the panel in part four 

              9     shouldn't be construed as the special, standing panel 

             10     that NBC was talking about.  That was a standing panel, 

             11     not an ad hoc panel.  And it's not -- if this document 

             12     is roughly acceptable as we go on, then we may not even 

             13     -- there may not even be a roll for that panel. 

             14               DR. CHODOSH:  407(a) won't cover this now.  

             15               DR. MORENO:  Well, I'm not sure.  It might.  

             16     It would be protocol by protocol, that's all. 

             17               I think we do need to open it up and so we'll 

             18     hear from our ex-officio members, first, anybody who 

             19     would like to take the microphone, and please identify 

             20     yourself. 

             21               David. 

             22               MR. TRAU:  I'm David Trau with the National 

             23     Institute of Health.  I'm very pleased that you decided 

             24     to change the wording from this order that this poses 

             25     to since the various problems that would come up in 
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              1     that at regard were certainly aired during the NBC 

              2     discussion.  

              3               In terms of Dr. Levine's point regarding the 

              4     range of impairment that may occur, certainly now we're 

              5     seeing much more use of consent monitors, IRB 

              6     representatives, third party clinicians or advocates to 

              7     assess whether people who might have an impairment 

              8     really do have an impairment or not.  But my concern is 

              9     that while these additional safeguards are already 

             10     called for in the regs and can be required by the local 

             11     IRB, it seems unclear whether a person who is evaluated 

             12     for capacity based on these provisions and found able 

             13     to consent, it's not clear to me whether that person 

             14     would then fall into this just because they had a 

             15     questionable impairment, and if the person is found not 

             16     to be significantly impaired, would they in fact go 

             17     back to the adult regulations rather than be treated 

             18     like a child which is what these do. 

             19               My more specific comments or questions have 

             20     to do with number one.  It doesn't mention consent 

             21     waivers which, of course, are currently part of the 

             22     adult regulations.  Is it your intention to outlaw 

             23     consent waivers for individuals who have some 

             24     impairment of capacity?  

             25               And the final question that I'll ask, because 
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              1     I know time is of the essence at this point, concerns 

              2     number four, and the question of how long you expect 

              3     this process to take?  People have told me that going 

              4     to a Secretary's panel is in effect a death sentence 

              5     because it will take a matter of years before they get 

              6     an answer.  I told people that was not the case, but, 

              7     unfortunately I was wrong.  Is there some way to 

              8     indicate in this language that this is to be done in a 

              9     reasonably timely fashion so that the research is not 

             10     impossible to do by the time a decision is made? 

             11               DR. MORENO:  You could say "all deliberate 

             12     speed." 

             13               Greg, did you want to comment on either of 

             14     those? 

             15               DR. KOSKI:  Yeah, on a couple of things.  I 

             16     think we want to be careful, David, in using terms 

             17     like, you know, treating people with impaired decision-

             18     making ability like children.  While there are 

             19     analogies, certainly between the constructs here there 

             20     are also special provisions for protection of prisoners 

             21     that are similar as well now as in protection of 

             22     pregnant women and fetuses and so on.  So I understand 

             23     the sensitivity.  There is an analogy there and I think 

             24     we would want to be careful in the way we use the words 

             25     there. 
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              1               With respect to the process and I can tell 

              2     you no one is -- or no group is more concerned about 

              3     the slowness of the process that's been, you know, 

              4     there for dealing with some of the special panel 

              5     requests that have come up within the past year, as has 

              6     been stated previously, although this stuff was in 

              7     regulations for 20 years, in fact, there had only been 

              8     two situations where in fact those had been invoked 

              9     over those two decades.  And, indeed, a lot had changed 

             10     over two decades.  When the regulations were written, 

             11     those people who had -- you know, the majority of 

             12     things weren't done in multi-center trials and so on.  

             13     They're still not the majority, but I think the only 

             14     point is there are a number of difficult issues around 

             15     privacy, intellectual property, as well as multi-center 

             16     trials, a whole host of things for which there was no 

             17     process.  And as you all know, developing and 

             18     implementing processes within the federal bureaucracy 

             19     is not always a minor undertaking. 

             20               So I want to credit the crew in our office 

             21     who have had to take this bull by the horns, and 

             22     particularly Annette Baden and Cliff Sharkey as well as 

             23     Irene Stith-Coleman who have really been dealing with a 

             24     number of compensated issues here and people, some of 

             25     whom are on this panel, who have contributed their time 
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              1     to those reviews.  We will get a full -- I think Mary 

              2     Faith mentioned it, we would like to give a full report 

              3     and updating on that process, how it works, will work. 

              4      I think though that we share your sense that this has 

              5     to occur in much less than a year in order to be 

              6     effective.  It has to be something that helps to 

              7     support research that in fact has already been 

              8     determined that it holds out a prospective -- we have 

              9     to look at it that way while we move forward with 

             10     making sure that there are adequate protections there. 

             11      And, again, you know, we're making a commitment to you 

             12     to ensure that the process moves forward in a timely 

             13     manner, and I don't think that needs to be specifically 

             14     written into the regulations.  Thank you very much. 

             15               DR. SHAMOO:  I think Dr. Shore made the other 

             16     comment that if you -- if the person -- decision 

             17     suspect of decisional impairment was tested and found 

             18     not decisionally impaired of course he goes back to the 

             19     regular adult regulations, the normal, that's the whole 

             20     purpose.  That's all in here and in all the NBC 

             21     recommendation and in all working group.  So I think it 

             22     doesn't even need an argument, at least in my mind.  

             23               DR. MORENO:  Jeff. 

             24               MR. COHEN:  I'm Jeff Cohen again from OHRP.  

             25     I want to go way back to Mary Faith's comment early on 
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              1     in the discussion about the fact that we need to focus 

              2     on the consent process.  And particularly we need to 

              3     get the individual subject involved in the process as 

              4     much as is possible depending on their individual 

              5     circumstances.  I think that should be very explicit in 

              6     this section.  Because we have to take every 

              7     opportunity to make that case as strongly as possible 

              8     and to make it clear that if you get away from this 

              9     event, considering consent is an event concept, and in 

             10     light of that, I would also like to ask if the working 

             11     group considered asset issues involved in this that the 

             12     individual, even if they have decisional impairment 

             13     still should be involved in the process and the concept 

             14     of assent as it's applied in the children's regulations 

             15     may be appropriate. 

             16               DR. MORENO:  It's also included in the 

             17     invisible NBC recommendations that are presupposed. 

             18               Thank you, Jeff.  

             19               Bob. 

             20               DR. R. LEVINE:  I think Dr. Shore -- his 

             21     concern about whether this might be ambiguous is very 

             22     well founded.  Because each of the recommendations say 

             23     that adequate provisions are made to solicit informed 

             24     consent which implies that the thing he's concerned 

             25     about may actually be true, that anyone who is 
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              1     considered would have to be tracked in this system 

              2     rather than going to what we are now horrified to say 

              3     --  

              4               DR. MORENO:  Standard system.  

              5               DR. R. LEVINE:  -- what we are now calling 

              6     the adult regulations. 

              7               DR. MORENO:  Standard system.  

              8               DR. R. LEVINE:  I think though that if we 

              9     mean this to apply only to those who are found to be 

             10     decisionally incapacitated that we've got to take 

             11     informed consent out of each of the recommendations and 

             12     replace it with assent.  If they can give consent, 

             13     they're not incapacitated.  

             14               David, am I hitting on what you were 

             15     concerned about? 

             16               MR. SHORE:  I think that's a large part of it 

             17     point that it's unclear whether people who may be --  

             18               DR. MORENO:  Step to the microphone, please, 

             19     David. 

             20               MR. SHORE:  I think that's exactly right, 

             21     Bob, that the issue is whether people who might be 

             22     impaired or might be considered as was originally in 

             23     the language to have a condition that might impair 

             24     their capacity whether the current means to evaluate 

             25     that, the additional safeguards would be sufficient to 
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              1     not require a person to be in this particular scenario. 

              2               And I think if you mean what Adil suggested 

              3     that it would be useful to say that here because 

              4     certainly that wasn't the impression that I took from 

              5     reading this in the same way that I had a problem with 

              6     the language about disorder that it disposes them to or 

              7     as Jonathan said in his introductory remarks, people 

              8     who are actually lacking capacity.  Because that's a 

              9     very, very different distinction. 

             10               I would also like to remind you about my 

             11     question about consent waivers and whether you would 

             12     eliminate them from this group. 

             13               DR. MORENO:  I feel awkward talking about 

             14     this because the workgroup did not discuss the consent 

             15     waiver question.  So I think we're going to have to 

             16     take that on advisement and I really don't feel I can 

             17     say anything about that right now for the workgroup. 

             18               Is there anybody else who wants to say 

             19     anything about this document at all?   

             20               DR. FLEISCHMAN:  Do we want a Mark Barnes 

             21     motion?  

             22               DR. MORENO:  No, no, let's not Mark Barnes it 

             23     yet.  I think in fact what we've learned is there is 

             24     more work to be done.  And this discussion has been 

             25     extremely helpful, I think.  We have advanced the ball 
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              1     down the field as it were, at least five yards or so, 

              2     which is a lot for this topic, if I do say so myself. 

              3               Greg, did you want to say anything at all, 

              4     before I --  

              5               DR. KOSKI:  I think in fact you've gone a lot 

              6     further than five yards.  And I want to congratulate 

              7     you.  And this is really tough work, but I think you're 

              8     making very significant progress on that. 

              9               I just wanted to -- I think we're either 

             10     going to break or move on to something else.  I'll talk 

             11     just very quickly about process.  As you know the 

             12     department has remanded its working group report to us 

             13     to move forward.  We need the advice from NHRPAC on 

             14     these four specific points and it sounds like we're 

             15     close to getting that.  There will be additional work 

             16     to be done. 

             17               Once we do have that advice our intent is to 

             18     work with the other federal agencies, our policy group 

             19     will look at this and the department has essentially 

             20     two courses of action that it can take here.  One is to 

             21     offer, you know, further guidance on these issues or if 

             22     the Secretary were to choose to do so, then the 

             23     Department could move forward with specific 

             24     regulations, perhaps the subpart to the existing 

             25     regulation to afford special protections.  
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              1               Again, the decision is to how the department 

              2     will be moving forward is one that will be determined, 

              3     you know, by the Secretary's Office, basically.  And, 

              4     as I said, in concert with the other agencies within 

              5     HHS.  And I do think that we would like to see this as 

              6     Jonathan said, move forward in this century. 

              7               So I'm happy to see it moving forward and 

              8     thank you all very much.  

              9               DR. SHAMOO:  I want to thank Jonathan for his 

             10     leadership.  It's really hard work.  This has been an 

             11     intractable seven-year-old problem and we have made 

             12     progress, and I think this panel should appreciate that 

             13     despite there are some differences here, here and 

             14     there, and remaining.  So we are grateful to Jonathan.  

             15               DR. MORENO:  Thank you.  Elliot did you want 

             16     to --  

             17               DR. DORFF:  Here, here. 

             18               [Applause.]  

             19               DR. DORFF:  This is just a light sort of 

             20     comment on the issue of vitally important research.  

             21     There was David Dalvi a professor of law at UC-Berkeley 

             22     was giving several lectures at the University of 

             23     Judaism and I was driving him from one place to another 

             24     and he said that there are two problems that academia 

             25     has always had and he has the solution to both of them. 
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              1               One of them is that freshmen never get full 

              2     professors and the other one is that professors need to 

              3     publish this inane research simply to be able to get 

              4     promoted.  So the solution is very simple.  When you 

              5     get your Ph.D. you are appointed a full professor, that 

              6     way freshmen get a lot of full professors.  And then 

              7     every time you publish a book you're demoted.  

              8               [Laughter.]  

              9               DR. DORFF:  Now that would be vitally 

             10     important research.  

             11               [Laughter.]  

             12               [Applause.]  

             13               CHAIRPERSON MARSHALL:  We will break for 15 

             14     minutes. I guess that brings us back at 20 after three. 

             15      But before we -- folks, don't leave. 

             16               Before we break for our -- stand up for our 

             17     break I want to acknowledge because I know that 

             18     Jonathan has to leave a little early, I want to 

             19     acknowledge the fact that Elliot's term is nearing to a 

             20     close.  Our desire is that he be reappointed to the 

             21     committee.  We are sort of in the process of moving 

             22     along with those things and I'm not sure what the 

             23     outcome of that might be.  But, Elliot, I want to thank 

             24     you and we would like to thank you for all of your hard 

             25     work and for being here and for your charm and good 
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              1     humor and your most wonderful scholarship.  And I also 

              2     want to say that he's not going necessarily that far, 

              3     because he does co-chair this very important workgroup 

              4     and I think that detail might be for life.  

              5               [Laughter.]  

              6               CHAIRPERSON MARSHALL:  And I'll say goodbye 

              7     later too, but I wanted, because some folks may have to 

              8     wander out early or leave early, to thank you, 

              9     especially.  

             10               [Applause.]  

             11               CHAIRPERSON MARSHALL:  And now we can break. 

             12      We'll be back at 20 after. 

             13               [Brief recess taken at 3:05 p.m.] 

             14               CHAIRPERSON MARSHALL:  Thanks to everyone who 

             15     is still here.  We have had such a productive and 

             16     fruitful two days.  We are really doing good work, I 

             17     think.  Just super work.   

             18               I want to make just a couple of housekeeping 

             19     announcements before we move on just because I know 

             20     some of you may not be able to be here until the bitter 

             21     end.  One is that Kate and I have been talking about 

             22     this for a while, but what we are going to do at our 

             23     next meeting and all of our future meetings is to have 

             24     two sets of tables, actually, sort of up here in the 

             25     front of room, one for the committee and one for the 
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              1     committee ex-officio members.  We'll be sending out 

              2     sort of an announcement or an invitation so all of the 

              3     ex-officios know that they will have a seat and a 

              4     microphone and name plaque and that we will invite 

              5     their even more active participation than we have had 

              6     in the past. 

              7               [Paragraph deleted.] 

              8               CHAIRPERSON MARSHALL:    So let's move on to 

              9     Felice and Jeff and they are going to update us on the 

             10     very hard work that the social and behavioral sciences 

             11     workgroup has been doing at the wee hours of the 

             12     morning, I do believe.  Felice, truly does not sleep. 

             13               DR. F. LEVINE:  It's amazing how many coasts 

             14     you can hit.  At two in the morning you get the five 

             15     o'clock people getting up.  

             16               Thank you.  

             17               We actually have one item that was, I guess I 

             18     would say, mentored and developed under the aegis of 

             19     the social and behavioral science working group, but 

             20     was accepted actually with a tremendous amount of 

             21     enthusiasm by NHRPAC in January and that was the 

             22     confidentiality statement.  And then two of us were 

             23     designated with the task of making some revisions to 

             24     that and I passed it out yesterday, and that is Susan 

             25     Kornetsky and I as with our NHRPAC hats on were 
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              1     designated with what I call a process of migrating this 

              2     to being a NHRPAC document, but actually there were 

              3     only two elements of recommended change for those of 

              4     you in the audience who didn't -- we had a stack of 

              5     copies, but who might not have picked one up.  And that 

              6     was that in the embracing of the document to make it 

              7     clear that this was generic and that recommendations 

              8     with respect to confidentiality were not in any respect 

              9     sui generous to the social and behavioral sciences 

             10     although that may be a particular issue with respect to 

             11     risks that we were conscious of safeguarding. 

             12               And the other which was a little bit more 

             13     modest statement was to ensure that in our saying that 

             14     as risk goes up confidentiality protections also need 

             15     to handshake and be as secure and as firm as possible 

             16     that the antithesis of that is not the case, that as 

             17     risk goes down that one's clear visions of 

             18     confidentiality are agreed on that that doesn't mean 

             19     that that is any less resolute.  But obviously the 

             20     numbers of firewalls, I guess you would say, needed to 

             21     be more secure. 

             22               So what we want to do really on behalf of 

             23     both the working group, and in a way NHRPAC, is to 

             24     review these and hopefully NHRPAC will be in a position 

             25     to take action on that. 
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              1               Then move to just a brief overview of what 

              2     the social and behavioral science working group is 

              3     working on now which will be very brief so that one of 

              4     the key issues that we discussed at our meeting on the 

              5     22nd of April, and that is the discussion of course 

              6     research and student training in courses.  We can have 

              7     an initial discussion and report on because then we 

              8     want to work on that more and bring a more final report 

              9     and recommendations to the group in July.  And Jeff 

             10     will sort of take the lead in presenting that.  So 

             11     those are really, from our point of view the sort of 

             12     two key issues that are on our agenda today. 

             13               There was a subgroup and I can't remember all 

             14     of my colleagues, I know it included Elliot and I think 

             15     it included -- I think it actually included Abbey, but 

             16     several of us do need to do the same thing that we did 

             17     with confidentiality for risk and harm which was also 

             18     supported in January.  And, indeed despite my staying 

             19     up all night, that was one that slipped from the menu. 

             20      So we'll bring that back in July. 

             21               With that, let's -- Susan do you want to say 

             22     maybe a few introductory words about the 

             23     confidentiality?  

             24               MS. KORNETSKY:  The only thing that I think 

             25     we had brought up last time was it was written so well 
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              1     and so beautifully and I just kept thinking about it 

              2     from a biomedical perspective and there was nothing 

              3     there that didn't apply.  And I thought it was all 

              4     important.  So Felice went through and we have just 

              5     made changes and maybe inserted a couple of examples of 

              6     areas that may apply in the biomedical.  There was no 

              7     enormous number of changes.  I don't think the content, 

              8     the context changed just to really expand it to make it 

              9     applicable. 

             10               DR. F. LEVINE:  You can see that from the 

             11     opening line and then in a lot of the "e.g." whereas in 

             12     the third paragraph we had previously drug abuse, high 

             13     risk sexual behavior and violence as areas where 

             14     confidentiality protections really need to be secure. 

             15               We added the spread of HIV and genetic 

             16     predispositions as to other similarly situated arenas 

             17     of work.  So that was well within the spirit of being 

             18     more inclusive.  Similarly on page 2, third paragraph 

             19     from the bottom, where we're trying to explain that 

             20     when confidentiality is provided, it must be secure, 

             21     and that indeed there needs to be a higher level of 

             22     scrutiny in more vulnerable kinds of circumstances.  

             23     And we had one example from the social and behavioral 

             24     sciences. 

             25               We juxtaposed laboratory studies on the level 
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              1     of boredom which if confidentiality is provided it 

              2     certainly needs to be protected and secure and then we 

              3     said, "associated with repetitive tasks does not 

              4     involve the same risk of data disclosure as surveys of 

              5     personal sexual orientation and experience." 

              6               And then Susan added a very nice one, 

              7     "clinical laboratory data does not involve the same 

              8     risk of disclosure as genetic testing."  So that we 

              9     tried to kind of achieve that inclusive balance.  I 

             10     wanted to cite that one in particular because that was 

             11     also an area where we wanted to make very clear that -- 

             12     and we say, "explicitly in all cases where 

             13     confidentiality is included in the consent agreement it 

             14     must be granted and secured regardless of the level of 

             15     risk." 

             16               So that's an absolute, you know, that's 

             17     floor. 

             18               So I open it up to my colleagues.  

             19               DR. SHAMOO:  I would presume your 

             20     recommendation number you is the same for biomedical.  

             21     Because if it is, it's a good recommendation.  The 

             22     report looks really very reasonable.  However, if I was 

             23     the other investigator and all I have to do is sign up 

             24     a sheet of paper that I'm going to abide by everything, 

             25     it doesn't have the impact.  There has to be some kind 
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              1     of a process.  So the new investigator who has not been 

              2     involved in IRB or I think the protocol et cetera, to 

              3     impact on him, this is an important issue and you've 

              4     got to really conform to all the needs of 

              5     confidentiality, et cetera. 

              6               So I would sort of have that paragraph either 

              7     have a process sort of defined a little bit or 

              8     emphasized just for your thoughts.  

              9               DR. F. LEVINE:  I think that point is well 

             10     taken.  In a way it grafted on to the public use 

             11     recommendations on the one hand and also with data that 

             12     are not accessible but somehow analyzed by other 

             13     investigators that ORP should develop guidance to make 

             14     it clear to those investigators that they must abide by 

             15     all original agreements if there's any sharing with 

             16     other investigators of that data. 

             17               We could add a few words beneath that to -- 

             18     although I think it's actually above it and hopefully 

             19     it made it clear, but we'll take another look, I guess. 

             20               Susan, did you --  

             21               DR. CHODOSH:  Doesn't that bring up this same 

             22     issue of how does that get transferred, that 

             23     information from the IRB that originally approved it to 

             24     an investigator in another -- in the jurisdiction of 

             25     another IRB that these are the conditions?  That part 
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              1     isn't clear.  And it seems to me that there are some 

              2     logistical problems and perhaps legal problems that 

              3     happen when you're going from institution to 

              4     institution.  You know, we're saying that other 

              5     investigators using the data must abide by the 

              6     confidentiality that was originally granted, but it may 

              7     not have been granted by the same IRB.  Is that a 

              8     problem?  

              9               MS. KORNETSKY:  I think what this is saying 

             10     -- what this is saying here is that acknowledging that 

             11     this is an issue when investigators share data, whether 

             12     it's even within the institution or with outside, and 

             13     we can either -- this not solving that problem, but 

             14     it's basically saying is OHRP should develop guidance. 

             15      Now, I guess this group feels that we're the ones to 

             16     develop the guidance, then we can take that forward.  

             17     But this is acknowledging that it is an issue and there 

             18     needs to be guidance. 

             19               DR. CHODOSH:  Except what we're talking about 

             20     is the investigator's responsibility, but, yes, each 

             21     one has a responsibility to their IRB.  And maybe 

             22     something about the IRB's responsible must insure.  I'm 

             23     not sure about that, but it seems to me that like all 

             24     it says is that the investigator is now under the 

             25     control of another IRB because he has to follow the 
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              1     rules of that IRB in terms of the confidentiality that 

              2     they imposed. 

              3               DR. F. LEVINE:  Let me just say, I think in 

              4     this case we were not suggesting that -- we were really 

              5     trying to underscore that the confidentiality must be 

              6     maintained under any circumstance both by the 

              7     investigator in bringing a protocol forward and the IRB 

              8     in reviewing it.  And this was not making a statement 

              9     about one IRB deferring to another because it was also 

             10     dealing with restricted datasets, not just public use 

             11     datasets.  So it was only trying to address the limited 

             12     notion, that confidentiality cannot be -- I guess it 

             13     was saying, could not be waived by a -- in any way 

             14     could not be relaxed by an IRB or an investigator under 

             15     a second set of circumstances.  

             16               Alan. 

             17               DR. FLEISCHMAN:  I think we're all agreeing, 

             18     but one process approach which our IRB has used is to 

             19     obligate the investigator who is giving the dataset to 

             20     assure that before the dataset is given there are 

             21     adequate confidentiality protections created.  Since, 

             22     you know, our IRB can only obligate our investigators. 

             23      I think that's Sandy's point.  I think that's a way of 

             24     doing it that just makes it clearer. 

             25               DR. F. LEVINE:  Why don't we add that, that 
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              1     we do it both ways.  And this was addressing the 

              2     sharing of nonpublic use data.  So there is a 

              3     subsequent IRB in this case.  So let's add a sentence 

              4     that reaffirms the binding nature of the primary 

              5     investigator as well as any secondary end user.  That 

              6     would meet it?  Okay.  

              7               DR. CHODOSH:  The identified data is then not 

              8     really a great problem.  It just then becomes a problem 

              9     when it's still identified. 

             10               DR. MORENO:  Move approval? 

             11               CHAIRPERSON MARSHALL:  We'll take a verbal 

             12     vote.  All of those in favor?  

             13               [Chorus of ayes.]  

             14               CHAIRPERSON MARSHALL:  Those opposed?  

             15               [No response.]  

             16               CHAIRPERSON MARSHALL:  Any abstentions?  

             17               [No response.]  

             18               CHAIRPERSON MARSHALL:  Vote carries. 

             19               I left out the discussion part, didn't I? 

             20               [Laughter.]  

             21               MS. DeWOLF:  I'm Jenny DeWolf and I work at 

             22     the Committee on National Statistics at the National 

             23     Academy.  I know a little bit about confidentiality 

             24     protection and de-identification is necessary, but not 

             25     a sufficient step.  I don't have the document, by the 
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              1     way.  

              2               Felice, in this document did you deal with 

              3     the record linkage, the linkage issue, of the potential 

              4     of someone taking a de-identified dataset and merging 

              5     it with another dataset on certain variables and 

              6     inferring the identity of the anonymous participants.  

              7     Am I being clear? 

              8               DR. F. LEVINE:  Yeah, Janet.  This document 

              9     is really focusing on the confidentiality provisions 

             10     and the firewall at the front end.  I think in the 

             11     public use dataset, I think, recommendations, we were 

             12     explicit that the linking of two otherwise anonymized 

             13     datasets does require rereview because you might create 

             14     a new linkage. 

             15               MS. DeWOLF:  What happens if --  

             16               DR. F. LEVINE:  And that was in the other set 

             17     of recommendations. 

             18               MS. DeWOLF:  I'm listening as closely as I 

             19     can, and let's say the New York Academy of Medicine's 

             20     IRB where Alan is, allows a PI to release a dataset.  

             21     Right?  To share a dataset.  What prevents the 

             22     recipient from trying to re-identify those individuals? 

             23               DR. MORENO:  A de-identified dataset?  It 

             24     should not be possible for that to happen if it's 

             25     appropriately de-identified.  
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              1               MS. DeWOLF:  It depends on -- there's a 

              2     researcher at Pittsburgh, LaTonya Sweeney who has re-

              3     identified the medical records of the former governor 

              4     of Massachusetts by matching -- it's been de-

              5     identified, no names, but it had zip code and age, and 

              6     she bought the voting records from Cambridge and was 

              7     able to match on three variables finding out Governor 

              8     Weld, I guess is his name, information.  Now, as a 

              9     statistician you don't release universe data.  Maybe as 

             10     a medical person you do.  But there is so much stuff ou 

             11     there, how do you know that it's not going to happen?  

             12               DR. F. LEVINE:  I think we covered that 

             13     adequately or sought to in the public use data files 

             14     recommendation.  This, to the extent that this has one 

             15     section on confidentiality -- on data sharing it is in 

             16     the limited situation where non-public data are shared 

             17     in accordance with the protocol.  So this isn't -- the 

             18     confidentiality statement doesn't deal with public use 

             19     data files at all. 

             20               DR. MORENO:  Can I suggest that when we 

             21     create these kinds of recommendations, we're taking 

             22     about people whose intentions are honorable.  And, you 

             23     know, that we're trying to make a system so that 

             24     confidentiality is maintained with people who not 

             25     intending to do bad things. 
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              1               So the only way to get around, I would think, 

              2     people with evil intentions is to punish them. 

              3               MS. DeWOLF:  I'm sort of playing a devil's 

              4     advocate role because faculty members have students -- 

              5     I'm sorry, students think this is a great thing.  I'm 

              6     just going through hypothetical inadvertent disclosure, 

              7     okay.  Somebody says, I want to add this other dataset 

              8     to this file, and I want to do my own research.  It's 

              9     going to be groundbreaking.  And all of a sudden they 

             10     figure out that it's, you know, Greg Koski.  I don't 

             11     know, I'm making this up.  

             12               [Laughter.]  

             13               MS. DeWOLF:  But they --  

             14               DR. KOSKI:  I have no secrets.  

             15               MS. DeWOLF:  I know, I figured you don't.  

             16     But I'm not trying to say that anyone is evil or 

             17     malevolent, I'm just trying to say that even with 

             18     nonpublic microdata there is a risk.  And, again, I 

             19     have read that document, because I didn't pick up a 

             20     copy yesterday and there's no more out there, there are 

             21     no more out there.  But the federal statistical system 

             22     deal an awful lot with the reidentification risk even 

             23     in non-public data.  And I just raise it as an issue. 

             24               DR. F. LEVINE:  The public use data file 

             25     recommendation explicitly says, "Users seeking to merge 
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              1     public use data files or enhance a public use data file 

              2     with identifiable or potentially identifiable data, 

              3     need to obtain IRB review and approval."  So that --  

              4               MS. DeWOLF:  [Off mic.]  -- the same thing 

              5     occur if Alan gave me a data file? 

              6               DR. F. LEVINE:  Correct.  

              7               MS. DeWOLF:  [Off mic.] So I would have to 

              8     get -- okay as long as it's covered.  I just wanted to 

              9     raise it --  

             10               DR. F. LEVINE:  Yes.  We --  

             11               CHAIRPERSON MARSHALL:  Just remember, use the 

             12     microphone because we do publish our transcripts on the 

             13     web site and we would like to have everything there for 

             14     those who want to read it. 

             15               DR. F. LEVINE:  I'm just curious that from 

             16     what you're saying, for example, drug companies in 

             17     order to tell how well their salesmen are doing 

             18     purchase information from your local drug store about 

             19     how many prescriptions were written for which medicine 

             20     so that they can say, okay, the salesman did well in 

             21     this district, but not in the next district.  And so, 

             22     you know, what are the laws for violation of 

             23     confidentiality for somebody purposely going and 

             24     looking up to see what medicine you take from your 

             25     local drug store, or student?  As you said is there a 
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              1     punishment?  Federal punishment?  

              2               DR. FLEISCHMAN:  Actually, John Fanning may 

              3     want to address that, but for information that is 

              4     available in the public domain, in fact, I'm not aware 

              5     that there is any penalty for putting it together and 

              6     identifying someone apart from, you know, if someone 

              7     did something to harm someone as a result of that, then 

              8     there would be legal recourse under the legal system.  

              9     But just because there's information that one group 

             10     has, another group has, you know, if it's all publicly 

             11     available and the people who have made it available 

             12     more or less know it's available one way or another, if 

             13     they signed the acceptance agreements when they sign up 

             14     for their new software that they're going to download 

             15     and all that.  They may not be paying close attention, 

             16     but there, in a sense a buyer-be-ware caveat emptor 

             17     mentality to all of that. 

             18               That's not what I got up to say though.  I 

             19     was going to simply comment that a properly -- one of 

             20     the lessons that we've learned from LaTonya's work, or 

             21     she was only capable of doing that because she was at 

             22     MIT at the time, but I think one of the lessons that we 

             23     learned from her work was that we have to be careful 

             24     about what we call "non-identifiable" because in fact 

             25     we can string together birth dates, which it's 
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              1     interesting, but, you know, birth dates tend to 

              2     identify to a certain extent a group of people born on 

              3     that day and it narrows it down somewhat. 

              4               So I think we've learned from those lessons 

              5     and properly constructed and de-identified a database 

              6     for public use, it really should not be "practicable" 

              7     -- is the word -- in order to do that.  But, again, I 

              8     think that this is part of the construct that came 

              9     forward from the working group of defining a 

             10     essentially a standard whereby these datasets could in 

             11     a sense be certified as to meeting a standard for de-

             12     identification that would prevent that from happening.  

             13               DR. FLEISCHMAN:  And that's essentially the 

             14     recommendations that were approved and sent forward on 

             15     public use data files, though to, let's say, dot the 

             16     "I"s between the confidentiality, we actually make 

             17     textual reference to this so that, well, why don't we 

             18     put a footnote that actually sites that recommendation 

             19     to make it very clear to someone looking at this that 

             20     this links to a broader discussion of public data, but 

             21     that this is addressing non-public data. 

             22               Jenny, am I seeing a head shake?  

             23               MS. DeWOLF:  I just think it should be 

             24     acknowledged just because somebody honorable says 

             25     something, you know, and somebody honorable receives 
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              1     it.  You just don't know what happens and so it should 

              2     be -- you know, caution should be taken.  So that would 

              3     be a good approach, I think.  

              4               DR. F. LEVINE:  Okay.  Did we call the 

              5     question?  

              6               DR. MORENO:  We called the before the 

              7     discussion.  

              8               CHAIRPERSON MARSHALL:  We still have a 

              9     quorum, I'm assuming.  So shall we have vote then?  

             10     Those in favor?  

             11               [Chorus of ayes.]  

             12               CHAIRPERSON MARSHALL:  Those opposed?  

             13               [No response.]  

             14               CHAIRPERSON MARSHALL:  Any abstentions?  

             15               [No response.]  

             16               CHAIRPERSON MARSHALL:  Motion carries. 

             17               [Pause.]  

             18               CHAIRPERSON MARSHALL:  Yes, conflict of 

             19     interest and risk and harm, yes.  Third parties. 

             20               We repressed that, Abbey, but --  

             21               DR. F. LEVINE:  All right.  I think that 

             22     given the time we would like to turn to courses in 

             23     student research.  

             24               DR. COHEN:  This topic of student research is 

             25     one, if you remember we began our efforts as a working 
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              1     group by reaching out to professional organizations and 

              2     trying to get input from the research community, the 

              3     social and behavioral science research community about 

              4     problems that they perceive with IRBs and so forth.  

              5     And one of the most prevalent problems and one of the 

              6     most irritating and troublesome problems that the 

              7     research community was having had to do with student 

              8     research and with IRB review of student research and 

              9     the issues regarding IRB review of student research.  

             10     And so that prompted us to turn our attention to that. 

             11               And what we have done is come up with some 

             12     questions.  We really haven't -- we're just at the 

             13     beginning part of our discussion about this and we've 

             14     posed some questions so what we are looking for is 

             15     input and feedback to these questions as the working 

             16     group proceeds with some recommendations with regard to 

             17     student research.  

             18               The first point on the handout you're getting 

             19     is probably the most important one to keep in mind and 

             20     that is most student research is not covered by 45 

             21     C.F.R. 46, because it doesn't generally constitute 

             22     generalizable knowledge as much as we would like it to, 

             23     perhaps.  It rarely does.  

             24               DR. RICH:  [Off mic.]  I think if you're 

             25     going to say that you need to say undergraduate student 
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              1     research.  Because graduate student research is --  

              2               DR. COHEN:  Well, some graduate student 

              3     research does.  Certain thesis and dissertations 

              4     certainly do. 

              5               DR. RICH:  I would not make an assertion that 

              6     student research is not intended to lead the 

              7     generalizable knowledge.  I mean, I think that's a very 

              8     dangerous assertion and I would, at the very least say 

              9     a sense, you know, in the event that it's not intended 

             10     to lead to generalizable knowledge then it may not be 

             11     covered.  But I certainly would not assert that as a 

             12     generalization.  Because I think that many professors 

             13     hope that their student research -- and, in fact, even 

             14     undergraduate student research, if it's done well, I 

             15     suspect sometimes is used by a professor in the course 

             16     of some scholarly work.  So I think this is an 

             17     important issue.  

             18               DR. COHEN:  Okay.  That's a very good point. 

             19     I think we are focusing at our questions here and our 

             20     discussion does primarily focus on that research it is 

             21     not intended to.  Although it also addresses some of 

             22     the types of student research that is intended for the 

             23     general knowledge. 

             24               The point the working group wanted to make 

             25     was that even if it did not -- it was not covered by 45 
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              1     C.F.R. 46, that did not mean that it did not need 

              2     oversight.  And that there needed to be some guidance 

              3     on what appropriate oversight over student research it 

              4     consists of. 

              5               And the main issue that has come up 

              6     repeatedly is that some institutions require all 

              7     student research to go an IRB, in which case on 

              8     occasion maybe even often, that it is extremely 

              9     burdensome and perhaps on occasion overly burdensome 

             10     and in some cases prevents the research from being done 

             11     in a semester's time when it needs to be done.  And so 

             12     that's some of the questions that we were addressing. 

             13               Should all class projects that involve data 

             14     collection go through a formal IRB process?  

             15               What conflicts might arise between 

             16     pedagogical and IRB issues? 

             17               To what degree can submitting a brief 

             18     proposal to an IRB fulfill an educational role?  I 

             19     mean, to say it shouldn't go -- that no student 

             20     research should go to an IRB because it's not covered 

             21     under 45 C.F.R. 46, are we doing the students a 

             22     disservice because they're not getting the full 

             23     research experience? 

             24               Should undergraduate students be required to 

             25     submit the same type of proposal as faculty and 
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              1     graduate students?  

              2               Should the process be streamlined? 

              3               Should undergraduate students who conduct 

              4     original research projects for course credit be 

              5     required to go to an IRB? 

              6               Should faculty who give a class assignment be 

              7     allowed to submit a blanket proposal? 

              8               Should IRBs set a broad exemption criteria 

              9     for student research?  

             10               And when IRBs do review student research, how 

             11     might they expedite the process?  

             12               I think the main points that the working 

             13     group was focused on in this discussion in its last 

             14     meeting is that there should be oversight, but the 

             15     oversight should be appropriate to the student 

             16     research.  And going through a full IRB review may not 

             17     necessarily be the appropriate procedure, but some 

             18     procedures might be appropriate. 

             19               DR. F. LEVINE:  Let me just add before we 

             20     open it up that these were intentionally framed as 

             21     questions because these are the kind of questions we 

             22     are grappling with.  So in a way we are in our early 

             23     phases of deliberation having had this issue come to us 

             24     from the field fairly repeatedly.  And this is a very 

             25     important issue across all field, but why it's coming 
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              1     up, we think, in the social and behavioral sciences is 

              2     because these are fields where training and education 

              3     in the doing if those sciences begins very early on in 

              4     the career line, indeed sometimes in high school.  And 

              5     in a way that it does in physics and chemistry, et 

              6     cetera, but where probably the first set of human 

              7     sciences where it happens so expansively even including 

              8     on issues of health and well-being at an undergraduate 

              9     level.  So while it has broader implications, of 

             10     course, for all human subjects research, it's probably 

             11     not surprising that it percolated first within the 

             12     contours of our field as opposed to other kinds of 

             13     feedback we've gotten. 

             14               Why don't you go first. 

             15               DR. RICH:  I think for exactly that reason 

             16     that's why it's particularly important that students 

             17     learn the processes and procedures early on as part of 

             18     what they do.  Whether or not it is explicitly required 

             19     by 45 C.F.R. 46.  I mean, I think there are some 

             20     pedagogical opportunities to teach about how one does 

             21     human subjects research. 

             22               That being said, I think the other thing that 

             23     I would suggest somehow get into this is that there at 

             24     the very least should be formal mechanisms in the 

             25     classroom setting for determining exemption in a formal 
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              1     kind of way and that that exemption ought not to be 

              2     made -- the decision on exemption obviously ought not 

              3     to be made by the professor.  It ought to be made by 

              4     the IRB.  So that there should be a mechanism where the 

              5     IRB declares that this proposal is exempt as opposed to 

              6     simply somebody deciding without any review whatsoever 

              7     that it's exempt.  And I think -- because much of this 

              8     research would be exempt.  I don't think there is 

              9     probably too much question about that.  But I am always 

             10     concerned about people deciding for themselves that 

             11     their research is exempt as opposed to having some sort 

             12     of process in place that the decision on exemption is 

             13     at arm's length from the research. 

             14               DR. F. LEVINE:  Alan and then Sandy.  

             15               DR. FLEISCHMAN:  Well, I guess, Bob, I was 

             16     just thinking about this research a little differently. 

             17      I mean, I don't know whether it's exempt or it isn't. 

             18      And I would have been really more comfortable if the 

             19     working group started out by making an assessment as to 

             20     what harms or risks do human subjects have from human 

             21     research.  I don't think student research is inherently 

             22     benign.  In fact, it might be very risky to human 

             23     subjects in terms of confidentiality breeches and 

             24     various things.  I mean, I can think of students who 

             25     might want to do some really very creative 
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              1     anthropologic or sociologic research that would be 

              2     incredibly risk to the subjects of the research.  So, 

              3     one thing I think we have to say is that there could be 

              4     harms.  And therefore, there is some need for some 

              5     supervision. 

              6               And then the second issue is, what is the 

              7     responsibility of the professor or teacher?  And if the 

              8     students are required to do research within a 

              9     professor's course, and ought not the professor be 

             10     responsible for the student's ethical conduct? 

             11               So that as part of the course not only do you 

             12     get a pedagogical benefit, you actually, you know, 

             13     obligate the teacher to be responsible. 

             14               I'd feel much more comfortable if I knew that 

             15     the professors were taking the responsibility to assure 

             16     the ethicality of the work.  

             17               DR. F. LEVINE:  Sandy. 

             18               DR. CHODOSH:  Well, I guess just reading this 

             19     as it just came to us that I'm a little bit concerned 

             20     that the approach wasn't from a point of view of the 

             21     protection of the human subject which really speaks to 

             22     some of the things we're talking about and that that 

             23     shouldn't be the primary concern for then how we build 

             24     a system that's going to work for students.  

             25               Having had experience with a nursing school 
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              1     that required a research project by a nurse before they 

              2     could graduate with a masters, we used to get an 

              3     amazing number, you know, of protocols which were very 

              4     bad.  And some of them were rather sensitive, talking 

              5     to pregnant teenagers for content, et cetera, et 

              6     cetera.  And when I called the mentor the professor, 

              7     she said, "Well, I don't really know much about 

              8     research." 

              9               Now, how can a -- you know, I'm sure this 

             10     goes on in many places.  It's a requirement set down by 

             11     that school, but without putting in requirements for 

             12     those who are monitoring the students at least be 

             13     knowledge and be the teacher.  So that I think, you 

             14     know, we really need to have protection in this area.  

             15     I agree that we probably had to think out of the box in 

             16     order to know how to do this.  And it may be that 

             17     people have to develop their projects before they even 

             18     start the course, you know, which is a tough thing to 

             19     do, but that might be one of the possibilities.  

             20               DR. COHEN:  One of the particular 

             21     complexities of that is issue that we've wrestled with, 

             22     and I'll tell you how we've dealt with it is the issue 

             23     of certification of investigators.  Because that adds 

             24     another complexity to all of this, is who has to be 

             25     certified if they're going to be doing this kind of 
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              1     research.  We have a special pathway for certification 

              2     of social and behavioral scientists so that it's a 

              3     different exam, it's a different curriculum than the 

              4     biomedical scientists.  But we require the professors, 

              5     at least, to go through the certification process. 

              6               And I agree completely with Alan that this is 

              7     a place where you put the onus on the professor and 

              8     then the -- I mean, the professor basically passes that 

              9     burden, in a sense, onto the student, but it's not 

             10     practicable to certify every student in the conduct of 

             11     social and behavioral research just because they're 

             12     going to be in a course doing a particular project.  

             13     But it is practicable to require the professor go 

             14     through that process.  

             15               DR. F. LEVINE:  It's hard to really know when 

             16     you're getting such a range of feedback from a range of 

             17     persons at a variety of institutions.  I think the 

             18     faculty do in general own -- take responsibility.  The 

             19     question is how to align that with what goes on the 

             20     classroom and how that grafts into the human research 

             21     protection system.  So I think this conversation has 

             22     been really very helpful in conceptualizing and then 

             23     coming up with some models that could work and offer 

             24     the human subjects protections system in colleges and 

             25     universities some options to consider in a way that it 
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              1     achieves both goals.   

              2               Greg.  

              3               DR. COHEN:  One of the things that the 

              4     working group in its discussion focused on, one of the 

              5     reasons we have IRBs and don't leave it up to well-

              6     trained investigators to make these determinations -- 

              7     there needs to be some independent, objective review.  

              8     And so that concept of independent, objective review 

              9     also applies in the classroom research. 

             10               The instructors who often are teaching 

             11     assistants in large institutions are too close, just as 

             12     the principal investigator is too close to the 

             13     research.  They have a pedagogical motive to doing this 

             14     and they are very close.  So the question is, what kind 

             15     of outside -- or what kind of independent review is 

             16     appropriate?  And I think that was, a lot of the time 

             17     at the working group was spent discussing that.  

             18               DR. KOSKI:  I would just comment that the 

             19     notion of allowing investigators be they students or 

             20     others to engage in human subjects research without 

             21     participating in the appropriate process for protection 

             22     of human subjects just reinforces what is a perception 

             23     among too many investigators still that either this 

             24     process is somehow a pain in the butt that's to be 

             25     avoided at all costs or that in fact they don't need 
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              1     to. 

              2               So I think there really is value.  I would 

              3     agree strongly with Bob and others who said there is 

              4     true value in incorporating at the earliest possible 

              5     opportunity the education as to what responsible and 

              6     ethical conduct of research and protection of human 

              7     subjects is all about as part of are research training. 

              8      So I would strongly endorse that and I think it should 

              9     be inherent in the way whatever recommendations might 

             10     come out. 

             11               But two approaches that have actually been 

             12     used in many instances and I don't -- I haven't heard 

             13     them mentioned, so obviously I'm not there.  One is to 

             14     accept this notion that the faculty member is indeed 

             15     responsible as the investigator.  The investigator, 

             16     that faculty member submits an overall protocol for the 

             17     research that would be done in the student environment 

             18     and says, these are the types of studies that we are 

             19     going to do.  It establishes a framework for the kinds 

             20     of projects that are done by the students in that 

             21     particular educational setting where it does involve 

             22     real human research and then the faculty member as the 

             23     investigator is charged with making sure that the 

             24     research that's done is in fact within that framework. 

             25      And that's been one mechanism to have an IRB oversee 
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              1     the protocol, if you will, but allow for this 

              2     flexibility and implementation in the actual 

              3     educational setting.  That's worked well in many 

              4     places. 

              5               Another approach is to take advantage of 

              6     what's there under the regulations for using a 

              7     designated member of the IRB for expedited review and 

              8     basically assign some willing volunteer to serve in 

              9     that function on behalf of the IRB so that the 

             10     protocols that are developed by the students under the 

             11     supervision of a faculty member can go to this 

             12     individual who can then make the determination on 

             13     behalf of the IRB whether it's exempted, whether it's 

             14     human subjects research, or whether it's something that 

             15     would be either approvable by expedited review in which 

             16     case they can do that and can do it on the spot or for 

             17     those instances where it involves significant risk 

             18     that's not expeditable.  It can be then sent to the 

             19     full IRB.  Those are two very functional models we 

             20     already have wide experience with.  They both work, 

             21     they're both consistent with the regulation.  

             22               DR. COHEN:  A third model which I've been 

             23     sort of promoting and haven't been adopted yet, and 

             24     that's the idea of a student IRB.  And you have to take 

             25     advanced students and train them and set them up and 
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              1     really do peer review.  I think one of the main points. 

              2               DR. FLEISCHMAN:  You could combine that with 

              3     Greg's suggestion and have the expedited reviewer --  

              4               DR. COHEN:  Sit on the --  

              5               DR. FLEISCHMAN:  -- sit on it or chair it 

              6     with the students as members.  

              7               DR. COHEN:  One of the main points that the 

              8     working group discussed was the idea that because much 

              9     of this research does not fall under 45 C.F.R. 46 gives 

             10     more flexibility to the institutions to be creative in 

             11     how they adopt the appropriate oversight.  So I think 

             12     there are institutions that I've heard of and others 

             13     that have taken the position, well, it's not covered 

             14     under 45 C.F.R. 46, so we don't have to do anything.  

             15     And one of the points we want to make and we feel 

             16     NHRPAC should make is that is probably not the 

             17     appropriate response, nor is having it go through 

             18     thorough, equivalent, full IRB review necessarily the 

             19     appropriate response.  But --  

             20               DR. F. LEVINE:  Sandy. 

             21               DR. CHODOSH:  I'm sorry, but if an 

             22     institution has an assurance which covers, quotes, "all 

             23     research" not just funded research, and most assurances 

             24     now read that way, doesn't that mean that it is 

             25     covered?   
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              1               DR. COHEN:  No, it covers all research that 

              2     meets the definition of research under 45 C.F.R. 46.  

              3     This research --  

              4               DR. CHODOSH:  We're not allowing students to 

              5     do non-research -- non-scientific work as research?  

              6               DR. COHEN:  This goes back to the point of 

              7     not for -- in order to meet the definition under 45 

              8     C.F.R. 46, it has to further generalizable knowledge.  

              9               DR. CHODOSH:  Yes.  

             10               DR. COHEN:  And most student research -- some 

             11     student research does not meet that definition. 

             12               DR. RICH:  It's like when you go into the 

             13     organic chemistry lab, are you really doing research or 

             14     are you doing an exercise?  And I mean, I think that's 

             15     an analogy from somebody with a scientific background 

             16     understands.  You go into the lab --  

             17               [Simultaneous conversation.]  

             18               DR. RICH:  -- you go through an exercise.  In 

             19     this case it happened to involve human subjects.  So, I 

             20     mean, I happen to think that part of the learning about 

             21     how you do human -- part of the exercise ought to be 

             22     learning something about human subjects protections 

             23     too. 

             24               DR. SHAMOO:  Two questions.  One, do we know 

             25     what percent of magnitude of research now is done with 
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              1     human subjects?  Which they don't go through an IRB in 

              2     universities?  

              3               DR. COHEN:  You mean student research?  

              4               DR. SHAMOO:  Yes, student research, of 

              5     course.  

              6               DR. COHEN:  It's a lot.  

              7               DR. SHAMOO:  Okay.  So there is a lot.  

              8               DR. COHEN:  That's a highly sophisticated 

              9     qualitative analysis.  

             10               DR. SHAMOO:  Okay.  

             11               DR. F. LEVINE:  But -- I'm going to also say, 

             12     but a lot doesn't increasingly so just as a lot of non-

             13     funded research now does as well.  

             14               DR. SHAMOO:  The second question is, students 

             15     have only 15 weeks in a course.  Are we now going to 

             16     expand it such that we're going to interfere so much 

             17     with the educational process that they are going to be 

             18     inhibited from doing those exercises because there are 

             19     so much limitations of time and money and resources, 

             20     especially in undergraduate colleges, those are not 

             21     medical schools.  So I in one way promote greater human 

             22     research protection, at the same time I want to stop 

             23     the educational process of the students and training 

             24     them.  So I am really concerned about that.  

             25               DR. COHEN:  I think that's the point of the 
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              1     his discussion is to provide assistance to institutions 

              2     to come up with creative ways, efficient ways to do 

              3     that -- to provide the oversight without unduly 

              4     interfering with the educational process.  

              5               DR. F. LEVINE:  Well, indeed integrating the 

              6     two.  Phil.  

              7               PARTICIPANT:   And that's already happening, 

              8     that inhibitory effect.  The extremist -- or the most 

              9     extreme example being the case raised by a linguist, 

             10     Gregory Ward in a case where IRB potentially being 

             11     brought in with a student at a blackboard and the 

             12     student is asked by the instructor to go -- well, to 

             13     say -- you write a word on the board and say, please 

             14     pronounce that word.  And someone said, well, this 

             15     needed to be subjected to a potential IRB review 

             16     because of potential embarrassment to the participant 

             17     in the classroom.  So we don't want a chilling effect 

             18     on stuff.  At the same time I totally agree with Greg. 

             19               My suggestion on the way to do this is we 

             20     should instill an ethical culture throughout the 

             21     research enterprise and promote that.  That's that 

             22     message that I would like to hear and let the 

             23     universities -- a message that we think they should 

             24     promote it, we shouldn't see a chilling effect and 

             25     either handle it at the departmental level, but that 
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              1     should be part of the educational system. 

              2               And Jeff's idea was very innovative of how 

              3     the student IRBs -- whatever it is to instill an 

              4     ethical culture is the goal we should have.  But we 

              5     should be very careful that we don't get the IRBS 

              6     involved in this except where they need to be or the 

              7     chilling effect will get worse.  At the same time 

              8     protection of the participants is the primary goal.  So 

              9     a bit of common sense should be also instilled.  If 

             10     somebody sees anybody in the process, any potential for 

             11     harm coming in, they should immediately step in. 

             12               DR. F. LEVINE:  Karen. 

             13               MS.           :  I'm Carolyn [indiscernible] 

             14     from the Bureau of Prisons.  I'm also on the working 

             15     group.  I would just like to see if there would be some 

             16     way to add into the recommendations something that says 

             17     along the lines of, if the student research isn't 

             18     contributing to generalizable knowledge that we should 

             19     encourage them not to try to use vulnerable 

             20     populations.  I think that would be a nice addition.  

             21               DR. COHEN:  Just speaking from my experience 

             22     at the university before I came to OHRP where we did 

             23     actually have a very broad requirement that all student 

             24     research went to the IRB.  And our incentive to get 

             25     students who were inexperienced not to work with 
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              1     vulnerable populations or do very risky research was to 

              2     say that that research had to go to the full IRB.  We 

              3     didn't say you couldn't do it, but the odds of your 

              4     completing your study within this semester were 

              5     minimal.  

              6               [Laughter.]  

              7               DR. COHEN:  But if you wanted to do research 

              8     that was exempt or eligible, for expedited review, here 

              9     was a nice easy way to do it and that was an incentive 

             10     without being authoritarian about it.  So there are 

             11     ways to do that.  

             12               DR. F. LEVINE:  Well, I think from our 

             13     advantage we got the quality of feedback that we both 

             14     wanted and needed to help give this the kind of form 

             15     that will let us continue this conversation and indeed 

             16     from posting on web sites and web pages as well as in 

             17     our next rounds of meetings with the research 

             18     community.  We are also getting very fine examples of 

             19     how it's done well.  And I think therefore it can be a 

             20     full report that we'll bring to you in July.  

             21               Thank you.  

             22               CHAIRPERSON MARSHALL:  Thank both of you.  

             23     Thank you very much, and to the members of your group. 

             24      Super work.  

             25               [Applause.]  
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              1               CHAIRPERSON MARSHALL:  I just want to observe 

              2     that as soon as those couple of changes are made in the 

              3     confidentiality draft document, we will be putting that 

              4     on the web.  So that should be happening very soon. 

              5               We may actually adjourn a little bit early 

              6     today.  I think that we've really had a productive 

              7     meeting both days.  We've got lots of good products 

              8     coming, lots of hard work being done. 

              9               Greg and I and Alan were talking a little bit 

             10     during the break and one thing that I think we need to 

             11     be mindful of is that although there are lots of 

             12     wonderful opportunities waiting for us in terms of 

             13     things that we have been asked to put on our agenda and 

             14     would like to put on our agenda for the future is that 

             15     we focus our energy on the tasks that we have at hand 

             16     as well and not become too diversified and so bring 

             17     some of things, you know, our front-burner projects to 

             18     fruition and then once those are done we will replace 

             19     them with the other things that we would like to do and 

             20     that others have very much asked us to do. 

             21               So, I would like to thank all of you, 

             22     committee members, and ex-officios, and public members 

             23     for the very hard work that you've been doing, not just 

             24     here over the last couple of days but I think primarily 

             25     in the interim between the meetings.  I also want to 
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              1     say or just observe that Kate is, you know, sort of 

              2     single-handedly running this committee and she works 

              3     tremendously, tremendously hard and is passionate and 

              4     dedicated to the work that we do.  And Greg and I are 

              5     going to be meeting and talking about how we can beef 

              6     up the resources that are available to her and to the 

              7     committee.  But I do want to acknowledge Kate's 

              8     invaluable assistance to all of us.  

              9               [Applause.]  

             10               CHAIRPERSON MARSHALL:  Yes, Mary Kay. 

             11               DR. PELIAS:  A few of us are going to be here 

             12     tomorrow for a meeting.  The genetics workgroup is 

             13     going to be meeting and there was a question about 

             14     whether or not we're going to get started at 8:30 or at 

             15     9:00.  Whether or not we're going to 5:30 or whether we 

             16     intend to quit at 4:00.  The official e-mails that have 

             17     come out of this group said 8:30 to 5:30, but Kate, I 

             18     distinctly remember that you and I talked about 9 to 

             19     4:00.  So --  

             20               MS. GOTTFRIED:  I think you're right.  And I 

             21     think though, I don't know if the official message 

             22     about 9:00 -- particularly the starting time of 9:00 

             23     got transmitted, so let's assume that we'll start at 

             24     8:30.  I will be at the front of the HHS building at 

             25     8:30.  I think, Bob, Mary Kay, Sandy, and Margaret are 
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              1     the members of this workgroup -- committee who will be 

              2     on that workgroup and should be there then by say 8:25 

              3     and we'll -- and you're going to call in.  Right.  

              4     Because my concern is that those people calling in may 

              5     be calling in at 8:30.  So we want to make sure we're 

              6     there.  

              7               And certainly if we end by 4:00 or whatever, 

              8     that's fine.  

              9               DR. PELIAS:  Okay.  So we'll all be there at 

             10     8:25.  We'll be there at 8:25 and we'll get started 

             11     about 8:30. 

             12               CHAIRPERSON MARSHALL:  All right.  And thank 

             13     all of you and ex-officios you'll have a seat at the 

             14     table the next time.  So forewarned and so forth. 

             15               [Whereupon, at 4:25 p.m., the proceedings 

             16     were adjourned.] 

             17                              - - - 

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                              CERTIFICATE OF OFFICIAL REPORTER 

                     

                              This is to certify that the foregoing 

                    proceedings before the National Human Research 

                    Protections Advisory Committee held Tuesday, April 30, 

                    2002, was held as herein appears, and that this is the 

                    original verbatim transcript thereof, and is a full 

                    correct transcription of the proceedings. 
                     
                     
                     
                                                                         
                                                  Cynthia D. Thomas 
                                                  Official Reporter 
                     

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