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  CT 
                  
                  
                  
                  
                  
                  
                  
                  
                  
                            Department of Health and Human Services 
                  
                  
                                        Meeting of the 
                              NATIONAL HUMAN RESEARCH PROTECTIONS 
                                  ADVISORY COMMITTEE (NHRPAC) 
                  
                                    Monday, April 29, 2002 
                  
                  
                  
                                           VOLUME I 
                  
                  
                  
                  
                  
                                 Hilton Washington Embassy Row 
                                        Ambassador Room 
                                 2015 Massachusetts Avenue, NW 
                                    Washington, D.C.  20036 
                  
                  
                  
                   

                 

                  
                  
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                                          A G E N D A 
                  
                  
                 Monday, April 29, 2002 

                  
                 AM Session 
                  
                 8:30-8:35 WELCOME:  OVERVIEW OF MEETING 
                                     Mary Faith Marshall, Ph.D. 
                                     Chairperson, NHRPAC 
                  
                 8:35-9:00      OPENING REMARKS 
                                     Edward D. Miller, M.D. 
                                     Dean, Medical Faculty and Chief 
                                     Executive Officer 
                                     Johns Hopkins Medicine 
                  
                 9:00-11:00     CHILDREN'S WORKGROUP:  MINIMAL RISK, MINOR 
                                INCREMENT OVER MINIMAL RISK, & 
                                DISORDER/CONDITION 
                                     Alan Fleischman, M.D. 
                                     Chair, Children's Workgroup 
                                     Senior Vice President 
                                     The New York Academy of Medicine 
                  
                 [10:15-10:30]  Break 
                  
                 11:00-11:15    CLASSIFIED RESEARCH -- UPDATE 
                                     Greg Koski, M.D., Ph.D. 
                                     Director, Office of Human Research 
                                     Protections  
                  
                 11:15-12:00    HIPAA:  NHRPAC RESPONSE TO HHS NPRM AMENDING 
                                THE FINAL HIPAA REGULATION 
                                     Mark Barnes, J.D., LL.M. 
                                     Partner 
                                     Ropes and Gray 
                  
                 12:00-1:00     LUNCH 
                  
                 1:00-1:30 PESTICIDE TESTING IN HUMANS -- UPDATE ON HUMAN 
                           STUDIES ISSUES AT EPA 
                                     William Jordan, J.D. 
                                     Senior Policy Advisor 
                                     Office of Pesticide Programs 
                                     Environmental Protection Agency 

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                 AGENDA - Continued 
                  
                 1:30-3:00 PESTICIDE TESTING IN HUMANS -- OTHER PERSPECTIVES 
                                     Moderator:  Mary Faith Marshall 
                                     Richard Wiles 
                                     Senior Vice President 
                                     Environment Working Group 
                                     Howard Sandler, M.D. 
                                     President 
                                     Sandler Occupational Medical Associates, 
                                     Inc. 
                                     Russell Katz, M.D. 
                                     Director of Neuropharmacologic Drug 
                                     Products 
                                     Center for Drug Evaluation and Research 
                                     Food and Drug Administration 
                  
                 3:00-3:00      TBD 
                  
                 3:30-3:45      Break 
                  
                 3:45-5:30      UPDATE:  INFORMED CONSENT -- DISCUSSION OF 
                                THREE ISSUES: 
                                     Elliot Dorff, Ph.D. 
                                     Co-chair workgroup  
                  
                 5:30      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:  8:30 a.m.] 

              3               CHAIRPERSON MARSHALL:  Good morning.  Thank 

              4     you all for being here.  Welcome to NHRPAC.  We are 

              5     very much in the news these days.  I'm sure everyone 

              6     has seen or perhaps saw the April 22nd issue of "Time 

              7     Magazine" with its strange -- I don't know whether it's 

              8     an unfortunate cover, but I'm sure it captured 

              9     attention. 

             10               So we have important business before us and 

             11     important business to do.  And we are going to move 

             12     sort of straight into our agenda because we have a 

             13     packed day. 

             14               I do want to just inform you of one slight 

             15     schedule change, and that is, at 8:15 when we're 

             16     scheduled for our break we are going to give -- 10:15, 

             17     I'm sorry. 

             18               [Laughter.]  

             19               CHAIRPERSON MARSHALL:  Yes, we've had our 

             20     break.  We are going to give Greg Koski some time on 

             21     the schedule because he has to leave us for just a 

             22     little bit, and then we will have our break at 10:30. 

             23               I can't tell you how delighted I am to 

             24     introduce to you my good friend and colleague, Ed 

             25     Miller, who is the Dean and the CEO -- he's the Dean of 
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              1     the Medical School at Johns Hopkins University and the 

              2     CEO of their Medical Center. 

              3               But Ed and I go back a long way.  We grew up 

              4     together at the University of Virginia and ran the 

              5     surgical ICU there together for many years.  It was a 

              6     formative experience, I think, for both of us.  

              7               It was, as my mentor John Fletcher likes to 

              8     say, the Vietnam of ICUs.  We had every surgical 

              9     service in one ICU back then, 16 beds.  Everything from 

             10     open heart surgery from 90-year-olds to one-day-old 

             11     patients, to trauma.  If you had surgery and were sick 

             12     you came to our unit.  And we were very proud of 

             13     ourselves.  We sort of considered ourselves the Navy 

             14     Seals of the critical care world because we knew it all 

             15     and could do it all and cracking chests was just, you 

             16     know, nothing.  It was passe for us. 

             17               [Laughter.]  

             18               CHAIRPERSON MARSHALL:  But I will tell you 

             19     the whole time that I was there in the unit, I think 

             20     the most exciting day we had was the day that Ed was 

             21     attending.  It was the first time that I had ever seen 

             22     anyone perform a cricothyroidotomy in the unit.  So I 

             23     can tell you that he has good hands.  And not only does 

             24     he have good hands, but he has a good mind and a good 

             25     heart.  And, Ed, thank you so much for being here.  We 
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              1     are just delighted and honored to have you. 

              2               DR. MILLER:  Thanks. 

              3               As said, Mary Faith and I go back longer than 

              4     we like to talk about, but it was -- "formative" is 

              5     correct, is the only way to say it. 

              6               What I would like to do this morning is talk 

              7     a little about our experience at Johns Hopkins which 

              8     has been in the news. 

              9               On June 2, 2001, Ellen Roche, who was a 24-

             10     year-old lab technician working at Hopkins, died after 

             11     participating in a human volunteer -- as a human 

             12     volunteer in an asthma study.  And, of course, this is 

             13     everyone's worst nightmare. 

             14               What I would like to do today is to kind of 

             15     set the framework about what went on, so you have some 

             16     facts, which doesn't always come out; and secondly, 

             17     what we did; third, where are we now; and fourth, where 

             18     are we going and give some time for some questions and 

             19     answers. 

             20               Greg and I have been on many panels together 

             21     and so this is not news to him at all. 

             22               Now, first, let me just tell you a little bit 

             23     about Johns Hopkins.  For those of you that are not 

             24     familiar, it's a very large institution. 

             25               Johns Hopkins Medicine has the hospital and 
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              1     health system and the school of medicine are combined 

              2     into this one entity with one Dean CEO.  It has three 

              3     hospitals.  It has the Johns Hopkins hospital, it has 

              4     the Bayview hospital which is the old Baltimore City 

              5     Hospital that has been totally reconfigured and brand-

              6     new, and we also have Howard County General Hospital. 

              7               We see about 1.5 million outpatient visits a 

              8     year.  We have over 80,000 discharges.  We have a $2.5 

              9     billion budget, we have $600 million in research, and 

             10     we have a faculty greater than 2,000.  So it's a very 

             11     large, big, complex organization. 

             12               And in terms of clinical research, we do 

             13     about 2,600 clinical trials are open at any one time.  

             14     And in the year we have about 50,000 patients enrolled 

             15     and admittedly a tremendous increase in the number of 

             16     studies that go on there over the last ten years. 

             17               Let me tell you about the study in which 

             18     Ellen died in.  It was an NIH-funded study.  It was to 

             19     be done of human volunteers.  These are healthy 

             20     individuals who did not have asthma.  And we were 

             21     looking at the mechanisms responsible why some people 

             22     get severe bronchospasm and then are able to relax 

             23     their lungs, so to speak, while others cannot. 

             24               We were going to do something new and 

             25     different in the study.  Three previous studies had 
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              1     been done in the '80s using a similar technique, but 

              2     there were some nuances to this study. 

              3               Number one, we were using a substance called 

              4     hexamethonium which had been a drug in the '60 which 

              5     actually is a ganglionic blocker known to 

              6     anesthesiologists and people that treat hypertension, 

              7     by the way. 

              8               Secondly, we could measure nitric oxide, a 

              9     substance that was not known when the studies in the 

             10     '80s were done or just starting to be recognized, and 

             11     the idea was to look at non-antigenic, non-cholinergic 

             12     nerve fibers of the lung.  That is, some extra nerves 

             13     that innervate the lung.  And what we would do is we 

             14     would challenge these healthy volunteers with a 

             15     substance that would -- methacholine which would give 

             16     them some broncho constriction and then we would either 

             17     pre-treat or treat afterwards with hexamethonium, a 

             18     gram of it, which is inhaled. 

             19               Ellen consented to participate in the study 

             20     on April 16, 2001.  She actually had participated in 

             21     other studies, and, as most of you know, many human 

             22     volunteers are on panels.  And she was in one of the 

             23     panels.  She had filled out, kind of, who she was and 

             24     the things that she did and the areas that she was 

             25     interested in and so she was in a databank along with a 
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              1     significant number of people so that when studies came 

              2     along we could go to the databank and ask volunteers if 

              3     they wanted to participate. 

              4               She was the third patient in the study.  The 

              5     first patient was started on April 23rd and underwent 

              6     the study with inhaling a gram of hexamethonium.  And I 

              7     should point out that that first patient had some cough 

              8     and some shortness of breath which was followed -- 

              9     thought by the clinician to be just a URI, an upper 

             10     respiratory tract infection, and actually the symptoms 

             11     went away.  And, as a matter of fact, were gone prior 

             12     to her study. 

             13               On May 4th Ellen started the study.  She 

             14     inhaled a gram of hexamethonium.  On May 5th she had a 

             15     dry cough.  And then on May 9th she was admitted to the 

             16     hospital because of increasing shortness of breath.  On 

             17     May 12th things got much worse.  She was taken to the 

             18     intensive care unit, intubated, ventilated, and over 

             19     the next 15, 16 days, she had a progressive down-hill 

             20     course whereby she died from multi-organ system 

             21     failure, coagulopathy, liver renal failure, and 

             22     ultimate lung failure.  And on June 2nd, she died. 

             23               Well, as I say, this is the worst nightmare 

             24     that you can imagine; a healthy human volunteer who 

             25     comes into a study and these are events that you never 
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              1     anticipate will occur. 

              2               Well, what did we do?  Well, as soon as we 

              3     knew there was trouble with this patient or volunteer, 

              4     excuse me, we stopped all human volunteer studies at 

              5     Hopkins.  We had informed OHRP and the FDA that we had 

              6     a patient in trouble and we kept them informed of where 

              7     we were and what was happening. 

              8               Well, when she died we immediately formed an 

              9     internal review committee that had total access to all 

             10     the data.  We asked them to be as critical of our 

             11     processes as possible so that we would have all of the 

             12     information and that we could present the information 

             13     as factually as possible.  And I guess I want to 

             14     emphasize that because there was a tremendous pressure 

             15     from the press to get information out to the public and 

             16     we didn't have all the information. 

             17               And, secondly, we had tremendous pressure 

             18     from the family not to release any information 

             19     whatsoever.  But we had, really, the Baltimore Sun 

             20     constantly coming at us which is a very difficult issue 

             21     to deal with. 

             22               On July 16th, we had a press conference and 

             23     we had the report available from the internal review 

             24     committee.  And the report I will just summarize by 

             25     some of the significant points. 
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              1               First, they thought her death was probably 

              2     related to hexamethonium but it could not be proved.  

              3     It was just -- there wasn't anything that we could say 

              4     that it wasn't due to, but there wasn't proof perfect. 

              5               Secondly, that the review committee -- 

              6     internal review committee -- was very concerned that 

              7     the first subject who had the cough had not been 

              8     reported by the investigator to the IRB, and should 

              9     have done that. 

             10               Now, I want to point out that in the 1980s a 

             11     similar study was done at the University of California 

             12     in San Francisco.  They also had a subject who had a 

             13     cough, was worked up extensively by an internist -- 

             14     pulmonologist -- who was removed from the study and 

             15     decided that it was not related to this.  But that did 

             16     not appear in the report that was published.  So the 

             17     investigators had not heard of any complications. 

             18               Third is that there were small changes in the 

             19     protocol that were not reported.  The difference 

             20     between saline and water is the diluent for the 

             21     administration of the hexamethonium. 

             22               Fourth that the literature review was not 

             23     complete.  Our investigator did a typical Medline 

             24     search of the literature.  If he had put in to Yahoo, 

             25     "hexamethonium lung disease" old literature in the '50s 
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              1     would have popped up. 

              2               Now, let me point out that that drug, 

              3     hexamethonium, which at that time was a drug, was 

              4     infused intravenously or given very large doses in 

              5     patients with very severe pulmonary hypertension to 

              6     treat -- and systemic hypertension, and that's why the 

              7     drug was used.  And the pulmonary complications in 

              8     those case studies were all related to long-standing 

              9     administration of very high doses of the drug not given 

             10     by inhalation. 

             11               The internal review committee was very 

             12     critical of the fact that hexamethonium was not a drug. 

             13      It had been a drug in the '60s, had been pulled off 

             14     the market because it was not effective as some of the 

             15     newer anti-hypertensive agents and we did not have FDA 

             16     clearance to use this.  And this we can talk a little 

             17     bit about the problem that we have in terms of 

             18     substances that are not new drugs, they're substances 

             19     that we want to look at mechanisms in human physiology 

             20     or pathophysiology and we need some way to get some 

             21     clarification. 

             22               And then last, and probably most importantly, 

             23     there was a sense from the report that the IRB had not 

             24     been as critical as it could be. 

             25               On July 16th, that afternoon that the 
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              1     external -- the internal report was released to the 

              2     press, OHRP came in, and in the afternoon at 1:00 we 

              3     had an entrance interview.  They examined this case, 

              4     they found some other cases, Tuesday, Wednesday, and 

              5     then Thursday morning OHRP came in and you have to 

              6     imagine in the board room one side OHRP, Hopkins on the 

              7     other side, not a very interesting or enjoyable time 

              8     for anybody in that room.  And they essentially read to 

              9     us the findings that they were concerned about and at 

             10     the end said, all of your clinical trials are closed 

             11     down as of this time. 

             12               Now, we have 50,000 people in clinical 

             13     trials, including people that are undergoing bone 

             14     marrow transplants and, you know, new drugs, et cetera, 

             15     et cetera.  

             16               So we closed down all the trials.  We were, I 

             17     will say, shocked at the response from this.  But over 

             18     the weekend we worked with OHRP and Greg and I were in 

             19     constant contact, we revised a variety of procedures 

             20     and then over the next four to five months we 

             21     rereviewed all 2,600 protocols and by mid-December we 

             22     were up and running and in many of the studies we were 

             23     up and running earlier than that because of rapid 

             24     review of these protocols and for patients that needed 

             25     to be in these protocols. 
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              1               I will say OHRP said, "do no harm" in 

              2     shutting these patients down, make sure that we were -- 

              3     making sure that patients who were in critical 

              4     protocols continued in those while some of the other 

              5     ones we could move more slowly on. 

              6               At the same time we had an external review 

              7     committee come in because we didn't want anybody to 

              8     think that our internal review was mild-mannered.  So 

              9     we had both the internal, OHRP, the FDA, and then the 

             10     external review committee and I cay say they 

             11     essentially said that the consent form was grossly 

             12     inadequate because it did not point out that the 

             13     hexamethonium was no longer a medication but rather a 

             14     substance.  There was not any idea that there was a 

             15     possibility of death on the consent form.  But, more 

             16     importantly, they felt that our review of protocols was 

             17     grossly inadequate and not to the current standards. 

             18               And let me just say that Hopkins had been 

             19     working with OHRP in trying to look at how we did it, 

             20     and our system had been different than others and it 

             21     had served -- we thought had served us well. 

             22               We would review -- we would take a protocol 

             23     and we would get three or four experts in the area to 

             24     review the protocol.  That subcommittee then would 

             25     bring it to the big board and often the big board would 
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              1     have a few comments, but the real substance was done at 

              2     the small group which is not adequate for the rules and 

              3     regulations that OHRP had set forth. 

              4               Well, what did we do?  First I would say that 

              5     we changed our attitude from really a combative 

              6     relationship between OHRP and probably -- that's 

              7     probably too strong a word.  I wouldn't say "combative" 

              8     I would say there was no communication, no way to talk 

              9     between the two sides about what we could do to move 

             10     forward.  And as I said, we worked very hard over the 

             11     weekend and we actually worked very hard over the last 

             12     nine to ten months to make sure that OHRP, the FDA, and 

             13     Hopkins are all kind of in the loop in where we're 

             14     going because these are tough areas.  These are not 

             15     easy area. 

             16               We have gone from two IRBs, actually, to six. 

             17      We have spent about a million dollars in this in the 

             18     past.  We now spend two in infrastructure.  I have a 

             19     new vice dean for clinical investigation, Mike Clagg, 

             20     who has a long history in clinical investigation.  The 

             21     infrastructure is significantly improved and the number 

             22     of people there to make sure that we have all the 

             23     processes in place are correct, and we have worked with 

             24     a western IRB, a for-profit IRB, to take a look at: 

             25               Number one, can they help us in finding 
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              1     people for our infrastructure? 

              2               Secondly, can they help us review those 

              3     multi-centered studies that perhaps they review because 

              4     they do it across so many different places, and so we 

              5     have used those. 

              6               Well, what has been the most difficult?  

              7     Well, I will tell you the most difficult, of course, 

              8     was talking to Ellen's father.  He, himself, had been a 

              9     human volunteer, so he understood the studies.  And I 

             10     met with him before the internal report was released 

             11     and I've actually met with him subsequently.  He's a 

             12     wonderful person, actually, and has actually no 

             13     animosity toward Hopkins, but how can we make the 

             14     system better? 

             15               The most difficult and second most difficult 

             16     has been dealing with the press.  And I have to say, 

             17     that has been really tough.  They are always at you and 

             18     they were really pushing very hard and they would 

             19     literally walk into the hospital and start talking to 

             20     people before we had all of our data put together.  And 

             21     we finally just said, this has got to stop because it's 

             22     really damaging to everyone and especially the family. 

             23      But, you know, the press is the press. 

             24               What good has come out if it?  Well, 

             25     certainly I think we have changed our culture.  We 
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              1     certainly have a culture of compliance now.  And I will 

              2     say that it cuts across not only in clinical 

              3     investigation, but animal care, grants and contracts, 

              4     billing, et cetera, et cetera.  

              5               Everybody understands that we definitely have 

              6     to have compliance in place to move forward and we've 

              7     got to do it as best we possibly can. 

              8               There has not been a fall-off in the studies. 

              9      Patients and subjects still come to Hopkins, and so we 

             10     continue to work very hard in that area. 

             11               So what are some of my suggestions, or what 

             12     did we learn? 

             13               Well, first, I said, we have used this as a 

             14     wake up for everybody, that we have to make sure that 

             15     we are compliant, we have to make sure that we have the 

             16     best processes in place.  Because it's hard to say 

             17     this, but even if we had all of the things in place, 

             18     even if we had known the literature review, even if the 

             19     first patient we knew about it and we had looked at it 

             20     because everything got better, we probably still would 

             21     have gone ahead with that study and we could have still 

             22     had the same effect, but we didn't have all the "t"s 

             23     crossed and all the "i"s.  We didn't do everything 

             24     humanly possible.  And, therefore, you know, we have to 

             25     accept the blame for that. 
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              1               We have training for our faculty.  I was 

              2     mentioning to Greg, you know, it's easier to get a 

              3     driver's license than -- or harder to get a driver's 

              4     license than to become a clinical investigator because 

              5     there is really -- the training is pretty slipshod, I 

              6     would say.  You kind of always learn from the person 

              7     ahead of you and so we have put together a very 

              8     extensive orientation for our new faculty that are 

              9     being involved and our current faculty, we do give a 

             10     masters and a Ph.D. in clinical investigation and have 

             11     had that for years.  But you can imagine the number of 

             12     investigators that are involved, they don't all enroll 

             13     in all of these programs.  But we have put a variety of 

             14     modules in place so that we cover the various aspects 

             15     that we need to.  And, we have put additional resources 

             16     into that. 

             17               We have used the for-profit IRB model for 

             18     some studies, and I think we have to look closely about 

             19     how that works, especially for large drug studies 

             20     sponsored by pharmaceutical industries that cover 20, 

             21     30, 50 centers.  Do they all have to be reviewed by the 

             22     individual centers?  That's a question that I think is 

             23     on the table. 

             24               The issue of using volunteers that come from 

             25     your own institution.  The external report was critical 
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              1     that there was perhaps coercion of the patients -- of 

              2     the subjects that enrolled.  We didn't think so.  We 

              3     hadn't really thought about it that way because so many 

              4     people want to work at Hopkins, we are the largest 

              5     private employer in Maryland.  People come and work at 

              6     medical centers for a variety of reasons, they want to 

              7     make a difference and they feel they can participate in 

              8     studies, but Ruth Vaden and her people are a group 

              9     looking at this so we can get an opinion. 

             10               And then, lastly, I guess the question is, 

             11     what are we going to do about certification of clinical 

             12     investigators?  And I think there could be grades of 

             13     certification for simple studies, and more complex and 

             14     so forth, who is going to pay for it, how could you do 

             15     it, it would be in the best interest of the large 

             16     pharmaceutical industries to do it.  What you see in 

             17     the pharmaceutical industry is 10 to 12 new drugs or 

             18     new compounds in the early stages of testing in man. 

             19               That is a dramatic increase of just over 

             20     three or four years ago when people were dealing with 

             21     one or two.  So if you multiply that times the 

             22     pharmaceutical industry, you've got this tremendous 

             23     number of potential drugs coming down the line with a 

             24     very limited number of clinical investigators, how do 

             25     we increase this?  They would be well to have some kind 
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              1     of funding pool so that we could increase that.  

              2               So those are some of the issues that we have 

              3     to deal with.  As I say, this has been a very tough 

              4     time for Hopkins.  There is absolutely no question 

              5     about it.  But clinical research is incredibly 

              6     important.  And the way I look at it is, you know, we 

              7     could probably either cure polio or make better 

              8     ventilators.  I think we should cure polio and not make 

              9     better ventilators.  And the only way we're going to do 

             10     that is through clinical investigation, but it has to 

             11     be done right, and it has to be done as safely as you 

             12     possibly can.  And when something like this happens in 

             13     our institution it really, really shakes the 

             14     foundations.  So with that, I turn it back to you. 

             15               CHAIRPERSON MARSHALL:  Thank you, Ed, very 

             16     much. 

             17               Our pattern of running meetings is that we 

             18     give time to our committee members to ask questions and 

             19     then an equal amount of time to our public members.  So 

             20     I know we are scheduled to go until 9:00, I think maybe 

             21     we could go a couple of minutes over.  So let me open 

             22     the floor up to questions from the committee and then 

             23     we'll open it up to our other folks.  Adil and then 

             24     Jonathan and then Judy. 

             25               DR. SHAMOO:  Thank you.  Thank you, Dr. 
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              1     Miller, for coming here. 

              2               I have two questions.  One, Johns Hopkins 

              3     between 1990 to the year 2000 probably over 400,000 

              4     human subjects passed through. 

              5               DR. MILLER:  Probably.  

              6               DR. SHAMOO:  They reported to OHRP zero 

              7     deaths and only a handful, less than a doze adverse 

              8     events.  How could that be?  If you take any other 

              9     adverse events in hospitals, in any other setting in 

             10     medical care, you will have at least dozens of deaths 

             11     and thousands of adverse events.  That's  one question. 

             12               The second question is, part of leadership is 

             13     accountability and stepping forward.  Hopkins in the 

             14     first three weeks, not only did not step forward and 

             15     take leadership -- moral leadership in this area, they 

             16     obfuscated, they did not want to release any 

             17     information and at times they really did not tell even 

             18     the truth.  The press it's for the whole First 

             19     Amendment rights.  And they serve a good purpose 

             20     despite all their flaws.  And what has happened at 

             21     Johns Hopkins that indicate leadership -- leadership 

             22     means accountability.  Who took the responsibility and 

             23     was held accountability for the flaws what I consider 

             24     for the past ten to 20 years. 

             25               Thank you.  
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              1               DR. MILLER:  Well, first, there were no 

              2     deaths in the trials.  So, number one, that's the only 

              3     death that we had in a human volunteer in over 100 

              4     years, and that's the truth. 

              5               Number two, I can't comment on the adverse 

              6     events other than the fact that the significance of how 

              7     you define a adverse event is very difficult for 

              8     different people.  Did we underreport?  Perhaps we did. 

              9      I don't know that.  I was not in charge. 

             10               Third, we did not delay information from 

             11     anyone other than at the wishes of the family.  And I 

             12     can assure you that the family wanted no information.  

             13     And I feel our responsibility was to the family and not 

             14     to the Baltimore Sun.  

             15               The last point is, we did not lie about 

             16     anything and I would like you to show me where we lied. 

             17      Lastly, I take full responsibility for this as the 

             18     head of the institution. 

             19               CHAIRPERSON MARSHALL:  Thank you, Ed.  Greg. 

             20               DR. KOSKI:  A clarifying remark in this 

             21     discussion around adverse events versus serious 

             22     unanticipated events. The reporting that's required or 

             23     expected in the different types of studies that are 

             24     done, the clinical trial under FDA regulation versus a 

             25     physiologic study of the type that was being conducted 
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              1     here are very different. 

              2               The expectation for sort of conducting a 

              3     survey of all of the adverse events in order to form a 

              4     profile of the expected events that might occur, the 

              5     frequency of those events in the context of developing 

              6     a new drug is a situation where basically you have to 

              7     capture ever event no matter how minimal or how serious 

              8     so that one gets a full spectrum of the events.  That's 

              9     a very different set of expectations than in a 

             10     physiologic study where one is looking to see where 

             11     there is just a serious unanticipated event that 

             12     actually results in harm or the potential for harm 

             13     either to one of the participants as a subject or even 

             14     one of the investigators. 

             15               In most of the studies of the type that Dr. 

             16     Miller has described, the events are in general 

             17     reported locally and dealt with locally and relatively 

             18     few of those have been reported or even need to be 

             19     reported to the Office for Human Research Protections. 

             20      That's the nature of the distributed system under 

             21     which we've operated.  That doesn't mean that there 

             22     isn't real room for improvement of this system and 

             23     certainly greater clarity because if an investigator is 

             24     involved in two types of research, it ultimately leads 

             25     to confusion as to what should be reported to whom.  
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              1     And certainly we saw this in the wake of some of the 

              2     gene transfer studies after the death of Jesse 

              3     Gelsinger. 

              4               So this is an area that certainly I think Dr. 

              5     Miller and Adil have drawn attention to.  It's an area 

              6     that our office is actively working on and it's one of 

              7     those -- I think one of the great challenges that we 

              8     have to address and we look forward to continuing to 

              9     work with both of you in that. 

             10               CHAIRPERSON MARSHALL:  I have Jonathan and 

             11     then Judy, and then Mark, and then I'd like the open 

             12     the floor up to our public members. 

             13               DR. MORENO:  After these last remarks that 

             14     Greg made and Dr. Miller made, both go to the concern 

             15     that I had, namely, how do we ramp up the system for 

             16     getting this information available and probably even 

             17     more complicated than that, sort of just from a logical 

             18     point of view is, how do we tell what's relevant to the 

             19     drug or substance and what isn't?  And that's partly, I 

             20     guess, a problem of helping investigators, once a 

             21     consensus has been reached about the criteria to know 

             22     what those criteria are.  So it's a pretty complicated 

             23     business. 

             24               CHAIRPERSON MARSHALL:  Judy. 

             25               DR. SIEGEL:  Thank you for your remarks.  My 
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              1     question actually goes to training of clinical 

              2     investigators which I think -- my background is from 

              3     the pharmaceutical side, so you can put my comments 

              4     into perspective.  But you mentioned that it problem is 

              5     the pharmaceutical industry that should seriously 

              6     consider putting some more money into training.  And 

              7     while I don't disagree, I think many of the issues that 

              8     we've seen have actually been from non-industry-

              9     sponsored trials.  NIH-sponsored trials, other 

             10     sponsored trials.  And so I would like to say that 

             11     probably this is more a joint responsibility. 

             12               I think as far as when you're doing -- at 

             13     least FDA-sponsored trials the reporting requirements, 

             14     the oversight requirements are actually much greater 

             15     than non-FDA-sponsored trials and therefore a lot of 

             16     the education is sort of on the ground education as you 

             17     see what's going on at a site.  So I think I would sort 

             18     of put into the mix that if we're going to have 

             19     education then it probably should be from two sources 

             20     at least. 

             21               DR. MILLER:  No, I totally agree.  I was just 

             22     thinking that that pharmaceutical houses have -- since 

             23     they're changing so dramatically now, they're going to 

             24     have to figure out how to get this thing done and done 

             25     right.  And I totally agree, there's multiple sources 
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              1     of funding for it. 

              2               CHAIRPERSON MARSHALL:  Mark and Alan and then 

              3     we'll open it things up to the floor. 

              4               MR. BARNES:  Hi, Dr. Miller. 

              5               Just a couple of brief questions.  One is, 

              6     can you describe a little bit about the extent to which 

              7     you decided -- Hopkins decided to beef up the staffing 

              8     for the IRBs in response to this situation? 

              9               DR. MILLER:  Sure.  

             10               MR. BARNES:  And the other question is, if 

             11     you had to identify just one single reform that you 

             12     think is the most important reform that Hopkins 

             13     undertook to protect human subjects, what would that 

             14     be? 

             15               DR. MILLER:  Well, I think the first answer 

             16     was, we looked at the entire process and in order to 

             17     decide what kind of infrastructure what needed to have 

             18     in place, and we decided we needed in areas of the 

             19     database that was better than the old database that we 

             20     had, so we totally reconfigured that. 

             21               Secondly, the issue about how do you get your 

             22     minutes transcribed more quickly?  And I mean, it's 

             23     kind of down at that level. 

             24               Third, the number of IRBs became very 

             25     important because if you had a greater number they saw 
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              1     less protocols, they could spend more time on the 

              2     protocols.  We scheduled meetings every week, and we 

              3     made sure that we had people that were fully trained. 

              4               OHRP came in Saturday and Sunday.  We had a 

              5     room full of people to continue to go over all the 

              6     rules and regulations, so that was another piece of 

              7     what went in. 

              8               The most important thing that we've done, I 

              9     would just say that we have, in a variety of forums, 

             10     emphasized not only that we put the infrastructure in 

             11     place, but that everybody in the institution knows how 

             12     important this is.  I mean, we had town meetings, big 

             13     town meetings with the president of the university 

             14     there.  And we have hit on it.  I had a retreat on the 

             15     eastern shore, brought all my chiefs, all my hospital 

             16     chiefs, and Greg agreed to come and we spent a whole 

             17     day just on this issue.  So, if you want to ask one 

             18     thing, I think it wasn't one thing, but a whole host of 

             19     things that talks about this.  How can we do it better?  

             20               I mean, Hopkins has always been a leader, we 

             21     want to continue to lead.  So that's where we are. 

             22               DR. FLEISCHMAN:  As we go around nationally 

             23     and look at IRBs, many of the professors who sit on 

             24     IRBs do it out of altruistic goals.  And it's very hard 

             25     to get people, as you well know, to sit on these 
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              1     groups. 

              2               DR. MILLER:  Yes. 

              3               DR. FLEISCHMAN:  So what do you think your 

              4     experience teaches all of academe about how do we 

              5     incentivize IRB membership and work?  Ought the medical 

              6     school be sharing some dollars with the clinical 

              7     departments about such people?  How does the promotions 

              8     process take this into account?  I mean, each of those 

              9     issues, I think, we'd benefit from your wisdom. 

             10               DR. MILLER:  Well, first, essentially as 

             11     things have gotten tough in medicine over the last ten 

             12     years, the proverbial P&L sheet for every physician, 

             13     you can't have a young professor -- assistant professor 

             14     spending 20 to 30 percent of their time on IRB 

             15     activities and not figure a way to pay them.  So we 

             16     have started that process.  After, admittedly, going 

             17     through Ruth Vaden's group to say, now are we doing 

             18     something wrong here by paying, and we actually asked 

             19     Greg and they thought it was not a bad idea.  We had 

             20     always paid the head of it and the vice chair of that 

             21     IRB for their time, but we had not done that for the 

             22     other people on the committee. 

             23               Now, we don't necessarily give them the full 

             24     20 or 25 percent, but we put dollars toward that. 

             25               Secondly, we make sure that there's 
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              1     infrastructure in place and easy for them to do their 

              2     job on the IRB.  So Internet technology and so forth so 

              3     they have access to things, able to query things. 

              4               And then, third, the issue of promotions.  

              5     Admittedly, we still have a one-track promotion system 

              6     at Hopkins and we probably always will.  There's no way 

              7     to change that.  We tried that, lost that one.  Tried 

              8     that, lost that.  

              9               [Laughter.]  

             10               DR. MILLER:  But we certainly put that as 

             11     part of the mix of why someone should get promoted at 

             12     the professor level at the associate professor level.  

             13     That's service, community service, that's a very 

             14     important piece of what makes Hopkins and that counts 

             15     toward it.  And I can tell you, someone who has only 

             16     gotten their RO1s and hasn't done any of those other 

             17     things doesn't get through the promotions committee any 

             18     more. 

             19               CHAIRPERSON MARSHALL:  Let me ask if there 

             20     are any of our ex-officio members or public members who 

             21     would like to ask Dr. Miller a question. 

             22               And if you could just please tell us who you 

             23     are. 

             24               DR. MATHER:  Dr. Miller, I am Dr. John Mather 

             25     and I head the Office of Research Compliance and 
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              1     Assurance in the VA with a $1.4 billion portfolio and 

              2     as you can imagine, many, many protocols across the 

              3     system of some 115 VA medical centers. 

              4               I would like to make one comment and then ask 

              5     one question.  I think the commentary about AEs, SAEs, 

              6     unsuspected and all the rest of it is an issue that 

              7     we're all struggling with.  

              8               Greg had convened a group a couple of weeks 

              9     ago and out of that meeting it became abundantly clear 

             10     that those of us that were a table from across many 

             11     agencies were immediately more and more concerned about 

             12     how this can be clarified for everybody.  Because 

             13     within our system it's very clear, there's not point in 

             14     sending every unsuspected SAE to my office which is 

             15     basically what goes on right now.  And for my office to 

             16     be struggling with that is an immediacy that concerns 

             17     me because the word needs to be out, not in my office, 

             18     but at a level where it matters, and that's 

             19     particularly in cooperative studies where it's going on 

             20     in several sites.  And I don't think we have that right 

             21     yet. 

             22               My question is to probe with you a little bit 

             23     more about the issue of the training and education of 

             24     investigators.  

             25               DR. MILLER:  Yes. 
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              1               DR. MATHER:  We in the VA declared 18 months 

              2     ago that you couldn't put in a merit proposal without 

              3     some sort of certification that you had taken an 

              4     education training program.  At that time somewhat 

              5     unspecified, but since then required that you had to 

              6     pass some sort of examination in the concert of 

              7     whatever, you know, test you take.  I'm troubled that 

              8     we don't really have a keen sense of what are the core 

              9     requirements of investigators whether you're doing 

             10     clinical trials, whether you're doing health services 

             11     research, or whether you're doing all brands of 

             12     research and maybe on top of that what specifically 

             13     investigators need because they're diversifying or 

             14     specializing in certain tracks such as clinical trials. 

             15               From what I've seen, the Association of 

             16     Clinical Research Professionals, ACRP, is taking this 

             17     on as an issue mainly for the area of clinical trials 

             18     which is the farmer piece of it.  But everybody needs 

             19     some sort of basically notion. 

             20               Do you have a feel for where the focus for 

             21     getting that done might need to be?  I mean, is it a 

             22     government function?  Is it a nongovernment function to 

             23     take that lead?  Would you favor mandated education for 

             24     investigators in some manner or another so that it says 

             25     you cannot due human subjects research without having 
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              1     this little piece of paper that says you're somehow 

              2     certified in that regard?  

              3               DR. MILLER:  I think this is a very difficult 

              4     issue and we're struggling with it right now because I 

              5     don't think we want to get to the point of just having 

              6     a little piece of paper that kind of you got through 

              7     the test and you don't have any real understanding of 

              8     why you're moving forward.  So we've been a little 

              9     cautious in going to that. 

             10               And what we've done is, we've put now 

             11     together a two-day course.  There is a summer course 

             12     that also goes on.  And I think we're going to move to 

             13     some kind of certification and I think it's going to be 

             14     various levels of certification.  But, again, I'm 

             15     afraid to do that until we really pin down the most 

             16     important things that that investigators needs to know 

             17     to move forward.  And I' not sure we're there yet, to 

             18     tell you the truth.  I wish we were.  But I don't think 

             19     we're there.  There's a lot of stuff out there that we 

             20     haven't nailed down as to the point that my senior 

             21     people satisfied yet. 

             22               DR. MATHER:  Who takes the lead?  

             23               DR. MILLER:  And I personally think since 

             24     basically clinical investigation it ends up to be 

             25     either the subject or the volunteer at the local level, 
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              1     and the accountability has to be at the local level.  

              2     How you interact with OHRP and other agencies to help 

              3     you form that I think is something that needs to be 

              4     worked out.  But I'm still pretty much a pragmatist and 

              5     say, local level is the best way to do it. 

              6               CHAIRPERSON MARSHALL:  Elliot and then I'll 

              7     call on this lady. 

              8               DR. DORFF:  Along those lines, one model that 

              9     you might want to think about is what happens with 

             10     accreditation for universities where its done not by 

             11     government, but it's done by the profession, as it 

             12     were.  Because presumably the expertise in doing 

             13     clinical research is in the profession.  But that -- I 

             14     mean, it does sound as if, I mean, if you have Ph.D. 

             15     programs in this, it does sound as if there are some 

             16     people around that should know how to figure out what's 

             17     really important. 

             18               DR. MILLER:  And that's why we're developing. 

             19      I don't think many institutions don't have that 

             20     luxury.  So --  

             21               MS. BLEVINS:  My name is Sue Blevins and I'm 

             22     with the Institute for Health Freedom.  I have a 

             23     comment and then a question.  My first comment is, I 

             24     want to say, Dr. Miller I worked and trained at Johns 

             25     Hopkins and I have great respect for the institution.  
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              1     I know how hard the doctors and nurses work there.  I 

              2     was there way back in the 1900s -- in the 1980s and I 

              3     know the dedication of all the people there, and I know 

              4     the intent is always to heal and make patients better. 

              5               Having said that, I want to share this one 

              6     anecdote that I think is also important for the record 

              7     and it raises a question.  Having said that I know the 

              8     motives are good, I know the motives are pure of the 

              9     doctors, the hospitals, the researchers.  At the time 

             10     in the 1980s I was roommates with two other nurses and 

             11     one came home one time crying.  She worked on a bone 

             12     marrow transplant unit.  And she said, you know, 

             13     patients are being told what the outcomes of this 

             14     certain protocol is. 

             15               They were getting a transplant and then 

             16     drugs, I guess, chemotherapy, I'm not -- I worked on 

             17     the urology unit, I wasn't familiar with that.  And she 

             18     said, but they're really dying from the side effects, 

             19     but the cancer is being cured and they're not being 

             20     told this.  And she was very upset and thought it was 

             21     an ethical dilemma. 

             22               And, of course, she wasn't going to interfere 

             23     with the protocol, but that raises the question of, I 

             24     have always wondered, when you're counting deaths, or 

             25     when you're counting adverse events, you know, 
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              1     sometimes that patient is considered a cure when really 

              2     they're dying from the -- the drugs are causing major 

              3     organ failures.  And I'm sure the drugs and the 

              4     protocols have improved over the years, no doubt about 

              5     it.  

              6               But I guess I question a little bit the, how 

              7     are the deaths counted?  I'm not challenging your 

              8     honesty.  I know you're being honest, but sometimes 

              9     there are side effects that aren't always included in 

             10     the protocol and how do we get that information out to 

             11     patients so that we can make, not only informed 

             12     decisions, but even better informed decisions? 

             13               DR. MILLER:  Well, as you know, bone marrow 

             14     transplant, that whole history is one of the two places 

             15     that started it.  And there is no question in the '80s 

             16     there were a lot of issues about complications of how 

             17     big the does, how high the dose.  I think today we try 

             18     to best categorize it.  But in these studies, for 

             19     instance, patients with multi myeloma are going to be 

             20     in these trials.  And some who get bone marrow 

             21     transplants, do they die from their therapy, or do they 

             22     die from their progression or their disease or is there 

             23     a complication?  

             24               I don't have a good answer to that.  That's 

             25     an individual -- I mean, how you report that out, there 
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              1     probably needs to be more clarity.  Maybe Greg wants to 

              2     speak to that.  It's a toughy. 

              3               DR. KOSKI:  Just quick.  I think that it is 

              4     tough.  But if one approaches it by having an 

              5     appropriate capture of the information in a time frame 

              6     where it can be put to use and have it analyzed by 

              7     individuals who understand the situation and can look 

              8     at it objectively as to reach a determination as to, 

              9     you know, whether or not the treatment is better than 

             10     the disease so to speak is probably as close as we can 

             11     get, I think, to the kind of approach that would serve 

             12     everyone's interest.  

             13               I mean, obviously in a clinical trial that's 

             14     exploring, you know, a new approach to treating a 

             15     disease, if one knew whether or not it was going to 

             16     work, whether or not it was going to be safe and 

             17     effective, one wouldn't be doing the study in the first 

             18     place.   So that it has to be made clear, you know, on 

             19     the front end that indeed there are risks, there are 

             20     unknown, but then it's our responsibility to very 

             21     carefully watch and monitor the progress. 

             22               Now, how we do this, what is the appropriate 

             23     role of an institutional review board in that process? 

             24      What's the appropriate role of a medical monitor, a 

             25     data monitoring committee, or a data and safety 
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              1     monitoring report?  They all play a roll.  And, of 

              2     course, this thing keeps coming up, you know, no matter 

              3     where we look at the discussion in human research, we 

              4     do have these kinds of shared goals and 

              5     responsibilities.  

              6               But this whole process of actually what's 

              7     happening to the progress of trial studies that are 

              8     under way and how we can get information in real time 

              9     and use it to prevent harm to individuals who are 

             10     actually actively enrolled in trials underway, I think 

             11     is one of our great challenges now and we are working 

             12     to address that issue. 

             13               DR. CHODOSH:  Let me introduce myself by 

             14     saying that this is my 50th year after graduating from 

             15     Hopkins.  And I --  

             16               [Laughter.]  

             17               DR. MILLER:  Now, let me see, you've given to 

             18     the fund already; right?  

             19               [Laughter.]  

             20               DR. MILLER:  The letter is in the mail and 

             21     I'll be glad to send you a thank you letter too.  

             22               [Laughter.]  

             23               DR. CHODOSH:  Well, I must say that when all 

             24     this started I was feeling a little bit abashed and 

             25     ashamed of that fact that I had been a graduate and 
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              1     that I am a graduate.  However, I also have a long 

              2     experience in clinical research.  And what Greg is 

              3     saying is very important, but also there's this other 

              4     aspect which we can't ignore. 

              5               Number one, investigators by and large are 

              6     not in a position to be judging whether that side 

              7     effect is important to that particular situation.  And 

              8     we need to have monitoring boards.  They are essential. 

              9      We have not had them.  It is less likely to happen in 

             10     a non-multi-center study, but it's just as important 

             11     there because, if anything, you need to have 

             12     independent people looking at these. 

             13               And the FDA, although I don't agree with 

             14     everything they do, one thing they do, do, and that is, 

             15     you report all severe things.  And they define them, 

             16     any hospitalization, any prolongation of 

             17     hospitalization, any of this kind of thing.  Even 

             18     though you know deep down it has nothing to do with the 

             19     study, someone else has to evaluate that in a prompt 

             20     way.  Otherwise we're kidding ourselves. 

             21               DR. MILLER:  Now, we do have monitoring 

             22     boards in place at Hopkins.  Just so that you do know 

             23     we do that independent.  But, for example, in this 

             24     particular case, you know, that investigator made a 

             25     decision that that subject's cough played no role.  
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              1     That was a decision made by the investigator.  

              2               DR. CHODOSH:  That wasn't my problem.  I 

              3     could understand why -- I'm a pulmonologist.  What I 

              4     didn't understand is when I heard of that death, my -- 

              5     said, my God, that's hexamethonium."  Because I knew 

              6     about it and I wasn't a cardiologist.  I was a 

              7     pulmonologist and it was well-known that this did 

              8     occur. 

              9               CHAIRPERSON MARSHALL:  One last question. 

             10               MS. CAMP:  My name is Robin Camp, just a 

             11     private citizen.  Can you speak more specifically about 

             12     what the informed consent form was for the person who 

             13     died versus the improvements in informed consents now 

             14     and whether these forms are very specifically drawn or 

             15     they're more general in nature? 

             16               DR. MILLER:  Well, first, they're 

             17     specifically drawn for each study.  So that's one. 

             18               Secondly, in the particular consent form it 

             19     did not have all eight elements.  It did not mention 

             20     the fact that the patient might die, the subject might 

             21     die.  And also importantly, it mentioned hexamethonium 

             22     as a medication, giving the patient a false sense of 

             23     security that this was a drug.  And it really no longer 

             24     was a drug, it was a chemical substance.  

             25               I think I answered all three pieces. 
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              1               MS. CAMP:  But in terms of the improvements 

              2     now for --  

              3               DR. MILLER:  Oh, all the element are there.  

              4     They're looked at very carefully.  We make sure that 

              5     we've got all the pieces there.  And I would say 

              6     there's probably more discussion at the IRB about the 

              7     consent form then had occurred in the past. 

              8               MS. CAMP:  Thank you.  

              9               DR. MILLER:  Certainly a significant 

             10     improvement on that. 

             11               CHAIRPERSON MARSHALL:  Ed, I want to thank 

             12     you so much for coming.  I asked Ed just this past 

             13     Wednesday to come and he immediately said yes.  And 

             14     he's given us an extra half hour of his time. 

             15               I guess I would like to close this session by 

             16     observing that I think one of the things that is 

             17     emerging as a theme in the current will to reform the 

             18     system of protecting human research subjects is the 

             19     fact that maybe one of the most important things that 

             20     we can do is to have responsibility and accountability 

             21     at all levels and at many levels within a research 

             22     organization; responsibility for protecting human 

             23     subjects.  And the real way to make that happen is to 

             24     have the head of the institution be the one who sends 

             25     out a very clear message as to the importance of that 
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              1     and to set the institutional culture and the tone. 

              2               And, Ed, it sounds as though you're providing 

              3     that leadership and I don't think that really there's 

              4     anything perhaps that's more important than that.  And 

              5     rewarding those who do well, and sanctioning those who 

              6     don't do well in terms of the expectations that are set 

              7     out.  So, Ed, thank you so much for coming.  We really 

              8     do appreciate it and it's great to see you again.  

              9               [Applause.]  

             10               CHAIRPERSON MARSHALL:  We do have some 

             11     flexibility in our schedule.  I'm not sure necessarily 

             12     that Mark will need all of the time that he's got 

             13     coming. 

             14               So I would like to move along to Dr. Alan 

             15     Fleischman.  The children's workgroup has been working 

             16     very hard and I think perhaps doing some of the hardest 

             17     work that can be done.  And that is really going back 

             18     to basics and fundamentals and looking at definitions, 

             19     and I think trying to provide OHRP and the research 

             20     community, IRB members, investigators with some 

             21     guidance as to interpretation of the regulations 

             22     governing the research with children.  And also some 

             23     concrete examples of how protocols or individual 

             24     situations might fit into an interpretation of the 

             25     regulation and it's very clear that that is sort of 
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              1     guidance, I think is desperately wanted and needed by 

              2     the research community. 

              3               So, Alan, thank you very much for the 

              4     leadership you've been providing the children's working 

              5     group and the very hard work that has been done. 

              6               DR. FLEISCHMAN:  Thank you, Mary Faith.  And 

              7     let me say first of all that the children's workgroup 

              8     has been working extremely hard.  It's easy to lead a 

              9     group of really competent wonderful people who are 

             10     interested in working hard to solve some tough issues.  

             11               I want to remind you that the first task of 

             12     the children's workgroup was to answer a question that 

             13     Dr. Koski had raised, and that was to look at the 

             14     regulatory structure for children and consult for OHRP 

             15     in its goal to consult for Congress about the adequacy 

             16     of regulation for children. 

             17               And I will remind you that the workgroup and 

             18     then NHRPAC and then OHRP did in fact suggest that the 

             19     regulations were sufficient, but there were issues of 

             20     accountability, there were issues of clarification, 

             21     there were issues of definition that needed work. 

             22               So the workgroup has begun to take those 

             23     issues that OHRP reported to Congress needed some 

             24     clarification.  We report today on two of a whole host 

             25     of issues that we would like to attack and are 
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              1     attacking.  We are doing them systematically and 

              2     serially. 

              3               We understand that we haven't completed the 

              4     task.  We are at the beginning and we started with 

              5     perhaps the two most easy and yet most controversial 

              6     within the children's regulations.  We are attempting 

              7     here in our report to clarify interpretation of the 

              8     concepts of minimal risk and minor increase over 

              9     minimal risk which are basically in 46.404 and 46.406 

             10     in the Federal Regulations. 

             11               Today we report on what is a close to final 

             12     draft of what we would like NHRPAC's support on in 

             13     terms of the clarification of those two concepts.  It 

             14     is the workgroup's hope to be able to present examples 

             15     in addition to these definitional issues.  We have not 

             16     come to closure on our examples, so we decided not to 

             17     present them today.  And the workgroup will be back 

             18     with examples.  But we would like to come to closure on 

             19     the substance, if we can. 

             20               So let me just go through this very quickly 

             21     starting with minimal risk.  And I think everyone has 

             22     in front of them the report and I hope -- do our public 

             23     members have copies?  

             24               CHAIRPERSON MARSHALL:  It's available on the 

             25     table out front.  So if you didn't pick one on the way 
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              1     in -- pick one up, please feel free to grab yourself 

              2     one. 

              3               DR. FLEISCHMAN:  So we start merely by 

              4     defining "minimal risk" as it is defined in the Federal 

              5     Regulations in the Children's regs reminding you that 

              6     it's probably and magnitude of harm or discomfort 

              7     anticipated in the research and that that is not 

              8     greater in and of themselves than those ordinarily 

              9     encountered in daily life or during the performance of 

             10     routing physical or psychological examinations or 

             11     tests. 

             12               We interpret the definition, "we" the 

             13     workgroup, of "minimal risk" to be the level of risk 

             14     associated with the daily activities of normal, 

             15     healthy, average children.  Risks includes all harms, 

             16     discomforts, indignities, embarrassments, and potential 

             17     breaches of privacy and confidentiality associated with 

             18     the research.  Conceptually this minimal risk standard 

             19     defines a permissible level of risk in research as the 

             20     socially allowable risks which parents generally permit 

             21     their children to be exposed to in non-research 

             22     situations.  This is our take on clarification.  

             23               Now a couple of codicils.  First, children of 

             24     different ages in their general average, normal, 

             25     healthy lives are exposed to different levels of risk. 
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              1      We believe that needs to be taken into account.  And, 

              2     certain groups of children are routinely exposed to 

              3     greater risks as part of their daily lives because of 

              4     circumstances in which they live, circumstances of 

              5     poverty, marginalization in our society.  This level of 

              6     increased risk ought not -- underline the word "not" -- 

              7     be interpreted as minimal risk just because it is part 

              8     of the common experience of these otherwise healthy 

              9     children.  

             10               So the standard, as we see it, is that 

             11     standard of the average healthy normal child within our 

             12     society.  Now, that, of course, is going to require 

             13     interpretation still by local IRBs. 

             14               Now, we also interpret the phrase, 

             15     "ordinarily encountered in the daily life" or during 

             16     the performance of routine physical or psychological 

             17     examinations or tests.  We believe that there is an 

             18     equivalence of risk standard here.  That we ought not 

             19     only include those things that are done during a normal 

             20     routine physical or psychological exam.  But we ought 

             21     to look to those things that are equivalent in risk 

             22     that are done with children in research. 

             23               And then we remind our colleagues in IRBs and 

             24     investigators that all participation in research is 

             25     voluntary and that there ought be no obligation to 
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              1     participate even when the risks are minimal, and as 

              2     you'll see later on, we get to our obligation to even 

              3     ameliorate minimal risk and make it as minimal as 

              4     possible. 

              5               Let me pause there which is a brief outline 

              6     of the minimal risk substantive issues and get 

              7     comments, questions or thoughts.  Elliot. 

              8               DR. DORFF:  My basic question is, why?  Okay. 

              9      In other words, I'm talking about the paragraph at the 

             10     bottom of page one, top of page 2.  If people both in 

             11     terms of age and in terms of the situation in which 

             12     they live, if children are exposed to certain kinds of 

             13     risks that are different from the ones that other 

             14     children are exposed to of different ages or different 

             15     social conditions, why do you say that that should not 

             16     be understood as minimal risk? 

             17               I mean, what I have in mind is in terms of 

             18     age.  For example, if you were doing a test on, I don't 

             19     know, physical stamina or something on that order, I 

             20     mean, you would expect a teenager to have more physical 

             21     stamina than a six-year-old.  And so shouldn't that 

             22     then -- shouldn't then whatever minimal risk is 

             23     understood to be reflect that difference? 

             24               And similarly in terms of if you were doing, 

             25     let's say, a sociological study of children who grow up 
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              1     with alcoholic parents, now, that's clearly a higher 

              2     risk than -- hopefully than the norm of our society.  

              3     But, nevertheless, if you were to do this -- I mean, if 

              4     you were trying to define what minimal risk is for that 

              5     child, it seems to me that you really have to take that 

              6     into account.  I'm worried about the kind of objective 

              7     standard that you're presuming which probably is, what 

              8     middle class, white America, or something like that.  I 

              9     mean, is that -- now that's what I'm worried about. 

             10               DR. FLEISCHMAN:  Well, the standard in 

             11     minimal risk we do believe is an objective standard.  

             12     We'll invoke the Levine approach, if the tiger is in 

             13     the community.  I don't want to go -- I don't want to 

             14     tell Bob's story, but I think our workgroup believes 

             15     that just because children are living within less than 

             16     optimal environments ought not redefine what level of 

             17     risk is acceptable with no compensating benefit unless 

             18     they fit into the category of having a condition or 

             19     disorder which would allow them then to be the subject 

             20     of research that might be a minor increase over 

             21     minimal. 

             22               And I think we specifically have dealt with 

             23     the child of the alcoholic the child within poverty, 

             24     the child in less than optimal social circumstances in 

             25     the minor increase over minimal risk category. 
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              1               The reason we do that, is because we believe 

              2     that category requires more careful scrutiny to protect 

              3     those otherwise vulnerable subjects. 

              4               Now, the age issue that you raise, we do 

              5     believe is within minimal risk.  So the enhanced 

              6     stamina of the adolescent would be under minimal risk 

              7     if that was consistent with their age appropriate 

              8     levels.  So the only thing that we've eliminated is the 

              9     social circumstances.  We believe age has to be 

             10     relative within the standard of minimal risk. 

             11               DR. DORFF:  Then I would just suggest that 

             12     you separate them out in that paragraph.  Because the 

             13     way that the paragraph reads is that the last sentence 

             14     refers to the two previous sentences.  

             15               DR. FLEISCHMAN:  Okay.  

             16               DR. DORFF:  And the two previous sentences, 

             17     one talks about age and one talks about social 

             18     circumstances.  So if you understand age to be 

             19     different, then social circumstances you should 

             20     indicate that. 

             21               DR. FLEISCHMAN:  Thank you.  Abbey. 

             22               MS. MEYERS:  I think what you're talking 

             23     about would address one of the questions that I wanted 

             24     to ask about the Johns Hopkins study on children, the 

             25     lead paint study which also got a lot of publicity and 
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              1     which is, don't take it for granted that because these 

              2     children are being raised in the slum that they're 

              3     going to be exposed to lead paint and therefore it's 

              4     all right to put them in an environment where they're 

              5     purposely going to be exposed to it. 

              6               But my question is, I read through all of 

              7     this.  I think it's very, very good, but it's really 

              8     written for testing of antihistamines.  It doesn't talk 

              9     about sick kids in here.  You know, I mean, what is a 

             10     minor increase over minimal risk if the child has 

             11     cancer.  One of the big problems with the whole 

             12     pediatric exclusivity thing is that they're studying 

             13     the antihistamines.  But they're not studying cancer 

             14     drugs in children.  And, so I'd like to see very sick 

             15     children addressed here, you know, maybe more than a 

             16     minimal increase in risk is worth it. 

             17               DR. FLEISCHMAN:  Well, Abbey, we 

             18     wholeheartedly agree with you.  And we're about to 

             19     embark on that if NHRPAC agrees with this beginning.  I 

             20     mean, we've got to start somewhere.  We decided not to 

             21     bite it all off and present you with an entire analysis 

             22     of all the work we plan to do.  Our next approach will 

             23     be on the prospect of direct benefit, research 

             24     including questions about drug trials.  We have now 

             25     added to our workgroup an oncologist ethicist 
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              1     pediatrician, Rick Codish [ph] who has written 

              2     extensively in informed consent in clinical trials in 

              3     cancer, specifically to address the kinds of concerns 

              4     that you raise, but we're about to embark on those.  

              5     Placebo-controlled trials, prospective direct benefit 

              6     trials will be our next move into this area.  But we 

              7     feel that unless we can come to closure on these two 

              8     categories, it's going to be very hard to get to 46.405 

              9     which is the next category.  

             10               Bob. 

             11               DR. R. LEVINE:  Some of you have ample proof 

             12     that I'm technologically challenged.  

             13               DR. FLEISCHMAN:  I think we all knew that 

             14     before today, Bob.  

             15               [Laughter.]  

             16               DR. R. LEVINE:  I think this report is 

             17     terrific.  I think that with the suggestion, the 

             18     addition that Elliot made and I think was accepted that 

             19     it will be terrific plus. 

             20               The only one thing that I am concerned about, 

             21     and this was suggested by Abbey's comment, is that it 

             22     clearly says that minimal risk standard is defined in 

             23     relation to interventions or procedures that do not 

             24     hold out the prospect of direct benefit.  I would think 

             25     it would be of great help to people out there and some 
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              1     in here if it went on to say very clearly that minimal 

              2     risk has nothing whatever to do with procedures that do 

              3     hold out the prospect of direct benefit. 

              4               When Abbey talks about the need to look at 

              5     children with cancer and evaluate treatments there, we 

              6     don't evaluate the treatment as to whether or not it 

              7     presents more or less than minor increase above minimal 

              8     risk, in that case the risk benefit balances between 

              9     the risks of the drug and the benefit in terms of 

             10     treatment of the trials disorder.  "Minimal" does not 

             11     relate to that at all.  And I do hope that that 

             12     clarification will be made prominently. 

             13               About my tiger story, it was a leopard. 

             14               [Laughter.]  

             15               DR. FLEISCHMAN:  Sorry.  

             16               DR. R. LEVINE:  No problem.  Except that I 

             17     was in Africa where they have leopards, but not tigers. 

             18      And I was saying something that in a perhaps amusing 

             19     way is relevant to this discussion, and that is, I 

             20     visited a place where leopards and lions wandered 

             21     freely between people's houses.  And when I got there 

             22     that a leopard had eaten the neighbor's dog the week 

             23     before.  And I said, this would give special meaning to 

             24     contemplating what goes on in the everyday-life 

             25     experience of the child.  And I think Alan has been 
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              1     very careful to say, that is not what we're talking 

              2     about.  That is not an everyday experience for the 

              3     average child.  Thank you.  

              4               DR. FLEISCHMAN:  Felice. 

              5               DR. F. LEVINE:  I just wanted, as a member of 

              6     the working to underscore the reasoning of our working 

              7     in making the distinction, Elliot, to the issue that 

              8     you raised about social circumstances.  We actually 

              9     struggled with it for some time, especially in the 

             10     context of let's say, non-intervention kinds of studies 

             11     where you are interviewing or perhaps observing 

             12     children or adolescents who are in challenging social 

             13     circumstances, but even there we still thought that 

             14     taking the additional precaution to make sure that 

             15     children in those circumstances weren't essentially 

             16     being exploited as additionally vulnerable populations 

             17     was a worthwhile thing to do.  And that's how we sort 

             18     of parsed that distinction. 

             19               DR. FLEISCHMAN:  Sandy. 

             20               DR. CHODOSH:  I guess I still have one area 

             21     of concern.  And, you know, everything that is written 

             22     here is just beautiful, except the fact that if you're 

             23     not going to allow research that has no benefit to the 

             24     individual, in this case a child, how are we going to 

             25     obtain information about normal children?  There seems 
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              1     to me that, you know, the base for looking at 

              2     abnormality is to know what "normal" is.  And there's a 

              3     lot, as you well know, that we still do not know about 

              4     the differences of why children are different than us 

              5     big folks.  

              6               Is that going to be addressed?  Because that 

              7     seems to be sort of a black hole that's developed in 

              8     all of this.  You know, either it's not risky to the 

              9     individual and it's within a "normal" standard of 

             10     living or it's going to be a benefit and there's this 

             11     thing in between.  

             12               DR. FLEISCHMAN:  Can we bracket that question 

             13     for a comment and I'll call on you right after we talk 

             14     about the minor increase over minimal risk and see if 

             15     we come back to that conversation.  My rapid fire 

             16     response is that the way we've defined "condition" 

             17     would allow for research our normal physiology at a 

             18     certain level of risk would not allow research on 

             19     normal physiology at a higher level of risk unless 

             20     there was the prospect for direct benefit.  And having 

             21     begun my career on IRBs in the '70s arguing with some 

             22     nephrologist about how would they ever know if they 

             23     didn't do and they had a whole host of things they 

             24     needed to do with normal children, somehow it took them 

             25     a little longer, but we figured it out but we would 
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              1     never let them do it. 

              2               But I think there is a question when we have 

              3     a non-consenting patient consent through surrogacy as 

              4     to what level of risk we would allow.  And I think 

              5     we'll come back to that after the minor increase, if 

              6     you don't mind. 

              7               Mark. 

              8               MR. BARNES:  Alan, I'm sorry, I don't mean to 

              9     be dense, but let me ask a question I think has been 

             10     asked a couple of different ways again.  How does this 

             11     standard take into account the difference in perception 

             12     of sort of acceptable level of daily risk by geography? 

             13      That is, you know, IRBs are really local decision-

             14     making bodies.  And when I think of the kind of people 

             15     who tend to sit on IRBs in New York City and they tend 

             16     to be, you know, pretty well-educated people who have a 

             17     very minimal risk standard for their children, and I 

             18     compare that to, for example, where I grew up in the 

             19     south where one-third of the adults at any one time are 

             20     mentally ill, one-third are alcoholic, and one-third 

             21     are barely functional and they --  

             22               [Laughter.]  

             23               MR. BARNES:  -- and there is a very high 

             24     tolerance for the fact that children beat each other 

             25     with sticks and bricks and things like that.  And I --  
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              1               MS. MEYERS:  I disassociate myself with that 

              2     remark.  

              3               [Laughter.]  

              4               MR. BARNES:  And I do wonder about the, you 

              5     know, the perceptions of risk really do markedly differ 

              6     between, you know, rural areas versus urban areas, even 

              7     if you -- even leaving aside, you know, the 

              8     socioeconomic factor and just looking at geography.  

              9     And so I guess my question is, do you see this -- does 

             10     the working group see this as a national standard or 

             11     does it really allow for local variations?  

             12               DR. FLEISCHMAN:  I think the whole process of 

             13     IRB review allows for local variation, but it is a 

             14     national standard in the sense that what we are trying 

             15     to do is objectify this standard, look at it in a way 

             16     that suggests that there is a limit on what we will 

             17     allow for children in this category.  And I too wish to 

             18     be disassociated with your comment as a New Yorker who 

             19     would be thought to have those thoughts.  

             20               [Laughter.]  

             21               DR. FLEISCHMAN:  I want to be, you know, I 

             22     want to be sure --  

             23               MR. BARNES:  I can say it, you can't.  

             24               DR. FLEISCHMAN:  Absolutely.  

             25               [Laughter.]  
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              1               DR. FLEISCHMAN:  But I do think that it is 

              2     important and Elliot raised it right at the beginning 

              3     that we do consider the socially compromised children 

              4     as unduly vulnerable and we do have to think about 

              5     protections at the IRB level, that there have been some 

              6     untoward events that are in the history of research 

              7     ethics, and I think we need to think carefully about 

              8     how IRBs relate to that group.  I mean, that's our 

              9     working group's standard.  

             10               I'll go back to Felice. 

             11               DR. F. LEVINE:  In that context I think, 

             12     Mark, your underlying point is also a very good one and 

             13     it will take some degree of education, I think, of IRBs 

             14     nationally and maybe all of us as well as locally to 

             15     also not stereotype the notion of a normal healthy 

             16     child as someone who also doesn't exist.  I mean, that 

             17     all of this texture is part of the range of what is in 

             18     the normal healthy zone and that it's not some, you 

             19     know, white, ineffective person who doesn't hustle and 

             20     tussle in the way that children and youth do.  And 

             21     we'll need a much more variegated understanding of what 

             22     childhood and adolescence is like so that we know what 

             23     normal and healthy is.  

             24               DR. FLEISCHMAN:  Greg and then Bob and I 

             25     would invite our public commentators to come to the 
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              1     microphones now for just on the minimal risk question. 

              2               DR. KOSKI:  One just quick comment on the 

              3     notion of locality of IRB decision-making.  While 

              4     everyone agrees that there's a critical importance to 

              5     being aware of local situations and all of that, we've 

              6     also seen examples of what I call regional disparities 

              7     in IRB decision-making that are sometimes like medical 

              8     decision-making, it's not really based on rational.  

              9     And to the extent that total, you know, local reference 

             10     points could result in some IRBs allowing research that 

             11     would basically be considered unethical in other parts 

             12     of the country represents a range of non-uniformity, 

             13     perhaps, that I think probably exceeds what may be in 

             14     the best interests of research subjects, whether they 

             15     be children or adults. 

             16               And so this notion that you know, every local 

             17     IRB should be given complete autonomy to reach whatever 

             18     decision they want to is one that I think we have to 

             19     give some further thought to.  

             20               DR. FLEISCHMAN:  Bob.  

             21               DR. R. LEVINE:  Thank you.  I want to 

             22     underscore the importance of what Sandy said and add 

             23     one thing to it.  

             24               First, ever since the children's regs were 

             25     published in '83, we have had this problem on getting 
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              1     normal control data for procedures that presented minor 

              2     increase over minimal risk, and it's a persistent 

              3     problem.  And I hope -- I wish you well in dealing with 

              4     it.  But the other problem that's very important is 

              5     that it really -- if you read the regulations, 

              6     literally, which is perhaps the only way you can read 

              7     words, it says you can't do phase one oncology in 

              8     children. 

              9               Now, what we've done is shuffled around that 

             10     by saying it's become fashionable to call it phase 

             11     one/two.  But I hope you address that most thorny issue 

             12     very carefully. 

             13               Going back to the minor increase and normal 

             14     volunteer, child volunteer, I also hope you'll throw in 

             15     real cases like OHRP's reaction to the NICHD's protocol 

             16     where they use siblings of children with a condition.  

             17     That seemed to attract severe criticism while only 

             18     about five or six years earlier virtually the same case 

             19     was published in the IRB journal as a celebration of 

             20     how to solve the thorny problem.  So there's mixed 

             21     messages out there. 

             22               Thank you.  

             23               DR. FLEISCHMAN:  Susan.  And then we're going 

             24     to go on, if I don't see anybody at the microphones 

             25     we're going to go on to our second part which is the 
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              1     minor increase over minimal risk. 

              2               MS. KORNETSKY:  Yes, I'll just make a final 

              3     comment sort of about the variability and some of the 

              4     issues that have been raised.  Having working with an 

              5     IRB for the last 18 years with this definition, I think 

              6     part of the problem is that there are still IRBs and 

              7     many IRBs will use a relative standard or an absolute 

              8     standard.  So I think there still always will be some 

              9     variability, buy this will at least be a national way 

             10     that we can begin to bring things a little bit closer. 

             11      So I think this will do a lot more than you think for 

             12     those institutions that review IRBs for children. 

             13               DR. FLEISCHMAN:  Thank you.  Would you 

             14     identify yourself, please. 

             15               MR. DOYLE:  Yes, I'm Bill Doyle from 

             16     Pittsburgh.  In Pittsburgh we are born and bred.  We 

             17     don't leave, we stay.  The local IRBs only have, 

             18     usually, a flavor of Pittsburgh.  I think by making a 

             19     national standard or applying that we are going to take 

             20     away some of the autonomy.  Because that's all we know 

             21     is Pittsburgh.  We don't know New York.  We don't know 

             22     the south that you were talking about.  We know our 

             23     neighborhood, and we know what kind of risk that we're 

             24     going to expose our kids to.  We shoot BB guns at each 

             25     other as long as we're wearing leather jackets nad 
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              1     goggles. 

              2               I'm concerned about -- they use paint balls 

              3     now, but I'm concerned about this idea that we don't 

              4     have a local flavor and that we want to make a national 

              5     standard.  I agree that minimal risk should be an 

              6     absolute definition within constraints.  But the local 

              7     flavor is very, very important. 

              8               DR. FLEISCHMAN:  Thank you.  Yes. 

              9               MR. SCHATZ:  My name is Gerald Schatz and I'm 

             10     a budding bioethicist and a reformed lawyer.  I am a 

             11     former member of the NICHD IRB.  I am not familiar with 

             12     the sibling study.  But there are a few things I 

             13     learned on the NICHD IRB.  Having represented abused 

             14     and neglected children in the District of Columbia, I 

             15     was especially interested in the approach of social 

             16     intervention experiments.  I am delighted to see in 

             17     this Fleischman paper the reference to unwanted 

             18     disclosures. 

             19               And I think it will be very helpful if we 

             20     observe the spirit of it which is that simply that a 

             21     child lives at a higher degree of risk daily does not 

             22     mean that we can further expose that child to higher 

             23     risks.  And here I would urge that we not 

             24     compartmentalize our thinking, and this subgroup has 

             25     not.  And that's when we see people living at a higher 
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              1     degree of risks daily, we consider them as more 

              2     vulnerable.  

              3               DR. FLEISCHMAN:  Thank you. 

              4               Let me go on to the second part of the report 

              5     and that will bring these two together, I think, and 

              6     Sandy will have the first comment after the second 

              7     presentation. 

              8               In 46.406, research involving greater than 

              9     minimal risk and no prospect of direct benefit is 

             10     permitted if it is likely to yield generalizable 

             11     knowledge about the subject's disorder or condition. 

             12               And I'll remind you that there are some 

             13     predicates here.  The risk must represent a minor 

             14     increase over minimal.  The intervention or procedure 

             15     presents experiences to subjects that are reasonably 

             16     commensurate with those inherent in their actual or 

             17     expected medical, dental, psychological, social or 

             18     educational situations.  That the intervention or 

             19     procedure is likely to yield generalizable knowledge 

             20     about that disorder or condition.  And that that 

             21     generalizable knowledge reaches a very high standard, 

             22     that is, a vital importance standard for understanding 

             23     or ameliorating the subjects' disorder and that 

             24     adequate provisions are made for soliciting assent and 

             25     permission as is part of the regulations. 
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              1               We put into this report a little bit of 

              2     history here only because we wanted to highlight that 

              3     all the way back -- all the way back -- at the National 

              4     Commission --  

              5               [Laughter.]  

              6               DR. FLEISCHMAN:  -- in the early -- no, at 

              7     the National Commission, the report research involving 

              8     children and these -- this concept was integrated into 

              9     the final federal regulations precisely because of the 

             10     problem that's been raised about how would we be able 

             11     to find out important things about children in order to 

             12     be able to enhance taking care of children, 

             13     understanding children, bringing therapeutic 

             14     interventions to children. 

             15               So this area was created to allow research a 

             16     vital importance that would not otherwise be 

             17     permissible based in the minimal risk standard.  These 

             18     regulations impose a significant limit on the 

             19     discretion of parents to permit participation of their 

             20     children, but at the same time do allow some research 

             21     that entails more than minimal risk without the 

             22     prospect of direct benefit. 

             23               I have to say in looking back at those 

             24     discussions, having not participated in those 

             25     discussions at that time, I think it was really a very 
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              1     thoughtful way to deal with this very difficult issue.  

              2               So we have embraced this concept.  We remind 

              3     in that second paragraph on page three that while the 

              4     definition of minimal risk is indexed to the risks 

              5     encountered in the daily lives of normal, healthy, 

              6     average children, the minor increase over minimal risk 

              7     is not an absolute standard, that the permissible level 

              8     of risk associated with a minor increase over minimal 

              9     risk should be just a bit more than the level of 

             10     minimal risk, and that's an important concept.  

             11               You know, we've thought about drawing a 

             12     continuum scale with minimal risk over here and 

             13     significant risk over here, and a minor increase over 

             14     minimal risk, not on my nose, but close to my left 

             15     hand.  And I think that we see it that way in the 

             16     workgroup and that it is an important concept so that 

             17     it's just a bit more than minimal, it must be 

             18     commensurate with experience or with expected 

             19     experience, that both has something to do with the 

             20     level of risk, but not absolutely to do with the level 

             21     of risk because some of these children are going to 

             22     have experiences of very significant risk which would 

             23     not be consistent with this standard.  But it has to at 

             24     least be within their commensurability so that there 

             25     might be some concept of consent or assent based either 
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              1     in experience or in expected experience. 

              2               And, thirdly, that the significance of this 

              3     research much yield generalizable knowledge of vital 

              4     importance.  Now, I haven't met a researcher that 

              5     doesn't think that their research will realize 

              6     generalizable knowledge of vital importance.  But I 

              7     have met an IRB that's questioned it. 

              8               So I do think that we must ask the 

              9     investigators to make that case and the IRB must review 

             10     that case.  It isn't going to be hard for them to make 

             11     the case, but it will be important for IRBs to review 

             12     the case.  And it's two issues, both generalizable 

             13     knowledge and vital importance.  And generalizable 

             14     knowledge speaks to the validity of the study, the 

             15     biostatistical and approach to the study and the 

             16     research design of the study.  If you can't answer a 

             17     question, then you ought not be doing the study and 

             18     then it has to be of importance to the -- and even 

             19     vital importance to the subjects.  

             20               Do you want to just break in there? 

             21               DR. R. LEVINE:  [Off mic.]  

             22               DR. FLEISCHMAN:  Okay.  Now, we did bite off 

             23     the question of disorder and condition and perhaps this 

             24     is the most controversial part of this report, we think 

             25     it's critically important.  We've spent a good deal of 
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              1     time thinking about it to speak to the question that 

              2     Sandy raised, and that is, what constitutes a disorder 

              3     or condition within these regulations for which the 

              4     minor increase over minimal risk standard would then be 

              5     applicable. 

              6               And we have argued that the phrase "disorder 

              7     or condition" refers to a characteristic of the group 

              8     of potential research subjects and implies that this 

              9     characteristic can be understood more broadly than 

             10     simply a specific disease or diagnostic category. 

             11               We interpret the concept of disorder or 

             12     condition as relating to a specific characteristic 

             13     which describes a group of children, a physical or 

             14     social condition affecting children or the risk of 

             15     certain children developing a disease in the future 

             16     based on diagnostic testing or physical examination. 

             17               Thus, for example, and this is just examples, 

             18     thus for example, prematurity, infancy, adolescence, 

             19     poverty, living in a compromised physical environment, 

             20     institutionalization, or having a genetic 

             21     predisposition to future illness are some of the 

             22     disorders or conditions of children that can, under 

             23     appropriate circumstances based on IRB review warrant 

             24     permissible research that presents levels of risk that 

             25     are a minor increase over minimal without the prospect 
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              1     of direct benefit. 

              2               So that's on the table for conversation.  And 

              3     I've got Sandy first, then Bob, then Mark, and Adil. 

              4               DR. CHODOSH:  I'm still not sure that the 

              5     black hole has been filled and that we're still talking 

              6     about a minor degree over minimal risk and there are 

              7     lots of situations where that would be exceeded and 

              8     there would be no benefit to the individual and perhaps 

              9     benefit to the generalizable knowledge.  Okay. 

             10               And I think that it depends on how you tie 

             11     those things together that if we don't have an avenue 

             12     or a pathway to lead to generalizable -- important 

             13     generalizable knowledge that exceeds the bit more than 

             14     minimal risk that we are not going to ever achieve what 

             15     we need to do with children.  I'm not a pediatrician 

             16     but I know that as a clinician for many years, one of 

             17     the big problems is that you didn't know how to treat 

             18     children with drugs.  Okay.  Because they were never 

             19     tested in children. 

             20               And those were, of course, sick situations.  

             21     But how do you establish general, good physiologic 

             22     business when it does go a bit more than minimal risk 

             23     and there is no benefit?  And so I don't see that this 

             24     hole has been filled.  I think there is still going to 

             25     be a problem for IRBs.  I think there is still going to 
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              1     be a problem for science.  

              2               DR. FLEISCHMAN:  Well, Sandy, I think the 

              3     pediatric research community has sometimes voiced those 

              4     concerns.  The regulations gave us the 407 section.  

              5     The 407 section was in fact to deal with those kinds of 

              6     very important vital research studies that could not 

              7     fit into a minor increase over minimal risk, did not 

              8     have the prospect for direct benefit, but could be 

              9     elevated to the level of the Secretary for review.  

             10               Now, you will remember that before recent 

             11     history, before the last couple of years, and we could 

             12     argue why it's increased in the last couple of years, 

             13     but before the last couple of years there were really 

             14     very few research projects of that level that came to 

             15     the Secretary's attention.  In fact, two.  

             16               Now, there is perhaps a broader number now 

             17     and it may -- some of us think it may be to do with 

             18     IRBs that are a bit more paranoid about making some of 

             19     these judgments in an atmosphere of concern about 

             20     compliance, et cetera, and lack of clarification of 

             21     some of these definitions.  But the 407 committee still 

             22     sit there ready, I am told, to deal with these issues 

             23     and that would be where the issues of concern that 

             24     you're raising would be placed.  I mean, in the 

             25     regulatory structure that's -- it's not a total black 
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              1     hole, there is the possibility of that.  And I mean, 

              2     that's where it sits right now.  We will get to the 407 

              3     questions ultimately with our workgroup, although there 

              4     has been some good work, I think, already promulgated 

              5     on the 407 side. 

              6               Bob, and then Mark, and then Adil.  

              7               DR. R. LEVINE:  I just want to add a bit of 

              8     an extension to something Alan has already said, and 

              9     that is, what is the purpose of the commensurability 

             10     standard?  I feel confident I can talk about that 

             11     because being much older than Alan, I was part of the 

             12     process that developed it and he would have been 

             13     invited if he was my age.  

             14               [Laughter.] 

             15               DR. R. LEVINE:  The purpose of 

             16     commensurability standard is not to say, well, the kid 

             17     is going to have ten bone marrows anyhow, another two 

             18     or three don't make any difference.  That's not what it 

             19     is meant to say.  What is it meant to say is that 

             20     children who have had a bone marrow examination or who 

             21     are in a setting where they can expect to have one 

             22     will, by virtue of their much greater familiarity with 

             23     the procedure, know exactly what it is or what it's not 

             24     that they are agreeing to have.  They'll know how much 

             25     it hurts and so on.  So it's exclusively to reinforce 
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              1     the power of the assent or what the Commission also 

              2     called "knowledgeable agreement."  Thank you.  

              3               DR. FLEISCHMAN:  Thank you, Bob.  

              4               Mark. 

              5               MR. BARNES:  Yes, thank you.  Alan, there's 

              6     something that has always troubled me about the 

              7     standard that we did before with the minimal risk 

              8     versus the increase and it's actually just brought into 

              9      sharper focus by the working group's interpretation of 

             10     the minimal risk standard as really being a kind of 

             11     national standard.  And that is that if you accept your 

             12     -- and I think it's wise, I don't have a quarrel with 

             13     it, if you accept your national standard for minimal 

             14     risk as being the ordinary average healthy child, I've 

             15     always been troubled by the criterion B which the 

             16     intervention or procedure presents experiences to 

             17     subjects that are reasonably commensurate with those 

             18     inherent in the actual expected medical, dental, 

             19     psychological, social or educational situations which 

             20     actually allows you to import all of their 

             21     socioeconomic variables in making it sort of a -- 

             22     almost a class-specific inquiry as to whether the 

             23     experiences of this particular enhanced risk, this risk 

             24     over minimal risk would really be how it will be 

             25     gauged.  It will be measured by their actual lives 
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              1     rather than by a national standard.  

              2               And, I mean, it's always troubled me, but it 

              3     particularly troubles me given the -- I think -- 

              4     appropriate interpretation that the subgroup -- that 

              5     the working group has given to the minimal risk 

              6     standard.  And I wonder if you guys thought about that 

              7     or talked about it?  

              8               DR. FLEISCHMAN:  Uh-huh.  

              9               MR. BARNES:  And the sort of the larger 

             10     question is really, is the purpose of the working group 

             11     to kind of adumbrate or kind of do an exegesis of the 

             12     existing rule, or is the -- sorry. 

             13               DR. FLEISCHMAN:  I'm going to go to my lawyer 

             14     over here to find out what he means.  

             15               [Laughter.]  

             16               MR. BARNES:  -- or is the purpose really to 

             17     say that the regulations themselves, you know, may 

             18     actually be inappropriate and need to be -- that the 

             19     text itself needs to be worked over rather than just 

             20     putting a gloss on the existing text. 

             21               DR. FLEISCHMAN:  We think -- I mean, the 

             22     workgroup has thought a good deal about this and 

             23     believes that the regulations actually both were 

             24     intended to support this kind of work based in the 

             25     history of the conversations that the Commission and 
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              1     that the federal regulations have.  And we embrace that 

              2     argument. 

              3               We do believe that it's important to look at 

              4     children who are in uncertain circumstances who are 

              5     marginalized, who are socially impacted upon by their 

              6     environments.  And to study how one might help those 

              7     children to learn more about children of alcoholic 

              8     families or children in poverty, or children in lead 

              9     toxic environments is an important part of pediatric 

             10     research.  We think the regulations intended that. 

             11               What we are trying to do is to clarify that 

             12     in the sense to say that those are conditions worthy of 

             13     research.  We put it into this category rather than 

             14     into minimal risk.  We think it's safer for the IRB to 

             15     be more wary of that.  These are youngsters who could 

             16     be coerced into research or could be more likely to 

             17     have things done to them or for them that we ought to 

             18     at least scrutinize carefully.  And that, in a sense, 

             19     argues that the IRB, you know, in this categorization 

             20     in 406 rather than 404, really has to take that more 

             21     carefully into consideration. 

             22               It doesn't mean you can't do the research, it 

             23     means that you have a very -- a bit of a higher 

             24     standard, higher scrutiny, this generalizable knowledge 

             25     of vital importance.  It, for me as an IRB member, 
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              1     pumps it up a little bit in terms of what we're asking 

              2     of the researchers and what we're asking of our own 

              3     review.  I mean, that's where -- that's how I've seen 

              4     it right from the beginning. 

              5               And let me comment to Robert that I didn't 

              6     have the pleasure of being on it, but I did testify.  

              7     So I was old enough to do that. 

              8               MR. BARNES:  Could I just follow-up quickly? 

              9      Is that okay?  

             10               DR. FLEISCHMAN:  Yes. 

             11               MR. BARNES:  I mean, but I'm not quarrelling 

             12     with the idea that you would define the disorder or 

             13     condition as including -- that the definition of 

             14     disorder or condition in criterion C is really about 

             15     what you would study.  And I'm not quarrelling with the 

             16     idea of condition as broadly defined.  What I'm 

             17     quarrelling with and what's always troubled me is 

             18     criterion B which allows you -- which seems to me to 

             19     actually relax the standard.  In other words, for the 

             20     minimal risk what you guys have said, I think 

             21     appropriately, again, is that there is a national 

             22     standard for minimal risk and that's appropriate. 

             23               CHAIRPERSON MARSHALL:  And socially 

             24     allowable.  I mean, and that's a concept that we wanted 

             25     to get at this problem. 
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              1               MR. BARNES:  Yes.  But then in the allowable 

              2     risk under 406, it seems to me the criterion B is 

              3     actually saying that you are allowed to take into 

              4     account the fact that this particular child may come 

              5     from a riskier environment and therefore you can you a 

              6     lower risk standard.  That's my problem. 

              7               DR. FLEISCHMAN:  Well, we're trying to 

              8     separate out that commensurability standard and maybe 

              9     we haven't done it well enough in that second paragraph 

             10     on three.  What we are saying is the commensurability 

             11     standard does speak to assent and permission because 

             12     both parents and the child will have some understanding 

             13     of what it means that particular research intervention 

             14     or procedure, it does relate to the little bit more 

             15     than minimal, but it doesn't allow for those increased 

             16     risks that would be more than a little bit over 

             17     minimal. 

             18               Now, perhaps we can say that better in that 

             19     paragraph, but that's our intent.  And I think it 

             20     speaks to some of the issue that you're raising.  I 

             21     don't know if it speaks to all of it.  

             22               I've got Adil, then Judy, and then Abbey, and 

             23     then Bob.  

             24               DR. SHAMOO:  Thank you.  I think Mark 

             25     introduced my concerns very well in a much more fancier 
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              1     language, thank God.  

              2               [Laughter.]  

              3               DR. SHAMOO:  The problem still the issue 

              4     brought up under the minimal risk problem potentially 

              5     exploiting children is the same under this category.  

              6     And the one concerning me the most is the word "or 

              7     condition."  "Disorder" I can understand, "or 

              8     condition."  "Condition" as the dictionary defines is 

              9     state of being.  It could be anything, height, place 

             10     they work, age, gender, broken leg, social conditions, 

             11     poverty like you said, even race to be very honest, a 

             12     state of being.  It can be used as an excuse to exploit 

             13     children in any kind of research.  Literally there is 

             14     an elephant. 

             15               The intent of the National Commission was 

             16     really first to close this loophole, period.  It was a 

             17     member of this panel here since he is older than all of 

             18     us -- he's the one who opened the door for -- 

             19     rightfully -- for some kind of other research into this 

             20     category.  But the intent of the National Commission 

             21     was that window of opportunity was small, not as large 

             22     as it's been. 

             23               For example, being a sibling of an 

             24     incarcerated individual, a healthy child, just because 

             25     he has a brother, a child, in prison, that should not 
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              1     make him a human subject volunteer on these kind of 

              2     definition of a condition.  And that's what is 

              3     happening.  This thing has been interpreted very 

              4     broadly.  Let me read to you what the National 

              5     Commission said which you quoted, which is nice, but 

              6     you quoted the soft part of what the Commission said. 

              7               The Commission said, "research with children, 

              8     to the extent that it involves any exposure to 

              9     otherwise non-existent risks raises a serious ethical 

             10     question and calls for particular ethical 

             11     justification."  Furthermore, Kenneth Ryan, the 

             12     Chairman of the Commission, after he heard all the 

             13     argument and the discussion, he said, let me make it 

             14     very clear and he reiterated his own understanding.  He 

             15     said, and I quote, "The Commission's intention in 

             16     46.406 is to permit the conduct of research intended to 

             17     develop important knowledge of disease state from which 

             18     certain children suffer and for which they are the only 

             19     appropriate subjects." 

             20               And I'm saying is, your definitions here of 

             21     "condition" or the way you have placed it, I could pass 

             22     any, any social, behavioral characteristics to allow 

             23     children to be exploited in this kind of research.  And 

             24     the sibling issue in fenfluramine is a good example of 

             25     how that definition is being used and this definition 
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              1     will not excluded the fenfluramine experiment. 

              2               DR. FLEISCHMAN:  I think that our workgroup 

              3     would go a step further than Dr. Ryan in that quote.  

              4     Our workgroup would argue that condition is a 

              5     characteristic of a group of children that warrants 

              6     examination.  Our workgroup would lean on the Belmont 

              7     report and its argument of beneficence obligations to 

              8     enhance the health of children through careful analysis 

              9     of the disorders and conditions that children suffer 

             10     from. 

             11               So I think that we do have a difference in 

             12     interpretation here.  We do think our workgroup does 

             13     think that it is consistent with the regulations.  It 

             14     does not require rewriting of the regulations, and that 

             15     it is defensible.  

             16               DR. SHAMOO:  I think the word "condition" 

             17     should be narrowly defined than you have.  The way you 

             18     have it now will allow literally -- will eliminate 

             19     literally almost none of the research which is 

             20     objectionable which is social and behavioral issues or 

             21     poverty or whatever it is you want to put in this large 

             22     tent.  We will allow that kind of -- and of the word 

             23     condition of that particular group.  Because you got 

             24     away from the "disorder" it's "condition" and that 

             25     condition is broadly defined as you have it in your 
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              1     paper. 

              2               DR. FLEISCHMAN:  So I think, Adil, you and I 

              3     may agree on what specific research projects should or 

              4     should not be approved.  What we are trying to do here 

              5     is to give IRBs some clarification.  We may have done 

              6     it inadequately.  But you and I, I think, would agree 

              7     that there's some research that has been done, some 

              8     research that has been proposed that ought not be under 

              9     this category.  But what you're asking is for the 

             10     definitions to be more constrained so that there would 

             11     be less flexibility at the local IRB level.  The 

             12     workgroup has not come down on that side of the 

             13     analysis. 

             14               Judy.  

             15               DR. SIEGEL:  I think my comments actually 

             16     relate to, Alan, just to what you're saying.  On the B 

             17     item commensurate with actually not having been around 

             18     at all, Bob --  

             19               [Laughter.]  

             20               DR. SIEGEL:  Not for age reasons.  

             21               DR. FLEISCHMAN:  Right.  Judy was an 

             22     adolescent enrolled in studies.  

             23               DR. SIEGEL:  Most probably.  

             24               I thought that your explanation of what the 

             25     National Commission had in mind of what commensurate 
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              1     was actually to imply which was that the children and 

              2     parents involved would understand what was coming and 

              3     could give better assent.  I think that's what's 

              4     missing.  I mean, if a clarification of that point 

              5     could be put right in there about what commensurate 

              6     actually means.  Because it actually explained it to me 

              7     better because actually what that says is, you don't 

              8     want to do something to somebody that they've never had 

              9     done to them before because you don't think that maybe 

             10     they can give good assent in that.  So I think that 

             11     would be a good point of clarification. 

             12               And, also, I think that Adil's point about 

             13     where do the boundaries around the conditions and what 

             14     conditions would actually be applicable for research 

             15     purposes, it's the next thing of vital importance.  I 

             16     think some guidance to local IRBs about what justifies 

             17     research of vital importance because I, to my mind, 

             18     don't know how you do that.  And, so, again, you could 

             19     argue that if we could give some sort of discussion 

             20     even on what vital importance might mean, it might help 

             21     a local IBR decide whether some research on a condition 

             22     actually meets those criteria. 

             23               DR. FLEISCHMAN:  Thank you.  Madam, 

             24     Chairperson, I understand we have a change in the 

             25     agenda that we need to deal with.  
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              1               CHAIRPERSON MARSHALL:  We do have a change in 

              2     the agenda.  So just let me -- I'll outline the next 45 

              3     minutes or so for you.  We're going to give Greg Koski 

              4     some time now to talk about classified research because 

              5     he does have to leave for a bit.  So we will have Greg 

              6     from 10:15 to 10:30.  We will break at 10:30 for 15 

              7     minutes, resume at 10:45 and the proceed on until 

              8     11:30. 

              9               Thanks, Greg. 

             10               DR. KOSKI:  Mary Faith, thank you very much 

             11     for the flexibility and my apologies to everyone that I 

             12     do have to flip my schedule around a bit today.  But we 

             13     did at least want to give you a brief update on the 

             14     events that are underway in follow-up, in fact, to the 

             15     discussion that we had before this committee back at 

             16     the January meeting when we discussed the certain 

             17     events around bioterrorism, the impact that that has 

             18     had on the climate in which research is conducted.  And 

             19     I believe Jonathan Moreno who pointed out that in these 

             20     times, as well as in others, there is an appropriate 

             21     place for classified research done appropriately.  But 

             22     that there are certainly special challenges that are 

             23     raised by conducting research in the classified domain 

             24     and that those challenges deal particularly with the 

             25     protections for the subjects of that research. 
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              1               Now, much of our discussion in January went 

              2     back to the report from the President's advisory 

              3     committee on human radiation experiments where indeed 

              4     it became knowledge that classified research had been 

              5     conducted on individuals sometimes without their 

              6     informed consent, sometimes without appropriate 

              7     reporting and so on.  And that was one of the bases for 

              8     the recommendations issued by that advisory committee 

              9     that included not only mechanisms for improving the 

             10     sort of reporting and tracking, recordkeeping around 

             11     classified research so that people are aware of what's 

             12     going on and there are some appropriate accountability 

             13     and oversight brought to that, but also recommendations 

             14     for amendments to the Common Rule, the regulatory 

             15     structure to ensure that when such research is proposed 

             16     that it is both appropriately reviewed and that due 

             17     consideration is given to the protection of human 

             18     subjects.  

             19               The types -- actually, I believe there's 

             20     information in the books and perhaps available out 

             21     front for others that have to do with the specific 

             22     wording of the recommended language for the amendments 

             23     to the Common Rule.  But the requirements included such 

             24     things as ensuring that there was a lay individual who 

             25     had appropriate security clearance who was required to 
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              1     be present at the time of review.  And that there be 

              2     appropriate mechanism for appealing the decision of a 

              3     committee.  And in the case that the individual who was 

              4     bringing an outside consciousness to that group 

              5     concerns about the research as to whether or not it 

              6     should go forward on that right of appeal would be made 

              7     to the White House to the President. 

              8               Now, I'm not going to review all of the 

              9     provisions there because we have done that and so it's 

             10     written.  But in response one of the many parts of the 

             11     response of the then Clinton administration to the EG 

             12     report was an executive directive that called upon the 

             13     federal agencies that operate under the Common Rule to 

             14     adopt the proposed amendments and actually to do so on 

             15     an accelerated timeframe.  

             16               All of the agencies save, I believe two, 

             17     perhaps three, in fact did put their signature to that 

             18     within the appropriate time frame, but it never quite 

             19     got to completion.  And so in the context of today's 

             20     circumstances we are revisiting that recommendation.  

             21     We basically have discussed the issue before the human 

             22     subjects research subcommittee of the committee on 

             23     science. 

             24               We have asked the federal agencies to once 

             25     again review these recommendations within their 
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              1     agencies and to make some determination as to whether 

              2     or not the positions that they would adopt today are 

              3     the same or different from the provisions that they 

              4     have taken previously.  Whether there might be 

              5     additional changes that might be required within any 

              6     proposed amendments to the Common Rule, or whether what 

              7     had been previously proposed might go forward. 

              8               Now, the recommendation actually, as it 

              9     ultimately went forward was in the form of what was 

             10     called an "interim final rule" which would mean that 

             11     once it is put out there, although there would be a 

             12     period for public comment, it becomes effective 

             13     immediately and that's done in order to bring the 

             14     immediacy of the protections to bear. 

             15               So at the present time we are actively 

             16     engaged in this process indeed at the HSRS meeting 

             17     which is coming up next Wednesday.  We will be 

             18     discussing this once again and already many of the 

             19     agencies are actively engaged in the process of taking 

             20     it through their own houses to see where they stand.  

             21     So that, Madam Chairman is the current status. 

             22               CHAIRPERSON MARSHALL:  Greg, we do have -- we 

             23     are actually ahead -- some time for questions from the 

             24     committee or our ex officio or public members.  

             25     Jonathan, I see your hand is up. 
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              1               DR. MORENO:  First of all, I want to thank 

              2     Greg and the other members of the HSRS for picking up 

              3     what I think is really an important issue because I'm 

              4     persuaded, as I said before, that there will be the 

              5     political will for classified research on human 

              6     subjects in the future.  Although we're told that's not 

              7     the case now.  And we don't want to make our generation 

              8     responsible for the mistakes of previous generations 

              9     and to repeat those mistakes.  

             10               The language it seems to me in the interim 

             11     final rule is pretty good.  I only want to say at this 

             12     point that I think this group will, once the rule is 

             13     finalized, want to look at the following problem. 

             14               The problem is one that has been encountered 

             15     in the past for 40 or 50 years in this area.  Namely, 

             16     what counts as research with respect to national 

             17     security issues.  If -- and I can give you chapter and 

             18     verse of the way that this problem has unfolded over 

             19     the years, but to take a couple of examples, the 

             20     400,000 plus men who were deployed in the nuclear test 

             21     shots in the late '40s through the early '60s were not 

             22     considered to be human subjects.   And, yet, in many 

             23     cases they were given radiation badges, their blood and 

             24     urine was tested, and so forth. 

             25               Only in two kinds of activities, 
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              1     psychological panic studies and flash blindness studies 

              2     were they considered to be part of human experiments.  

              3     So everything turns really in this area on the question 

              4     of what counts as an experiment or what counts as 

              5     research.  So which box bureaucratically that gets put 

              6     in is absolutely critical.  

              7               CHAIRPERSON MARSHALL:  Thank you, Jonathan. 

              8               I have Judy and then Bob.  No, I'm sorry.  

              9     Okay.  Bob. 

             10               DR. R. LEVINE:  Once again, what did the 

             11     National Commission do about this.  The National 

             12     Commission had extensive hearings on research that was 

             13     conducted by what was called the intelligence 

             14     community.  And one of the problems that seemed not 

             15     susceptible to resolution was that if and when they 

             16     would establish IRBs, they would have required that 

             17     every member of the IRB, including the community 

             18     representatives would have to have the appropriate 

             19     level of security clearance.  

             20               This, even in the 1970s, was somewhat alien 

             21     to the idea of having what since has been called 

             22     "transparency" applied to the deliberations.  It 

             23     strikes me that that might be an intractable problem 

             24     because you don't want people without security 

             25     clearance getting access to things that have security 
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              1     clearance for some good reason.  

              2               The other thing that Jonathan suggested is 

              3     the issue of what counts as research.  In the last ten 

              4     years, when I've seen various specialties wonder about 

              5     how they're going to make careful determinations of 

              6     whether what they're doing or which of their activities 

              7     count as research, I've become increasingly impressed 

              8     that there's an awful lot of stuff on the -- an awful 

              9     lot of stuff that various agencies and disciplines 

             10     engage in that the definitions don't work very well. 

             11               I was chair of the CDC committee and we 

             12     looked at such things as outbreak investigation, 

             13     routine surveillance, case studies, in case of 

             14     something outlandish happening.  And many of these 

             15     exercises use all of the devices that researchers 

             16     commonly use.  More recently I've seen the same thing 

             17     in health policy research where some, but not all of it 

             18     is exempted from coverage.  And in -- what's it called 

             19     -- quality improvement activities in the health care 

             20     setting.  

             21               I'm beginning to think more and more that we 

             22     should not be working with the definition of research 

             23     trying to gerrymander it so that it fits here, but not 

             24     there and so on.  But to do what the health policy or 

             25     the public health policy, what was done on behalf of 
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              1     this group, and that is to create some well-circumcised 

              2     --  

              3               [Laughter.]  

              4               DR. R. LEVINE:  Sorry about it.  Well-

              5     circumscribed exemptions to coverage from -- not from 

              6     all the regulations.  I think exemptions in coverage by 

              7     all the regulations is a mistake.  But to exempt 

              8     certain sorts of things from some aspects of the 

              9     regulations that are pretty onerous.  And I hope we 

             10     have a chance to worry about that later.  Thank you. 

             11               CHAIRPERSON MARSHALL:  Abbey and then I'd 

             12     like to open the -- we have about two minutes.  So, 

             13     Abbey, and then anyone, ex officio. 

             14               MS. MEYERS:  I would just worry about 

             15     exempting this kind of research from anything.  Because 

             16     if experiments can be done on soldiers who are more or 

             17     less like prisoners, I mean, they have no choice if 

             18     they're in the military but to obey orders and 

             19     participate in an experiment.  So I really would want 

             20     those guarantees of human protections to be even 

             21     stronger in the case of defense. 

             22               DR. MORENO:  Again, this misses the point.  

             23     The problem is that whenever there's been an issue like 

             24     this, Abbey, it's simply been defined as not an 

             25     experiment but as part of training for some potential 
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              1     combat situation.  So the overreaching problem is what, 

              2     as Bob said, what do we put within that framework -- 

              3     what do the powers that be at the time put within that 

              4     framework. 

              5               CHAIRPERSON MARSHALL:  We have time on the 

              6     agenda later, I would like to just get to the folks who 

              7     are standing in line here.  John. 

              8               DR. MATHER:  Dr. John Mather with the VA.  I 

              9     want to identify myself clearly with Jonathan Moreno's 

             10     remarks.  I think this issue is a very serious one 

             11     about what constitutes the scope of research that is 

             12     classified research and how it might or might not 

             13     differ from our classic definitions, Bob Levine, that 

             14     appear in the Common Rule. 

             15               We have seen survey research done which 

             16     doesn't theoretically, you know, hurt anybody, but 

             17     clearly does, by the very nature of the questions.  So 

             18     it doesn't just have to do with radiation exposure and 

             19     those kinds of things.  So I think we need to think 

             20     very seriously and carefully about what is classified 

             21     research. 

             22               Greg mentioned the human subjects research 

             23     subcommittee which has been reengaged with this issue 

             24     over the past couple of meetings.  And there's a very 

             25     clear impetus to get this done and done quickly.  And I 
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              1     think we need to move it along and move it along with 

              2     haste, but not to the point that haste makes waste. 

              3               I think this issue of security clearance has 

              4     come up.  Clearly those agencies that have an 

              5     intramural program, they will have to make sure that 

              6     IRBs as per CIA and so forth appropriate security 

              7     clearances and I don't think that's inappropriate in a 

              8     broad national sense.  There are other agencies like 

              9     the VA that probably will be really challenged on that 

             10     issue because IRBs are down at the VA medical center 

             11     level. 

             12               So if there's any kind of research that's 

             13     done in a classified nature, it's not exactly clear how 

             14     that will play out.  One may have to do it depending on 

             15     the particular site and it may just be that, you know, 

             16     the chair of the IRB there will be the person that 

             17     would have to get security clearance. 

             18               So it does raise some other issues for those 

             19     of us that don't have naturally intramural IRBs that 

             20     run the full gamut, maybe like Polly is going to 

             21     mention about DOD and agencies like that. 

             22               CHAIRPERSON MARSHALL:  We have about three 

             23     minutes, but I do want to observe that we can continue, 

             24     I think, part of this discussion tomorrow afternoon or 

             25     tomorrow morning at 10:30. 
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              1               So, Greg has to walk out the door in about 

              2     three minutes. 

              3               MS. BLEVINS:  Sue Blevins, Institute for 

              4     Health Freedom.  My question is, how do you reconcile 

              5     informed consent with classified research?  And is 

              6     there an assumption here that if it's classified 

              7     research that the individuals receiving the treatment 

              8     or intervention are not giving written informed 

              9     consent?  Because if they are, they could be sharing 

             10     with family members. 

             11               I would also make a recommendation that if 

             12     there isn't an IRB or somebody overseeing the research 

             13     that perhaps whoever is involved in the treatment at 

             14     least one person out of that group would also be 

             15     receiving the treatment or intervention.  Just a 

             16     recommendation. 

             17               DR. KOSKI:  The recommendations do not 

             18     basically allow for a waiver of informed consent in 

             19     these kinds of situations except under those conditions 

             20     where it might otherwise be waived under the 

             21     regulations so that indeed the presumption would be 

             22     that for any research that involved greater than -- 

             23     that it would clearly carry with it the requirement for 

             24     informed consent.  And that poses special challenges as 

             25     we've already heard from Jon and others in a situation 
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              1     where the individuals who participate may in fact have 

              2     to have security clearance in order to go ahead 

              3               But there are a number of logistical issues 

              4     that have to be considered here and quite frankly I 

              5     think that even if one moves ahead expeditiously to put 

              6     forth the rules there is still going to be a need for 

              7     extensive guidance and further work on how the rules 

              8     would actually be applied. 

              9               CHAIRPERSON MARSHALL:  Thank you.  Please 

             10     just let us know who you are. 

             11               MS. BOLL:  Hi, I'm Patty Boll, I'm with the 

             12     Department of Defense and I would like to make a couple 

             13     of comments on what was spoken here.  In reverse order, 

             14     we do -- we have covered subjects and their legal 

             15     access to classified information.  And all of our 

             16     subjects do have to have the appropriate clearances so 

             17     they are given truly informed consent.  They are given 

             18     all the information they need because they have the 

             19     right tickets and the right access to have that 

             20     information.  So because of that they are bound by the 

             21     same security constraints as a soldier would for a 

             22     classified mission.  They can't talk about this with 

             23     family, but we give them enough access to resources to 

             24     discuss the risks.  They can still talk to physicians, 

             25     to lawyers, to things like that as to what's going on 
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              1     so that we make sure they can truly give informed, 

              2     voluntary consent. 

              3               And on the lines of voluntary consent, in our 

              4     DOD directive we have special clauses for the 

              5     protection of military subjects.  When you are asking 

              6     military to participate as volunteers, we make sure 

              7     that the chain of command is not part of that process. 

              8      So soldiers, sailors, marines, flyers have the ability 

              9     to truly decline participation and their chain of 

             10     command is not part of recruitment.  And we are very 

             11     specific that that cannot happen and under certain 

             12     situations when you are trying to recruit groups of 

             13     people, we make sure that there is an ombudsman as part 

             14     of that process to ensure it is fair and there is no 

             15     coercion. 

             16               We are still grappling with how do we define 

             17     research versus training and under what scenario are 

             18     you looking at this question?  Is it research, is it 

             19     training?  Because you're right, when it is training, 

             20     your unit goes.  That's what you volunteered to do when 

             21     you raised your right hand and joined the military.  

             22     But we do want to make sure that we are not 

             23     misclassifying an activity as training when it is in 

             24     fact research.  

             25               CHAIRPERSON MARSHALL:  Thank you very much. 
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              1               Greg, thank you.  I know you've got to run. 

              2               As Greg is walking out the door, I just want 

              3     to make the observation before break that there is an 

              4     interesting appendix to the book, "The Nazi Doctors and 

              5     the Nuremberg Code" by George Annes and Michael Groden 

              6     that actually is comprised of documents that have been 

              7     declassified that describe the protections process in 

              8     some of the formerly classified research that the 

              9     government has entered into.  And so I would commend 

             10     that to you as an interesting resource and then also, 

             11     of course Jonathan's book on "Secret State 

             12     Experiments."  

             13               So let us break then and come back at quarter 

             14     till the hour. 

             15               [Brief recess taken at 10:35 am.] 

             16               CHAIRPERSON MARSHALL:  Time to resume.  If 

             17     committee members could take their seats, please. 

             18               We are just going to start.  If those of you 

             19     who are in the room could please take your seats.  We 

             20     will turn the discussion back over to Alan. 

             21               DR. FLEISCHMAN:  Refocusing on the children's 

             22     report, we have Abbey, Bob, and Jonathan, if he comes 

             23     back on the list.  And then Felice.  Felice is back.  

             24     Good.  Abbey. 

             25               MS. MEYERS:  I absolutely agree with what 
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              1     you've written on disorder and condition.  And I have 

              2     to tell you that in the Orphan Drug Act we've used the 

              3     same terminology about disorder and condition.  The 

              4     reason is, a disorder is something like a syndrome or a 

              5     disease.  But a condition can be caused by an accident 

              6     or trauma or anything.  A broken leg is not a disease, 

              7     it's a disorder.  So you have to differentiate between 

              8     the two. 

              9               And I wanted to know if what you've written, 

             10     from what I've seen here, if it -- how it would address 

             11     something like taking a spinal tap on a person with 

             12     Down's syndrome?  Because, in my mind, I would not 

             13     allow a spinal tap on somebody with Down's syndrome 

             14     based on what you've written. 

             15               DR. FLEISCHMAN:  Well, Abbey, the devil is in 

             16     the details.  So we would need to understand the 

             17     context of the research, what the question is, whether 

             18     that child with Down's syndrome might also have 

             19     leukemia.  And having had experience with spinal taps, 

             20     and having dealt with them reasonably which some Down 

             21     syndrome children can, the age of the child.  I mean, 

             22     there would be a whole host of questions.  

             23               MS. MEYERS:  But it's more than minimal risk, 

             24     isn't it, for anybody?  

             25               DR. FLEISCHMAN:  Well, our table that's 
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              1     evolving would agree that a spinal tap for children is 

              2     more than minimal risk.  

              3               MS. MEYERS:  Sure.  

              4               DR. FLEISCHMAN:  I'm not going to talk about 

              5     incapacitated adults at this moment. 

              6               MS. MEYERS:  Right.  

              7               DR. FLEISCHMAN:  But for children --  

              8               MS. MEYERS:  Or for any child. 

              9               DR. FLEISCHMAN:  -- we would agree, I think, 

             10     the workgroup, that a spinal tap is more than minimal 

             11     risk.  There may be some circumstances, however, in 

             12     which it fits into a minor increment over minimal risk. 

             13      And those circumstances have to do with the 

             14     commensurability standard.  So, for instance, just to 

             15     give you an example, if there were a child with 

             16     leukemia who had had a couple of spinal taps in the 

             17     evaluation, and two or three spinal taps in the 

             18     continuing assessment of the child's wellness, and 

             19     there were a protocol which required another spinal tap 

             20     only for research purposes and not for clinical 

             21     purposes, it is possible that that spinal tap could be 

             22     consistent with a minor increase over minimal risk with 

             23     appropriate permission and assent if we met all the 

             24     other criteria.  

             25               So we are not precluding that potential. 
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              1               I am going to skip to Mary Kay because she 

              2     has that concerned look on her face that we need to 

              3     deal with. 

              4               DR. PELIAS:  My furrowed brow.  I know.  Why 

              5     did you bring -- I'm asking Abbey this, why bring in 

              6     the child with Down syndrome?  What was the purpose of 

              7     that? 

              8               MS. MEYERS:  Because of the stipulation that 

              9     the research could be done, the child will not benefit 

             10     from it, but more can be learned about their disease or 

             11     condition, you see.  So it seems to me that a minor 

             12     incremental increase in risk to learn more about Down 

             13     syndrome from which the child will not benefit, you 

             14     know, how does this address that? 

             15               DR. FLEISCHMAN:  I think the commensurability 

             16     standard might argue that a child with Down syndrome 

             17     could not have a spinal tap as a minor increase over 

             18     minimal risk unless that child also had had other 

             19     circumstances or characteristics.  And we would not 

             20     learn about the spinal fluids of children with Down 

             21     syndrome potentially.  And that might be a bad thing 

             22     that we didn't learn about it, but we wouldn't be able 

             23     to based on our concern about that level of risk for 

             24     that group of subjects. 

             25               We also have this concept of amelioration and 
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              1     let me take a moment to just go through those two last 

              2     paragraphs.  The workgroup feels very strongly it is 

              3     the obligation of investigators and IRBs to decrease 

              4     the level of risk at whatever level it begins.  And 

              5     that includes using appropriate people to do 

              6     procedures, that is to say, people who have experience 

              7     with children, and who are competent to do the kinds of 

              8     tests and procedures that are used in children.  Also, 

              9     to try to teach children about the particular 

             10     procedures and to try to ameliorate risks through 

             11     education of children, through having environments that 

             12     are child friendly and comfortable.  

             13               So, theoretically, one could give an 

             14     argument, and I'm not about to give it here, but one 

             15     could give an argument that in our Down syndrome 

             16     program we have relationships with children in our 

             17     program with their parents and with their loved ones, 

             18     and dah-dah-dah-dah-dee, and with people who they know 

             19     and love where we might be able to do something more in 

             20     the minor increase over minimal risk than in somebody 

             21     else's Down syndrome study.  And we would make that 

             22     case.  I don't think it would rise to the level of a 

             23     spinal tap.  But we could make that case that our 

             24     relationship with those children in our very special 

             25     program which involves them and does various things for 
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              1     them and with them might create an environment which 

              2     might allow for certain things to be done in that 

              3     program that could not be done in somebody else's 

              4     program. 

              5               And that's where we argue that some levels of 

              6     research, thus, in this last paragraph, even in 

              7     research studies that have risks deemed minimal or a 

              8     minor increase over minimal, every attempt should be 

              9     made to minimize the risks and some places might be 

             10     able to have a higher level of risk because they've 

             11     done things to minimize that level that wouldn't be 

             12     acceptable in other places.  So that we've tried to 

             13     deal with it there.  

             14               And, again, with the Pittsburgh argument that 

             15     local IRBs really are important in making some of these 

             16     judgments understanding the environments in which 

             17     children will have research performed, and those 

             18     environments do allow for local IRBs to make differing 

             19     assessments. 

             20               Bob, or Susan, are you right on point there? 

             21      Susan, on that point?  May I, Bob?  Thank you. 

             22               MS. KORNETSKY:  Yes, I just want to comment 

             23     on this because I think this is very important and 

             24     having thought a lot about this and taking sort of 

             25     responsibility for this part in this document is that I 
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              1     think it's important that you have to take into context 

              2     the location where things are being done, who is doing 

              3     it, and that that can minimize the risks, even 

              4     sometimes to the extent of making something minimal 

              5     risk. 

              6               And I think that what has happened previously 

              7     is that people look at procedures and is it minimal 

              8     risk or is it not?  I believe that there may be some 

              9     procedure that in an academic medical institution may 

             10     be considered minimal risk and may be outside in a 

             11     general pediatrician's office isn't.  So that has to 

             12     really be brought into context here. 

             13               DR. FLEISCHMAN:  I've got Bob, Jonathan, 

             14     Felice, and Margaret. 

             15               DR. R. LEVINE:  Thank you.  When I raised my 

             16     hand quite some time ago I wanted to respond to 

             17     something Mark had said.  He suggested that the idea of 

             18     commensurability removed the uniformity of the 

             19     protection for children, that it took away the idea 

             20     that there was an objective standard.  There still is 

             21     an objective standard.  The standard is minimal risk, 

             22     minor increase above minimal risk. 

             23               What the commensurability does is specify 

             24     which children are to be considered legitimate 

             25     candidates for a certain minor increase.  So if the 
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              1     child has leukemia, it might be a bone marrow 

              2     aspiration.  If the child has meningitis, it might be a 

              3     spinal tap.  But the fact remains that it's only a 

              4     minor increase of minimal risk that applies to all 

              5     children in the U.S. who have a disease, condition, or 

              6     disorder. 

              7               Another point I wanted to make is in response 

              8     to what Judith brought up.  She wanted to see a 

              9     specification of vital importance.  And I am, I 

             10     believe, that it's going to be -- it would not be a 

             11     good idea to get too specific about that.  I expect 

             12     we'll see some of this come out in the case studies 

             13     that Alan and his group are going to prepare for us.  

             14     But whenever you start specifying these general 

             15     categories, they lose their flexibility and it's like I 

             16     hear many people say, well, we ought to specify what is 

             17     meant by "reasonable."  It's terms like this that are 

             18     meant to have sort of an elastic definition and I see 

             19     the philosopher nodding. 

             20               If you specify exact definitions for them, 

             21     you have to invent another term that will allow you to 

             22     describe what you want to. 

             23               The National Commission chose not to specify 

             24     this and it chose not to specify many other terms.  One 

             25     of the concerns I have is that in public policy we 
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              1     frequently specify or stipulate definitions for terms 

              2     that have separate meanings or different meanings in 

              3     the common usage.  I lobbied against use of the term 

              4     "minimal" to describe minimal risk.  Because people who 

              5     weren't in on the conversation might look at the 

              6     dictionary and find that it means "least possible."   

              7     And so now when we hear about cutting back the risks 

              8     even in minimal risk studies unless you're in on this 

              9     special conversation, you might think that that's a 

             10     very zany conversation.  Thank you. 

             11               DR. FLEISCHMAN:  We need to shut off that 

             12     microphone, if you would.  And then we'll go to 

             13     Jonathan.  

             14               DR. MORENO:  Bob has already said much of 

             15     what I wanted to say.  We'll find this again tomorrow 

             16     with the report of the workgroup on decisional 

             17     incapacity.  And it was a sort of a flag that I wanted 

             18     to raise last time, namely that we need to be careful 

             19     since were are all policy wonks by virtue of the fact 

             20     that we're sitting around this table not to think that 

             21     a document can capture every case. 

             22               I think we can all agree, probably, on 

             23     certain cases, specific cases if we were to work as a 

             24     sort of a de facto IRB around this table, but no 

             25     regulation and no set of terms is going to capture 
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              1     every possible case in advance. 

              2               I think we need to, as a group, start 

              3     thinking about these matters something like the way the 

              4     IOM has proposed, namely that this language, this 

              5     guidance, the regs, the IRBs, conflict of interest 

              6     committees, et cetera, et cetera, are all part of a big 

              7     human research protections program.  And so there 

              8     should be multiple opportunities to catch bad cases 

              9     that concern us.  And this will only be one of those 

             10     filters. 

             11               That's not an excuse not to bang away at this 

             12     language, or at the language of the decisional capacity 

             13     workgroup report or others.  But there's a point at 

             14     which we can sit around and bring up every possible 

             15     nightmarish example and we'll undermine our confidence 

             16     that we can get the system to be better, which I think 

             17     we can.  

             18               DR. FLEISCHMAN:  Thank you, Jonathan.  

             19     Felice. 

             20               DR. F. LEVINE:  I think that Bob and Jonathan 

             21     covered what I was going to say from the vantage of our 

             22     working group, and let me just emphasize that in our 

             23     effort to think through where the bar was that the word 

             24     "vital importance" had meaning.  That it -- that there 

             25     needed to be a relationship between the condition and 
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              1     the inquiry in a way where at least a PI going before 

              2     an IRB would not just be able to say some throw away, 

              3     this is important, but that's vital too, was an 

              4     adjective that really was saying, you know, this is an 

              5     important part this has to be a piece of research that 

              6     really made meaningful minor increment over minimal 

              7     risk kind of input. 

              8               DR. FLEISCHMAN:  Thank you.  Margaret. 

              9               MS. BORWHAT:  I just have concern about the 

             10     last paragraph, but I understand what you're saying 

             11     about making sure that professionals that are skilled 

             12     with the children are able to minimize risks where in 

             13     other environments they're aren't and that we would 

             14     rely to a good extent on the IRB.  But I am concerned 

             15     that the local IRB would be able to as objectively as 

             16     necessary be able to say, you know, our staff isn't as 

             17     skilled as needed for this particular study.  And so, 

             18     you know, I think it could be enhanced with either more 

             19     examples or in your case studies to really try and 

             20     pinpoint perhaps the academic medical center where lots 

             21     of this type of research is done as opposed to solely 

             22     relying on an IRB that has an inherent interest in this 

             23     research being put forth in their institution and in 

             24     supporting their own researchers. 

             25               DR. FLEISCHMAN:  Thank you.  As some of you 
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              1     will recall, the working group in its early comments 

              2     actually had great concerns about IRBs in general 

              3     settings have sufficient pediatric expertise.  And 

              4     we've shared that with OHRP and feel very strongly 

              5     about the need for IRBs that are reviewing research 

              6     relative to children to have appropriate members, with 

              7     an "s" that have some knowledge and expertise in 

              8     children as well as community representation that it in 

              9     some sense represents the interests of children.  Now, 

             10     most of us represent the interest of children being 

             11     parents or having been children.  Right.  I knew Mark 

             12     was going to do that.  

             13               [Laughter.]  

             14               DR. FLEISCHMAN:  Some of us still are 

             15     children.  Right.  Okay.  

             16               [Laughter.]  

             17               DR. FLEISCHMAN:  But I do think that it is 

             18     important to make the case, Margaret that you're making 

             19     and we'll see if we can add that. 

             20               Adil and then Elliot and then Mark.  

             21               DR. SHAMOO:  Having several members of this 

             22     committee voice the opinion that they don't want to be 

             23     specific because policy wonks shouldn't do that because 

             24     we have to leave the interpretation.  The counter 

             25     argument to that, I mean, I agree with you 
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              1     philosophically.  

              2               DR. MORENO:  For the record, that wasn't my 

              3     argument.  That wasn't what I said. 

              4               DR. SHAMOO:  All right.  Go ahead and state 

              5     it again so --  

              6               DR. MORENO:  What I said was, that as policy 

              7     wonks we tend to over read and over write.  We have 

              8     this fantasy that somehow a priori the document can 

              9     correct and avoid all the problems in the real world in 

             10     advance.  And what I'm saying is that we need to avoid 

             11     that delusion. 

             12               DR. SHAMOO:  Okay.  Having reheard it all 

             13     over again, I still say from comments that somehow we 

             14     don't want to -- we don't need to be specific or -- and 

             15     if that is true, why are we here?  The reason we are 

             16     here because the current regs were not sufficient, 

             17     there were problems.  Otherwise, we won't be here.  

             18     There has been scandals, there has been shutdowns.  And 

             19     more importantly all the time I bring this -- I know 

             20     it's like a broken record, we want to depend -- Susan 

             21     is laughing already because she knows what I'm going to 

             22     say.  We bring all that responsibility to the local IRB 

             23     as if the local IRB is such an objective, independent 

             24     body to deliberate. 

             25               Well, guess what, they are employees, paid 
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              1     monthly or biweekly salaries from the research 

              2     institution.  There is only one out of 20 or 15 members 

              3     who are from the community also chosen.  So I am 

              4     telling you, rely on some of the IRB alone without 

              5     having some specific directions to them in the language 

              6     leaves the problem all over again where we were several 

              7     years ago.  So we have to be some specific.  And we 

              8     have to reform the IRB system also itself. 

              9               DR. MORENO:  Just again, Adil, as you know, I 

             10     wasn't saying we shouldn't be specific.  I want to say 

             11     that specifically.  

             12               [Laughter.]  

             13               DR. FLEISCHMAN:  Let's go on to Elliot and 

             14     then Mark and Susan.  Susan on point. 

             15               MS. KORNETSKY:  I just want to respond to 

             16     Adil.  I the think having thought about these 

             17     guidelines and these clarifications, this is a lot -- 

             18     being a lot more specific than what is thought about in 

             19     the community right now for review in pediatric 

             20     regulations.  So I don't think that, I mean, I think we 

             21     have tried to sort of have a medium where we haven't 

             22     defined everything, but even with my own IRB in looking 

             23     at this, many IRBs really like a total rubber band 

             24     approach this may not totally permit that.  This gives 

             25     guidance and concrete ways to think about these things. 
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              1      So I don't think this does nothing.  

              2               DR. FLEISCHMAN:  Bob on point.  

              3               DR. SHAMOO:  I never said "nothing".  

              4               DR. R. LEVINE:  Very quickly, I never said, 

              5     don't get specific.  I just called attention to the 

              6     peril of stipulating definitions for words in common 

              7     usage.  People might actually think you're speaking 

              8     English.  

              9               [Laughter.]  

             10               DR. FLEISCHMAN:  The theologian and 

             11     philosopher, Elliot, would you like to --  

             12               [Laughter.]  

             13               DR. DORFF:  Along those lines, I actually 

             14     have two questions.  One is the word "vital" which in 

             15     common English means, I think, a considerably stronger 

             16     criterion than I would imagine goes on in the research 

             17     community.  Because if you really restricted research 

             18     to only that which is literally vital, you would do 

             19     maybe 2 percent of what you're doing now.  And I mean, 

             20     if I were really to hold you to a standard of vital.  

             21     So I mean, I think one of the things you may want to 

             22     talk about is, you know, is what exactly does that 

             23     mean? 

             24               I mean, I assumed that it meant, and it 

             25     probably would have been better to have said it this 
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              1     way is that it has a substantial promise of 

              2     ameliorating some disease or disorder or condition.  

              3     And that it's not just simply going fishing or 

              4     something like that.  Right?  I mean, that there is a 

              5     serious purpose to it and that there is some 

              6     reasonable, to use another word, a reasonable hope that 

              7     using the -- going through this research will lead to 

              8     some kind of cure or some kind of at least amelioration 

              9     of the condition.  So, I mean, I think maybe you may 

             10     want to define vital in that sort of a way.  Because 

             11     it's frankly much too strong a term for what I think 

             12     you have in mind. 

             13               The second point that I wanted to ask was 

             14     really along the lines that Susan was just talking 

             15     about.  Since I really don't know this area well, how 

             16     do you understand the status of this document?  In 

             17     other words, are you now summarizing more or less what 

             18     good research on children is all about and is already 

             19     happening?  Or are you -- or is this a prescriptive 

             20     document?  In other words, is this a document that will 

             21     -- that you intend to use to actually change the way 

             22     that research is being done in children? 

             23               DR. FLEISCHMAN:  May I do a brief answer to 

             24     that?  

             25               Our understanding as a workgroup is that we 
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              1     bring to NHRPAC our wisdom and deliberations and in 

              2     about three minutes I'm going to give to the 

              3     Chairperson a recommendation that NHRPAC approve the 

              4     work of working group in order to move it closer toward 

              5     getting to OHRP which is where NHRPAC does its work as 

              6     I understand it, in recommending to OHRP.  And what we 

              7     said at the very outset of our report, it is our hope 

              8     -- it is our hope that this report will result in 

              9     creating an informative guidance to IRBs around the 

             10     country, and that guidance could be used by IRBs in 

             11     order to justify the work that they do and to 

             12     understand better the work that they do.  And as Susan 

             13     has said, I think it would be of some benefit if they 

             14     had such documents just to go to the vital question.  

             15     And I think I'm convinced now that we need to speak to 

             16     that. 

             17               I'll try to draft something that's consistent 

             18     with this substantial promise idea.  Understanding the 

             19     importance of serendipity, understanding the importance 

             20     of investigator-generator research at the NIH level 

             21     that has resulted in things that people never expected, 

             22     but in this particular case in which children have no 

             23     prospect of direct benefit from the work, I think that 

             24     the substantial promise idea is a reasonable idea.  But 

             25     it is, you know, it's a difficult point. 
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              1               Robert. 

              2               DR. RICH:  Simply to that point also, I agree 

              3     completely with Elliot that the word "vital" is an 

              4     inappropriate use of the term.  In fact, I would submit 

              5     that IRBs are generally speaking, unable to judge how 

              6     vital.  I think IRBs are well-qualified generally to 

              7     judge whether research is valid, perhaps even whether 

              8     it substantially holds substantial promise.  I think to 

              9     really judge that a research is vital assumes a level 

             10     of professional expertise in a very specific area that 

             11     IRBs generally don't have.  So I think it would 

             12     actually put a burden on an IRB that it's not prepared 

             13     to accept.  

             14               DR. FLEISCHMAN:  We go back to Mark. 

             15               MR. BARNES:  Just a couple of things.  One is 

             16     that I take Bob Levine's point about the commensurate 

             17     standard.  And from the discussion I basically divined 

             18     that the group seems to think that there are two 

             19     meanings or two purposes in standard B about the 

             20     commensurability.  One is that one would look at the 

             21     situation of the child and his or her parents in terms 

             22     of understanding what the content of the informed 

             23     consent process ought to be so that you understand 

             24     their condition, generally speaking, in order to give 

             25     them adequate informed consent. 
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              1               And then the second thing would be, as Bob 

              2     Levine was saying that one would look at 

              3     commensurability in terms of the -- that one would look 

              4     at the risks, the inherent risks for the condition of 

              5     the child that was actually being studied rather than 

              6     the general kind of socioeconomic condition of the 

              7     child. 

              8               So those are the two things that I have heard 

              9     commensurability mean and if that is what the working 

             10     group understands, or whether it's even not what the 

             11     working group understands, I would suggest that there 

             12     really be, you know, in the next iteration of the 

             13     document that there really be a greater delineation of 

             14     actually what that is.  And certainly a definition that 

             15     what standard B is not meant to say is that there is 

             16     basically a sliding scale with greater risk allowed for 

             17     children who are from riskier environments, which I 

             18     think everyone agrees that that's not what standard B 

             19     is meant to be.  That's not what standard B is meant to 

             20     be or meant to mean. 

             21               And my suggestion really is that that could 

             22     be clearer in the document. 

             23               With that said, what I would also say to you 

             24     and the working group is thank you for all the meetings 

             25     and the efforts and everything else that you've had.  
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              1     And I know that you spent a lot of time, personal time, 

              2     Alan, you know, drafting these pages in previous 

              3     iterations and certainly the group owes you a debt of 

              4     gratitude for that. 

              5               And what I would propose is that with all of 

              6     the comments taken into account that we really approve, 

              7     you know, what's happened and what you've done and the 

              8     work that the working group has done and that you have 

              9     the blessing of the committee, as it were, to go ahead 

             10     to the next step. 

             11               DR. FLEISCHMAN:  Madam Chairperson, Mr. 

             12     Barnes has made a motion, I think. 

             13               [Laughter.]  

             14               DR. FLEISCHMAN:  But we are going to continue 

             15     with Susan and Sandy.  Susan.  Sandy. 

             16               DR. CHODOSH:  I just want to reiterate just a 

             17     little bit about the vital business.  And that is that 

             18     the assumption is that science progresses by leaps, in 

             19     truth it progresses by crawls.  And the crawls are, as 

             20     has been pointed out I think appropriately, not always 

             21     self evident when they're being done.  So that the 

             22     emphasis and, Bob, I think brings this out, the science 

             23     has got to be good.  If the science isn't any good, 

             24     then none of this stuff should be going on, it's 

             25     unethical. 
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              1               And the other implication was that -- an IRB 

              2     had the ability to judge what would be vital.  Well, 

              3     the truth of the matter is that they could judge that. 

              4      I would say the research shouldn't be done because you 

              5     already know the answer.  You know, if it's that 

              6     obvious that it's going to be a very important thing, 

              7     you probably don't even need to do it.  So that, you 

              8     know, the research means that you don't know the 

              9     answer.  And if you do know the answer, you shouldn't 

             10     be doing that. 

             11               DR. FLEISCHMAN:  Sandy, let me understand 

             12     that a little better.  Because I think my concept of 

             13     "vital" is that it is important to the subject's 

             14     disorder, disease, or condition to study this issue.  

             15     You may not know the question.  The question is 

             16     important.  You may not know the answer at all.  But it 

             17     is very important to look at this question within this 

             18     group of children. 

             19               And, in fact, we may not get the answer in 

             20     this study, but we're going to move closer to it.  I 

             21     mean, that's where I'm looking at.  And the promise of 

             22     amelioration argument may be even too distal.  That at 

             23     least it moves in the direction of finding significant 

             24     information which may move us toward an intervention 

             25     which will result in amelioration, you know, that kind 
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              1     of language is where I'm willing to say that's vital to 

              2     children with various levels of characteristics. 

              3               DR. CHODOSH:  I guess you said importance and 

              4     brought that in and importance makes more sense, in a 

              5     way, than vital, that's all. 

              6               DR. FLEISCHMAN:  Jonathan. 

              7               DR. MORENO:  I have to say that when I read 

              8     that phrase in context, I read vital importance, not in 

              9     the abstract, but in the context of the phrase, vital 

             10     for the understanding or amelioration.  So I read it as 

             11     a necessary condition for understanding or 

             12     ameliorating.  But not that it in itself would help us 

             13     -- would get us to a full understanding or fully 

             14     ameliorate the subject's disorder or condition. 

             15               DR. FLEISCHMAN:  Last comment, Bob, and then 

             16     we are going to move to Felice for a few minutes. 

             17               DR. FLEISCHMAN:  I don't think using the term 

             18     "necessary condition" we're reaching the goal.  It's 

             19     going to work here if we really take "necessary" apart. 

             20      What they're talking about is that you can make a good 

             21     case that you're pointed in the direction of 

             22     accomplishing something very important or at least 

             23     important, substantially important.  That the thing you 

             24     are trying to accomplish is relevant to the disease or 

             25     condition that your subject pool has and that you have 
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              1     to acknowledge that there are quite a few false starts. 

              2               Anybody who gets a vitally important result 

              3     every time he or she does research is probably a data 

              4     faker. 

              5               DR. FLEISCHMAN:  Felice speaking to the 

              6     issues, the general issues now of social and behavioral 

              7     within the context of children; is that where we're 

              8     going? 

              9               CHAIRPERSON MARSHALL:  Yes.  Yes.  And then 

             10     bearing in mind that Mark Barnes has the floor at 11:30 

             11     -- 11:35. 

             12               DR. F. LEVINE:  He'll probably have it 

             13     faster. 

             14               This was really in a way looking ahead to 

             15     some of the other activities of what might be the 

             16     children's working group on the children's working 

             17     group agenda of which there are many both internal 

             18     issues relating to the specialized subparts dealing 

             19     with children that cross over to other working groups 

             20     consent may be perhaps the most obvious of them. 

             21               In the social and behavioral science working 

             22     group we've been, of course, addressing issues that 

             23     also intersect with childhood and adolescents in 

             24     particular.  And I must say my own experiences on both 

             25     working groups really see the benefits of the 
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              1     connection and that a lot of what we were doing with 

              2     risk and harm I think very supportively fit into the 

              3     discussions of the children's working group and in 

              4     particular our discussions about amelioration. 

              5               So I'm hoping that with some of the other 

              6     topics that are of importance in the context that's 

              7     studying orphan conditions, orphan with nonintervention 

              8     kinds of research, that the synergies between our 

              9     working group and the children's working group will be 

             10     equally beneficial. 

             11               I think some of the key issues, some of which 

             12     also had consent that we're both hoping to address and 

             13     feed into the conversation and in part through me 

             14     within the children's working group is the issue with 

             15     respect to the wide variation and the definition of 

             16     "emancipated minors."  And there's a lot of variation 

             17     between and among states on that and that is an issue 

             18     that we need in a way or NHRPAC in a way needs to 

             19     engage in and on issues with respect to children. 

             20               Also, the topic of children primarily 

             21     adolescents who are functioning as adults, the most 

             22     obvious case, for example, being adolescent parents, 

             23     not just female adolescent parents, but male adolescent 

             24     parents and the relationship between that and consent 

             25     and assent in particular. 
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              1               Certificates of confidentiality, when the 

              2     interests of the children, minor children are not 

              3     necessarily compatible with the issues of parents and 

              4     how can we reflect on what a certificate would look 

              5     like that could take ito account what might be not 

              6     necessarily complimentary interest, but competing 

              7     interests.  Also, the whole area which I guess in part 

              8     links to that, the waiver of parental permission.  You 

              9     know, we talk about the most obvious case, let's say 

             10     studies of runaway kids. 

             11               So that, you know, we have in much of our 

             12     conversations sort of an assumption that the research 

             13     is place-based often in a clinical environment or a 

             14     medical environment.  And thus there's a parent, an 

             15     identified parent, an identified child that's on the 

             16     same page and that often the nature of the kind of work 

             17     in social and behavioral contexts are not necessarily 

             18     intervention kinds of studies and also studies where 

             19     there is not necessarily a known or identified parent 

             20     and yet it's a condition.  But recognize also that 

             21     that's why in the children's working group we moved it 

             22     to the status of minor increment over minimal because 

             23     one should not be facile in assuming that therefore you 

             24     don't really have to look very long and hard about 

             25     those issues. 
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              1               And then I think one of the challenges, 

              2     especially when we're working out of health-related 

              3     contexts is that the primary context for research 

              4     outside of the health-related context is the 

              5     educational context, not just educational research, but 

              6     research in educational settings.  Because that is a 

              7     primary site where there are inquiries of large, 

              8     certainly at both national and local levels, non-

              9     trivial access to large numbers of children.  Which I 

             10     think raises a generic issue that I think in part lands 

             11     with the children's working group and in part relates 

             12     to all of NHRPAC and that is that there are contexts in 

             13     which there are parallel pieces of either legislation, 

             14     in the case of the two pending bills that have now, 

             15     Congresswoman DeGette and Senator Kennedy.  But over 

             16     time there have also been any number of other instances 

             17     where pieces of legislation or parts of pieces of 

             18     legislation speak to issues of concern to NHRPAC.  The 

             19     one that I most want to make mention of with respect to 

             20     children's research has had a long and up and down 

             21     history. 

             22               But in the Elementary and Secondary Education 

             23     Act passed in January there has been essentially a 

             24     delegation to state and local communities, the decision 

             25     with respect to how -- not to IRBs, but to state and 
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              1     local communities, the decision as to how best to 

              2     obtain consent and written consent.  And I am concerned 

              3     in the context of the children's working group between 

              4     decisions that could occur in that context outside of 

              5     what is the human subjects protection system and the 

              6     IRB role in that system.  Most particularly, for 

              7     example, the New Jersey piece of legislation that 

              8     delegated this to -- or actually the New Jersey 

              9     legislation that actually requires written consent in 

             10     all school-based research, all school-based research, 

             11     not just educational research, but any research that 

             12     otherwise occurs in schools that has led at least one 

             13     university, understandably so, Princeton University to 

             14     issue a statement to its faculty that it must in all 

             15     work that it now pursues include written consent as the 

             16     sole mechanism. 

             17               Now, I raise this generically because, of 

             18     course, the current procedures have a much more 

             19     nuanced, I mean, we can raise this in the context of 

             20     the consent working group -- a much more nuanced 

             21     understanding that consent is a process and that that 

             22     process certainly takes account of the importance of 

             23     written consent, but doesn't have that as the sole and 

             24     only mechanism.  And how we reconcile some of our 

             25     discussions in the working group around that issue and 
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              1     other subjects with other kinds of parallel activities 

              2     that may constrain our capacity to enhance the system I 

              3     think is a challenge.  And one particularly on -- of 

              4     relevance to research on children and youth, I think, 

              5     just because of the saliency of that arena.   And so I 

              6     welcome both continuing the children's working group 

              7     and the crossovers between these issues that come to us 

              8     in other contexts. 

              9               DR. FLEISCHMAN:  Adil. 

             10               DR. SHAMOO:  Since you mentioned the runaway 

             11     kid, I want to ask an example of what could be 

             12     quote/unquote condition to qualify those children for 

             13     research?  A sibling of a runaway child under your 

             14     definition, with spinal tap to measure neurotransmitter 

             15     levels in those siblings who are children in order to 

             16     investigate is there something in biochemistry of the 

             17     brain that makes them runaway, these are healthy 

             18     siblings, will that qualify quote/unquote as a 

             19     condition to allow that kind of research to go forward? 

             20               DR. F. LEVINE:  Sounds like, when did you 

             21     stop beating your mother-in-law.  You know, we have on 

             22     our working table many complex cases.  I must say, this 

             23     would be a challenge.  

             24               DR. FLEISCHMAN:  Can I deal straight with 

             25     that?  No. 
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              1               DR. SHAMOO:  Good. 

              2               DR. FLEISCHMAN:  In fact, the spinal tap on 

              3     those runaway children -- a spinal tap on those runaway 

              4     children would be hard for me to conceive of where we 

              5     would go with that today. 

              6               DR. SHAMOO:  How about ten samples of blood? 

              7      Because that's exactly what happened before. 

              8               DR. FLEISCHMAN:  Adil, now we have an 

              9     important -- now we have an important discussion if we 

             10     were an IRB.  Now we have an important discussion as to 

             11     the environment in which it's done, the process, 

             12     whether it's an indwelling catheter or it's ten sticks, 

             13     what the experience is of the environment, what, if 

             14     anything, is going to be given to those youngsters in 

             15     order to then invoke the need for ten samples.  I mean, 

             16     now you've got a research protocol that an IRB needs to 

             17     look at.  So I wouldn't give you the same crisp answer 

             18     on the ten samples.  If they were small samples, if 

             19     there was a catheter in place so you didn't have to 

             20     stick them ten times, if there was in a certain 

             21     situation in a clinical research center or an 

             22     environment that was comfortable for the kids, I mean, 

             23     there's a whole host of things. 

             24               But, generally when you're doing ten samples, 

             25     you've done it after you gave something to a child in 
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              1     order to invoke the need for serial measures.  And, of 

              2     course, then we would have to look at what are you 

              3     giving and what is that substance and what does that 

              4     mean and all those kinds of things.  

              5               DR. SHAMOO:  And there are certain conditions 

              6     where you would allow such research for healthy 

              7     children, just the fact that they are siblings of 

              8     runaways; is that what you are telling me? 

              9               DR. FLEISCHMAN:  There are characteristics of 

             10     groups of children that warrant IRBs to consider them 

             11     having a condition that is worthy of examination.  

             12     Okay.  So that's the first hurdle is for the IRB based 

             13     in an investigator is making a case about why that 

             14     might be a reasonable thing to do, I don't know the 

             15     epidemiology of that group of children.  But one might 

             16     -- might -- make the case that the characteristics of 

             17     that group of children would warrant a research study. 

             18      Then we would have to get into the specifics of the 

             19     study, the specifics of the vital importance of what 

             20     we're going to learn, the specifics of the intervention 

             21     or the procedure in terms of was it just a little bit 

             22     more than minimal and then the specifics of the 

             23     institutional setting and the environment. 

             24               And after we did all that work, which we 

             25     should do at our IRB meetings, we would then make a 
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              1     judgment or we might find that we need to negotiate 

              2     with that investigator to help that investigator to do 

              3     a more ethical study.  And then we would have to deal 

              4     with the issues of assent and permission.  And assuring 

              5     that the parents were not feeling coerced because their 

              6     other child was in an important place getting important 

              7     therapy and this child, you know, if they didn't get 

              8     permission might do something for the other child.  I 

              9     mean, we need to deal with each of those issues that 

             10     you've written eloquently about and you and I agree on. 

             11     But we would have to do it case-specific. 

             12               DR. SHAMOO:  Well, this is where my answer 

             13     would be as crisp as your first answer.  That kind of 

             14     research, in my view, should not be allowed because the 

             15     child is healthy, runaway is not really quote/unquote a 

             16     disorder, not a condition where there are obligations 

             17     that we have to use that child for ten blood samples. 

             18               DR. FLEISCHMAN:  Let me just clarify now so 

             19     we clarify what you're meaning.  Runaways might be a 

             20     condition.  Siblings of runaways might not.  

             21               DR. SHAMOO:  That's what I'm saying.  

             22               DR. FLEISCHMAN:  Might not.  I don't know the 

             23     epidemiology.  But, I would argue that siblings of 

             24     diabetics might be a condition.  

             25               DR. SHAMOO:  I agree with you with diabetic. 
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              1      I agree with you obesity.  But I'm talking about a 

              2     social quote/unquote condition which is so broad that 

              3     you could get any child to qualify for exploitative 

              4     research.  That is my concern.  And those, what you 

              5     have written so far with the definition of condition 

              6     does not exclude that kind of research.  As a matter of 

              7     fact, if anything, it allows it. 

              8               DR. FLEISCHMAN:  Susan. 

              9               MS. KORNETSKY:  The condition -- I mean, 

             10     you're looking at the word "condition" but that has to 

             11     be taken into context within the whole protocol.  What 

             12     is the purpose?  I mean, you're making some -- you 

             13     know, some general-type statements but you can't say 

             14     yes or no without understanding the protocol, the types 

             15     of things that -- you know, you would have to explain 

             16     to an IRB, why runaways?  Why not other kids?  Why this 

             17     population?  There are so many other questions there 

             18     that I find it troubling just to make a general 

             19     statement, you're going to be able to use children.  

             20     You can't take it out of context. 

             21               DR. FLEISCHMAN:  Okay.  We are going to need 

             22     to move on, so we're going to have Elliot and Felice 

             23     and then I will turn the chair back to Mary Faith.  

             24               DR. DORFF:  Just a similar comment, namely 

             25     that I think that if you're talking about runaways, the 
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              1     kinds of research that would be more likely I think 

              2     would be sociological research of one sort or another. 

              3      And there the risks would be questions of, you know, 

              4     privacy and of sharing of information that other people 

              5     should not have.  And there, I think, whoever is 

              6     supposed to approve this kind of research would have to 

              7     go into those kinds of risks in terms of that kind of 

              8     research. 

              9               DR. FLEISCHMAN:  Felice. 

             10               DR. F. LEVINE:  And those are the very kinds 

             11     of examples that we're seeking to develop for the 

             12     tables and charts.  Your own -- Adil, your own contrast 

             13     was really not to the -- what we would consider to be 

             14     the subject of the study, but yours was really to 

             15     whether it would be appropriate to introduce sibling 

             16     control groups and obviously that would have to be 

             17     carefully examined based on the -- what we might now 

             18     call the relevance standard versus the vital importance 

             19     standard as to whether studying those siblings -- how 

             20     we could study them in a way that would be important, 

             21     noninvasive, of minimal risk and one that would enhance 

             22     our understanding of that --  

             23               DR. SHAMOO:  That's a really unfair answer 

             24     because you just said minimal risk and Elliot's example 

             25     was also minimal risk.  We are talking about greater 
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              1     than minimal risk.  

              2               DR. FLEISCHMAN:  See, Adil, I think the 

              3     answer to your concern -- I share some of your concern, 

              4     perhaps not all of it.  I think the answer is in 

              5     accountability.  It's in retrospect of review of the 

              6     work of local IRBs.  I think it's in the whole issue of 

              7     credentialing and review of IRBs.  Because we can do 

              8     anything, you know, prospectively in telling IRBs how 

              9     they wished they would behave.  But unless we are 

             10     willing and, you know, OHRP, and the accrediting, not-

             11     for-profit agencies are willing to go out and review 

             12     how it's actually being implemented, we're not going to 

             13     able to get to the level of assurance that you're 

             14     raising which I share. 

             15               You're raising the prospective, if we're more 

             16     restrictive in the language, then it's less likely IRBs 

             17     will sin.  And I understand that.  I do. 

             18               What I think most of the workgroup in the 

             19     children's issues are saying, we need to allow certain 

             20     levels of research in children for the sake of future 

             21     children.  And what we are trying to do is to put 

             22     fairly good parameters around that and then we've got 

             23     to go back to those IRBs and be sure they're 

             24     implementing them in ways that we're proud of.  I think 

             25     that's the difference in the argument from the 
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              1     workgroup's perspective and from the perspective that 

              2     you're arguing.  I think we would like to get to the 

              3     same place.  

              4               CHAIRPERSON MARSHALL:  And as a mechanism of 

              5     getting to that place, I would like to call on Mark to 

              6     reiterate his proposal that he made just a moment ago. 

              7               MR. BARNES:  Thank you, Mary Faith. 

              8               My proposal was, I guess to add two parts, 

              9     one is that we ask the working group and especially 

             10     Alan who is the leader of the working group to go back 

             11     and try to take these -- all the concerns that were 

             12     expressed and the points of view into account in the 

             13     next iteration of this draft.  That's one request or 

             14     motion, and the second part of the motion would be that 

             15     with that understanding that he and the working group 

             16     will do that, that we approve this interim report and 

             17     that we ask the working group to continue on the path 

             18     that it's on.  And thank them.  

             19               And the third part is to thank them.  That's 

             20     right. 

             21               CHAIRPERSON MARSHALL:  All right.  Thank you. 

             22      And so we have a proposal on the table.  Just a couple 

             23     of minutes of discussion and then I'm going to call a 

             24     vote on this.  Bob.  Bob and then Abbey. 

             25               DR. R. LEVINE:  Second the motion. 
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              1               CHAIRPERSON MARSHALL:  He seconds it.  Thank 

              2     you very much.  

              3               Abbey. 

              4               MS. MEYERS:  I just want to clarify.  This is 

              5     the beginning of a process.  It doesn't address the 

              6     problem of children who are sick and seriously ill 

              7     children, and that that is going to happen in the 

              8     future.  That will be added to this; right? 

              9               CHAIRPERSON MARSHALL:  Okay. 

             10               DR. FLEISCHMAN:  Each of our workgroup 

             11     reports hope to stand on their own.  I just want you to 

             12     understand, we're trying to move this along to OHRP 

             13     because we think they need to do something.  And, you 

             14     know, we can't produce it much faster, but we would 

             15     like to.  So the next document on prospect of direct 

             16     benefit will hopefully stand on its own and be moved 

             17     through this process.  So we are not going to hold this 

             18     waiting for the next piece to be attached is what we're 

             19     saying. 

             20               MS. MEYERS:  But basically that all children 

             21     have to be categorized in these two sections that 

             22     you've written up about minimal risk and small 

             23     increment.  Okay. 

             24               DR. FLEISCHMAN:  We've only spoken to two 

             25     sections of the regulations and we hope to speak to 
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              1     many of the others that Felice has raised and the 

              2     remuneration questions, the assent questions, the 

              3     adolescent consent and assent questions, I mean, we're 

              4     going to bite them all off, because as the report to 

              5     Congress said, they need clarification.  We are just 

              6     doing it at a rate as rapidly as we can come to 

              7     consensus under the present circumstances. 

              8               CHAIRPERSON MARSHALL:  All right.  We have a 

              9     lot of work to do.  So brief comment and then feel 

             10     free, from the floor.  Adil. 

             11               DR. SHAMOO:  I need clarification.  Because 

             12     your second point almost is opposite of the first 

             13     point.  First they have to take the concern of this 

             14     committee and redraft it and bring it back.  The second 

             15     part is really we're blessing the process, not the 

             16     final draft -- I mean, not the current draft.  

             17               MR. BARNES:  I'm not asking that we bless the 

             18     current draft.  What I'm asking is a motion for the 

             19     sense of the committee that with the emendations and 

             20     amendments that we've talked about today, with the 

             21     suggestions and the directions to Alan and the 

             22     workgroup that with that included that we bless this as 

             23     an interim product, but not as a final product and ask 

             24     the committee --  

             25               DR. SHAMOO:  Okay.  
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              1               MR. BARNES:  -- to continue on their process 

              2     and thank them for their efforts.  

              3               DR. SHAMOO:  Thanks for the clarification.  

              4               MR. BARNES:  Okay. 

              5               DR. FLEISCHMAN:  Madam Chairperson, can we, 

              6     within the process of NHRPAC, if we do, do the 

              7     reiterating, is it possible that we could get an 

              8     approval prior to the next meetings of NHRPAC through 

              9     some process other than face-to-face meetings? 

             10               CHAIRPERSON MARSHALL:  Yes.  We can do it as 

             11     we have in other contexts, and that is, send it out 

             12     electronically and have that sort of discussion.  So, 

             13     yes, we can do that.  John. 

             14               DR. MATHER:  John Mather with the VA.  I just 

             15     want to thank you, Alan, and your committee for taking 

             16     it as far as you have.  You may be surprised to know 

             17     that the VA is involved in 25 of its VA medical centers 

             18     in childhood research.  And I have been amazed at the 

             19     questions that have come back to us like, well how 

             20     different is this from adults.  And I said, let me 

             21     remind you as a fully trained pediatric 

             22     otolaryngologist I was reminded one time children are 

             23     not little adults.  So, you need to, you know, think it 

             24     through very, very carefully. 

             25               And I want to support what the motion is that 
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              1     Mark has put on the table.  But Madam Chairperson, I 

              2     think we need to think also about this at sometime or 

              3     another in a broader context of some -- what Bob Levine 

              4     was talking about, you know, is more than semantics to 

              5     take these words and give them meaning.  And one of the 

              6     troublesome parts is, which is the vignette that 

              7     applies to it, you know, in using these particular 

              8     words and they're different for adults, they're 

              9     different for children, they're slightly different for 

             10     pregnant females, they're slightly different for 

             11     prisoners, you know, they're slightly different for 

             12     whether you're talking about clinical trials as opposed 

             13     to a survey, you know, epidemiological research. 

             14               So I would commend you the thought at some 

             15     time or another to spend some time drilling down on 

             16     what these very words mean for us all.  I mean, Bob 

             17     Levine thought it was very eloquent.  You know, the 

             18     English language is the English language.  But some of 

             19     us come from a different ilk and when you're Scottish 

             20     it really troubles you.  

             21               [Laughter.]  

             22               CHAIRPERSON MARSHALL:  Well said, and we do 

             23     plan to provide those sorts of concrete examples and 

             24     then ask OHRP to further elucidate and that that should 

             25     be a continuing process, not something that's a static 
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              1     event. 

              2               MS. FISHER:  Barbara Lowe Fisher with the 

              3     National Vaccine Information Center.  As a member of 

              4     the public I'm very concerned that there are strong 

              5     informed consent protections in these guidelines.  

              6     Under these guidelines under what circumstances and for 

              7     what justification, if any, can scientific research be 

              8     performed on children without the voluntary informed 

              9     consent of their parents because the research is deemed 

             10     by the IRB to qualify for an informed consent waiver. 

             11               DR. FLEISCHMAN:  Well, we have not, in thee 

             12     documents at all addressed the other parts of the 

             13     regulations that speak to assent, consent, and waiver 

             14     of consent.  It is our hope that we will deal with 

             15     those as has been importantly addressed in Felice's 

             16     comments around the adolescents.  But our conversations 

             17     here in these documents do not change or make any 

             18     recommendations about decreasing the power of the 

             19     importance of parental permission in anything we've 

             20     written here.  

             21               MS. FISHER:  But you are going to be 

             22     addressing that in the future? 

             23               DR. FLEISCHMAN:  We plan to address that in 

             24     the rubric of assent and permission and the potential 

             25     questions of when ought the permission of parents be 
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              1     waived.  We will address that. 

              2               Actually, the working group has addressed 

              3     that directly vis-a-vis the FDA and the regulations 

              4     that we are on record as having argued that there are 

              5     times when parental permission might be waived in 

              6     specific -- specific situations around adolescents with 

              7     certain procedural safeguards, so we have already laid 

              8     out the arguments around that.  And we will readdress 

              9     those questions as we get into asset, consent, and 

             10     permission.  

             11               CHAIRPERSON MARSHALL:  One last question and 

             12     then I'm going to call a vote.  Thank you. 

             13               MR. DOYLE:  Yes, Bill Doyle from Pittsburgh. 

             14      I would just like to point out that I've been on the 

             15     pediatric IRB for about 15 years.  It's very 

             16     specialized.  We don't have those pressures, that was 

             17     brought up here.  I have never felt the need to do 

             18     something.  But I do think that we have the right 

             19     representation.  Is there going to be a recommendation 

             20     that we have some specialty IRBs such as a pediatric 

             21     IRB, an IRB that deals with some other issue?  I think 

             22     it's very important that a pediatric IRB be constituted 

             23     at universities that are large enough to constitute 

             24     them. 

             25               DR. FLEISCHMAN:  Well, I can only say that 
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              1     the workgroup is already on record as arguing that 

              2     there is a need for pediatric expertise at a meaningful 

              3     level on every IRB that's going to review research 

              4     concerning children.  We've shared that view that with 

              5     OHRP and I think in general that is a standard that 

              6     ought to be fulfilled.  We have not gone any further as 

              7     to specify what that would mean.  

              8               CHAIRPERSON MARSHALL:  So I would like to 

              9     call the vote then and ask that all of those in favor 

             10     of the personal that Mark has put on the floor -- I 

             11     think perhaps say aye would be the best thing to do.  

             12     All of those in favor? 

             13               [Chorus of ayes.] 

             14               CHAIRPERSON MARSHALL:  Those opposed? 

             15               [No response.]  

             16               CHAIRPERSON MARSHALL:  Anyone abstaining? 

             17               [No response.]  

             18               CHAIRPERSON MARSHALL:  Then the motion 

             19     carries.  Thank you, Mark.  

             20               And, Alan, I also would like to reiterate the 

             21     huge debt of gratitude -- the continuing debt of 

             22     gratitude that we owe you.  This is very, very hard 

             23     work and the working group, your leadership; these are 

             24     very important conceptual issues.  And it's exceedingly 

             25     hard work.  So thank you for the leadership.  Thank 
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              1     those of you who are in the audience who are members of 

              2     the working group and who are on the committee as well. 

              3      We will be back to you with words on paper 

              4     electronically. 

              5               Kate would like the floor for just a moment. 

              6               MS. GOTTFRIED:  Just with respect to what 

              7     Alan mentioned regarding waiver, parental permission, 

              8     and the letter regarding assent.  That is on our web 

              9     site for individuals who are interested in looking at 

             10     it.  The letter that was send to the FDA in response to 

             11     their proposed adoption of the children's regulations 

             12     with that particular exception. 

             13               Also I just want to, on behalf of the 

             14     committee as well, and the staff, which is myself, 

             15     yours truly, thank Alan and the entire workgroup for 

             16     its immense work and all of the -- well, really this 

             17     was a very laborious process.  It is still ongoing.  It 

             18     is incremental and that should be impressed upon 

             19     everyone here that part of the reason it's a little bit 

             20     slower than we would anticipate is because we are under 

             21     resourced.  And that is a reality that we are trying to 

             22     change.  But it is a current reality and so we will be 

             23     biting off these other issues as we can and move 

             24     forward throughout the year. 

             25               CHAIRPERSON MARSHALL:  And we're sorry that 
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              1     Dr. Koski was not here for this part of the discussion, 

              2     but we will certainly reiterate it later. Yes. 

              3               So I would like to move, we as a committee, 

              4     at our last meeting voted to weigh in on the HIPAA 

              5     regulations as they pertain to human subjects research 

              6     and we have been busy.  I would like to call on Mark 

              7     Barnes to update the committee on what we have done and 

              8     sort of continue our discussion about that. 

              9               Mark, thank you. 

             10               MR. BARNES:  Mary Faith, could I say one 

             11     thing just about the children's workgroup? 

             12               Alan, I would think that you and the 

             13     workgroup, given that you're doing so much work and 

             14     that you're actually in a systematic way going through 

             15     all of these different research issues and Common Rule 

             16     issues regarding pediatrics, I would encourage you guys 

             17     really to think about an article at the end of this 

             18     that really outlines, you know, that sets forth in a 

             19     very coherent way all of the work that you've done, 

             20     because I think that would be of enormous use to 

             21     everyone, not just as a report from the committee that 

             22     actually has an article.  

             23               [Laughter.] 

             24               CHAIRPERSON MARSHALL:  And we know who is 

             25     good at putting words on paper on this group.  
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              1               MR. BARNES:  Right.  Okay.  Thank you, Mary 

              2     Faith.  

              3               We have had sort of a rolling discussion over 

              4     the past, I guess, maybe four or five months about the 

              5     issue of the privacy regulations under the Health 

              6     Insurance Portability and Accountability Act and the 

              7     potential impact of those regulations which will go 

              8     into effect in April of 2003 is the enforcement or 

              9     compliance date on the conduct of human subjects 

             10     research.  We talked about it.  We had a presentation, 

             11     I guess, about four or five months ago from Julie 

             12     Kaneshiro [ph] who was -- who I think is here today -- 

             13     Julie, are you here?  

             14               CHAIRPERSON MARSHALL:  Julie. 

             15               MR. BARNES:  There she is.  

             16               Julie had been gracious enough to give us a 

             17     presentation and Julie had been working inside HHS on 

             18     the inner working group that was looking at the HIPAA 

             19     privacy regulations and the potential amendments to the 

             20     privacy regulations.  And then we had a letter that we 

             21     had floated in advance of what was actually an official 

             22     publication on March 27th of this year of what's called 

             23     the "Notice of Proposed Rule Making" or an NPRM, 

             24     whereby HHS working, Julie and the others working 

             25     within HHS had determined that a series of amendments 
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              1     ought to be made to the privacy regulations for a 

              2     number of purposes and therefore they proposed in the 
              3     Federal Register with a 30-day comment period that has 

              4     just closed on April 26th, a series of amendments to 

              5     the privacy regulations that would accomplish a number 

              6     of things. 

              7               These are only proposals and there was the 

              8     comment period and then probably we won't see a final 

              9     kind of publication of these regulations until 

             10     sometime, I would say, in my estimation, although, 

             11     Julie, please, if you have other information then we 

             12     would love to hear it, I would be looking forward at 

             13     the earliest in the late summer and probably sometime 

             14     in the fall of this year.  But that's my outside extra 

             15     HHS perspective on it. 

             16               Before I go ahead, Julie, do you want to make 

             17     any comments about sort of the process or where it 

             18     stands or how many comments were received or any kind 

             19     light that you could shed on the process of the 

             20     publication of the NPRM? 

             21               CHAIRPERSON MARSHALL:  And we're putting you 

             22     on the spot, Julie, but could you do it at the 

             23     microphone? 

             24               MR. BARNES:  And if you don't want to, you 

             25     don't have to.  
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              1               [Laughter.]  

              2               CHAIRPERSON MARSHALL:  We would never coerce 

              3     anyone. 

              4               MS. KANESHIRO:  I'll give you my verbal 

              5     informed consent. 

              6               We did complete the public comment process, 

              7     as you mentioned, on Friday the 26th.  And I'm really 

              8     not certain how many comments we received.  We were 

              9     expecting in the order of, you know, several tens of 

             10     thousands -- or, sorry, tens of thousands of comments, 

             11     but I really don't know the final count.  I imagine 

             12     we're still going through them.  

             13               We do expect, as Mark mentioned, to publish 

             14     final rule in response to those public comments 

             15     probably towards the end of the summer, but it really 

             16     is difficult to say at this point given we haven't seen 

             17     the substance of what those comments are and the amount 

             18     of policy thinking that we'll have to be doing over the 

             19     coming months. 

             20               But I thank you for your comments on the 

             21     rule. 

             22               MR. BARNES:  Oh, thank you, Julie.  And 

             23     people should know that Julie actually -- we're lucky 

             24     at OHRP and NHRPAC that Julie has now moved over to our 

             25     staff at OHRP and NHRPAC.  So I know that Greg is glad 
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              1     to have her on board.  

              2               So what occurred is that we were in the 

              3     process of actually trying to comment on the problems 

              4     we saw with the HIPAA regulations and then in the 

              5     middle of our process of commenting the NPRM came out 

              6     which actually answered some, but not all of the 

              7     concerns that we had expressed in our original draft 

              8     letter.  And, therefore, Mary Faith had asked me to 

              9     redraft the letter that had already been approved by 

             10     this committee trying to take into account the fact 

             11     that some, but not all of our concerns had been 

             12     answered by the NPRM.  

             13               I should point out also that in the NPRM 

             14     probably about a third or maybe even 40 percent of the 

             15     NPRM actually was devoted to issues of human subjects 

             16     research and the impact of HIPAA on human subjects 

             17     research which I think is good.  It shows that HHS is 

             18     listening and it also shows that the national research 

             19     community was speaking up about the issues and the 

             20     problems.  And I would like to think that we had some 

             21     impact on the process of the formulation of the 

             22     proposal.  

             23               We therefore did send a letter which I think 

             24     it's fair to say was completely consistent in tone, and 

             25     in substance with the letter that had been approved 
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              1     before that had been worked on, circulated throughout 

              2     the committee, worked on by a subcommittee which 

              3     consisted of Adil, Sandy, myself, and Bob Rich.  And 

              4     was there anybody else on that little subcommittee?  

              5     Was Judy on -- Judy, were you on -- no, okay.  So if I 

              6     missed anybody, I'm sorry.  

              7               And we had worked on it to try to hammer out 

              8     a kind of consensus document.  The difficulty frankly 

              9     in hammering out a consensus document among this 

             10     committee is that there were people on the committee 

             11     who took radically different views of the world of 

             12     HIPAA as it applies to human subjects research.  There 

             13     were some on the committee who took the position that 

             14     in fact human subjects research because it is regulated 

             15     by the Common Rule and the Common Rule requires 

             16     consideration by the IRB of privacy and confidentiality 

             17     information that therefore HIPAA should not actually 

             18     apply to human subjects research. 

             19               There were others who thought that the 

             20     standards that HIPAA applied were not strict enough in 

             21     protecting research subjects.  And so what we tried to 

             22     end up with here, and I think what we did end up with 

             23     was a document that recognizes that the likelihood is 

             24     that HIPAA will apply to human subjects research and 

             25     therefore how can we make it workable for researchers, 
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              1     but still protective for research subjects?  And that's 

              2     what I think this document tries to set forth. 

              3               Let me just make a few comments about the 

              4     content of the document briefly.  Just to take you 

              5     through the points in the document and I'll try to be 

              6     quite brief about this. 

              7               One is that there is a lingering concern 

              8     about the ability, or the way in which HIPAA privacy 

              9     rules would allow or not allow institutions to compile 

             10     patient data and also data connected to patient tissues 

             11     or patient specimens which are not collected for the 

             12     purpose for a particular research project but rather as 

             13     a database that could later be mined for particular 

             14     research projects.  And the way that I think the better 

             15     reading of the HIPAA privacy regulations as they stand 

             16     now, and including the way that the NPRM looks, it's 

             17     not exactly to me clear as an attorney who does advise 

             18     IRBs and research institutions that in fact that this 

             19     kind of pre-research use of data would actually be 

             20     allowed. 

             21               And so one of the things that we specified is 

             22     that there should be a process for approving by which a 

             23     privacy board or somebody or some entity could actually 

             24     look at these issues and approve the compilation -- the 

             25     pre-research compilation of data. 
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              1               The second issue was the problem of the 

              2     potential that a subject, once they -- if they 

              3     experience that they -- if they enrolled in a trial 

              4     with full informed consent and experience an adverse 

              5     event, they may decide, in fact many do decide and for 

              6     understandable reasons, to in fact pull back and not 

              7     continue in the study because they had experienced an 

              8     adverse event. 

              9               The difficulty is that under HIPAA when they 

             10     revoke their consent to participate in the study, they 

             11     also could revoke their authorization under HIPAA to 

             12     allow the researcher and the research team, and the 

             13     sponsor to continue to use the data even about their 

             14     adverse event. 

             15               If that occurred and there were a revocation 

             16         not only of consent for the research, but also 

             17     revocation of the data -- of the authorization to use 

             18     the data, then the actual experience itself of the 

             19     adverse event which could be extremely beneficial for 

             20     medical science and for people with that condition that 

             21     would be basically off limits for the use -- continued 

             22     use by the research team which we thought was really 

             23     not appropriate.  And therefore we recommended that 

             24     there be actually a process by which the continued use 

             25     of data might be in those situations, could be reviewed 
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              1     by the privacy board or the IRB and could be approved 

              2     in that sense. 

              3               And, in fact, I understand, in fact, directly 

              4     from some HHS staffers that that was -- that this was 

              5     in fact -- it has been of great receptivity on the part 

              6     of HHS to this particular recommendation of NHRPAC. 

              7               The third issue was the duration of the HIPAA 

              8     authorization and that is that under HIPAA an 

              9     authorization that would be signed by the research 

             10     subject would have to have a termination event.  And 

             11     the difficulty with a termination event in the context 

             12     of human subjects research is that research data often 

             13     has to be used -- often there's a need for researchers, 

             14     sponsors, and the FDA to use the research data long 

             15     after the actual research has ended and the apparently 

             16     final publication of data had been accomplished.  And 

             17     so HHS and the NPRM had tried to get around this by 

             18     saying, well, you can simply put in the authorization 

             19     form the idea that the authorization would end at the 

             20     termination of the research. 

             21               But what we pointed out in our letter is that 

             22     that really is not good enough and we made an alternate 

             23     formulation suggestion to HHS in terms of a defining 

             24     event as being the termination of the research project 

             25     or the extinguishing of the need to review, analyze and 
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              1     consider the data generated by a research project, 

              2     whichever is later, as being an appropriate termination 

              3     event. 

              4               The fourth point is that we actually praise 

              5     HHS for eliminating the distinction in the NPRM between 

              6     the category of research not involving treatment and 

              7     research involving treatment which in many ways greatly 

              8     complicated the final regulation that was issued at the 

              9     end of the year 2000. 

             10               The fifth point which had a lot of hot 

             11     discussion among the committee was a somewhat obscure 

             12     but a very important point which is that under the 

             13     strict reading of the HIPAA regulations one's treating 

             14     physician actually could not talk to a patient about 

             15     the possibility of the patient enrolling in a clinical 

             16     trial because that very conversation would be a use or 

             17     disclosure of data which would not be allowed under the 

             18     terms of the patient's consent to the HIPAA practices. 

             19      The reason for that is that research is not treatment, 

             20     it's not payment, and it's not health care operations 

             21     which are the only things, the only purposes for which 

             22     health care providers could actually use and disclose 

             23     data. 

             24               It also means that the health care provider 

             25     could not discuss with colleagues who have clinical 
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              1     trials the eligibility of that particular person's or 

              2     physician's patient for trial even if the patient 

              3     wanted to enroll in trial.  And what that would 

              4     necessitate therefore would be that before a physician 

              5     could actually talk to another clinicians about a 

              6     patients eligibility they would have to go back to the 

              7     patient in each and every circumstance and get a new 

              8     signed authorization from the patient allowing the next 

              9     discussion to occur, which clearly would clog the mills 

             10     of patient enrollment into clinical trials.  And these 

             11     are clinical trials that patients in many cases want to 

             12     get into.  They're trials of people who are really 

             13     quite eager to enroll in oncology studies or AIDS HIV 

             14     studies or other studies. 

             15               Therefore, we recommend actually two 

             16     different possibilities.  One is that these, the 

             17     treating clinicians be allowed under regulations to 

             18     communicate with other physicians or other researchers 

             19     who are conducting clinical trials with two conditions. 

             20      One is that the information discussed between the 

             21     treating physician and the clinical investigator would 

             22     be the minimum necessary to try to investigate the 

             23     patient's eligibility for a trial without -- and 

             24     hopefully therefore and without revealing the name, 

             25     because one can't imagine that the name would actually 
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              1     be necessary to have the eligibility discussion.  And 

              2     the second would be the stipulation that the clinical 

              3     investigator to whom the information would be disclosed 

              4     would himself or herself be bound by HIPAA privacy 

              5     obligations as part of a covered entity.  So they would 

              6     not be able therefore to redisclose the information 

              7     without specific authorization from the patient or 

              8     subject. 

              9               That was one suggestion we made. 

             10               The other suggestion that we made would be 

             11     actually to have a process that would be sanctioned by 

             12     -- would be allowed by the final HIPAA regulations so 

             13     that a patient and a physician could have a discussion 

             14     up front about whether the clinician -- about whether 

             15     the patient wants the clinician to have those 

             16     eligibility discussions and the patient would be able 

             17     to execute a kind of blanket authorization for that 

             18     process of discussion so they would not have to come in 

             19     the office each time and sign a new authorization.  But 

             20     in order to have such a blanket authorization it would 

             21     require actually a change in the HIPAA regulations. 

             22               The sixth point is that we endorsed and 

             23     thanked HHS for reducing the waiver criteria for the 

             24     waiver of the HIPAA authorization.  They reduced it in 

             25     the NPRM from eight criteria to three criteria.  The 
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              1     three criteria being minimal risk and the actual -- the 

              2     impracticability of gaining an authorization from 

              3     patients or subjects.  We said that that was actually a 

              4     very welcome development because it greatly simplifies 

              5     -- it's a more accurate way of looking at the issues, 

              6     we thought and it certainly simplifies the lives of 

              7     those who have to apply these criteria on either an IRB 

              8     or a privacy board. 

              9               And finally we asked HHS to look at the very 

             10     rigorous standards for deidentification of data.  There 

             11     was a part of HIPAA which says that if 18 different 

             12     data categories are shed out of clinical data, then the 

             13     deidentified information can be used and disclosed 

             14     freely for research purposes or for any purpose 

             15     actually, even for marketing purposes.  And there has 

             16     been a lot of consternation among the research 

             17     community because the datasets, the 18 datasets are 

             18     actually so extensive, meaning that in some cases the 

             19     data that would be left would not actually be usable 

             20     for some research studies.  

             21               So we, although not making some very specific 

             22     suggestions, we know that many, many entities and 

             23     people have made suggestions for which of the 18 

             24     categories they would allow to be left in the data and 

             25     it could still be regarded as deidentified.  We 
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              1     certainly say that it ought to be what ought to be 

              2     looked at least is the issue of zip code and address as 

              3     being important for epidemiologic and public health 

              4     studies, particularly in regard to environmental 

              5     exposures and development, for example, of cancer among 

              6     certain populations geographically defined.  And that 

              7     basically is our letter which was delivered on April 

              8     24th to HHS.  

              9               CHAIRPERSON MARSHALL:  Fait accompli.  Abbey, 

             10     I'm just going to allow a couple of minutes because 

             11     we're over time and it's lunchtime. 

             12               MS. MEYERS:  Well, I just want to put it on 

             13     the record officially that I abstained from signing on 

             14     to this letter.  I think there is nothing in my memory 

             15     that has made the patient community more angry than the 

             16     fact that HHS has taken away the confidentiality thing 

             17     by requiring -- taking away the requirement that 

             18     patients consent -- give their written consent up front 

             19     and it has infuriated a lot of patient community. 

             20               There is a sentence in here that says, "The 

             21     individual members of NHRPAC have come to understand 

             22     and appreciate in a direct, first-hand way some of the 

             23     problems associated with the implementation of the 

             24     HIPAA rules in the context of research involving human 

             25     subjects." 
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              1               And I have to say that I think there's only 

              2     two of us on this panel who are consumers and we're not 

              3     in the business of research.  That the people I hear 

              4     from are the women who had a baby out of wedlock at the 

              5     age of 15 and gave it up for adoption and don't want 

              6     their husband and children to find out.  Or the 

              7     politicians who have a serious mental illness diagnoses 

              8     and know that they'll never win an election and want to 

              9     keep it secret.  And the pilots, and the teachers of 

             10     children, and they're the ones who are saying, how 

             11     could this have happened.  So that's why I could not 

             12     sign on to this. 

             13               I think that the patient community is so 

             14     furious that they've taken away the requirement for our 

             15     written permission that this information will be able 

             16     to get out to anybody who wants to have access to our 

             17     records.  I think it's a terrible thing and I think 

             18     that if the HHS is smart, they will understand how 

             19     angry people have gotten over this.  Because it has 

             20     been so many years that we've been fighting for medical 

             21     privacy and they've taken it away just by simply 
             22     issuing a Federal Register notice. 

             23               [Applause.]  

             24               MS. MEYERS:  Thank you. 

             25               CHAIRPERSON MARSHALL:  Thank you, Abbey. 
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              1               Alan, did you --  

              2               DR. FLEISCHMAN:  I think I'm going to have to 

              3     rise to comment on that which I wasn't planning on 

              4     doing.  But I just don't read these complex regulations 

              5     with that same concern.  I think the intention was well 

              6     served to protect privacy.  It still can protect 

              7     privacy and still allow important work to continue. 

              8               But the reason I raised my hand is to comment 

              9     that we owe an incredible debt of gratitude to Mark.  

             10     If NHRPAC, in my opinion, thinks the children's 

             11     workgroup did hard work, not even a log difference.  

             12     Since there are only eight people in the United States 

             13     who truly understand the HIPAA regulations --  

             14               [Laughter.]  

             15               DR. FLEISCHMAN:  -- and we're lucky enough to 

             16     have one of them over there and another one of them 

             17     OHRP now, I really think we are in Mark's debt and the 

             18     United States is in his debt for having really 

             19     carefully thoughtfully crafted some comments that I 

             20     think are incredibly helpful. 

             21               CHAIRPERSON MARSHALL:  Yes.  Just so.  We 

             22     should have applause.  I will second that motion as 

             23     well.  

             24               [Applause.]  

             25               CHAIRPERSON MARSHALL:  The folks who are at 
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              1     the podium and then we will break for lunch.  

              2               MS. KANE:  I'm a private citizen who did read 

              3     the 1,500 page medical privacy regulations and I have 

              4     to say I'm also an attorney, but I don't do this as my 

              5     practice.  I'm just doing this because I'm a concerned 

              6     private citizen.  And I have to tell you, I do not know 

              7     how --  

              8               CHAIRPERSON MARSHALL:  Could you tell us who 

              9     you are?  I'm sorry. 

             10               MS. KANE:  My name is Robin Kane. 

             11               CHAIRPERSON MARSHALL:  Thank you.  

             12               MS. KANE:  I don't understand how we can have 

             13     a medical privacy regulation in which we remove the 

             14     written patient consent forms.  To me that is just 

             15     mutually exclusive. 

             16               And what has happened here in the recent 

             17     proposed changes by the federal government is that 

             18     they're taking away the very mild consent provision 

             19     that the Clinton administration had put in and there 

             20     will be an ability for patients to go to doctors now 

             21     and for purposes of health care treatment, payment, and 

             22     what's called health care operations, you will no 

             23     longer be provided with the written consent form that 

             24     you sign before your medical records are released.  

             25     Instead, you will be given an authorization, basically 
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              1     notice, of who the doctors are going to share your 

              2     information with.  That puts the federal government and 

              3     doctors and others in the driver's seat, not the 

              4     patient, who goes to the doctor and tells such personal 

              5     information to be healed, not to be revealed.  And it's 

              6     a limited use, basically.  You go to your doctor so 

              7     that he can heal you. 

              8               But what's happening now is we're removing 

              9     the patient consent forms and instead the federal 

             10     government through its Office for Civil Rights can go 

             11     to any doctor's office or hospital without prior notice 

             12     or a subpoena, or the patient's consent, or the 

             13     doctor's consent, and go in and track those medical 

             14     records, get access to the medical records.  We also 

             15     have health researchers, law enforcement, public health 

             16     officials, countless others getting access to this 

             17     information again without the patient's consent.  So 

             18     what we've done is substituted regulatory permission 

             19     rather than patient permission. 

             20               So I'm here to make, you know, I basically 

             21     stand here for the thousands of people that did send 

             22     comments to the federal government and say, "what about 

             23     the little man?"  It seems that the health care 

             24     industry has prevailed here.  Perhaps through, you 

             25     know, campaign contributions or perhaps through other 
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              1     means and reasons, I cannot say.  But I think that the 

              2     patient's rights should be considered first and 

              3     foremost. 

              4               Thank you. 

              5               CHAIRPERSON MARSHALL:  Thank you very much. 

              6               I appreciate that.  You know, my area of 

              7     research in the past has been perinatal substance abuse 

              8     and I have serious concerns about privacy or lack 

              9     thereof and the impact that it can have on people's 

             10     lives. 

             11               John. 

             12               DR. MATHER:  John Mather with the VA.  Mark, 

             13     I do think this is a contribution and a positive 

             14     contribution to the getting issues on the deck.  And I 

             15     think further than that, along with all the other 

             16     contributions we made somewhere it will filter out.  

             17     For the health care system that's at VA, of course, 

             18     it's not just where research goes on in one facility, 

             19     it's what that permission might mean for rippling 

             20     across to other facilities. 

             21               And more especially, the only area I think 

             22     it's weak is in part three where it's alluded to, but 

             23     the issue of repositories and depositories of data.  

             24     And what is the necessity for protecting those 

             25     particular sets of data.  I mean, we talked literally 
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              1     about biological specimens and such repositories or 

              2     depositories.  But when you talk about data and it's 

              3     sort of kept on line, and so on, you hint at it in part 

              4     three, but you don't come right out and deal with that, 

              5     I think, as an issue.  Really for us in the VA, that's 

              6     a very significant issue because you can imagine data 

              7     being dumped into depositories with all kinds of 

              8     identifiers on it.  And if it's not clearly identified, 

              9     then probably somebody needs to give a second consent 

             10     to that data being used.  Then what is that 

             11     depository/repository of data?  

             12               You get to it a little bit, but I think, 

             13     Madam Chairperson, it's something, not just in respect 

             14     to data and HIPAA, but also biological specimens, this 

             15     issue is, who owns that when the experiment is over and 

             16     terminated and done.  It sits there somewhere.  Is it 

             17     automatically to be destroyed?  Or if it is valuable in 

             18     the public interest, not just the public data set, but 

             19     in the public interest, what is it that it means for 

             20     those individuals who have been enrolled as human 

             21     subjects in that part -- need to be reapproached again 

             22     or maybe approached up front.  We're going to put that 

             23     is into a repository/depository.  I think there's only 

             24     one weakness in your letter in that regard. 

             25               CHAIRPERSON MARSHALL:  Thank you.  I think 
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              1     Mark probably would like to respond to that.  

              2               MR. BARNES:  Yes, I take your point.  I think 

              3     that one of the issues -- when HIPAA -- when you try to 

              4     understand how HIPAA applies to human subjects 

              5     research, it turns out that really it casts into doubt 

              6     or raises questions about the ways in which we are 

              7     conducting human subjects research and about data 

              8     practices, you know, in general.  And one of the issues 

              9     that is touched on in here, but is not fully outlined 

             10     or discussed is this issue of whether there ought to be 

             11     IRB approval for the pre-research compilations of data 

             12     and whether there ought to be actual informed consent 

             13     for a person to have their tissue or their information 

             14     put into a kind of pre-research data platform or tissue 

             15     bank platform. 

             16               The practices -- you know, my impression, and 

             17     I actually talk about this in an article I published 

             18     about a week in BNA which is about the effect of the 

             19     NPRM on human subjects research and I treat this issue 

             20     more fully there.  I didn't feel like I had latitude to 

             21     treat it here because we really didn't have a -- we had 

             22     not discussed it among the committee.  But one of the 

             23     things I say in my article and I do believe is that I 

             24     think that people really, IRBs and institutions really 

             25     do need to clean up their act in regard to how and why 
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              1     they're conducting these pre-research compilations of 

              2     data.  And there needs to be, really, I think some kind 

              3     of national policy about it or some kind of guidance 

              4     from OHRP.  Particularly because IRBs are splitting all 

              5     over the place and in many cases they are simply 

              6     following widely varying state law, state law 

              7     requirements, and all of which really doesn't add up, I 

              8     think, for adequate, you know, understanding or 

              9     oversight as to what these databases are being used 

             10     for. 

             11               So I agree with you. 

             12               CHAIRPERSON MARSHALL:  Thank you, Mark.  So 

             13     brief, please.  

             14               MS. BLEVINS:  I read the rule as well, and I 

             15     think it's important to recognize that if you are here 

             16     to protect humans, you are not fulfilling your mission. 

             17      And I say that in that having read every single word 

             18     of the proposed rule and then the final rule, and then 

             19     also the proposed revisions, every one in here, if any 

             20     of you have a secret, if any of you have ever consented 

             21     to anything in your past, if any of you have ever been 

             22     to marital counseling, psychological counseling, had an 

             23     STD, anything, that information will be available to 

             24     others. 

             25               The consent that you gave in your past is 
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              1     being eliminated.  And I really want to encourage you, 

              2     I'm here to support you and to tell you that I support 

              3     research in humans and if you force people to hand over 

              4     data without their consent they will do one thing, they 

              5     will lie and all research in this country will be based 

              6     on a database of lies and that will be very, very 

              7     unfortunate for the research community.  Thank you. 

              8               CHAIRPERSON MARSHALL:  Thank you.  And I'd 

              9     like to observe that if we -- I think we will have some 

             10     extra time between 3:00 and 3:30 this afternoon and 

             11     that if we want to resume this discussion that we can 

             12     revisit there.  Because I want people to feel as though 

             13     there is ample time to discuss something that there is 

             14     serious concern over. 

             15               So, thank you very much.  

             16               Sure, Mark.  Mark can have the final word 

             17     before I have the final word. 

             18               MR. BARNES:  One thing I want to point out.  

             19     I mean, I understand this issue of written consent or 

             20     not written consent which actually went back and forth. 

             21      The Clinton administration first proposed no written 

             22     consent and then in the final rule they came out with 

             23     written consent, and then the Bush administration has 

             24     proposed pulling back on it.  I understand that that's 

             25     a great subject of controversy, but I should point out 
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              1     that what we're saying and what we put in this letter 

              2     is really true regardless of whether there is written 

              3     -- the requirement of written consent or not the 

              4     requirement of written consent at the first entry of 

              5     the patient into the health care system.  Because what 

              6     we're talking about applies to all the regulatory 

              7     regime and rules that would survive. 

              8               So I'm not -- I mean I have my personal 

              9     feelings about written consent or not written consent. 

             10      But I do want to point out that we are not -- we don't 

             11     treat that issue per se in here.  And, in fact, what we 

             12     try to do here is we do try to preserve patient choice 

             13     while also allowing human subjects research to proceed. 

             14               CHAIRPERSON MARSHALL:  Thank you very much, 

             15     Mark.  We can't thank you enough for your hard work. 

             16               I also want to thank you for observing that 

             17     the government has determined that research is not 

             18     treatment and those of you in the room who work at the 

             19     NIH, perhaps you could convey that notion back to them. 

             20      I've always been opposed to their use of treatment 

             21     rather than intervention or something like that in 

             22     their informed consent documents. 

             23               We have had an interesting morning.  We are 

             24     going to have, I think, an interesting afternoon.  I 

             25     want to pick up a few key words from our conversation 
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              1     this morning that as a group, and I'm being inclusive 

              2     of everyone in the room here, a group of delusional 

              3     policy wonks who have zany, but specific, conversations 

              4     about nothing that we will resume that activity at --  

              5               [Laughter.]  

              6               CHAIRPERSON MARSHALL:  -- and of vital 

              7     interest, we will resume that activity at 1:00 in this 

              8     room. 

              9               Thank you all very much. 

             10               Kate needs to speak to committee membership. 

             11               MS. GOTTFRIED:  I need Judy Siegel, Abbey, 

             12     Susan, Bob Levine, and Elliot. 

             13               [Whereupon at 12:17 p.m., the meeting was 

             14     recessed to reconvene this same day at 1:00 p.m.] 

             15 

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              1                A F T E R N O O N   S E S S I O N 

              2                                    [Time noted:  1:15 p.m.] 

              3               CHAIRPERSON MARSHALL:  We are going to 

              4     reconvene in about two minutes.  Thanks for your 

              5     patience. 

              6               Well, I hope you all managed to wolf some 

              7     nourishment down in the short time that we've had.  

              8     Thank you for being back.  Those of you who are back on 

              9     time.  

             10               We are going to begin.  It should be an 

             11     interesting afternoon.  I had the opportunity in the 

             12     interim between our last meeting and this meeting to 

             13     attend a meeting in New York that was organized by the 

             14     Mount Sinai Center for Children's Health and the 

             15     Environment and was co-sponsored by the New York 

             16     Academy of Medicine.  And I thought the theme of the 

             17     meeting which has to do with policy approaches to 

             18     pesticide testing in humans was something that might 

             19     interest the committee and talked to Kate about it.  It 

             20     certainly does involve health policy in research with 

             21     humans and I thought that you should know about it and 

             22     that we should have a conversation about it.   So we 

             23     have invited a number of folks to present to you this 

             24     afternoon on this issue.  

             25               We are going to begin with William Jordan who 
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              1     is Senior Policy Advisor, Office of Pesticide Programs 

              2     at the Environment Protection Agency.  And we welcome 

              3     you to the table and look forward to a fruitful 

              4     afternoon.  Thank you so much for being here.  

              5               MR. JORDAN:  Thank you, Dr. Marshall.  I 

              6     really appreciate the opportunity to be here with you 

              7     today and to provide a little bit of background on what 

              8     is a very controversial and complex issue.  I assume 

              9     that you figured out from the agenda that I'm a lawyer, 

             10     I'm not a scientist, I'm not an ethicist, I've been 

             11     working in the pesticide program for about 25 years.  

             12     So I know a lot about pesticide regulation and my hope 

             13     is to provide from that information some background 

             14     that will help you understand the issues that are going 

             15     to be debated ably by the members of the panel that 

             16     will follow my remarks. 

             17               I have only been working on this issue for 

             18     the last couple of months.  So I don't think I'm 

             19     qualified at this point to talk about the merits of the 

             20     testing, but I do know and do understand the context 

             21     within which we are tackling the questions, and so 

             22     that's what I want to try to provide for you this 

             23     afternoon. 

             24               First thing to make clear is that EPA is 

             25     committed to protection of human subjects.  We have 
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              1     adopted the Common Rule as have other federal agencies. 

              2      We have a record in that regard that we're very proud 

              3     of.  And we take very seriously the issues that have 

              4     been grappled with over the years and reflected in the 

              5     Common Rule. 

              6               We are also committed to using the best 

              7     possible science in making our regulatory decisions.  

              8     We don't see the issues of using good science and 

              9     protection of human subjects as being in any way in 

             10     conflict.  We think, in fact, the best science is the 

             11     kind of studies that involve rigorous, careful 

             12     protection of human subjects. 

             13               Today's focus is on pesticides.  But just a 

             14     footnote to point out.  There is a policy that EPA has 

             15     announced recently that we will not be looking at 

             16     certain kinds of human studies and that is the focus of 

             17     a good deal of the controversy.  It is not limited to 

             18     pesticides.  It is a policy that involves all of the 

             19     EPA's work in regulatory matters.  But since the topic 

             20     for today is pesticides that's where I want to start. 

             21               Most of you have, I'm sure, the same kind of 

             22     image that I did when I first started working in 

             23     pesticides and that is pesticides are the things that 

             24     farmers use.  They're the insecticides, the weed 

             25     killers that are sprayed on the fields, amber waves of 
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              1     grain, and tomatoes and so forth.  And that is, in 

              2     fact, a large part of the universe of pesticides, but 

              3     it is by no means the only type of product that is 

              4     included in this category.  And I hope that when you 

              5     think about this subject and ask questions and sort of 

              6     ponder where to go that you'll remember that there are 

              7     lots of other kinds of products. 

              8               Well, of course, there's the things that we 

              9     use to kill the cockroaches around the house.  There 

             10     are products that are used to kill the weeds along the 

             11     highways and there are a very large number of 

             12     fungicides that are used to keep the cooling towers 

             13     that are working with air conditioning in nuclear power 

             14     plants and industrial operations free of slime in the 

             15     pipes.  There are fungicides for killing mold and 

             16     mildew in paint products. 

             17               We have a whole range of public health 

             18     products that we regulate, disinfectants and sanitizer 

             19     products that are designed to control mosquitos that 

             20     spread west nile virus, for example.  Products used in 

             21     swimming pools to kill the germs or hot tubs to kill 

             22     the microbes that might be disease carrying agents.  

             23     Rodenicides and on and on. 

             24               So the universe of pesticides is actually a 

             25     very large variety of products.  And it's also 
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              1     important to bear in mind that the types of chemicals 

              2     that can serve as pesticides or materials, I should 

              3     say, are also pretty widely varied as well.  There are 

              4     microbes that can serve as pesticides. 

              5               There are, of course, conventional chemicals, 

              6     some of those conventional chemicals can be used for 

              7     industrial purposes as well, and, in fact, some of the 

              8     chemical substances have both pesticidal use and 

              9     pharmaceutical use.  Lindane and malathion are two 

             10     relatively familiar pesticides that also are used in 

             11     human drugs. 

             12               We regulate this universe of pesticides under 

             13     two different laws, one of which you may already be 

             14     well familiar with, the Food, Drug and Cosmetic Act.  

             15     The other has one of those peculiar Washington 

             16     acronyms, it's called the Federal Insecticide, 

             17     Fungicide and Rodenticide Act and that's abbreviated 

             18     FIFRA. 

             19               I digress here, but it seems appropriate for 

             20     a human subjects discussion.  My favorite mistake in 

             21     transcripts was when I read through the transcript and 

             22     somehow that came out as Federal Insecticide, 

             23     Fungicide, and Genocide Act.  

             24               [Laughter.] 

             25               CHAIRPERSON MARSHALL:  I was wondering 
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              1     whether you included husbands under that category.  

              2               [Laughter.]  

              3               PARTICIPANT:  You will get yours. 

              4               CHAIRPERSON MARSHALL:  I've already gotten 

              5     mine, this is merely self defense. 

              6               MR. JORDAN:  Both laws are based on a 

              7     premarket approval system.  That is to say, before 

              8     anybody may sell a pesticide product in the United 

              9     States, they have to come to EPA and get a 

             10     registration, a license, for the specific product, for 

             11     the specific way it's going to be used, and that we 

             12     issue under FIFRA. 

             13               The other law, the Food, Drug and Cosmetic 

             14     Act is directed at pesticides residues in food.  And 

             15     under that law we set what are called "tolerances" or 

             16     "maximum levels" that are allowed for a pesticide in 

             17     food.  And if there is no tolerance then the food is 

             18     considere adulterated.  So in both cases a company that 

             19     wants to sell a product or somebody who wants to use a 

             20     product needs to come to EPA and get an approval from 

             21     EPA before they may do so. 

             22               And our approvals are based on a very 

             23     comprehensive set of information.  Next to 

             24     pharmaceuticals or perhaps maybe even equal with that 

             25     category of products, pesticides are studied more 
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              1     extensively or as extensively as any chemical substance 

              2     that you can think of.  We have somewhere in the 

              3     neighborhood of 25 different animal toxicity studies 

              4     that we routinely require for a food use pesticide.  

              5     That's just to evaluate the potential effects of 

              6     mammalian systems and then we also have an abundance of 

              7     information about exposure, about effects on wild life, 

              8     water systems and so forth. 

              9               The laws that we regulate under have 

             10     different statutory standards.  And I want to take a 

             11     moment or two to talk about the standards.  The Food, 

             12     Drug and Cosmetic Act is a standard that you may have 

             13     heard about in other contexts because the same thing is 

             14     used for food additives.  It's a reasonable certainty 

             15     of no harm. 

             16               In other words, EPA needs to be confident 

             17     from the information that we have that the presence of 

             18     pesticide residues in food, together with other 

             19     exposures to the general population will not cause harm 

             20     and we have to have a reasonable level of certainty 

             21     about that conclusion before we may establish a 

             22     tolerance. 

             23               The decision under FIFRA is a little 

             24     different.  It is -- the statutory phrase is 

             25     unreasonable, adverse effects.  We may not approve a 
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              1     pesticide unless we are convinced that it will not 

              2     cause unreasonable adverse effects.  

              3               The law goes on to define unreasonable 

              4     adverse effects as involving a balancing of risks and 

              5     benefits.  And I think that reflects the congressional 

              6     judgments or certainly the legislative history makes 

              7     this point that pesticides products are used because 

              8     they have benefits, because people want to get rid of 

              9     the insects, or the weeds, or the mold or mildew and 

             10     yet at the same time these substances because of their 

             11     biological activity are also likely to have some risks 

             12     as well.  And we need to understand the risks and make 

             13     sure that those risks are outweighed by the potential 

             14     benefits that society gets. 

             15               Since there are different standards, there's 

             16     a need to coordinate the two laws together.  And 

             17     basically the way that we do that is that we make 

             18     certain that any residues in food will not have any 

             19     harm, potential harm to the society and then other 

             20     kinds of questions, perhaps wildlife effects, we may 

             21     look at risk benefit balancing kinds of issues. 

             22               As I suggest in my remarks, our concerns are 

             23     not limited just to human health, but include also 

             24     effects on wildlife, ecological systems, we focus on a 

             25     wide range even in the human health arena, a wide range 
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              1     of exposed groups from people who eat food or drink 

              2     water, to people who handle, mix, load, and apply the 

              3     pesticides, people who are bystanders who might be near 

              4     or re-enter a site that has been treated with a 

              5     pesticide.  We are concerned about a wide range of 

              6     effects.  Not only effects that would result from 

              7     single exposure, but also what consequences might 

              8     result from a lifetime of exposure either in the 

              9     workplace or as a result of residues and food. 

             10               And, it's also fair to point out that our 

             11     issues also include the efficacy of public health 

             12     pesticides.  If you go to a hospital you want to know 

             13     that the disinfectants that have been used on the 

             14     medical instruments actually work.  It would be 

             15     disastrous if they don't.  And, in fact, we found some 

             16     situation where people have proposed to us products 

             17     that were far less efficacious than they should have 

             18     been.  

             19               So that's the backdrop, that's the regulatory 

             20     system, if you will, for the pesticide program.  And I 

             21     want to talk now about how human studies fits into 

             22     that.  As I said at the beginning, we require a very 

             23     extensive database on chemicals before we are in a 

             24     position to make a decision on them.  We require 20 

             25     different toxicity studies for evaluating mammalian 
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              1     effects, another 60 one-to-one 80 different studies to 

              2     evaluate other types of ecological system, residue 

              3     levels in food, physical and chemical hazards among 

              4     others. 

              5               Generally speaking EPA does not require -- we 

              6     certainly do not encourage studies that involve 

              7     intentional dosing of human subjects.  We have received 

              8     data from time-to-time over the years on a wide variety 

              9     of studies that have involved human subjects and I want 

             10     to just give you a feel for the variety of products.  

             11     This is roughly in the order in which we get them. 

             12               The most that we get are generally on 

             13     exposure.  Passive dosimetry or biomonitoring studies. 

             14      We get a fair number of studies on efficacy of insect 

             15     repellents and stuff that you spray to keep mosquitos 

             16     off of you, we get occasional studies on skin 

             17     irritation and skin sensitization, or photo 

             18     sensitization.  This is typically for the products that 

             19     are applied or intended to be applied directly to 

             20     humans such as insect repellents.  We get a number of 

             21     studies on the efficacy of personal protective 

             22     equipment, gloves, aprons, masks, that sort of thing, 

             23     to see how successful they are in reducing potential 

             24     exposure. 

             25               We do occasionally, although far less often, 
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              1     get pharmacokinetic studies, and then occasionally we 

              2     get human toxicity studies; studies where human 

              3     subjects have been dosed intentionally in a laboratory 

              4     setting to evaluate what level will elicit some sort of 

              5     adverse toxic response. 

              6               We get epidemiological studies, and then we 

              7     have follow-up on incident reports. 

              8               As I said, with the exception of the exposure 

              9     in efficacy studies, and things related to protective 

             10     equipment, most of these are not required.  And so it 

             11     is relatively rare that we will get these other 

             12     studies. 

             13               Human studies represent altogether less than 

             14     1 percent of the studies submitted a year.  And the 

             15     subunit of that group that involved intentional dosing 

             16     to establish toxicity is less than half a percent most 

             17     of the time. 

             18               The Common Rule applies to any studies that 

             19     EPA sponsors or conducts.  But in addition to that, 

             20     studies that are conducted by third parties say, 

             21     companies that are trying to obtain an approval for 

             22     pesticide registration are also subject to a provision 

             23     in FIFRA that requires -- that makes it unlawful for 

             24     any person to use a pesticide in a test with human 

             25     subjects unless the participants are, first, fully 
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              1     informed; and, secondly, voluntarily consent to 

              2     participate in the study. 

              3               In the past we have used this authority to 

              4     take enforcement action where we have discovered 

              5     violations of this particular provision. 

              6               So, against that backdrop, why the 

              7     controversy? 

              8               In July 1998, the environmental working group 

              9     issued a report which appears in the binder that you 

             10     all have called the "English Patients" -- that was a 

             11     popular movie or close to, "The English Patient" was a 

             12     movie that was popular at the time -- and it called 

             13     attention to the testing that was being done by some 

             14     pesticide companies on the effects of their pesticides 

             15     on human subjects. 

             16               The tests were mostly conducted at a facility 

             17     in the United Kingdom, and the environmental working 

             18     group charged that this was an attempt to circumvent or 

             19     undercut the provisions of the newly passed Food 

             20     Quality Protection Act by eliminating what was then and 

             21     continues to be EPA's normal practice in risk 

             22     assessment of using a tenfold uncertainty factor or 

             23     safety factor in extrapolating from animal data to 

             24     human protections. 

             25               In response to the environmental working 
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              1     group's report, EPA acknowledged its own concern.  We 

              2     said, yep, there are some questions here, some serious, 

              3     important, scientific, ethical questions and we need to 

              4     look more deeply and closely at it. 

              5               We convened a blue ribbon advisory committee 

              6     jointly with two groups in EPA that advise us, the 

              7     Scientific Advisory Panel and the Science Advisory 

              8     Board and they took several years to meet about and 

              9     discuss the questions involving this type of testing. 

             10               They had representatives from the human 

             11     research community, the bioethicists, toxicologists, a 

             12     very broad group of disciplines and a very respected 

             13     group of people who are on the committee. 

             14               They met several times in public meetings, 

             15     took comments, and developed and issued a report in 

             16     September of 2000. 

             17               The report has both areas of consensus and 

             18     areas of disagreement.  In particular the committee 

             19     divided on the acceptability of no adverse -- no 

             20     observed adverse effect level studies or what we call 

             21     NOAEL studies.  One group, a minority group, said that 

             22     these studies in humans with human subjects should not 

             23     be accepted under any circumstances.  The other group 

             24     identified a set of criteria that they suggested EPA 

             25     consider. 
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              1               After mulling it over and changing 

              2     administrations and mulling it over some more and then 

              3     mulling it over some more, we decided that this really 

              4     was an area that continued to be controversial, that 

              5     continued to be one where at least with respect to this 

              6     critical issue of NOAEL studies we felt we wanted more 

              7     guidance.  And so in December of this year -- of last 

              8     year, excuse me, we asked the National Academy of 

              9     Sciences if they would be willing to provide us advice 

             10     on the subject.  And they have, in fact, agreed to do 

             11     so and we'll be convening and advisory committee with 

             12     composition we anticipate from some of the same 

             13     disciplines as our earlier group and will work with us 

             14     and work with each other to develop advice on how to 

             15     deal with this particular category of pesticides. 

             16               We have asked them to look at a variety of 

             17     issues, not exclusively ethical issues, although they 

             18     are certainly included, but also scientific issues, 

             19     what factors should we consider in determining whether 

             20     to accept or rely on human studies performed by third 

             21     parties.  Are there boundaries, clear lines that could 

             22     be drawn between those studies that are acceptable, 

             23     both ethically and scientifically or studies that can 

             24     be clearly put aside because they don't meet standards 

             25     of scientific and ethical acceptability. 
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              1               If you can't draw clear cut lines and say 

              2     this is okay and this is not, what factors, what kinds 

              3     of factors ought to enter into that consideration.  

              4     What kind of documentation do we need to have in order 

              5     to be able to assure ourselves that we have a basis for 

              6     making those kinds judgments.  Are there existing 

              7     standards, either in the Common Rule or in the 

              8     Declaration of Helsinki or some other source that we 

              9     could turn to and say, these represent the standards 

             10     that should be applied in terms of decision-making. 

             11               Are there different standards for different 

             12     kinds of tests?  Do studies that are designed to 

             13     quantify no observed adverse effect levels, should they 

             14     be treated differently from other types of human 

             15     studies that have been identified? 

             16               So we have issued -- we have asked the 

             17     Academy to undertake this endeavor for us and they have 

             18     agreed.  We are in the process of working out with them 

             19     the schedule and exact process that they will be 

             20     following.  We have asked them to make sure as they do 

             21     their work that there is ample opportunity for the 

             22     public to make their views known.  We will encourage 

             23     the Academy to have public meetings where they can hear 

             24     directly from people who have an interest in these 

             25     issues.  They will ask them to allow the public to 
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              1     submit written comments as well.  And at the end of it 

              2     we hope to get some advice that we can use and go ahead 

              3     and deal with this issue. 

              4               At the same time that we announced our 

              5     intention to talk with the Academy about this, we also 

              6     said that we were going to apply an interim policy 

              7     which essentially is that we will not look at and use 

              8     in our regulatory decision-making any studies conducted 

              9     by third parties that involve intentional dosing of 

             10     human subjects for the purpose of quantifying a toxic 

             11     end point.  That policy statement that we announced in 

             12     December is a continuation of an approach that we had 

             13     announced several years earlier in connection with our 

             14     statements about the study, the report issued by the 

             15     environmental working group. 

             16               One difference in what we said in December is 

             17     that this policy approach, this interim policy applies 

             18     not just to pesticides, but to all areas of EPA's 

             19     regulatory decision-making.  As I'm sure you'll hear 

             20     more about later, this subject is considerably 

             21     controversial and in mid-February the interim policy 

             22     was challenged by members of the pesticide industry who 

             23     argued that it was an illegal rule and have asked the 

             24     U.S. Court of Appeals for the District of Columbia to 

             25     set aside that policy statement and to order EPA to 
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              1     consider the results of this kind of study. 

              2               At present, the Court has not ruled on the 

              3     various motions that the parties have made and so we 

              4     continue that interim policy in effect. 

              5               I hope with this background that you have at 

              6     least come to the conclusion that there are lots of 

              7     subtleties and nuances in trying to figure out how to 

              8     approach this area.  I do want to point to one thing 

              9     that I think is different from what might be your 

             10     customary kind of approach to matters, and that is that 

             11     a lot of the human research that EPA -- well, not a 

             12     lot, but at least some of the human research that EPA 

             13     receives comes to our attention after the study is 

             14     completed.  We are not, as I said, in the business of 

             15     requiring or encouraging testing and sometimes 

             16     companies will come to us and ask us about a study 

             17     design, but more often studies will be started by a 

             18     company and completed before EPA is aware that they're 

             19     in the works. 

             20               And so the decision that we're facing then 

             21     is, not how to design the study in such a way that it 

             22     is designed to protect human research -- research with 

             23     human subjects -- but rather, what should we do after 

             24     the fact?  What should our approach be in those 

             25     circumstances? 
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              1               I guess I will stop there and let you all ask 

              2     questions.  Thank you.  

              3               CHAIRPERSON MARSHALL:  Thank you.  Thank you 

              4     very much.  That was a very nice overview and sort of 

              5     statement of the problem and the issue.  It really does 

              6     raise the forbidden knowledge question.  That's the 

              7     issue on the table.  And I have to say that when you 

              8     used the third party language that I saw the collective 

              9     shiver that went around the table of committee members. 

             10      But this is studies collected by third parties.  So 

             11     have no fear, that other issue is at rest. 

             12               Let me open the floor up to questions first 

             13     by the committee.  I have Abbey, I have Sandy, I have 

             14     Adil.  Abbey. 

             15               MS. MEYERS:  I have two questions.  First, 

             16     why hasn't EPA issued regulations for implementation of 

             17     the Common Rule? 

             18               MR. JORDAN:  EPA has issued regulations 

             19     implementing the Common Rule.  And as I said, we do 

             20     follow the Common Rule for studies that we sponsor or 

             21     conduct. 

             22               MS. MEYERS:  And just in what you sponsor.  

             23     But, for example, FDA doesn't develop drugs, but they 

             24     regulate the industry that develops drugs and so they 

             25     have regulatories that require all studies to be done 
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              1     in a certain way in order to be acceptable when they're 

              2     submitted.  And EPA hasn't done that? 

              3               MR. JORDAN:  No, we have not. 

              4               MS. MEYERS:  Well, that seems to be a big 

              5     problem.  The other question that I have is, in the 

              6     literature that we were given it seems that small 

              7     numbers of people, you know, a dozen or two dozen or 

              8     whatever have been studied for a short period of time. 

              9      And a lot of the public's fear about pesticides comes 

             10     from the fear that long-term exposure or exposure to 

             11     children in the food is causing all kinds of problems, 

             12     birth defects in women, or children with hyperactivity 

             13     or whatever.  And so the fear of the public seems to me 

             14     that there is something that EPA can do to at least 

             15     require, if you're going to accept human studies, to 

             16     require that these things be long-term exposure before 

             17     they're acceptable. 

             18               MR. JORDAN:  There are a couple of points.  

             19     Human studies database that we at EPA have include 

             20     studies that are in some cases more than ten or even 20 

             21     years old and other studies that have been conducted 

             22     fairly recently.  The more recently conducted studies 

             23     tend to have much larger numbers of participants, I 

             24     think usually over 50.  More recent ones, and I'm not 

             25     absolutely sure I've got the numbers right, but I think 
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              1     the smallest number of participants was 44 and at 

              2     different dose levels. 

              3               In terms of the study design, and the 

              4     chemicals study, most of them have been, as you 

              5     correctly point out, short-term studies involving 

              6     either a single exposure or sometimes exposure over the 

              7     course of a few days or maybe weeks, but seldom longer 

              8     than a month.  The reason for that, I think, is that 

              9     the chemicals of concern have been ones which in animal 

             10     studies have displayed short-term effects, generally 

             11     colon estrace inhibition and the intent of the studies 

             12     is to understand better the human dose response 

             13     relationship. 

             14               My impression is that in order to get a study 

             15     over a lifetime of exposure would -- or even a 

             16     substantial part of a lifetime would be prohibitively 

             17     expensive and we wouldn't see any of that sort of 

             18     study.  We do get and have been getting our 

             19     epidemiological data from a variety of sources 

             20     including a national agricultural study that has 

             21     followed people for close to two decades and that's 

             22     beginning to provide some very useful information in 

             23     terms of long-term effects. 

             24               MS. MEYERS:  Is it negative? 

             25               MR. JORDAN:  For the results that are coming 
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              1     up, the epidemiological data are mostly negative, but 

              2     some of them are suggestive and pointing in a positive 

              3     direction.  I don't want to talk about anything until 

              4     all the numbers are crunched and all the questions are 

              5     asked about confounding factors. 

              6               CHAIRPERSON MARSHALL:  I have Sandy, then 

              7     Adil, then Bob, then Margaret.  

              8               MR. CORTASI:  Could I interject a comment 

              9     here, please? 

             10               CHAIRPERSON MARSHALL:  Yes.  

             11               MR. CORTASI:   EPA --  

             12               CHAIRPERSON MARSHALL:  After you first tell 

             13     us who you are. 

             14               MR. CORTASI:  Roger Cortasi at EPA. 

             15               CHAIRPERSON MARSHALL:  Thanks, Roger. 

             16               MR. CORTASI:  EPA's approval of studies 

             17     involving human subjects on the basis of chronic 

             18     studies, we basically do not approve them if it 

             19     involves any deliberate dosing of a human being.  I'm 

             20     not saying that somebody couldn't come up and find a 

             21     case where we would, but so far we have not done and 

             22     our order prescribing how we will handle human studies 

             23     basically says there's a presumption that any such 

             24     study will not be approved unless you can think of some 

             25     pretty good arguments that we haven't thought of. 
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              1               CHAIRPERSON MARSHALL:  Thank you, Roger.  

              2     Sandy. 

              3               DR. CHODOSH:  I guess I have a few concerns. 

              4      One, you mentioned that when the third party industry 

              5     actually does the studies, you don't preapprove the 

              6     protocols, but you do expect them to have that the 

              7     subjects be fully informed and something about 

              8     scientific merit, nothing about IRB approval, and none 

              9     of the studies that I have seen reported in these 

             10     papers that we were given suggests that there was any 

             11     scientific validity considering the numbers of subjects 

             12     involved and there's an implication in these papers, I 

             13     know it sounds different from what you're saying, that 

             14     this data in fact was used to decrease the risk element 

             15     of quote, "the factors of ten."  If that were the case 

             16     and that was totally unethical, that's number one, and 

             17     so I don't understand, it said this -- Dr. Cortasi said 

             18     that the EPA did not accept any of that data in 

             19     determining the risk level, but these papers suggest 

             20     differently.  What's the truth? 

             21               MR. JORDAN:  I think that the papers do have 

             22     -- the papers in the binder do have some errors in 

             23     them.  Since -- let me make sure I get this right -- 

             24     since 1998, which is the time period that I think the 

             25     paper refers to, EPA has not relied on any human study 
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              1     to reduce the uncertainty factor that I'm aware of.  I 

              2     believe I would know about them if we had, in terms of 

              3     pesticides certainly.  An I can't speak to other parts 

              4     of the agency.  

              5               The question of how many human subjects need 

              6     to have been included in a study in order to have 

              7     scientific validity is one of the scientific issues 

              8     that we hope to get advice on.  The numbers of animals 

              9     in animal studies are generally considerably larger 

             10     than the numbers in these human studies, but the 

             11     question of how many is enough is one of the questions 

             12     to which we don't have an answer at this point. 

             13               CHAIRPERSON MARSHALL:  Adil. 

             14               DR. SHAMOO:  Thank you.  This is going to 

             15     sound strange, but I'm going to come to the defense of 

             16     EPA.  This is not an EPA problem.  Really, it is not. 

             17               And the reason is, nearly half of research 

             18     with human subjects is not regulated.  The industry can 

             19     do that with or without your approval.  They care less. 

             20      As a matter of fact, they could do this research to 

             21     defend themselves from future liability from individual 

             22     law suits.  So the problem is really for this committee 

             23     and for OHRP and for who else is involved in human 

             24     research protections is to make this issue that we need 

             25     a national human research protection act similar. 
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              1               This research with EPA cannot be done on cats 

              2     and dogs since 1966 because they have to comply with 

              3     the Animal Welfare Act.  So it's really not an EPA 

              4     problem.  This is all irrelevant, what we are talking 

              5     about.  All the questions to the EPA, EPA gets those 

              6     data after the fact.  Industry can do whatever they 

              7     wish because it's not just industry, private 

              8     foundations, state institutions, anybody.  Somebody in 

              9     his garage, they could do any kind of research as long 

             10     as it's not federally funded or FDA bound for drug 

             11     licensing.  And that is really the problem. 

             12               We are discussing now really the tail rather 

             13     than the dog.  Thank you. 

             14               CHAIRPERSON MARSHALL:  Thanks, Adil.  Bob. 

             15               DR. R. LEVINE:  Tu.  I have two questions.  

             16     The first one, well, first a comment and then a 

             17     question.  When you said you were looking around for 

             18     models you could draw on to develop your human subjects 

             19     protection policy, you mentioned Nuremberg and 

             20     Helsinki.  I think you have to be careful about that 

             21     because Helsinki was specifically developed to over 

             22     biomedical research which it does not do very well.  

             23     But it certainly doesn't cover any other type of 

             24     research.  So some of the particular articles of 

             25     Helsinki would be quite irrelevant to anything outside 
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              1     biomedical research. 

              2               Nuremberg might be a closer fit.  Although 

              3     we've come a long way since the Nuremberg standards 

              4     were articulated, but at least Nuremberg among the 

              5     examples they had to consider at the tribunals were 

              6     evaluation of the pesticides and poisons.  But, still, 

              7     in the 50 plus years since Nuremberg, understandings of 

              8     research have changed. 

              9               Now, the question that I wanted to bring up 

             10     is, if I heard you correctly, what I heard was that 

             11     there were no standards based upon human safety by EPA 

             12     that would control the entry into the marketplace of 

             13     new pesticides.  I said, if I heard you correctly.  

             14               MR. JORDAN:  Okay.  

             15               DR. R. LEVINE:  I wonder if there are any 

             16     safety standards for entry of these things into the 

             17     marketplace?  Thank you. 

             18               MR. JORDAN:  Okay.  I surely hope I did not 

             19     leave that impression with others, and if so I 

             20     apologize.  The laws under which we make our pre-market 

             21     approval decisions clearly articulate safety standards. 

             22      In the case of the Food, Drug and Cosmetic Act it is a 

             23     reasonable certainty of no harm.  That's a collection 

             24     of words that doesn't necessarily entail any specific 

             25     standard, but through years of application first within 
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              1     the Food and Drug Administration context and more 

              2     recently building on what we have been doing at EPA, 

              3     and now under the new law it has a very, I would say, 

              4     well-understood and pretty fully fleshed out 

              5     understanding and application within the Agency. 

              6               In general terms I'll give you a sort of 

              7     thumbnail sketch of the way we do our risk assessment 

              8     and use that as an explanation of the safety standard. 

              9               In terms of substances that display evidence 

             10     of being potential human carcinogens based on animal 

             11     data and other relevant information and structural 

             12     activity and epidemiological information, reasonable 

             13     certainty of no harm means using conservative models, 

             14     the anticipated exposure is less than one in a million 

             15     lifetime probability increase in cancer risk that in 

             16     given the conservative assumptions built into our 

             17     exposure assessments and so forth is regarded by our 

             18     scientists as biologically zero. 

             19               In the context of substances which are not 

             20     presumed -- which are presumed to have a threshold, we 

             21     apply -- we pick the no-observed adverse effect level 

             22     in animal data which is the most sensitive endpoint of 

             23     all of the different studies that have been performed. 

             24      In other words, if one were exposed to the pesticide, 

             25     what's the first effect that would be seen in terms of 
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              1     exposure levels?  And from that level we apply or 

              2     extrapolate an acceptable daily intake, sometimes 

              3     called a "reference dose," in EPA's terms, that is 

              4     typically 100 to 1000 times lower than the most 

              5     sensitive animal NOAEL. 

              6               And in judging against those hazard 

              7     benchmarks what we need -- what we do at EPA is to make 

              8     sure that the exposure that people get through the food 

              9     they eat, the water we drink, the exposure that we get 

             10     in the course of living places where pesticides may be 

             11     used that all of that exposure is less than the safety 

             12     benchmark. 

             13               So those are the standards that we apply in 

             14     judging whether or not to let a product on the market, 

             15     whether or not to set a tolerance. 

             16               CHAIRPERSON MARSHALL:  I have Margaret, Mary 

             17     Kay, and Judy, and then I'm going to open the floor up 

             18     for our ex-officio and public members.  We are running 

             19     a bit behind and imposing on Mr. Jordan's time.  So, 

             20     Margaret. 

             21               MS. BORWHAT:  I just want you to clarify, if 

             22     you would, that right now under interim guidance you 

             23     are not relying upon any deliberate dosage of human 

             24     subject, and does that include, you know, a combination 

             25     of any information from this type of study mixed with 
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              1     any of the animal models and information from the 

              2     animals. 

              3               And, secondly, I'd like to know if there's a 

              4     reason that you could state why the studies that were 

              5     mentioned in the article were conducted in England? 

              6               And, third, I'd like to know if you have any 

              7     data on profound chemical sensitivity in humans?  In 

              8     other words, you're looking to see whether there's a 

              9     rise or an increase in the number of people who are 

             10     having profound sensitivity? 

             11               And, finally, I might suggest as a model your 

             12     mentioning Helsinki that perhaps something as simple as 

             13     "do no harm" might suffice. 

             14               MR. JORDAN:  Okay.  If I miss any of those, 

             15     please don't hesitate to ask again.  

             16               First question had to do with combinations of 

             17     animal data and human studies.  To my knowledge we 

             18     haven't received any.  I, therefore, don't know exactly 

             19     how the policy would apply.  But I would think that 

             20     sort of methodologically one would construct the 

             21     studies separately with animals and with humans and we 

             22     would, under our interim policy look at the animal data 

             23     and the human intentional dosing of humans for 

             24     establishing a NOAEL we would not look at. 

             25               MS. BORWHAT:  If I could just comment.  There 
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              1     really is no way that you're discouraging in any real 

              2     fashion companies bringing forward this information. 

              3               MR. JORDAN:  As others have said, we cannot 

              4     prohibit them from conducting those studies.  But we 

              5     think it's a very strong signal to say we're not going 

              6     to look at them.  

              7               You asked a second question about chemical 

              8     sensitivity.  I do not know of any data.  Others who 

              9     are here from EPA may be familiar with information I'm 

             10     unaware of, about changes -- in the incidence of 

             11     chemical sensitivity in the human population.  

             12     Certainly through anecdotally in my years in EPA, what 

             13     I've seen is more expressions by people of concern 

             14     about that.  But whether that is simply improvement on 

             15     the part of medical science and being able to recognize 

             16     something that was there before, or whether it's in 

             17     increased incidence, I just don't know. 

             18               I'm missing one.  There was a third question. 

             19               MS. BORWHAT:  England. 

             20               MR. JORDAN:  England.  I don't know why these 

             21     studies were done in England.  I simply don't know. 

             22               CHAIRPERSON MARSHALL:  Thank you.  Mary Kay. 

             23               DR. PELIAS:  Thank you, Mary Faith.  I have a 

             24     rather direct question that doesn't have anything to do 

             25     with or has very little to do with adults who are 
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              1     exposed to pesticides.  I wonder what your protocols 

              2     provide for in the way of rigorous observations having 

              3     to do with teratogenic effects and mutagenic effects 

              4     that would show up in the next generation, but not 

              5     necessarily in this generation? 

              6               MR. JORDAN:  We are directed by the Food 

              7     Quality Protection Act to pay particular attention to 

              8     potential risks to infants and children.  And as part 

              9     of that we are directed to apply an additional 

             10     uncertainty factor of ten.  So when I was answering the 

             11     question earlier about are there safety standards, I 

             12     said our uncertainty factors range from 100 to 1,000.  

             13     That range is attributable to the FQPA provision 

             14     directing us to use an additional uncertainty factor of 

             15     10.  Unless we have reliable data that we believe 

             16     supports using some different factor from ten. 

             17               In terms of assessing that risk, the standard 

             18     data requirements include teratogenicity studies in two 

             19     different species as well as a two-generation 

             20     reproductive toxicity study.  And we have increasingly 

             21     been requiring a developmental neurotoxicity study and 

             22     we generally require mutagenicity studies for point 

             23     mutations, chromosomal aberrations and a sort of catch-

             24     all category that I'm not sure I technically qualified 

             25     or described.  It includes things like cystachromatid 
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              1     [ph] exchange and other assays that evaluate the 

              2     potential of a chemical to interrupt the genetic 

              3     replication. 

              4               DR. PELIAS:  Just one further question, are 

              5     these all in mammalian models? 

              6               MR. JORDAN:  The teratogenicity studies and 

              7     the reproductive toxicity studies and the developmental 

              8     neurotoxicities are all in mammalian species.  We do 

              9     have wildlife studies in both fish and aquatic 

             10     invertebrate and bird.  Thank you.  

             11               And the mammalian -- the mutagenicity studies 

             12     are in a range of systems some of which are mammalian 

             13     systems and others of which are not.  

             14               CHAIRPERSON MARSHALL:  Judy, and then we'll 

             15     open the floor. 

             16               DR. SIEGEL:  I think my question may have 

             17     been dealt with.  I also, from reading documents was 

             18     under the impression that although you didn't ask for 

             19     these studies they did, in some cases affect 

             20     regulation.  And so I guess my comment would be the 

             21     same as Margaret's at this point.  Is there -- you say 

             22     you won't look at it, but that doesn't discourage them 

             23     being done.  I think that that's clear which may not be 

             24     your issue, but may. 

             25               And then, again, the other questions that I 
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              1     was going to bring up really have to do with -- which I 

              2     think probably aren't appropriate -- when you do start 

              3     using these kinds of studies, what is the 

              4     predictability and the generalizability of these kinds 

              5     of results.  But if you're not using it, that's not the 

              6     issue.  I think more the issue is, are we actually 

              7     talking about regulating and non-regulated industry? 

              8               MR. JORDAN:  To be fair, I want to say that 

              9     prior to 1998, in some cases EPA has used human studies 

             10     as the basis for regulatory decisions, since 1998 we 

             11     have not done so.  I believe the article that I read 

             12     indicated that after '98 we had done so.  And that's 

             13     not correct.  

             14               CHAIRPERSON MARSHALL:  Thank you.  

             15               Any of our ex-officio or public members have 

             16     questions at this point?  Oh, yes, Sandy.  

             17               Please step up to the mikes if you would like 

             18     for us to hear from you. 

             19               DR. CHODOSH:  So far we have been hearing 

             20     about testing individual pesticides, but it's pretty 

             21     well-known now that we are being bombarded by a 

             22     multiplicity of all kinds of chemicals in our drinking 

             23     water, et cetera, et cetera.  Have any of the studies 

             24     been required to look at the effects of a pesticide or 

             25     a new agent in relationship to others that are now in 
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              1     our environment? 

              2               MR. JORDAN:  Generally speaking, no.  There 

              3     are research academic work being done by researchers 

              4     which do look at chemical substances in combination.  

              5     And whenever we are aware of such data we will 

              6     certainly look at it.  One thing though that does speak 

              7     to the concern that you raise it that the Food Quality 

              8     Protection Act directs EPA to, when we're regulating 

              9     pesticides, to take into account substances that share 

             10     a common mechanism of toxicity.  And, in fact, we have 

             11     just completed in this past December a cumulative risk 

             12     assessment looking at 39 different organophosphate 

             13     substances together where all of those chemical affect 

             14     colon estrace inhibition, cause colon estrace 

             15     inhibition and we have prepared an assessment that 

             16     takes into account the exposure that people get as a 

             17     consequence of eating food and potentially consuming 

             18     residues of all of those different substances as well 

             19     as the residues that might be present in drinking 

             20     water, as well as the residues that we might encounter 

             21     on golf courses, or as a result of spraying a cockroach 

             22     control agent or something like that. 

             23               It's something that, to summarize, took us 

             24     3,000 pages.  And the charts and graphs and data sets 

             25     behind it are, you know, sort of an order of magnitude 
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              1     almost greater than that.  It's something that took 

              2     years to produce and we're pretty proud of it.  And 

              3     it's a start. 

              4               CHAIRPERSON MARSHALL:  Elliot. 

              5               DR. DORFF:  Given the amount of food that 

              6     comes into that is country from abroad, does EPA deal 

              7     at all with pesticides on food that comes from abroad? 

              8               MR. JORDAN:  We do.  The food that is 

              9     imported in the United States and the food that is 

             10     grown domestically are subject to the same safety 

             11     standards.  The tolerances that EPA established apply 

             12     equally to both imports and domestically grown food. 

             13               The Food and Drug Administration maintains a 

             14     sampling program.  It's weighted more heavily toward 

             15     sampling imports than it is domestic foods.  By and 

             16     large both domestic and imported food have a relatively 

             17     low violation rate, although imports are somewhat 

             18     higher than domestic food.  And then that is 

             19     supplemented with a monitoring program that the 

             20     Department of Agriculture, U.S. Department of 

             21     Agriculture maintains that looks both at domestic and 

             22     imported foods.  

             23               CHAIRPERSON MARSHALL:  Mark. 

             24               MR. BARNES:  What occurs to me is that there 

             25     may be a category of sort of human subjects type 
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              1     research that sort of maybe is not contemplated by the 

              2     post-1998 practice.  And that is, if I were -- I mean, 

              3     just thinking about what I've learned today in looking 

              4     at this and listening to you talk. 

              5               If I were a pesticide company, and I knew 

              6     that EPA was not going to use the deliberate dosage 

              7     studies in approval, then what I would probably do is I 

              8     would go to a developing country and I welcome simply 

              9     give out my pesticide to be used there and then as 

             10     people wanted, and since it was free, I presume people 

             11     would use it, and then I would do population-based 

             12     studies to see what the toxicity would be based on the 

             13     use that was reported.  And then I would write that up 

             14     and I would give it to you because I would say that was 

             15     not deliberate dosing.  And so my question is, would -- 

             16     I mean, that kind of study would you -- how would you 

             17     treat that?  And I don't mean to be pejorative about 

             18     the pesticide industry, I'm just trying to -- I mean, 

             19     I'm a layer, so I think of where the loopholes are.  So 

             20     --  

             21               [Laughter.]  

             22               MR. JORDAN:  I don't know.  It certainly 

             23     raises a lot of troubling questions.  I am happy to say 

             24     that we haven't had that circumstance arise, and for a 

             25     variety of reasons I hope we don't. 
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              1               CHAIRPERSON MARSHALL:  I have a question, and 

              2     that is, you may not know the answer at this point, but 

              3     do you have a sense of time frame for the National 

              4     Academy Committee's work? 

              5               MR. JORDAN:  Preliminary discussions 

              6     indicated they would be done sometime summer of next 

              7     year and we asked if they could move somewhat more 

              8     expeditiously.  And we are in the course of discussing 

              9     that further with them. 

             10               CHAIRPERSON MARSHALL:  Thank you.  

             11               Any further questions?   

             12               [No response.]  

             13               CHAIRPERSON MARSHALL:  Then we will move on 

             14     to our panel and Mr. Jordan, thank you so much for 

             15     being here.  It was just a wonderful presentation.  

             16     Really appreciate it. 

             17               [Applause.]  

             18               CHAIRPERSON MARSHALL:  So I'm going to ask 

             19     the members of the panel if they would just come 

             20     forward and we're going to shuffle some chairs and 

             21     proceed right along. 

             22               [Pause.]  

             23               CHAIRPERSON MARSHALL:  So thank you, panel 

             24     members.  We're going to move right along.   We've 

             25     tried to provide balance in terms of overview and 
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              1     perspective and I think we have a wonderful panel. 

              2               We will begin with Richard Wiles how is 

              3     Senior Vice President of the Environmental Working 

              4     Group.  He will for example followed by Howard Sandler 

              5     who is President of Sandler Occupational Medicine 

              6     Associates and I think not directly associated with 

              7     CropLife America, I think that's -- yes.  

              8               DR. SANDLER:  No relationship with them. 

              9               CHAIRPERSON MARSHALL:  Right.  Thank you.  So 

             10     that is an error of ours. 

             11               And then Russell Katz who is director of 

             12     Neuropharmacologic Drugs Products, Center for Drug 

             13     Evaluation and Research the Food and Drug 

             14     Administration. 

             15               So, gentlemen, thank you all for being here 

             16     with us today.  And, Mr. Wiles, you're up. 

             17               MR. WILES:  Thank you, Mary Faith. 

             18               I'll try to make this a little bit direct and 

             19     maybe exciting and hopefully I won't be too unethical 

             20     or make anybody too mad, but this may be my last 

             21     chance.  It's my first chance in front of one of these 

             22     kinds of committees, so I want to get our view out 

             23     there clearly.  I want to talk about human subject 

             24     research in reality as opposed to sort of the theory of 

             25     human subject research which is where we tend to get 
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              1     bogged down in these arguments with EPA. 

              2               The distinction is critical because EWG and 

              3     other environmental groups could potentially support 

              4     some limited types of human studies -- emphasis on 

              5     "limited" -- with pollutants and pesticides in some 

              6     sort of a fantasy world that doesn't exit.  But 

              7     unfortunately, we don't live in that world and since 

              8     we're stuck in the real world, we are opposed to all 

              9     direct dosing studies on humans for all pollutants and 

             10     pesticides.  

             11               Having said that, we are very much in favor 

             12     of what you would call "biomonitoring studies"; 

             13     monitoring the population for their exposure to these 

             14     things on the market, passive dosimetry for workers and 

             15     those kind of things.  Obviously we're not opposed to 

             16     that.  We are opposed to direct dosing. 

             17               I'm going to talk about pesticides, but I 

             18     also will include chemicals and pollutants generally in 

             19     the argument as well.  Pesticides, pollutants and 

             20     chemicals have to be considered in a fundamentally 

             21     different light than medicines and other substances 

             22     where human subject research is involved for a number 

             23     of reasons. 

             24               First, these compounds are either designed to 

             25     be toxic as with pesticides or they are the unwanted 
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              1     byproducts of industrial processes.  They do not 

              2     provide direct benefits to the individuals who are 

              3     subject to the trials, to the studies that they're in. 

              4               And, importantly, as Bill Jordan mentioned, 

              5     but I'm going to say it again, human studies are not 

              6     required to get a pesticide on the market, or to get an 

              7     industrial chemical on the market.  They are not 

              8     required and they never have been required.  They've 

              9     been thrown over the transom, but they have not been 

             10     required.  

             11               They principally have been submitted in an 

             12     effort to erode safety margins that have been attached 

             13     to animal studies, and I'll get to that later. 

             14               At the same time, unlike medicines, for 

             15     example, a medicine, say that hasn't been approved for 

             16     the market, there is a widespread ongoing human 

             17     exposure to all these chemicals which we think makes 

             18     the case for biomonitoring as opposed to more direct 

             19     dosing studies. 

             20               There are estimates that we're all exposed to 

             21     about 500 pesticides and industrial chemicals in our 

             22     bodies today.  We don't know the number or the levels 

             23     of the health effects of these compounds on us mostly 

             24     because the industry that wants to do these direct 

             25     dosing studies has actively worked to make sure that 
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              1     tests to monitor the population exposure to the 

              2     chemicals currently on the market are not done.  They 

              3     are not required by law and they're not volunteering to 

              4     do these studies. 

              5               Now some background.  Bill gave a little bit 

              6     on the FQPA, Food Quality and Protection Act, and the 

              7     new standards they put in place to protect children. 

              8               The critical point here is that it required 

              9     an additional tenfold margin of safety attached to the 

             10     animal NOAEL unless the agency had explicit data to 

             11     support not doing that.  The agency has not 

             12     consistently followed the law in our view on that.  But 

             13     they have applied the tenfold sometimes and other times 

             14     they have not applied the tenfold.  But in any event, 

             15     the industry saw this as potentially a big problem. 

             16               In 1998, we investigated this issue and 

             17     produced a report called "The English Patients" -- 

             18     which you seen at least a part of -- and came to three 

             19     basic conclusions:  One, that EPA was routinely using 

             20     human data to establish safety standards at that time. 

             21     That's 1998. 

             22                Since then Bill, I presume, is correct, or 

             23     I'll have to take his word for it, I won't challenge 

             24     him today as to whether or not they've set standards 

             25     based on human data.  We know that we've seen internal 
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              1     memos since '98 where staff had recommended that safety 

              2     margins be rolled back based on human data.  Whether or 

              3     not that translated into a final regulation I'll have 

              4     to take Bill's word for it.  

              5               EPA had no policy governing the ethics or 

              6     scientific protocols of studies involving human 

              7     subjects that were not -- that were conducted 

              8     independently and submitted to the Agency.  And that's 

              9     the problem they still face today is that these 

             10     contractor studies are sort of out there with limited 

             11     control. 

             12               But most importantly, the industry had 

             13     developed an explicit plan to increase the volume of 

             14     human tests, the number of human studies they were 

             15     going to do as a strategy to avoid stricter regulation 

             16     under the Food Quality Protection Act.  But I'm not 

             17     going to ask you to believe me when I say that.  I will 

             18     read you from this document which is prepared for the 

             19     chemical industry, the pesticide industry, in 

             20     particular, and they say, they're talking about 

             21     implementing strategies to implement the Food Quality 

             22     Protection Act: 

             23               "Registrants" -- that's manufacturers of 

             24               pesticides -- "will find it increasingly 

             25               undesirable to rely on endpoints derived from 
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              1               animal data since this customarily requires 

              2               the application of a tenfold uncertainty 

              3               factor to account for interspecies variation. 

              4                For this reason there probably will be an 

              5               increased reliance by registrants on data 

              6               from human studies on acute or short-term 

              7               toxicity of organophosphates in this case 

              8               that could avoid the need for that tenfold 

              9               uncertainty factor from interspecies 

             10               extrapolation." 

             11               That may not be enough to convince you, but 

             12     here is Jay Vroom, the top lobbyist, head of the 

             13     Agricultural -- oh, wait, it's not called that, it's 

             14     called Croplife America, and he says in the Washington 

             15     Post in November of last year, "Testing pesticides in 

             16     people," Vroom said, "allows companies to show the 

             17     agency that humans can safely receive higher doses." 

             18               So it's clear why they're doing this.  

             19               We look at this for human testing in terms of 

             20     sort of an ethical hierarchy.  The question for us is 

             21     what are the most unethical practices in place and what 

             22     do we need to do to fix them, and overall what do we 

             23     need to do and what's the most pressing need in terms 

             24     of pesticide regulation to improve pesticide and 

             25     chemical safety?  So I've identified three that I'll 
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              1     throw out for you today, three particularly unethical 

              2     situations.  

              3               One, it should be for the chemical industry 

              4     as a whole where they basically have not tested or 

              5     there's very haphazard testing, no requirements for 

              6     thorough health and safety testing for commercial 

              7     chemicals, not pesticides, before they go on the 

              8     market.  So we walk around with them in our bodies, but 

              9     they're not very well tested.  That doesn't apply to 

             10     pesticides which are well tested by the same companies. 

             11               For the pesticide industry, the biggest -- 

             12     one of the biggest ethical concerns with us is their 

             13     resistance to this additional tenfold safety factor 

             14     required by law, the Food Quality Protection Act, and 

             15     in particular its opposition to the -- its explicit use 

             16     of human studies and the strategies to subvert that 

             17     extra tenfold factor. 

             18               And the broader thing that gets back to 

             19     biomonitoring is the fact that the pesticide and 

             20     chemical industry is exposing all of us on a daily 

             21     basis to pesticides and has refused systematically to 

             22     monitor the population in a statistically valid way to 

             23     find out where those exposures are, or if there's any 

             24     reason to be concerned.  And they have specifically not 

             25     been very cooperative with the Centers for Disease 
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              1     Control, or let's just put it this way, I wouldn't say 

              2     they haven't been cooperative, they don't volunteer a 

              3     lot.  They're probably cooperative when asked, but 

              4     they're not out there volunteering to give the 

              5     analytical methods for some of these pretty complicated 

              6     pesticides to the CDC so that they can look in the 

              7     blood samples and see if they're there or not.  So we 

              8     don't know. 

              9               Instead, we want to do direct dosing studies. 

             10               So in order to sanction a practice like human 

             11     subject research, we would argue that you need to show 

             12     that the human testing will directly address the 

             13     ethical shortcoming or the public health problem that's 

             14     caused by the industry in the first place.  If we're 

             15     going to do these studies, they ought to be advancing 

             16     some public health goal which we don't support the 

             17     studies, but at least they ought to make that 

             18     justification.  There is no way they can say that they 

             19     would do that.  Remember, this is not about finding 

             20     medicines to cure a disease.  I mean, it's not about 

             21     improving the ethics or the practice of the studies, 

             22     and it's not about getting the pesticide on the market. 

             23      It's specifically about undercutting the safety 

             24     margins. 

             25               So let's talk a little bit about the science. 
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              1     Our position basically is that these human studies are 

              2     bad science and bad science is inherently unethical. 

              3               First, there's no protocols for the conduct 

              4     of these studies which is pretty outrageous considering 

              5     that there are probably more than 100 studies required 

              6     to put a pesticide on the market and the protocols for 

              7     these animal studies have been peer reviewed and 

              8     publicly reviewed ad nauseam.  But when it comes to 

              9     human studies, there are no protocols at all, or let's 

             10     just say that they're ad hoc.  You can't find them 

             11     anywhere if you went to look for them as a member of 

             12     the public.  

             13               Second is the sample size issue that was 

             14     touched on earlier.  A lot of these studies had -- one 

             15     of my favorites was the human study on prisoners at the 

             16     Clinton Correctional Facility in Albany, New York that 

             17     was done in 1972 for Dow Chemical.  That study had 16 

             18     people, four controls, four per dose group.  It 

             19     supported the safety standard for a chemical called 

             20     cloroperofos [ph] it was the most widely used indoor -- 

             21     and it was the most widely used insecticide on the 

             22     market until it was finally banned -- based on dose 

             23     groups of four adult male prisoners extrapolated to the 

             24     entire U.S. population. 

             25               Now they've gotten these sample sizes up to 
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              1     maybe 20 or 30 per dose group which is still pretty 

              2     laughable if you're going to extrapolate out to a 

              3     population of 200-some-odd million that would be 

              4     exposed. 

              5               These small sample sizes have not stopped EPA 

              6     from looking at these studies.  Now, they look at them 

              7     and they do sort of a dance where they don't pay 

              8     attention to it.  They look at it, but they don't count 

              9     it.  You know, and it's very difficult for us in the 

             10     absence of a clear prohibition or a clear set of 

             11     procedures to know what they're doing when they're 

             12     looking at them.  That's why we do feel that if EPA did 

             13     have a formal policy that they would never, under any 

             14     circumstance use these that would stop industry from 

             15     doing them. 

             16               Third, federal pesticide law requires that 

             17     all pesticides in food be proven safe for the fetus and 

             18     infant.  That is the clear requirement of the law. 

             19               Human studies on adults don't produce data 

             20     that's valid to make a conclusion about the safety of a 

             21     pesticide for the fetus or the infant.  Indeed, they 

             22     may well provide you with an illusion of safety that 

             23     could lead to a dangerous relaxation of health 

             24     protections based on data derived from human adults in 

             25     small sample sizes than apply to the fetus.  That's 
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              1     exactly what industry is proposing.  They wouldn't say 

              2     that, but got mad at me when I say that, but that's 

              3     what they're doing. 

              4               Realistically, the last of these two problems 

              5     with human studies can never be fixed which means that 

              6     the studies will forever be bad science and therefore 

              7     forever be unethical.  Sample sizes of a thousand or 

              8     more in human studies, I hope, will never be reached.  

              9     And until you get to that size, you don't have any 

             10     power to extrapolate and find an effect that might 

             11     occur, let's say, in 1 percent of the population which 

             12     would actually be a pretty big effect.  If it's less 

             13     than that, you've got to go even higher and you just -- 

             14     hopefully we won't have these human studies done with 2 

             15     or 3,000 people in them.  And hopefully pesticides will 

             16     never be tested directly on the infants or the fetus.  

             17     Okay.  And that is the federally required target 

             18     population that has to be protected by law.  Okay.  So 

             19     hopefully we won't be doing the test inappropriate for 

             20     that on people. 

             21               That's the science questions.  The studies 

             22     are ethically challenged as well. 

             23               There is no application of the Common Rule to 

             24     research conducted by contractors and then submitted to 

             25     EPA.  So virtually all human subject research on 
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              1     pesticides is conducted by contractors and therefore 

              2     it's not subject to any rule.  There is this 

              3     prohibition in FIFRA that says you have to basically be 

              4     a nice person and you can't have people in these tests 

              5     that aren't volunteering to be in there.  But most 

              6     people that are in the studies that we've seen were 

              7     paid some pretty significant sums.  So I don't know if 

              8     that's volunteering to be paid to be in the study of if 

              9     thy's volunteering.  But in any event, I would argue, 

             10     or at least you should see that whether or not that 

             11     FIFRA requirement is as tough as the Common Rule.  

             12     Maybe it is, but I doubt it. 

             13               Second, there's no direct benefits to the 

             14     participants in pesticide and pollutant direct dosing 

             15     studies which violates a basic rule of all medical 

             16     human subject research.  It's particularly ironic given 

             17     the fact that industry is refusing to conduct 

             18     statistically valid biomonitoring for their products in 

             19     the population, yet they want to dose people up in 

             20     these studies. 

             21               Third, human studies can only be used to 

             22     weaken health standards and to erode safety margins 

             23     that would be required by animal studies. 

             24               Now, that's sort of a sweeping statement.  I 

             25     want to say it again because the industry won't like 
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              1     this one either.  But, I will argue that these studies, 

              2     in fact, only can be used to weaken standards.  And 

              3     that you would have to find such an outrageous 

              4     difference in effect or toxicity in these studies that 

              5     would never happen, so there only could possibly be 

              6     done for the purpose of allowing more pesticide than 

              7     would be allowed by an animal study.  And by that I 

              8     mean, remember that we have this tenfold margin of 

              9     safety and the three tens that go into FQPA, they give 

             10     you a thousandfold margin of safety. 

             11               If industry does a NOAEL study involving 

             12     human subjects, unless the data show a compound to be 

             13     more than ten times more toxic than the animal data the 

             14     standards won't be tightened because regulators in the 

             15     industry will argue that the current margins of safety 

             16     already account for that difference.  So even though 

             17     the human study showed that it was more toxic, we'll 

             18     just leave the standards the same. 

             19               On the other hand, if a study, say of 30 

             20     people, shows less toxicity, EPA is not very likely to 

             21     -- oh, EPA is, excuse me, all to eager to relax 

             22     standards.  And I do have one piece of paper that sort 

             23     of contradicts what Bill said, and this is from 1999, 

             24     where the agency concluded that they could apply a 

             25     threefold safety factor instead of a tenfold safety 
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              1     factor based on plasma colon estrace inhibition in dogs 

              2     and humans from a 21-day human toxicity study.  So this 

              3     may not have made it to regulation, but this was 1999. 

              4      And they are, in fact, using these very limited 

              5     studies to erode safety standards.  So it's just 

              6     extremely unlikely, and I would argue, almost 

              7     impossible for human data to produce results that will 

              8     strengthen standards. 

              9               Now, industry will rebut this and say that 

             10     one-third of the studies that they have done have shown 

             11     that the pesticide was more toxic than the animal data 

             12     showed.  And that may be true, but I'll challenge them 

             13     to find one case where that finding was then translated 

             14     into a tougher standard in the marketplace, a 

             15     restriction in the marketplace for those pesticides 

             16     where the tolerance and the legally allowable level was 

             17     actually reduced on the basis of those studies.  There 

             18     may be a few, but I'd like to see them. 

             19               So, in summary, pesticide and chemical 

             20     companies are not doing these studies to get their 

             21     products on the market.  They're not required.   

             22     They're doing them to erode safety margins, apply to 

             23     animal data, and they're doing them in a way that's 

             24     completely invalid scientifically using data on adults 

             25     to erode safety margins that are specifically targeted 
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              1     protecting infants, fetus and children.  

              2               I could probably eliminate all this blather 

              3     here because I think you got the basic point. 

              4               Just to say one last thing is that we do 

              5     support biomonitoring.  And I want to really emphasize 

              6     that.  We would like to see comprehensive analysis 

              7     done, for example, on the blood that's gathered in the 

              8     Nhanes studies to really look and see what's detectable 

              9     in the human blood supply?  What about the kids in that 

             10     study?  Could we do real -- could we expand that survey 

             11     to include a better dietary profile and some exposure 

             12     estimates and then really check that blood for every 

             13     pesticide in the food supply and the chemicals likely 

             14     to be found there so we -- in those studies which have 

             15     3 or 4,000 people and are statistically designed to 

             16     inform agencies about decisions regarding nutrition and 

             17     other things, wouldn't it be a good place to look for 

             18     these chemicals to see what's actually ending up human 

             19     blood and urine and those kind of things.  And so we 

             20     would definitely support that.  

             21               What we are opposed to is this direct dosing 

             22     of these studies, especially for the purpose of eroding 

             23     safety margins. 

             24               CHAIRPERSON MARSHALL:  Thank you.  I think 

             25     what I'm going to do is hold questions until each of 
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              1     the presenters has made his remarks.  So thank you very 

              2     much. 

              3               Let's move on to Dr. Sandler. 

              4               DR. SANDLER:  Thank you.  I appreciate the 

              5     opportunity to be here today. 

              6               My name is Howard Sandler.  I'm a physician. 

              7      I specialize in occupational and environmental 

              8     medicine.  I served as a medical officer with the 

              9     National Institute for Occupational Safety and Health. 

             10      I've been an advisor to the U.S. EPA for their own 

             11     staff, safety and health.  I've worked with OSHA and 

             12     NIOSH and the Consumer Product Safety Commission.  I 

             13     spend a lot of my time designing and implementing and 

             14     looking at programs to keep workers and general 

             15     community residents safe and healthy.  I work with 

             16     government.  I work with industry, I work with labor.  

             17     I've worked with activist groups.  

             18               I'm from Long Island.  We know something 

             19     about safety problems now.  We also have a big problem 

             20     with mold in schools and some concerns about what is 

             21     risk and what isn't risk.  Science is not inherently 

             22     bad.  It's what you do, how you do science, and how you 

             23     use science that can be bad. 

             24               What types of rules do we make decisions on? 

             25      We made decisions using epidemiologic data.  We make 
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              1     it using animal data, we make it using in vitro studies 

              2     of all different types.  Dr. Bruce Ames started a lot 

              3     of wonderful work for a lot of people around this table 

              4     and probably in other places.  And all of this is good; 

              5     the more we know, the better off we are. 

              6               The first rule of medicine, what I was taught 

              7     at the University of Maryland was, do no harm.  The 

              8     head of internal medicine who was a principal author on 

              9     rickettsial diseases, Ted Woodward, was a big influence 

             10     in my life.  And, you know, he just said to me, said, 

             11     "Treat everybody like your mother and you'll be fine." 

             12      He never met my mother.  

             13               [Laughter.]  

             14               DR. SANDLER:  But, you know, it's good -- and 

             15     by the way, she lives down here and I'm going to be in 

             16     big trouble because I cannot get the time to go see 

             17     her.  

             18               [Laughter.]  

             19               DR. SANDLER:  But there's no good deed goes 

             20     unpunished; right?  

             21               There's nothing wrong with looking at 

             22     science.  I think the question becomes, what health 

             23     endpoints are we really looking at.  Are you going to 

             24     be doing reproductive effect studies on pregnant women 

             25     with pesticides?  I don't think so, or at least I hope 
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              1     not.  Are you going to be dosing children?  No, I don't 

              2     think so and I hope not.  Certainly my son, Adam 

              3     Sandler, unfortunately not the real one, but --  

              4               [Laughter.]  

              5               DR. SANDLER:  -- I wouldn't want in a study. 

              6      Although he may end up doing his own dose response 

              7     studies on other things.  

              8               [Laughter.]  

              9               DR. SANDLER:  The question really comes down 

             10     to, can you design studies that are looking at the 

             11     right health endpoints?  For example, very limited 

             12     things such as colon estrace inhibition to see if there 

             13     really are changes in various types of groups.  It may 

             14     be certain groups right now the studies are looking at 

             15     adult males that are "healthy."  And we all know the 

             16     problems from the healthy worker effect in various 

             17     types of epidemiologic studies. 

             18               We use skin patches or testing frequently to 

             19     determine if people have problems.  Chemical 

             20     sensitivity was mentioned here.  And the bottom line is 

             21     that there are many practitioners out there who are 

             22     exposing people to chemicals in what we call chamber 

             23     challenges. 

             24               Dr. John Sellner did it, before he passed 

             25     away, and many times in Denver, and people down in 
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              1     Texas are doing these types of "challenges," 

              2     quote/unquote.  Unfortunately many of those don't get 

              3     before human experimentation subject boards and other 

              4     entities that make sense.  

              5               I read through, and by the way, just so it's 

              6     clear why I'm here, I was asked by CropLife America to 

              7     review material and to provide an independent 

              8     assessment, hopefully underlining the word 

              9     "independent" and objective assessment of what I've 

             10     done through my career and what I think about this. 

             11               I think what you have to do is provide, you 

             12     know, the first thing, a good research effort with good 

             13     safeguards, make sure that there are appropriate 

             14     approval steps and people looking over shoulders, and 

             15     use the data when it makes sense.  It should be part of 

             16     a certain process and maybe very, very focused and 

             17     specific.  I don't think you should use human 

             18     experimentation to set LOAELs and NOAELs.  You may end 

             19     up using it to refine a specific point within that 

             20     process after the animal studies certainly give you 

             21     some range of safety there.  But I don't think it's 

             22     appropriate to use that to begin with and I don't think 

             23     it's legislatively a good idea, nor do I think it's 

             24     ever been proposed by anybody. 

             25               I guess the bottom line to what I'm saying is 
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              1     that the report I read from the SAB, SAP working group 

              2     brought a lot of good common sense and I think a lot of 

              3     appropriate reasoning to this issue.  I didn't find 

              4     fault.  I read the minority aspect, excuse me, the 

              5     minority report aspect and certainly those concerns 

              6     need to be considered.  But we do make those tradeoffs 

              7     all the time, keeping kids healthy and fit and fed is 

              8     an important thing.  At the same time making sure that 

              9     you have the ability to keep them fed means a safe 

             10     productive food growth. 

             11               How do you do that in all populations is a 

             12     very important thing. 

             13               The National Academy of Science, I've served 

             14     on a committee there.  They do good work.  I'm 

             15     convinced that they will take the appropriate analysis 

             16     steps and do what's important and safeguard our 

             17     children. 

             18               Thank you.  

             19               CHAIRPERSON MARSHALL:  Thank you very much.  

             20     I want to just interject that if there's anyone who has 

             21     joined us this afternoon who wasn't here this morning 

             22     and hasn't signed in to please do so during the break.  

             23               All right.  Dr. Katz. 

             24               DR. KATZ:  Thank you.  I have a few slides.  

             25     Okay.  The file is called Phase I.  There's a few files 
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              1     on there. 

              2               Let me just say it's a pleasure to be here.  

              3     In particular it's a great pleasure not to be a party 

              4     to this particular controversy. 

              5               [Laughter.]  

              6               DR. KATZ:  It's a rare appearance by an FDA 

              7     person when we're not the center of a controversy or in 

              8     the cross hairs.  So I appreciate that very much. 

              9               I've been asked to speak about how we think 

             10     about introducing potential toxins, that is to say, 

             11     investigational drugs into human beings.  So I'm going 

             12     to talk about this issue in a generic way.  It's 

             13     something that we deal with every day and so some folks 

             14     thought that it might be useful to bring that sort of 

             15     experience to bear on this particular issue. 

             16               So, if I could -- let me just also issue a 

             17     sort of a mini-disclaimer, I'll be giving you one 

             18     division director's point of view about these issues.  

             19     We have rules that are subject to interpretation so 

             20     everybody interprets them a little differently.  I'm 

             21     going to give you sort of a general view of how we 

             22     interpret the rules in our division. 

             23               So if I could have the first side, please. 

             24               This is the first slide, but it doesn't 

             25     really say very much.   So could I have the second 
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              1     slide. 

              2               Okay.  I think there's a basic premise that 

              3     underlies drug development, at least as I understand 

              4     and that would be something along the lines of, we view 

              5     all investigational drugs to be worthless, that is to 

              6     say, ineffective and dangerous until proven otherwise. 

              7      And so in some sense all proposed investigational drug 

              8     treatments can actually be considered potential toxins 

              9     and nothing else. 

             10               Obviously somebody thinks that these things 

             11     are going to be useful at some point, in particular the 

             12     pharmaceutical sponsor.  But we know from experience 

             13     that lots of them don't make it either because they 

             14     just turn out not to work or not to be safe as we 

             15     understand the term.  And so at the beginning certainly 

             16     we know nothing about human response to it either from 

             17     the point of view of effectiveness and safety, so we 

             18     really consider them all potential toxins and perhaps 

             19     nothing else at the outset of the introduction of these 

             20     things to people. 

             21               And so the onus is on the sponsor to 

             22     establish that the drug -- the potential drug is safe 

             23     and will be effective for the indication that they're 

             24     going for.  

             25               By the way, everything we deal with, all the 
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              1     regulations I'm going to talk about and certainly the 

              2     statute under which we work, and you've heard about the 

              3     Food, Drug and Cosmetic Act, these rules, these 

              4     regulations apply to investigational drugs and the drug 

              5     is defined in the Act as a substance that's designed to 

              6     affect the structure or the function of the body or 

              7     treat disease or diagnose.  So somebody must think that 

              8     ultimately there is some use for these substances.  

              9               The next slide. 

             10               Okay.  So I said that the sponsor has to 

             11     adduce evidence that the drug is safe and effective.  

             12     And, again, I'm going to be mostly talking about what 

             13     we call "phase one" experience, that is to say the 

             14     initial introduction of an investigational drug into 

             15     people.  

             16               So the first thing we require is relatively 

             17     detailed information about the chemistry and the 

             18     manufacturing. In other words, what is the product?  Is 

             19     it what the sponsor says it is?  In other words, if 

             20     it's supposed to be 100 milligrams, is it 100 

             21     milligrams.  Of course, there's room for slight 

             22     variation, but is it in fact what the sponsor says it 

             23     is?  Is it pretty much within fairly rigorous standards 

             24     the amount that they say it should be. 

             25               Every drug has impurities, indegradance, some 
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              1     are built -- some occur as a result of the 

              2     manufacturing process and some are compounds that occur 

              3     over time as the product is left to stand, and there 

              4     are relatively strict rules about how much impurities 

              5     and degradance could be in a product.  So if it reaches 

              6     a certain threshold we require animal studies to 

              7     investigate the safety of these things. 

              8               If a product is a parenteral, in particular, 

              9     if it's an injectable product, there are fairly strict 

             10     standards that are imposed to determine that the 

             11     product is sterile and stability.  In other words, will 

             12     the product stay potent over time, particularly with 

             13     regard to how long the proposed human study is.  Do 

             14     impurities and degradance increase over time?  If they 

             15     do, that's a particular problem that needs to be 

             16     investigated further.  But we want to know that at 

             17     least the product is stable for the period of time that 

             18     humans are to be exposed.  And in particular, has it 

             19     been stable over the course of time that the animal 

             20     studies have been -- for the duration of the animal 

             21     studies that have been performed. 

             22               If I could have the next slide. 

             23               Okay.  So there's the manufacturing 

             24     information that's very important.  The other main type 

             25     of information that we require before drugs are 
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              1     introduced in humans is animal testing.  And there's a 

              2     general, I would say, overarching principal that is 

              3     applied to animal testing to determine whether or not 

              4     it's appropriate to support what the sponsor wants to 

              5     do in humans.  And that is that usually two species, 

              6     rodents and non-rodents should receive greater 

              7     exposures than humans are supposed to receive for 

              8     longer durations, to be an appropriate route and 

              9     regimen. 

             10               That is to say, if humans are going to 

             11     receive an IV folie, animals should receive an IV 

             12     folie.  If humans are going to receive a slow infusion, 

             13     animals should receive a slow infusion.  And the idea 

             14     here is to stress the system in terms of the greater 

             15     exposure and the longer durations to see what exactly 

             16     the drug is capable of doing, at least in animals.  

             17     Animals aren't, of course, perfect models at all for 

             18     what happens to humans.  But certainly we believe 

             19     they're the best we have. 

             20               And, again, the greater exposure, the longer 

             21     durations association make up for the fact that we 

             22     usually don't have very many animals in a particular 

             23     study.  That varies according to species, but certainly 

             24     nowhere near as many animals as you ultimately will 

             25     have humans exposed. 
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              1               If I could have the next slide.  All right.  

              2     Some more information about the animal studies.  The 

              3     first on here speaks to probably the critical factor in 

              4     animal studies.  That is to say there should always be 

              5     a linkage between the animal studies and the proposed 

              6     human studies.  That means that in particular the 

              7     duration of animal studies should always be at least as 

              8     long as human studies.  This is true up to a point. 

              9               Before a drug is ultimately approved, usually 

             10     we have several years' worth of data, at least in a few 

             11     patients.  Certainly we have relatively long-term 

             12     exposure, assuming it's a drug to be administered 

             13     chronically.  Animals don't have to be exposed for many 

             14     years for typical toxicity.  It's usually six months in 

             15     a rodent and up to nine months or 12 months in a non-

             16     rodent.  So there are limits for the duration of 

             17     animals.  But nonetheless, the animals, as drug 

             18     development is progressing and human exposure is 

             19     increasing, the animals need to always be one step 

             20     ahead of the humans, as it were.  

             21               Typically the initial proposed human studies 

             22     are single-dose studies, usually in healthy adult 

             23     volunteers, it depends on what the indication is, of 

             24     course, and to support those sorts of studies, the 

             25     typical animal studies are usually about two weeks.  
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              1     They can, by policy, be one single dose in animals if 

              2     only a single does is proposed in humans.  But 

              3     invariably sponsors will submit studies in animals of 

              4     at least two weeks duration at the outset.  Because 

              5     they're going to want to progress fairly rapidly into 

              6     multiple dose studies in humans. 

              7               So in addition there needs to be some, at 

              8     least beginning assessment of the genotoxic potential 

              9     in in vitro and in vivo studies with an eye towards 

             10     giving us an idea about potential carcinogenicity 

             11     although carcinogenicity studies in a formal way in 

             12     animals are usually completed fairly late in the 

             13     development of the drug.  

             14               If I could have the next slide. 

             15               More about animal studies.  Again, just to 

             16     give you some general form, the animal studies usually 

             17     evaluate three doses or so-called low, middle, and high 

             18     dose.  These doses are presumably determined on the 

             19     basis of dose finding studies in animals, what can they 

             20     tolerate, this sort of thing.  There's a couple 

             21     purposes to the animal or a couple aspects of animal 

             22     studies that are critical.  One is that a maximally 

             23     tolerated dose should be achieved in animals. 

             24               That is to say, again, under the heading of 

             25     stressing the system, we should give a dose to animals 
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              1     beyond which they could not tolerate to really get a 

              2     sense of, again, what's tolerated.  And these studies 

              3     all involve detailed histopathological examination of 

              4     essentially all tissues in the animals at all doses.  

              5     The idea here is to identify what, in fact, is the drug 

              6     capable of doing from a toxicity point of view, the 

              7     whole point being to give us an idea of at least where 

              8     to start to be looking in people. 

              9               It's also useful for a sponsor to detect no 

             10     effect level when you've heard something about that 

             11     already.  And the "no effect" level could be defined in 

             12     many different ways.  Either it could be a level below 

             13     which there is no minimal behavioral alterations or 

             14     histopathological alterations.  Again, there is no 

             15     absolute rule for what is a no effect level or for that 

             16     matter what is a maximally tolerated level. 

             17               Sometimes you can't reach a maximally 

             18     tolerated level.  The drug is so benign that animals 

             19     tolerate whatever you can give them.  In that case, 

             20     usually what we would require a sponsor to do is to 

             21     give what's called the maximum feasible dose.  That is 

             22     to say, sometimes you just can't get more in from a 

             23     physical point of view, the animal stomachs won't 

             24     tolerate it.  Well, you can't create an intravenous 

             25     solution concentrated enough to get in as much as would 
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              1     be necessary to induce toxicity.  So that would be 

              2     called the maximum feasible dose and that, you can only 

              3     do what you can do.  So that's, if not a maximally 

              4     tolerated dose, a maximal feasible does. 

              5               It's also very important to -- for us to know 

              6     that in fact for an oral drug that it actually is the 

              7     -- the animal is being exposed to it.  It is possible 

              8     you could give lots of drug and the animal doesn't 

              9     absorb it through the intestine.  So we like to have 

             10     some confirmation that in fact, as you increase the 

             11     dose of the drug, you actually are increasing the 

             12     exposure in the plasma or in the tissues. 

             13               If I could have the next slide. 

             14               We've head a lot about margins.  We tend to 

             15     use a margin of about one-tenth to no effect level as a 

             16     starting dose in humans.  But certainly there's no rule 

             17     that says human exposure can only go up to X if animal 

             18     exposure has only been X.  You like there to be a 

             19     margin ultimately between what animals can tolerate and 

             20     where humans get in terms of total exposure.  But if 

             21     humans can tolerate the drug with some exception which 

             22     I'll talk about a little later, if humans seem to be 

             23     tolerating the drug, you can push them slowly beyond 

             24     even what animals have been exposed to assuming animals 

             25     have reached the maximally tolerated or feasible dose. 
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              1               Okay.  And here this is very important.  It's 

              2     becoming much more important to us in recent years.  As 

              3     soon as we can, we like to get detailed information 

              4     about what's actually circulating in the plasma of 

              5     animals, the parent drug, any metabolites, the time 

              6     course of when they reach their maximum concentration, 

              7     both of the parents and metabolites.  Are the 

              8     metabolites so-called "active" in various assays.  And 

              9     you want to find out in humans if these same chemical 

             10     species are circulating in the same sorts -- in 

             11     general, the same sorts of proportions because it might 

             12     be that humans produce a metabolite that doesn't exist 

             13     in the animals, or in the animal species that have been 

             14     studied.  In which case the animals have really not 

             15     been exposed to the circulating species that may 

             16     actually be toxic in humans, so you have to search for 

             17     another animal species to do the toxicity.  This is 

             18     very important to learn very early in the proceedings. 

             19               Anyway, that's an important aspect, the 

             20     animal studies. 

             21               If I could have the next slide. 

             22               Let's move to human studies.  As I say, these 

             23     rules apply to drugs which have an intention ultimately 

             24     to have some utility against a disease or as a 

             25     diagnostic, but it's well-accepted, I believe, that at 
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              1     least in phase one of the early stages of development 

              2     in humans, the subjects enrolled in the early studies 

              3     cannot and will not benefit from the treatment.  That's 

              4     because usually they are normal volunteers and they 

              5     have no problem from which drug can give them a 

              6     benefit.  And this is also true even in patients.  

              7     Because these studies are usually designed to look at 

              8     tolerability, single dose and ultimately multiple dose. 

              9      They reach steady state, but nonetheless they're not 

             10     designed to look at effectiveness. 

             11               So if a patient has alzheimer's disease or 

             12     epilepsy and the study is one dose or a week long, 

             13     there's no hope that that pay will benefit from the 

             14     treatment. 

             15               So, again, to go back to this point, phase 

             16     one in general, although one could start to look at 

             17     preliminary efficacy in phase one, but phase one in 

             18     general can really be seen as representing exposure to 

             19     nothing other than a pure potential toxin.  Even if 

             20     ultimately the drug is shown to be effective and safe 

             21     for patients for the particular indications, certainly 

             22     the subjects enrolled in these early studies are being 

             23     exposed to a toxin to them and nothing else.  So how 

             24     can we justify what are the safeguards that exist to 

             25     permit this to proceed. 
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              1               So if I could have the next slide, please. 

              2               And, again, I'm sure you know a lot, if not 

              3     all of this, certainly why do we give it to humans at 

              4     all?  Well, because in order to get a drug approved for 

              5     humans, it has to be studied in humans.  That's part of 

              6     the law and that's almost always true.  There might be 

              7     rare exceptions, but as a general policy, you have to 

              8     study it and approve it to be safe and effective in 

              9     humans if you want to market it.  So it ultimately has 

             10     to be studied in humans.  So we need to be able to do 

             11     this. 

             12               Well, of course, these phase one studies, and 

             13     all studies, obviously, are required informed consent 

             14     with certain elements which you all know about must be 

             15     obtained.  There has to be local IRB approval, of 

             16     course, as you know, and then we are obliged to review 

             17     these studies.  All human studies have to be submitted 

             18     to us before they may be undertaken. 

             19               It's a little known fact that for the most 

             20     part sponsors don't have to wait to hear what we think 

             21     about these studies before they're permitted to perform 

             22     the studies.  

             23               It's only in the very initial submission of 

             24     investigation of the drug application, the sponsor has 

             25     to wait for 30 days while we have to review the data, 
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              1     the previous human data, if there are any animal 

              2     studies and the protocol and decide whether or not they 

              3     can proceed.  Or, if they are permitted to proceed, all 

              4     subsequent protocols which must be submitted before 

              5     they are undertaken can be started the day they're 

              6     submitted.  They don't have to wait for the agency's 

              7     response. 

              8               Could I have the next slide? 

              9               Well, what does our review consist of?  Well, 

             10     many things.  But there are basically four reasons.  

             11     There are actually a few more, but there are four main 

             12     reasons why we can say, no, you may not do this study 

             13     that you're proposing.  What are they? 

             14               Well, one is that the investigator is 

             15     unqualified.  We almost never make use of this 

             16     criterion.  We have a list of investigators, for 

             17     example, who have been disqualified.  We check that 

             18     list when somebody submits the name of an investigator, 

             19     but one almost never finds the particular or the 

             20     proposed investigator on that list.  So we almost never 

             21     -- plus, if someone is a licensed physician in general, 

             22     we consider them qualified. 

             23               Well, another criteria that would result in a 

             24     study being placed on what we call clinical hold would 

             25     be that the investigator's brochure is misleading, 
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              1     erroneous, or materially incomplete.  The 

              2     investigator's brochure is a document produced by a 

              3     drug company, handed out to their investigators which 

              4     is supposed to have all the relevant animal and 

              5     previous human data, if there is any, information that 

              6     would permit the investigator to use the drug safely 

              7     and intelligently.  It's in a sense analogous to 

              8     product labeling for an investigational drug. 

              9               If it's misleading, if it's erroneous, if 

             10     it's promotional, and many of them are on first blush, 

             11     it can be a reason to prevent the study in and of 

             12     itself from proceeding.  And we have certainly used 

             13     this as a reason to place the study on clinical hold. 

             14               If I could have the next slide. 

             15               The other two reasons are the reasons that we 

             16     invariably do invoke when we do place a so-called 

             17     "clinical hold."  That is to say that subjects are 

             18     exposed to unreasonable and significant risk.  And, of 

             19     course, these are called in terms of art, these are 

             20     obvious subject to individual judgment as to whether or 

             21     not these thresholds have been met, but nonetheless, 

             22     for example, the typical thing might be that animals 

             23     experiencing sudden death, let's say at all doses, and 

             24     we have no explanation for it, we would say, well, 

             25     that's -- until a sponsor understands that a little 
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              1     better or there's some significant hematologic --  

              2               [Laughter.]  

              3               DR. KATZ:  -- well, you'd be surprised, some 

              4     people don't impose that.  But we take these things 

              5     very --  

              6               [Laughter.]  

              7               DR. KATZ:  -- we take these things fairly 

              8     seriously.  So that's the kind of thing we would say, 

              9     well, you can't do this until you learn more about it. 

             10      And sometimes these sorts of things can be explained 

             11     away. 

             12               For example, it can be shown that a 

             13     particular adverse event is due to a specific 

             14     metabolite that a specific species makes.  Ultimately, 

             15     and maybe most other species don't have this problem, 

             16     don't make a particular metabolite and ultimately if 

             17     humans are exposed we may see that in fact humans don't 

             18     make that metabolite.  So that's the sort of thing that 

             19     can get somebody out of it.  But that would be a 

             20     reason.  Or there's insufficient information to assess 

             21     the risk.  In other words, the sponsor hasn't done the 

             22     traditionally required animal studies, this sort of 

             23     thing. 

             24               Okay.  If I could have the next slide. 

             25               And as I mentioned before there is this 
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              1     linkage, we hope, between the animal studies and the 

              2     human studies and so as additional human studies 

              3     proceed or particularly longer duration, we ask for the 

              4     longer-duration animal studies to proceed them.  There 

              5     are additional -- if significant numbers of women of 

              6     childbearing potential are to be exposed, then we would 

              7     expect that the required animal studies looking at 

              8     reproductive function, teratogenic potential of the 

              9     drug are done before that particular population is 

             10     exposed. 

             11               Here, again, when I say "circulating species" 

             12     I'm going back to what I said before, that is to say, 

             13     once you learn in humans what the metabolic profile is 

             14     you want to make sure that the animals in which you 

             15     performed the toxicity studies have been exposed to 

             16     those particular circulating chemicals. 

             17               And, of course, as exposure -- as development 

             18     goes on, data that are occurring in humans obviously 

             19     has a critical influence of subsequent human studies 

             20     regardless of what the animal studies show.  So if the 

             21     animals are clean but the humans are experiencing some 

             22     particular adverse event at a particular dose, this 

             23     sort of thing obviously has a profound effect on the 

             24     next clinical studies that are proposed. 

             25               The next slide. 
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              1               And, again, of course, one can approve a drug 

              2     for marketing in this country if all you have is animal 

              3     data.  So really, obviously, human data are paramount. 

              4      It has to be shown to be a drug before it can be 

              5     approved, it has to be shown to be safe at the doses 

              6     proposed with the proposed labeling in humans.  That 

              7     makes sense, I think.  

              8               However, there -- even if humans appear to be 

              9     tolerating a drug relatively well, I think there are 

             10     places where the animal studies either completely 

             11     substitute for an absence of human data, at the time of 

             12     decision about marketing is made, or other 

             13     circumstances, and I'll talk about that. 

             14               Basically, for example, carcinogenicity 

             15     studies.  For most drugs to be administered 

             16     chronically, we require long-term animal 

             17     carcinogenicity studies.  We get no information in a 

             18     typical drug development program about whether or not 

             19     the drug is potentially carcinogenic in humans.  

             20     Usually you need many more patients to be exposed. 

             21               So we rely very heavily on a provisional 

             22     conclusion about whether or not a drug could be 

             23     carcinogenic in humans based entirely on animal 

             24     studies.  Similarly with reproductive toxicity or 

             25     teratogenicity.  That sort of data is not obtained in 
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              1     humans prior to marketing.  And sometimes even though 

              2     there may be other sorts of toxicities that we are 

              3     going to be very worried about at the time of approval 

              4     even if the humans seem to be free of any significant 

              5     toxicity sometimes you can see pathologic changes in 

              6     animals and in many species in animals and in doses or 

              7     exposure that humans will be seeing, the humans my look 

              8     fine, because you haven't looked appropriately. 

              9               We've had a number of examples where animals 

             10     have had lesions in the brain, the humans look fine 

             11     because we didn't really know how to monitor for these 

             12     potential lesions in humans and we've asked folks to 

             13     stop drug development to see if they could develop a 

             14     way to monitor for it in animals before other human 

             15     studies proceed.  So even safe passage in humans 

             16     doesn't necessarily imply that the drug is not toxic.  

             17     One has to know how to look for specific toxicities and 

             18     a lot of that is driven from the animal studies. 

             19               And I think that's it.  So I'll stop there.  

             20               CHAIRPERSON MARSHALL:  Thank you very much, 

             21     that was a wonderful overview. 

             22               Let's just go right into questions.  Mark. 

             23               MR. BARNES:  I have something rather 

             24     provocative to say.  So you'll excuse me, but I guess 

             25     that's our role. 
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              1               This is in regard to Richard Wiles's point 

              2     that he did not, in his remarks, that he did see that 

              3     if there were human studies that it was somehow 

              4     different from medical research studies because there 

              5     would not be an actual benefit to the participant in 

              6     the study.  And I simply am not convinced that that's 

              7     true.  

              8               I'm an old public health person, and, you 

              9     know, even though the benefit may not be personal, 

             10     immediate, and direct, there could in fact be an 

             11     attenuated benefit to everyone in society including, 

             12     but not limited to the participant in the research if 

             13     in fact there is scientific validity to human studies 

             14     and if the human studies lead tot approval of a 

             15     pesticide which greatly increases crop yields and 

             16     therefore increases profits of farmers and crop yields 

             17     in developing countries and feeds more children and 

             18     everything else.  So, I'm completely -- I have to tell 

             19     you, I'm completely unconvinced about -- I understand 

             20     that the models are not exactly the same, but there is 

             21     -- but, you know, there are population-wide benefits to 

             22     doing some things that may not be immediately apparent. 

             23               That leads me to the next point which is 

             24     that, you know, I have to tell you, I'm from a -- I've 

             25     said this before, but I'm from a farming family in a 
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              1     very gothic corner of Alabama.  And when I was a child 

              2     -- my family farmed this same farmland for a couple 

              3     hundred years, and when I was a child I spent the 

              4     summers with my great grandfather who is a farmer and 

              5     had sharecroppers who worked his land and he worked 

              6     some of his own land.  And I can tell you that every 

              7     year, you know, when July and August come around and 

              8     people start wondering what the crop yields and what's 

              9     going to happen with the cotton and the corn crop this 

             10     year. 

             11               I can tell you in my childhood I remember 

             12     people, you know, black men and white men standing 

             13     around talking about it and they would say, "Thank God 

             14     for Dow Chemical Company."  And, you know, the reason 

             15     is, is because their crop yield that year meant whether 

             16     -- you know, whether a bunch of poor kids were going to 

             17     have a new coat and new shoes and everything else or 

             18     not. 

             19               So that's all to say that, you know, that 

             20     there really are -- I don't know anything about the 

             21     scientific validity of human studies or not human 

             22     studies because I'm not a scientist.  But I can tell 

             23     you that there are direct benefits, and if there is 

             24     some scientific validity to these human studies, and I 

             25     presume there must be some because the -- you know, the 
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              1     pesticide industry presumably wouldn't have offered and 

              2     EPA wouldn't have accepted, you know, those studies as 

              3     some evidence of something unless there were some 

              4     scientific validity to it. 

              5               And, you know, I'm not convinced but that 

              6     there is not benefit and there is a hidden -- there's a 

              7     hidden side to this story, and I'm sorry industry is 

              8     not here to present it, although I guess that falls to 

              9     us to say industry's piece.  But, you know, there are 

             10     -- the hidden costs that we're trying to prevent here 

             11     is the cost of unwanted side effects in humans.  But 

             12     there is another hidden cost which is, if needed 

             13     pesticides are not approved, then we don't even know 

             14     what that cost is. 

             15               MR. WILES:  Well, there's no shortage of 

             16     pesticides out there.  And I agree with you, pesticides 

             17     are an important component of food production.  This is 

             18     not about taking pesticides off the market.  And there 

             19     is definitely no shortage of food, witness our $70 

             20     billion farm bill that just went to bail out farmers 

             21     who are overproducing to such an extent that prices are 

             22     at all-time lows.  So the starving children analysis -- 

             23     the starving child that will be saved by a human study, 

             24     I just don't think that that really is supported by the 

             25     actual data.  
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              1               I'm not saying that we don't need pesticides 

              2     and we're definitely not against pesticides.  We are 

              3     very much for pesticides when they're used safely and 

              4     regulated properly.  There's also, like I said, no 

              5     shortage of pesticides out there.  In fact, there's 

              6     never been a case, in spite of industry's hysteria to 

              7     the contrary, where the imminent collapse of the food 

              8     supply or even really any significant price increase at 

              9     the consumer level occurred when a pesticide was 

             10     canceled, setting aside human data. 

             11               Farmers have been impacted, that's true.  But 

             12     not nearly as much as the Farm Bureau and others will 

             13     tell you.  And I think it's very obvious that the 

             14     biggest impact and threat to farmers is not whether or 

             15     not they have pesticide X and human studies are not 

             16     going to really have anything to do with whether or not 

             17     they do have pesticide X.  So maybe there is some 

             18     benefit, I suppose, in a hypothetical scenario, but I 

             19     don't think that really has any real world impact. 

             20               As far as the benefits go, I guess what I'm 

             21     trying to say is that it's clear that a drug in theory 

             22     -- you're developing the drug with -- there's an 

             23     intended benefit to some people who are sick.  And sine 

             24     people will be taking the drug, you want to test it on 

             25     people.  This is much different -- what you are trying 
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              1     to do is grow food and kill insects and control weeds 

              2     and control fungi, and then in the end protect the 

              3     population from a small residual amount of a compound. 

              4      There has really never been a case when if the 

              5     industry had actually not opposed the safety standards 

              6     that are required by law, and all the safety standards 

              7     that are required by law have been applied, there 

              8     aren't very many cases when that happened, when full 

              9     safety standards were in effect where there were 

             10     significant human harm done.  Where you get into 

             11     problems is when industry is push to not apply the 

             12     safety standards that are required to be applied to the 

             13     animal data and you get chemicals on the market that 

             14     either have an incomplete database or where safety 

             15     margins have been eroded due to pressure from industry 

             16     like these human studies. 

             17               So, it is a very fundamentally different set 

             18     up here sort of trying to control pesticide exposures 

             19     to the lowest amount that you can possibly get while 

             20     you still have efficacy in pest control versus 

             21     determining a dose for a drug that's going to be 

             22     directly taken by people.  

             23               So we are sympathetic that farmers -- in 

             24     fact, the environmental working group is probably the 

             25     central group that works on farm policy in the United 
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              1     States and we have spent a lot of time trying to get 

              2     more money to more farmers in the past year.  So we are 

              3     well versed in this.  And I don't think that the human 

              4     study issue is really related to farmer profitability 

              5     or pesticide availability.  

              6               CHAIRPERSON MARSHALL:  Bob and then Elliot. 

              7               DR. R. LEVINE:  Thank you.  Mr. Wiles was 

              8     pretty thorough in his critique of the direct dosing 

              9     studies and I think he was quite accurate.  However, 

             10     one could equally critique the biomonitoring studies.  

             11     If you're going to just take the samples of blood, for 

             12     example, from the N. Hanes [ph] study and try to find 

             13     the correlation between one chemical out of the 500 to 

             14     1,000 that our population has been exposed to and try 

             15     to establish a significant correlation between the 

             16     presence of that chemical and any particular mutagenic 

             17     or teratogenic result, you're going to have to look at 

             18     even more subjects than they have in the N. Hanes 

             19     studies which is many, many millions.  

             20               I also want to comment briefly something 

             21     Rusty Katz said to extend it.  You pointed out that an 

             22     analogy is in phase one drug testing.  Much of the 

             23     criticism of testing pesticides in people is that 

             24     you're exposing people to risks where there's no 

             25     expectation of direct benefit to that person. 
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              1               In phase one oncology studies, not only are 

              2     you exposing people to risks, but I don't think most 

              3     people here know how they're done.  It's a dose 

              4     escalation design and you keep pushing the dose up 

              5     until two out of three patients get life-threatening 

              6     toxicity.  That we call the dose above the maximum 

              7     tolerated dose.  Then we drop back one dose level.  So 

              8     we are talking about very, very heavy risks where 

              9     there's similarly no -- virtually no possibility of 

             10     direct benefit. 

             11               In the study done at the National Cancer 

             12     Institute in 1,200-and-some-odd consecutive phase one 

             13     drug trial subjects in oncology they did find that 0.16 

             14     percent of them got a complete remission.  So I can't 

             15     say no possibility. 

             16               MR. WILES:  I'll go and then you can respond. 

             17      On the N. Hanes sample size business, we agree with 

             18     you.  I mean, I definitely agree, you're not going to 

             19     be able to do any real epidemiology or find any cause 

             20     and effect relationship between those things.  But 

             21     here's how bad the situation is why we need that.  

             22     Because the situation is so bad that we don't know 

             23     where the pesticides are or if they show up in people. 

             24      For example, EPA has no idea, really where these 

             25     pesticides end up after they go through all of these 
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              1     approvals.  And when they do find out, it often drives 

              2     regulatory decision-making.  What really got the 

              3     insecticide durigban chlorpurifos, the most widely used 

              4     indoor insecticide off the market were two things; one, 

              5     a developmental neurotoxicity study in rats that showed 

              6     delayed and persistent effects in rat morphology in the 

              7     brain that have never been seen before and we don't 

              8     want to do that on humans, I hope.  And also some 

              9     biomonitoring that showed that the metabolites of 

             10     durigban were in about 90 of school children and about 

             11     85 percent of the N. Hanes participants.  

             12               EPA had no idea that the exposure was that 

             13     prevalent.  They didn't make any dose calculations 

             14     based on that, but that was very important to know 

             15     that.  And if you don't have the -- a lot of these 

             16     pesticides are very complicate chemistry.  Some of them 

             17     are, we would even say a good chemistry because they're 

             18     specific, they're looking for a toxic mechanism in an 

             19     insect that may not exist in humans and all those kinds 

             20     of things.  But it makes them very difficult to find.  

             21     They're not picked up by your standard sort of OP, 

             22     nitrogen scans and those kind of things.  You really 

             23     need to know -- and you need to have industry basically 

             24     show you how to do it.  And they're not required to, 

             25     they don't volunteer it.  So when you get into these 
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              1     situations, the simple fact of knowing just what the 

              2     percentage of the population has this in the urine or 

              3     blood, very important information.  

              4               CHAIRPERSON MARSHALL:  Elliot. 

              5               DR. DORFF:  Two questions, one very specific 

              6     and one much moe general.  The specific thing is, part 

              7     of the way in which the agricultural business has tried 

              8     to deal with problems with pesticides is to have 

              9     genetically engineered foods.  And I was sort of 

             10     wondering whether, you know, either the Food and Drug 

             11     Administration or EPA or anything like that has begun 

             12     -- has done testing on toxicity and the bioengineer of 

             13     foods, and in terms of their effects on human beings? 

             14               The other question that I have is much more 

             15     general which is that if you -- what do you want us to 

             16     do?  Right?  In other words, if you had your druthers, 

             17     what would you suggest to us to suggest to OHRP and all 

             18     and the rest? 

             19               MR. WILES:  Is this for me?  I'll go. 

             20               Okay.  We would like this committee to 

             21     recommend a clear prohibition on the testing of 

             22     pesticides, pollutants, and chemicals regulated under 

             23     the Toxic Substance Control Act.  We want the direct 

             24     dosing studies banned.  We would like -- you know, it's 

             25     got to be that type.  And it would be great if we 
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              1     weren't in the real world and we could talk about 

              2     science, it would be good to do.  We are so -- for good 

              3     science, I can't even tell you.  We make our entire 

              4     living off of good science and finding out when there 

              5     hasn't been good science.  

              6               That's basically how we exist.  We find out 

              7     where industry has done bad science and industry and 

              8     EPA has capitulated to bad science and that's when we 

              9     win.  We never -- we can't make any progress in our 

             10     business on hysteria in spite of what people like to 

             11     think.  So, you know, we're all for good science. 

             12               On GMOs, we don't have a position on GMOs 

             13     except that we have an observation.  We don't work on 

             14     it, we're not funded to work on it.  The observation is 

             15     this, is that when the chemical industry Monsanto, in 

             16     particular, came to the market with genetically 

             17     modified foods, the first thing they did was to try to 

             18     avoid comprehensive testing by getting a determination 

             19     out of the FDA that genetically modified food was 

             20     substantially similar to regular food.  And they got 

             21     that.  And that has been a big boon to the industry 

             22     because they have not had to test the food through a 

             23     standard battery of toxicity tests. 

             24               Now, I understand the difficulties with that 

             25     in that, you know, what's the maximum tolerated dose of 
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              1     a potato.  You know, you get to some obvious 

              2     methodological issues designing the study.  In our view 

              3     though, that's not a good enough reason to give the 

              4     industry a complete pass on the testing requirement.  

              5     What the requirement should have been is, all right, 

              6     you guys, let's come off with some real studies here so 

              7     that we can look for the obvious effects.  There have 

              8     been some booboos and no major disasters yet, but 

              9     that's mostly because we're not looking very hard at 

             10     the more subtle long-term impacts probably.  Like with 

             11     most of these things, 98 percent of what's done will be 

             12     fine.  Then there will be these things that slip 

             13     through the cracks because we don't have a 

             14     comprehensive system in place to look for it. 

             15               So we're against not testing GMOs, we don't 

             16     have any particular position at this point on GMOs, per 

             17     se. 

             18               DR. SANDLER:  I would just like to make one 

             19     point.  And that is that I don't think there's a mutual 

             20     exclusivity between say animal studies and human 

             21     studies.  For example, there is nothing that human 

             22     studies would prevent the testing -- the reproductive 

             23     testing of chlopurofos or any other active ingredient 

             24     to determine the reproductive effects.  And certainly I 

             25     would think that if there are specific endpoints 
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              1     meaning, you know, health consequences that you would 

              2     look at doing both as to be realistic and utilize the 

              3     specific benefits from each type of testing in the 

              4     appropriate fashion as I'm sure most government 

              5     agencies certainly try and frequently do.  

              6               MR. WILES:  Are you suggesting that we should 

              7     do direct dose dusting for developmental effects in 

              8     humans?  

              9               DR. SANDLER:  Of course not.  I mean, that's 

             10     --  

             11               MR. WILES:  I just was confused.  

             12               DR. SANDLER:  -- I didn't say that and you 

             13     know I didn't say that.  

             14               MR. WILES:  That's why I don't want to walk 

             15     away here --  

             16               DR. SANDLER:  That's not nice to do here.  

             17               MR. WILES:  -- with the impression you did. 

             18               Well then what did you say?  

             19               DR. SANDLER:  I said that human testing 

             20     wouldn't prevent doing animal testing for developmental 

             21     defects. 

             22               MR. BARNES:  Can you answer the question that 

             23     was asked though which is, what do you guys want us to 

             24     do as a committee?  What do you two guys want us to do? 

             25               DR. SANDLER:  My opinion is having come here 
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              1     and asked to do what I'm supposed to do and that is 

              2     consider the effective use of all aspects of science to 

              3     determine the questions that need to be asked. 

              4               If, for example, human studies can help you 

              5     with metabolites to see if there's a difference between 

              6     animals and humans and you don't need to dose somebody 

              7     at a huge level to do that, you certainly can dose them 

              8     at very low levels.  You can determine just in certain 

              9     populations how colon estrace levels jump at what 

             10     levels.  Do they go up and down real quickly at certain 

             11     doses?  When does the switch from say 10 percent to 25 

             12     percent, is that strictly dose response?  Or does it do 

             13     -- does it respond to a different curve, if you will?  

             14     So there are some real fine points that can be 

             15     extremely useful without saying that we're going to 

             16     take humans and dose them to see if they have children 

             17     who have birth defects.  Clearly no one wants to do 

             18     that. 

             19               CHAIRPERSON MARSHALL:  Judy.  And anyone who 

             20     wants to come from the ex-officio or public members, 

             21     please step up to the microphone. 

             22               DR. SIEGEL:  While I do agree that there is 

             23     benefit in human testing the way you're talking about 

             24     it, I think my concern is when you look at what we'll 

             25     call singleace tendon dose tolerance stuff for no 
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              1     effect levels or for maximum tolerated dose levels in 

              2     drug development, you're looking at the beginning of a 

              3     process.  I think what I was reacting to, again, what 

              4     we were reading was these studies seemed to be used as 

              5     an end product that would help make regulations.  And I 

              6     think that's in fact what I was reacting to when I did 

              7     this.  Because, as you see, this use of that type of 

              8     data is really the beginning of a very long process.  

              9     It's not the end. 

             10               DR. SANDLER:  Let me just comment that I 

             11     think what you said was extraordinarily important and 

             12     my question is, let's find out exactly how those 

             13     studies were done, how they were presented, and the way 

             14     that they were performed because I think that would 

             15     answer it.  

             16               I mean, we've heard one issue on that and 

             17     certainly a lot of rhetoric, or whatever you want to 

             18     call the term, on this issue.  I think it bears, you 

             19     know, some of the day of light to make sure that in 

             20     fact those studies were performed in that way and that 

             21     certain things were done in certain ways.  If they 

             22     were, they were.  If they -- and that needs to be 

             23     changed.  If they weren't, then that needs to come out 

             24     too. 

             25               CHAIRPERSON MARSHALL:  Mr. Katz.  
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              1               DR. KATZ:  Yes, again, I've been asked, I 

              2     guess, from both sides of the -- what we want.  I 

              3     cannot speak for the agency --  

              4               [Laughter.]  

              5               DR. KATZ:  -- about what we want.  And I'm 

              6     happy to be able to say that.  This is -- I'm not with 

              7     that part of the agency that deals with these issues, 

              8     so I abstain.  

              9               [Laughter.]  

             10               CHAIRPERSON MARSHALL:  Margaret.  And if 

             11     you're not speaking, please turn your microphone off.  

             12     There are a couple of mikes on.  Yes, thank you. 

             13               MS. BORWHAT:  Can any of you answer how 

             14     effective extrapolating from animals to humans is in 

             15     the various fields?  You're taking a certain level as a 

             16     starting point and in other ways you're looking at 

             17     different end points.  How has this level stood up over 

             18     time?  

             19               DR. KATZ:  Well, that's something I can try 

             20     again from my point of view answer.  We certainly would 

             21     not rely in any meaningful way particularly with regard 

             22     to effectiveness, for a particular indication from the 

             23     point of view of a drug development on what happens in 

             24     animals with the possible exception of there are 

             25     proposed regulations that deal with how to develop 
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              1     drugs to treat antidotes.  But you can't actually do 

              2     the studies in humans, ethically.  So there is some 

              3     question about that.  Those are pending proposed 

              4     regulations.  But in a typical drug development case 

              5     where there's a naturally occurring disease, half the 

              6     time there aren't even animal models that even speak to 

              7     the question of whether or not there will be -- the 

              8     drug is going to be effective.  So from an 

              9     effectiveness point of view it's essentially, and from 

             10     my point of view, not relevant.  Safety is a different 

             11     issue.  Sometimes the animals predict very well and 

             12     sometimes they don't predict at all. 

             13               CHAIRPERSON MARSHALL:  Bob, you comment is on 

             14     point? 

             15               DR. R. LEVINE:  Yes. 

             16               CHAIRPERSON MARSHALL:  Yes, please go ahead.  

             17               DR. R. LEVINE:  A footnote to that is that 

             18     one of the antidotes that would come under these 

             19     proposed regs would be the anti-colon estrace 

             20     inhibitors so that there would be things that would be 

             21     designed to prevent the toxicities that we've been 

             22     talking about this afternoon. 

             23               CHAIRPERSON MARSHALL:  Thank you.  

             24               MR. WILES:  Can I take a shot at this 

             25     question on the animal --  
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              1               CHAIRPERSON MARSHALL:  Sure.  

              2               MR. WILES:  Remember what you're trying to do 

              3     here is you take a no-effect level and the law and regs 

              4     which require you to take a no effect level in the most 

              5     sensitive species and then go down at least 100 and 

              6     under our reading of FQPA, a thousandfold.  And in how 

              7     many cases has that failed us?  Also FQPA requires some 

              8     more things.  You have to look at all routes of 

              9     exposure when you determine the thing.  You have to 

             10     look at any chemical with a common mechanism of 

             11     toxicity and add it all up from all routes.  Okay.  So 

             12     you get to a very safe system, if you will, with lots 

             13     of conservatism which is what industry will argue ad 

             14     nauseam that this is overly conservative.  

             15               And it's our view that if you take -- because 

             16     this regulation is so fundamentally different, you're 

             17     trying to get the doses down to the lowest you can.  

             18     You start with a no-effect level, go down a thousand 

             19     times from there and then add up all routes of exposure 

             20     to see if you no-go even lower.  We'd say you would be 

             21     very hard pressed to find cases where -- when that 

             22     system was used, not when we ended up not doing that.  

             23     But when that was used where you had adverse impacts 

             24     and then I think you'd even be further hard pressed to 

             25     find a point where you used all that system that's in 
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              1     the law the way it's supposed to be used and didn't 

              2     have an adverse impact but then would have found the 

              3     adverse impact if you've done direct dosing of humans.  

              4               I don't think that scenario really holds up. 

              5      And that's why I get back to reality.  I hear what 

              6     you're saying, but in reality this is what you're 

              7     talking about.  If you open the door just a little bit, 

              8     you'll get some situation down the road where some 

              9     variation on a study you thought was fine all of a 

             10     sudden turns into something else and then we're into a 

             11     totally different ball game.  

             12               CHAIRPERSON MARSHALL:  Thank you.  And could 

             13     you just tell us who you are? 

             14               MR. McALLISTER:  Yes.  My name is Ray 

             15     McAllister.  I'm the Vice President for Science and 

             16     Regulatory Affairs for CropLife America. 

             17               And my favorite quote from Richard Wiles is, 

             18     "I am not a scientist."  The information that's been 

             19     presented to the panel in advance, the two documents, 

             20     it's obviously very biased in one single direction, one 

             21     extreme direction.  It's been produced by an activist 

             22     group with a very definite political agenda.  

             23               We in industry learned of this discussion 

             24     with only a few days notice.  We have been unable to 

             25     provide counterbalancing background information or to 
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              1     prepare well to inform you today of our positions.  I 

              2     can make a few comments, but I can't provide 

              3     comprehensive detail. 

              4               Mr. Wiles has said we don't support 

              5     biomonitoring that we indeed discourage it.  And that 

              6     is basically false.  We have encouraged and supported 

              7     biomonitoring.  The CDC is currently conducting 

              8     biomonitoring.  Their first report came out a little 

              9     over a year ago showing the presence of certain 

             10     metabolites of pesticides and the CDC is expanding that 

             11     each year the number of compounds, including pesticides 

             12     that are to be included in these studies in 

             13     biomonitoring. 

             14               We have cooperated with and supported a long 

             15     going, long-term agricultural health study which looks 

             16     at the health effects of pesticides and the presence of 

             17     pesticide exposure to farm families.  Our industry has 

             18     financially supported a separate companion farm family 

             19     exposure study looking at specific exposures of a few 

             20     pesticides to farm families, both to spouses and 

             21     children of farm operators so that they can be tied to 

             22     specific application events.  

             23               The human studies we've been talking about 

             24     are not conducted in a scientific and ethical vacuum.  

             25     They each are reviewed by institutional review boards, 
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              1     not the independent review boards mentioned in these 

              2     papers.  They are conducted by the same laboratories, 

              3     the same scientists who do the phase one drug trials, 

              4     they're the same folks. 

              5               EPA, at least prior to 1998 when they changed 

              6     their policy has reviewed the science of the studies 

              7     and passed judgment.  When they have reservations about 

              8     the science in the study they will express it.  But 

              9     they have looked at the science there and passed 

             10     judgment. 

             11               If EPA won't consider the study in its 

             12     regulatory program, there is no incentive for industry 

             13     to conduct the study.  They're expensive and we're not 

             14     going to be out conducting studies simply for the 

             15     purpose of having that information if there's no 

             16     regulatory use for it. 

             17               In general pesticide testing in animal models 

             18     is much more thorough prior to any conducting of human 

             19     testing.  And as has been mentioned here today, human 

             20     may produce metabolites not present in animals.  It 

             21     seems to me that the only way you can conduct 

             22     biomonitoring efficiently and effectively is if you 

             23     know what metabolites are produced in the human system. 

             24               Yes, the volunteers in these studies are 

             25     paid.  So are the volunteers in all of the drug tests. 
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              1      My son, my 21-year-old son was a volunteer in a pain 

              2     medication study for dental work and he was paid, yet 

              3     he was still a volunteer.  

              4               EPA can reasonably apply the Common Rule to 

              5     studies involving pesticides and other chemicals.  It 

              6     seems to me that's a fairly straightforward regulatory 

              7     approach to handling these studies.  

              8               Thank you.  

              9               CHAIRPERSON MARSHALL:  Thank you very much.  

             10     I think Kate Gottfried wants to speak perhaps to one of 

             11     your initial observations. 

             12               MS. GOTTFRIED:  Just a point of clarification 

             13     with respect to your awareness of the agenda item.  On 

             14     or about April 15th, CropLife America was contacted and 

             15     Doug Nelson, the Senior Vice President and General 

             16     Counsel actually had originally committed to speaking 

             17     on the panel.  So the information in fact was out there 

             18     several weeks ago.  

             19               MR. McALLISTER:  April 15th is not several 

             20     weeks ago. 

             21               MS. GOTTFRIED:  Well, it's two weeks ago.  

             22               MR. McALLISTER:  Now, we -- I don't know what 

             23     the purpose of the panel is in discussing this subject 

             24     and that's been asked by a couple of folks on the panel 

             25     today.  If the panel is to have a future role in 
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              1     providing input either to EPA or through other means on 

              2     how this issue is resolved, we are certainly willing to 

              3     provide you background information.  

              4               CHAIRPERSON MARSHALL:  Thank you very much.  

              5     Abbey. 

              6               MR. WILES:  Can I clarify on that? 

              7               CHAIRPERSON MARSHALL:  Abbey. 

              8               MS. MEYERS:  The statement that most 

              9     volunteers in drug studies are paid, what makes you 

             10     think that? 

             11               Do you want to answer that? 

             12               DR. SHAMOO:  Nobody really knows, but there 

             13     are a lot of volunteers who don't get paid a cent.  So 

             14     I don't know what the breakdown is, but I know 

             15     hundreds, thousands who don't get paid.  But at the 

             16     same time there is overpayment, you know, in some 

             17     cases. 

             18               MS. MEYERS:  I think what is probably 

             19     happening is that in academia normally they're not 

             20     paid.  If they have a disease and they're in research 

             21     for their disease, but maybe because of all the 

             22     commercial interest in this kind of testing, maybe 

             23     families are paid when they take their children in fro 

             24     pediatric.  Judith, do you know?  Do you have an 

             25     answer?  
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              1               DR. KATZ:  Certainly subjects in drug studies 

              2     are paid.  Not all perhaps.  I have no idea what the 

              3     numbers are, what the rate is, but certainly as a 

              4     principal of whether or not somebody can be considered 

              5     a volunteer and also be paid there are many such 

              6     subjects. 

              7               CHAIRPERSON MARSHALL:  I want to continue 

              8     this discussion and we are sort of close to time.  But 

              9     I'm going to just give us a couple of minutes before we 

             10     break and then I'm going to have a conversation with 

             11     the committee about where we go from here. 

             12               But I do want to point out that the ground 

             13     rules that I generally lay out at the beginning of the 

             14     meeting call for civility in terms of discourse and 

             15     that is something that I will impose.  So, the 

             16     expectation is that when you make remarks or present 

             17     before the committee that what you present are facts 

             18     and not conjecture.  So that's a ground rule for 

             19     everyone.  And that we certainly, I think, on this 

             20     committee take great pains to be fair in terms of our 

             21     procedure and in terms of inviting everyone who should 

             22     be at the table to the table and make sure that they 

             23     have an opportunity for discussion and probably go 

             24     beyond most FACA committees in terms of providing time 

             25     on the agenda for anyone who hasn't been invited to 
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              1     have an opportunity to do so. 

              2               So I'm sorry if you feel as though we haven't 

              3     been fair in terms of our approach, but I guess my 

              4     sense is that we have. 

              5               Judy. 

              6               DR. SIEGEL:  I think as far as payment is 

              7     concerned, if you're talking about healthy volunteer 

              8     studies, I think probably the higher likelihood that 

              9     you will see payment, these are people for whom there 

             10     probably is no possibility for a direct benefit and I 

             11     know that these people are paid for their time and 

             12     sometimes for their inconvenience.  I think the amount 

             13     their paid has been the subject of a lot of discourse 

             14     around, but the fact is that these are people who are 

             15     paid for their participation.  

             16               I think when you go into the later phases 

             17     where you're actually treating patient populations the 

             18     payments more have to do with remuneration for travel, 

             19     time spent, meals, but it's of a different type than 

             20     paying for someone who has no direct benefit.  

             21               MS. MEYERS:  [Off mic.]  

             22               [Laughter.]  

             23               CHAIRPERSON MARSHALL:  One last remark and 

             24     then unless other committee members or anyone else who 

             25     is in the room today would like to ask a question, I'm 
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              1     going to thank our panelists and move on to a committee 

              2     discussion.  Mark has his hand --  

              3               MR. BARNES:  I guess my question or thought 

              4     is, where do we go from here with this particular 

              5     issue?  And it seems to me that -- I mean, as I sort of 

              6     thought about what this issue really is and what -- 

              7     it's actually a subspecies of a larger issue which is 

              8     sort of, what is research?  What kind of research ought 

              9     to be -- what ought to be regarded as research that is 

             10     subject to the Common Rule.  That's really sort of an 

             11     abstract level.  I think that's the issue.  And it's 

             12     not an easy issue because if you -- because of the 

             13     particular human risk in this area, we decide that 

             14     there ought to be a recommendation at some point from 

             15     this committee with a discussion and a deliberative 

             16     process that these kinds of things ought to be covered 

             17     by the Common Rule. 

             18               Then the question becomes, well, this is 

             19     private industry performing studies alone and not with 

             20     federal funding and not under federal assurance, then 

             21     what about all the social science research that private 

             22     industry does that also, you know, if you extend it 

             23     here, why not extend it there as well.  And so there 

             24     really are some very difficult issues about line 

             25     drawing on this.  Which reminds me of a point that Bob 
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              1     Levine made earlier today which is on the sort of 

              2     generic issue of, you know, that we're all grappling 

              3     with, sort of the frontier of the Common Rule which is, 

              4     when does quality assurance become research?  When does 

              5     quality improvement become research?  When do clinical 

              6     anecdotal studies or surveys of existing patients who 

              7     were treated in the clinically appropriate way, when 

              8     does that become research and need to go before the 

              9     IRB? 

             10               So, I don't know.  Where this sort of takes 

             11     me back is that there may be something that needs to go 

             12     on our agenda as a committee which is not so much, you 

             13     know, about EPA specifically and this recommendation 

             14     and that recommendation from the three gentlemen who 

             15     have spoken today and the gentleman from the EPA who 

             16     spoke.  But, instead, really, more toward the generic 

             17     issue of, you know, what are the five top issues that 

             18     need to be looked at in regard to what is research 

             19     under the Common Rule and how should we recommend new 

             20     interpretations of the Common Rule to cover that which 

             21     ought to be covered?  

             22               CHAIRPERSON MARSHALL:  Thank you, Mark. 

             23               Here's what I would like to do as we proceed 

             24     is I would like to thank all of the panel members very 

             25     much for your preparation and your remarks and your 
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              1     willingness to be here today.  We very much appreciate 

              2     it. 

              3               [Applause.]  

              4               CHAIRPERSON MARSHALL:  I would like to give 

              5     us somewhere between five and ten minutes as a 

              6     committee to discuss where we go and have a general 

              7     discussion.  Then we will have a break and move on to 

              8     informed consent.  

              9               So, thank you. 

             10               [Pause.]  

             11               DR. FLEISCHMAN:  I think there are some in 

             12     the room who think we're breaking, Madam Chairperson. 

             13               CHAIRPERSON MARSHALL:  We are not breaking.  

             14     I mean, you are certainly entitled to get up if you so 

             15     choose, but we're not going to break for another ten 

             16     minutes. 

             17               Alan. 

             18               DR. FLEISCHMAN:  Yes.  I think, Mark, I have 

             19     some concerns with how you've conceptualized the 

             20     problem.  I mean, I do think that it would be greatly 

             21     beneficial for us to talk about the issues you've just 

             22     put on the table.  But we've heard about and there have 

             23     been other conferences that have addressed the question 

             24     of putting toxic substances into humans in order to 

             25     find out how toxic they are.  And I was quite taken by 
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              1     Dr. Katz's presentation, but I don't think it's 

              2     relevant really to what we're talking about since those 

              3     toxic substances are intended to be beneficial.  These 

              4     toxic substances are intended to kill biologic entities 

              5     other than humans and we want to try not to kill the 

              6     humans while we hurt the mosquitos or whatever else. 

              7               It seems to me that -- and I do think we need 

              8     the insight of the industry representative.  But the 

              9     gentleman at the microphone argued that he didn't seem 

             10     to have any problem with the Common Rule being part of 

             11     the research in human subjects around pesticides.  Now, 

             12     he may have said that inadvertently, I don't know, but 

             13     he kind of said that, I think. 

             14               And one of the things I would really like to 

             15     understand better, and I'm sorry that Mr. Jordan had to 

             16     leave, is why the Environmental Protection Agency 

             17     wouldn't demand such compliance in such studies even if 

             18     they are at the end of the line having received them 

             19     and don't have any way of assuring that happens 

             20     prospectively.  They have a way of assuring it happens 

             21     retrospectively if they demand that they will not look 

             22     at such studies unless they have Common Rule 

             23     compliance. 

             24               So I just want to understand and we may not 

             25     be able to answer that question today.  But it would 
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              1     seem to me to be important for us to understand why 

              2     that isn't the case.  If there is a good reason for 

              3     that, I would be willing to hear it. 

              4               And that kind of statement from NHRPAC, that 

              5     the Common Rule ought to apply in this kind of case is 

              6     an opening then to a more comprehensive look at the 

              7     questions Mark is raising and that Adil raised at the 

              8     very beginning in which he argued that this is, you 

              9     know, this is a problem of looking at all human 

             10     subjects research.  I agree.  But here we have a very 

             11     specific kind of point where we ought to be able to 

             12     make some headway.  

             13               CHAIRPERSON MARSHALL:  Thank you.  

             14               There were other hands.  Felice.  Adil. 

             15               DR. F. LEVINE:  I must be sitting next to 

             16     Alan at too many meetings, because some of what he said 

             17     I was going to.  So let me just say that when Mark 

             18     spoke I thought -- I think there is a recurrent theme. 

             19      I mean, clearly we are talking about a form of human 

             20     subjects research.  But from a number of our speakers 

             21     over time, Susan rose some number of meetings ago that 

             22     we are -- it isn't just the surveys or the work that's 

             23     non-federally funded or that is in industry, and 

             24     clearly that's a segment of work that we need to 

             25     consider, but there's also this, what is research that 
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              1     is in a very ancient area.  Now, this clearly struck me 

              2     as research in that sense. 

              3               Alan is right, but this workplace 

              4     performance, product development, training, I've heard 

              5     from many of our ex-officio members over time, Susan 

              6     among them, some of our NASA folks, our AID folks that 

              7     sometimes both internal to the agencies as well as what 

              8     the agencies either support or look at there is contact 

              9     with humans and it is for a purpose that we as 

             10     researchers may say looks and feels like research, but 

             11     doesn't necessarily take the formal coloration of 

             12     research and yet involves human participants.  And I 

             13     think somehow we need to try to engage with that in 

             14     terms of its fit to the Federal Rules. 

             15               CHAIRPERSON MARSHALL:  Thank you, Felice.  

             16     Adil. 

             17               DR. SHAMOO:  Well, I think I want to comment 

             18     on his formulation that let's deal with this issue and 

             19     even Alan's formulation of the problem is really 

             20     piecemeal.  We are sort of avoiding biting the most 

             21     important bullet and that has been dealt with, with 

             22     animals.  Cats and dogs, you cannot do research in this 

             23     country regardless if you do it in your back yard, in 

             24     your garage, I keep saying that without following the 

             25     Animal Welfare Act.  
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              1               The National Advisory Bioethics -- National 

              2     Bioethics Advisory Commission, NBAC, recommended that. 

              3      We have recommended it before NBAC.  We have written 

              4     about it.  I have said it here, I think a dozen times. 

              5      We need to see regardless of what the definition of 

              6     research is, let's agree it's research. 

              7               I don't care how you define it, what big 

              8     circle it is, define it as narrow as you want.  But 

              9     whatever research narrowly defined should all follow 

             10     the Common Rule.  That is to me logical, and 

             11     reasonable, and common sense.  And I don't know why we 

             12     are trying to put piecemeal here for this and piecemeal 

             13     this for this. 

             14               CHAIRPERSON MARSHALL:  Thank you, Adil.  And 

             15     I have a response to that, but I will wait until the 

             16     end of the discussion.  

             17               Bob. 

             18               DR. R. LEVINE:  The Common Rule lists six 

             19     categories of things that are unambiguously researched 

             20     and exempts them from coverage by all federal 

             21     regulations including research which is paid for by the 

             22     federal government under grants or contract.  There is 

             23     reasons for this.  I think the definition of the 

             24     exemptions is a bit crude.  I would have defined the 

             25     boundaries a bit differently.  But the principle, I 
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              1     think, is important.  And I want to agree with Mark's 

              2     agreement with me. 

              3               [Laughter.]  

              4               DR. R. LEVINE:  That maybe it's time to stop 

              5     focusing so precisely on the definition of research and 

              6     to think more about what is it that we want to 

              7     regulate.  If we keep redefining research, we will end 

              8     up with some very funny looking thing that looks like a 

              9     gerrymander and nobody will really quite understand 

             10     what the purpose of all of this is. 

             11               CHAIRPERSON MARSHALL:  All right.  Here is 

             12     where I would like to go.  And, Adil, I do want to 

             13     respond to you.  You know, you've raised the meta 

             14     issue, you know, about universal protections.  And 

             15     certainly -- I mean, that goes back a long way.  The 

             16     NBAC has recently sort of reiterated the position that 

             17     has been taken by ACRE and other advisory committees in 

             18     the past about this.  And it's obviously something that 

             19     needs to be on our plate. 

             20               I guess my thought in terms of strategy is 

             21     that the Institute of Medicine Report on assessing the 

             22     overall system for protecting human subjects of 

             23     research will be out in September and I think that 

             24     there will probably be many things in there that we 

             25     will want to take up as a committee and it will 
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              1     probably be a challenge just to assign priority to 

              2     them. 

              3               So my thought and plan was to invite Dr. 

              4     Fedderman who chairs that committee to our October 

              5     meeting.  The report is due out in September.  And I 

              6     think all of us, each of us and the public at large 

              7     will have a chance to have read the report by then, and 

              8     there will be, I think, a host of issues that we can 

              9     look at and react to and I think sort of probably 

             10     appropriately my sense would be that those who asked 

             11     the IOM to undertake that large charge will then 

             12     perhaps subsequently have things that will arise out of 

             13     their report that they would like for us to take a look 

             14     at too. 

             15               So I couldn't agree with you more in terms of 

             16     where we should go in the future and things that we 

             17     should look at. 

             18               To get back to this specific issue, I'm not 

             19     sure necessarily that the committee needs to act on it 

             20     in a formal way.  We could, I have, you know, sort of 

             21     brought this before you in terms of information 

             22     sharing.  I think that the fact that the National 

             23     Academies will be taking a look at it in a very 

             24     concrete way is something that we should take into 

             25     consideration.  We should also take into consideration 
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              1     that there is a voluntary moratorium on the use of data 

              2     from human studies at the moment by the EPA that that 

              3     is something that we can endorse that should continue 

              4     to be the state of things until the National Academies 

              5     is finished with their process. 

              6               So I'll open the floor for a few minutes for 

              7     discussion in terms of how the committee would like to 

              8     proceed or not proceed. 

              9               DR. CHODOSH:  Let me just provide a little 

             10     bit of historical evidence in that.  This didn't start 

             11     with NBAC, it started before that.  And I specifically 

             12     challenged OPRR when they were developing the 

             13     regulations back in the 1970s that this was foolish to 

             14     just be doing this for government supported or FDA-like 

             15     research; and that it would seemed to me that a federal 

             16     organization such as NIH, OPRR, DHHS, not called that 

             17     at that time, should not in fact be concerned about all 

             18     Americans.  And that was not accepted at the time as, 

             19     quotes, "being unrealistic."  

             20               CHAIRPERSON MARSHALL:  Thank you.  Bob. 

             21               DR. R. LEVINE:  This is something that has 

             22     been considered back before the National Commission, 

             23     the President's Biomedical Research Council considered 

             24     it.  The issue of extending federal regulations to 

             25     cover all research involving human subjects seems to 
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              1     come up every time that there is a high level advisory 

              2     committee.  The thing that shoots it down every time is 

              3     that people make reference to the constitutional 

              4     authority of the federal government to look at to 

              5     review research. 

              6               And what has been repeated over and over 

              7     again, and I'll just anticipate it's going to be 

              8     repeated again this time is that the government has two 

              9     constitutional bases for regulating research.  One is 

             10     through the conditional spending power clause, and that 

             11     is, if the government pays for it, it can regulate it. 

             12      And the other is through the interstate commerce 

             13     clause which creates the authority for the Food and 

             14     Drug Administration to regulate drugs, but only those 

             15     drugs that are going to be labeled for use in 

             16     interstate commerce.  That's why we have had some 

             17     things like that clinic in Tennessee that made designer 

             18     drugs for people with cancer and the FDA couldn't get 

             19     at them because it all happened in Tennessee. 

             20               So this is what we are probably going to be 

             21     up against.  And before we make an investment, we might 

             22     want to get a legal consultation first.  Thank you.  

             23               CHAIRPERSON MARSHALL:  Kate. 

             24               MS. GOTTFRIED:  Just for those of you who 

             25     aren't aware, there was a hearing on the 23rd of April 
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              1     by Senator Kennedy's committee.  He and Senator Frist 

              2     were there and the two issues focused on, one was 

              3     whether or not all research ought to be regulated 

              4     regardless of the origin of funding, and they clearly 

              5     seemed that they were heading in the direction of all 

              6     research.  We're aware that there is pending 

              7     legislation -- proposed legislation from both Senator 

              8     Kennedy as well as from Congresswoman DeGette and 

              9     Greenwood.  They are both expected to say the same 

             10     thing with respect to that particular issue.  One other 

             11     issue they just focused on during the hearing was the 

             12     accreditation issue.  And it was clear again that they 

             13     embraced the notion of accreditation.  The question in 

             14     their mind seemed to be, should it be voluntary or 

             15     ought it be mandatory.  

             16               But I do think that should legislation emerge 

             17     and should it ultimately be approved we will see a 

             18     significant shift with respect to the issue of 

             19     regulation of all research. 

             20               DR. R. LEVINE:  Until there's a test of the 

             21     constitutionality, Mr. Frist wasn't around in the '70s, 

             22     but Mr. Kennedy advocated regulating all research in 

             23     that decade too. 

             24               CHAIRPERSON MARSHALL:  So let me just call 

             25     the question that is before us in terms of the 
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              1     committee's pleasure as to pesticide testing in humans 

              2     or the use by the EPA of data from human studies.  Bob. 

              3               DR. RICH:  It seems to me that if the 

              4     committee thinks that this is an area that it wants to 

              5     go into, we're just getting started with the issue and 

              6     that we ought not to come to any kind of conclusion of 

              7     fact today.  We obviously have not heard a balanced 

              8     scientific appraisal yet, and we surely would need 

              9     that. 

             10               I mean, I think the issues that Mr. Wiles 

             11     raised, which is to criticize the fundamental 

             12     scientific validity of it as a basis for saying that 

             13     it's fundamentally not ethical is an important 

             14     question.  But we obviously need to hear a balanced 

             15     presentation on that issue, and it's clear, I think, 

             16     from the comments that we've heard that that was not a 

             17     universally accepted notion.  And so I would urge us, 

             18     whatever we do on this, to go slow until we've actually 

             19     got more facts.  I do sympathize with the fact that 

             20     whether April 15th was a sufficient notice or not, it's 

             21     a short time and we ought not to be rushed into this 

             22     process.  

             23               CHAIRPERSON MARSHALL:  I couldn't agree more. 

             24      So I think really the basic -- I guess my sense is, 

             25     perhaps to guide the committee and its thinking is 
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              1     knowing that National Academies are about to take this 

              2     up, that there is a voluntary moratorium and if I heard 

              3     the FDA correctly that will persist until the National 

              4     Academy's report process is complete.  Is this 

              5     something that we want to put on the table or do we 

              6     want to wait until the process is finished at the 

              7     National Academies; that's the question.  

              8               Sandy. 

              9               DR. CHODOSH:  My only concern is that we're 

             10     talking at least 18 months down the road.  

             11               CHAIRPERSON MARSHALL:  From the Academies? 

             12               DR. CHODOSH:  From the Academies. 

             13               CHAIRPERSON MARSHALL:  That's true.  It takes 

             14     a while. 

             15               DR. CHODOSH:  And that I think that there are 

             16     some real basic kinds of things that we could recommend 

             17     at least to EPA and to Greg who chairs the Human 

             18     Studies Committee for the Common Rule, et cetera, on 

             19     how to proceed with this and that perhaps EPA needs to 

             20     start doing something -- and I'll bet that there are 

             21     other situations not dissimilar from this -- to at 

             22     least get some coverage of the human subjects wherever 

             23     they are or however they -- even the epidemiologic 

             24     studies, we don't know how they're handled.  

             25               CHAIRPERSON MARSHALL:  Are you making a 
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              1     motion that we ask HSRS to take a look at this, or that 

              2     we take a look at it? 

              3               DR. CHODOSH:  I think we should get a little 

              4     bit more information than, you know, right now we 

              5     really just have a fairly biased report that's 1998. 

              6               CHAIRPERSON MARSHALL:  Any other thoughts by 

              7     other committee members?  

              8               Alan. 

              9               DR. FLEISCHMAN:  Could we ask Mr. Cortezzi to 

             10     keep us informed at each of our meetings and the 

             11     progress of these discussions and perhaps even bring 

             12     together some of the information concerning EPA and the 

             13     Common Rule and ask industry to give us a report in 

             14     writing that we could distribute so we could keep 

             15     current while this process goes on. 

             16               CHAIRPERSON MARSHALL:  Elliot. 

             17               DR. DORFF:  The other thing that Mr. Wiles 

             18     brought up in response to my question that I think we 

             19     at least need to think about, namely, as he put it, 

             20     that the FDA gave genetically modified foods a pass 

             21     without ever -- you know, so that Monsanto and so on 

             22     never have to demonstrate the safety of them.  And I 

             23     think that's something that we at least should re-

             24     examine in some way. 

             25               CHAIRPERSON MARSHALL:  Mr. Cortezzi. 
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              1               MR. CORTEZZI:  Ask and it shall be given unto 

              2     you.  Seek and ye shall find. 

              3               [Laughter.]  

              4               CHAIRPERSON MARSHALL:  So would it be the 

              5     committee's pleasure then to ask Mr. Cortezzi for our 

              6     next meeting that we have the materials?  So a 

              7     background paper provided to --  

              8               MR. CORTEZZI:  Yes.  The next meeting is in 

              9     October?  

             10               CHAIRPERSON MARSHALL:  July. 

             11               MR. CORTEZZI:  Oh, July.  Okay. 

             12               CHAIRPERSON MARSHALL:  End of July 

             13               MR. CORTEZZI:  Yes, all right.  

             14               CHAIRPERSON MARSHALL:  All right.  Okay.  

             15     Thank you very much.  I agree.  We shouldn't sort of 

             16     run precipitously but we don't want to neglect an 

             17     important issue.  

             18               Abbey. 

             19               MS. MEYERS:  I just feel that to be careful 

             20     on this issue in the absence of any human protections 

             21     at all that EPA -- not EPA, that at least -- at the 

             22     very least, that there a certification that each person 

             23     who volunteered has gone through the informed consent 

             24     process.  I think at the very least that should be 

             25     something that they do for any information that's 
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              1     submitted to them.  

              2               CHAIRPERSON MARSHALL:  Any further 

              3     discussion?  

              4               [No response.]  

              5               CHAIRPERSON MARSHALL:  All right.  Then let 

              6     us -- well, timed, Dr. Koski, you made it for the 

              7     break.  

              8               [Laughter.]  

              9               CHAIRPERSON MARSHALL:  We will break for 15 

             10     minutes. 

             11               DR. KOSKI:  Timing in life is everything. 

             12               CHAIRPERSON MARSHALL:  We will begin promptly 

             13     at ten after four. 

             14               [Brief recess taken at 3:55 p.m.] 

             15               CHAIRPERSON MARSHALL:  We are going to go 

             16     ahead and start so that we can end on time.  Felice, do 

             17     you have a --  

             18               DR. F. LEVINE:  Could I just take two seconds 

             19     to pass out the document that Susan and I did to revise 

             20     the confidentiality draft for NHRPAC so that we can 

             21     talk about it tomorrow. 

             22               CHAIRPERSON MARSHALL:  Right.  Yes, thank 

             23     you.  Thank you very much, Felice, please do. 

             24               DR. F. LEVINE:  Because I'm afraid that 

             25     people will leave.  
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              1               CHAIRPERSON MARSHALL:  I'm sorry, you 

              2     mentioned that to me and --  

              3               [Simultaneous conversation.]  

              4               CHAIRPERSON MARSHALL:  -- fell through the 

              5     sieve-like memory that I have.  Yes. 

              6               It was said earlier that we are not terribly 

              7     specific always in our discussions and I would like to 

              8     point out that in our update on informed consent that 

              9     Elliot is going to lead us in the discussion on -- oh, 

             10     terrible grammar here.  

             11               At any rate, we're going to be talking about 

             12     not one, not two, but three issues as explicated in 

             13     agenda.  And I'm sorry that Mark is not here because we 

             14     have the perfect person to give us an exegeses on the 

             15     three issues.  

             16               [Laughter.]  

             17               DR. DORFF:  I have a piece of paper here in 

             18     front of me that says two minutes, so I had better --  

             19               [Laughter.]  

             20               DR. DORFF:  That's called induced humility. 

             21               [Laughter.]  

             22               DR. DORFF:  Okay.  I have some good things to 

             23     report.  The committee on informed consent has divided 

             24     into three.  Well, what has happened is -- I mean, we 

             25     have done considerable work actually in the last two 
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              1     months.  We had, if you remember, just to remind 

              2     everybody, at our last meeting the committee had an 

              3     opportunity to meet and we had met by conference call 

              4     before the last meeting to come up with a list, a 

              5     preliminary list of topics that we ought to be 

              6     considering under the rubric of informed consent.  

              7               We were told ahead of time that there's a 

              8     separate workgroup dealing with informed consent for 

              9     the decisionally impaired, so that piece of it was not 

             10     part of our agenda.  But we came up with a rather 

             11     larger agenda, and then during the course of the 

             12     meeting last time we had an opportunity to meet as a 

             13     committee together with other people who chose to join 

             14     that meeting and came up with yet a further list and 

             15     then at the meeting itself, remember, we came up with 

             16     yet a further list. 

             17               I played secretary and basically put all of 

             18     the various things into some kind of an order.  And 

             19     then we had -- and shared that with the committee.  We 

             20     had a conference call several weeks after the last 

             21     meeting in which what we tried to do was to prioritize 

             22     the many things that were raised.  And what we decided 

             23     on during that conference call was that there were 

             24     actually three things -- three general rubrics of the 

             25     many things that we had identified as being important 
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              1     in this area.  And that we then created sub-workgroups 

              2     to deal with each one of these three things. 

              3               There will inevitably be some overlap, but we 

              4     are in any case starting with these three.  

              5               The first deals with the information.  If we 

              6     are talking about informed consent, then the first part 

              7     deals with "informed" and what does it mean to make 

              8     sure that research subjects are in deed -- indeed have 

              9     the information that they need in order to be able to 

             10     make an informed decision. 

             11               The second workgroup is dealing with the 

             12     process of informed consent because one of the things 

             13     that we are all convinced about is that informed 

             14     consent cannot be reduced simply to documents, but 

             15     although documents play a role in it clearly, but that 

             16     the entire process needs to be examined in order to be 

             17     able to assure that there is indeed informed consent.  

             18     And the third group is dealing with voluntariness.  The 

             19     consent part of informed consent.  And, namely, the 

             20     various kinds of limitations on consent under various 

             21     circumstances and how to make sure that the consent is 

             22     indeed voluntary. 

             23               What has happened, once we had that meeting 

             24     is that each of the three subgroups has had the 

             25     opportunity to have a conference call to begin to do 
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              1     its work.  And the reason why we have not -- in two of 

              2     the three have actually produced very preliminary 

              3     documents, and the only reason why we haven't 

              4     distributed them to you is because of the preliminary 

              5     image just based on one conference call. 

              6               And the third group just had its conference 

              7     call last Thursday.  So there's not even that. 

              8               So we are very much at the beginnings of this 

              9     process, but nevertheless, I mean, I think we have 

             10     helped -- we honed this.  And I want to just 

             11     acknowledge right at the very beginning that Kate has 

             12     been absolutely wonderful in first of all helping us 

             13     organize ourselves, and in reminding us that we have 

             14     deadlines, and, you know, volunteers that we may be, 

             15     we're not supposed to work that way.  

             16               [Laughter.]  

             17               DR. DORFF:  And I seriously want to thank her 

             18     for her help in organizing all of this for us. 

             19               So what I've asked -- is Cathy here?  Cathy 

             20     Hannah? 

             21               MS. MEYERS:  I don't see her. 

             22               DR. DORFF:  Okay.  I don't see her either.  

             23     Okay.  So, Abbey, if you will.  Abbey will talk about 

             24     what the first group did, the one dealing with 

             25     information.  And then Judy will talk about the second 
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              1     group, the one dealing with process and then I'll talk 

              2     about the third group, the one dealing with 

              3     voluntariness.  Abbey. 

              4               MS. MEYERS:  We were discussing the 

              5     understanding of the informed consent because there's a 

              6     big problem with understanding.  And, of course, 

              7     everybody knows that the readability of an informed 

              8     consent document is very often a problem.  But it's not 

              9      just the readability, the process of informed consent 

             10     is a process and it seems to be the informed consent 

             11     document itself is often treated like a contract or 

             12     another piece of red tape that investigators have to go 

             13     through.  So a lot of things ought to happen and we 

             14     came up with some suggested solutions. 

             15               First is that maybe after the investigator 

             16     explains the whole thing to a person, they should take 

             17     that informed consent document home for a day or two 

             18     and speak to their clergy, their relatives, their 

             19     friends, and have a few days to digest it before they 

             20     sign it. 

             21               Second issue is perhaps it should be 

             22     videotaped so that the process itself people will feel 

             23     compelled to go through the process in the right way if 

             24     there's a videotaped record of it. 

             25               And then the third thing is that during the 
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              1     process, periodically, the investigator or whoever 

              2     gives the information to the subject should question 

              3     them like you would question a child, do you 

              4     understand, or what do you understand from what I just 

              5     said?  And maybe then we'll get people to truly 

              6     understand.  I think these things have to be done 

              7     because many times people will go through an 

              8     investigational process and when they're questioned 

              9     later, they don't even know that it was an experiment. 

             10      So it's very important that you're assured that they 

             11     understand its investigational during the informed 

             12     consent process. 

             13               DR. DORFF:  Good.  Thank you, Abbey. 

             14               I should have mentioned, I'm sorry, that 

             15     Cathy Hannah prepared for this working group a kind of 

             16     -- as she puts it -- notes from scanning the literature 

             17     so that she, you know, provided for us some of what the 

             18     literature has told us about conveying the information. 

             19               Among the things that she mentions here is 

             20     that in bioethics college have identified two distinct 

             21     standards for approaching the assessment of 

             22     comprehension of information.  That is, what would be 

             23     understandable to a reasonable person -- to a 

             24     reasonable person, that's number one. 

             25               Or secondly that which would be 
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              1     understandable to each individual patient.  In other 

              2     words, an individually tailored approach. 

              3               And the literature also makes it clear that 

              4     things like level of educational attainment is one 

              5     issue that clearly arises in terms of whether the 

              6     information is understood, and another issue that she 

              7     raises from the literature is that the issue is not 

              8     just simply the ability to cognitively understand what 

              9     the person has been told, but to understand it.  That 

             10     is, to be able to apply it to his or her own life.  And 

             11     that consequently when we're talking about information 

             12     here, we're not simply talking about something that can 

             13     be sort of, you know, repeated on a test or something 

             14     like that.  We are talking about much better kinds of 

             15     testing in which you actually try to apply the 

             16     information to the decision at hand. 

             17               And what Abbey was talking about, and this is 

             18     why I have to apologize to her, because I didn't put it 

             19     in the right context.  What Abbey was talking about was 

             20     some of the ways in which the workgroup is trying to 

             21     figure out how you assess whether that kind of 

             22     understanding has actually taken place. 

             23               MS. MEYERS:  Yes, I think that that was the 

             24     point of our conversation.  That since the problem is 

             25     that the subject may not understand what this is all 
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              1     about, that you have to find ways to test it throughout 

              2     the process and make sure before they leave the room 

              3     that they truly understand.  

              4               DR. DORFF:  Shall we take these one by one? 

              5               CHAIRPERSON MARSHALL:  It's at your pleasure. 

              6               DR. DORFF:  Okay.  So let's do that.  Let's 

              7     talk now about information.  Okay.  Robert. 

              8               DR. RICH:  Did you ever actually approach the 

              9     notion that an IRB should approve a quiz or something 

             10     with regard to the informed consent process?  I've 

             11     heard that discussed before, you know, that a subject 

             12     is not actually informed unless they can provide 

             13     appropriate answers to 70 percent of some set of 

             14     questions or something.  Was that an issue that you 

             15     discussed in your group?  

             16               MS. MEYERS:  We didn't because we felt that 

             17     the informed consent process should be a conversation 

             18     on the level that the subject would understand.  And to 

             19     go through something as formal as giving them a paper 

             20     and say, answer this true or false, would be too 

             21     artificial, I think, in that type of setting.  And that 

             22     it's best to just stop after the first couple of 

             23     paragraphs and say, now, tell me what I just said.  

             24     Explain to me so that I know if you understand it. 

             25               DR. RICH:  I wasn't suggesting a piece of 
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              1     paper, certainly.  I mean, I think pieces of paper are 

              2     the real problem.  The question is, should there be in 

              3     any kind of a formal process an oral iteration?  An 

              4     oral iterative process that an IRB has looked into?  

              5     That's the question I'm raising.  I have heard it 

              6     discussed. 

              7               MS. MEYERS:  Yes, we didn't really discuss 

              8     that.  No. 

              9               DR. DORFF:  So, Abbey, if you would, take 

             10     that question back to the committee.  

             11               MS. MEYERS:  Sure.  

             12               DR. SHAMOO:  May I comment just on that? 

             13               Abbey, just make sure that we don't fall into 

             14     the trap where they are doing some of that kind of quiz 

             15     for schizophrenia research.  They keep teaching them 

             16     the same material and it's the same test over and over 

             17     and over again until they get the required percent 

             18     passage and then they say, yah-hah, they understood.  

             19     That's like teaching a rat the same thing to do it over 

             20     and over.  Just make sure that it is appropriate and it 

             21     is -- you get the outcome you are seeking. 

             22               DR. DORFF:  Okay.  I have Mary Kay then Mary 

             23     Faith and Sandy and Susan.  I'm sorry.  Okay.  Bob. 

             24               All right.  Mary Kay.  

             25               DR. PELIAS:  Thank you.  
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              1               CHAIRPERSON MARSHALL:  Your microphone is 

              2     still on. 

              3               DR. PELIAS:  I have a serious question that 

              4     relates to the kind of information that you try to 

              5     impart and the population that you're trying to impart 

              6     information to.  If we are in situations where we are 

              7     doing research with a large indigent population that is 

              8     to a great extent illiterate, you're going to have to 

              9     make some kind provisions for those folks so that they 

             10     can demonstrate some level of understanding.  And my 

             11     experience with talking to patients like this has been 

             12     that they will agree to anything you say.  Do you 

             13     understand?  Yes, I understand.  And then it should be 

             14     more than that.  But you've got a basic problem with 

             15     people's whose education is extremely limited and who 

             16     will not understand, I'll bet, no matter what you do 

             17     for them.  This is a difficult question. 

             18               Thank you. 

             19               DR. DORFF:  Okay.  Mary Faith. 

             20               CHAIRPERSON MARSHALL:  I guess one thought 

             21     that I have in hearing about and reading about the work 

             22     of Jeremy Sugarman and others who have, you know, done 

             23     some empirical work in the area of informed consent -- 

             24     I mean, there's a huge, huge literature out there on it 

             25     -- is that there's an emerging new paradigm.  I mean, 
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              1     we all know that informed consent is not an event, it's 

              2     a process and so forth.  But that actually I guess the 

              3     new paradigm that Jeremy, who is on the working group, 

              4     espouses is that informed consent is really a 

              5     conversation and it occurs at every contact and 

              6     interaction between the investigator and the research 

              7     subject or participant and that it's really all about 

              8     decision-making on the part of the participant. 

              9               And so that rather than thinking that there 

             10     is a thing that happened sort of right up front that 

             11     involves what Tom Beauchamp would prefer to call a 

             12     disclosure document, not an informed consent form, that 

             13     this is something that is revisited in terms of the 

             14     patient's knowledge about what is happening now, what 

             15     went on before, and continued through a voluntary 

             16     participation that that happens at each encounter.  So 

             17     that we really don't think about it as a one-event 

             18     model, but just sort of something that unfolds until 

             19     the research is over.  And actually, you know, that 

             20     part of the proposal should be the investigator's plan 

             21     for disseminating the results of the study to the 

             22     research participant or subject and that that, you 

             23     know, sort of is perhaps and endpoint for this ongoing 

             24     conversation and decision-making process.  

             25               DR. DORFF:  Sandy was next. 
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              1               DR. CHODOSH:  I have a couple of concerns.  

              2     One, you mentioned videotaping the process.  I think 

              3     that raises a whole bunch of other problems in privacy, 

              4     confidentiality, maintaining of such records, I just 

              5     envision a whole new area of problems.  It's not a 

              6     problem for a lot of minor risk studies.  It certainly 

              7     would be a problem for the kinds of studies where you 

              8     really want to know what happened in terms of 

              9     maintaining that kind of a file.  You know, even if 

             10     it's on CDs, it's going to be a -- yes, you worry about 

             11     that. 

             12               My other is something I brought up at the 

             13     last meeting and that is that the idea of separating 

             14     these into two different kinds of functions, one about 

             15     the research and the other about all the legalistic 

             16     things that always have to be covered, but frankly 

             17     about which most subjects are not as interested in as 

             18     what's going to happen to me.  They're not quite as 

             19     concerned down the road if I get injured because 

             20     somehow they think they will be taken care of.  They 

             21     are concerned about are we going to have 15 needle 

             22     sticks in three minutes.  That would concern them. 

             23               It would really make sense if -- we go 

             24     through this business that the comprehension is aimed 

             25     mainly at the research and that, yes, there has to be 
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              1     some comprehension.  But maybe we need to make that a 

              2     contract, the other aspect, make it a contract.  You 

              3     know, if that's what people want, because that's what 

              4     the legal people at most institutions want, you know, 

              5     and just cover those items that clearly have some legal 

              6     implications for what will happen with that individual. 

              7               MS. MEYERS:  Could I answer that?  On the 

              8     videotape thing, all three of my children have been in 

              9     clinical research and all of them are videotaped when 

             10     they are given the informed consent.  And if they 

             11     didn't want to go into research, it wouldn't be a 

             12     problem.  But when they agree to go into research, part 

             13     of it is that they agree to be videotaped during the 

             14     process.  And it's not going to be shown on TV, it's 

             15     kept in some vault somewhere.  

             16               DR. DORFF:  Yes, I think what Sandy is asking 

             17     is, what are the privacy guarantees in regard to those 

             18     tapes?  

             19               MS. MEYERS:  I would hope that they're the 

             20     same as the privacy guarantees for the whole thing, 

             21     your medical records and videotapes and whatever. 

             22               DR. DORFF:  So that's one of the things that 

             23     the committee needs to at least mention; right?  I 

             24     think that's his point. 

             25               MS. MEYERS:  Uh-huh.  Okay. 
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              1               And the second thing is, I really would 

              2     object to making a contract.  I think that's been the 

              3     problem with informed consent over the last ten years, 

              4     at least, that they have proceeded to become a legal 

              5     contract.  And many times I'll say to an investigator, 

              6     this informed consent is different than the one that I 

              7     saw six months ago.  And they'll say, well, the lawyers 

              8     got ahold of it.  And the lawyers are always putting in 

              9     legal things to protect the institution and it has 

             10     really eroded the effect of informed consent documents. 

             11      And I think that people are -- do care very much about 

             12     how much am I financially responsible for?  What 

             13     happens if my insurance doesn't pay?  What happens if 

             14     I'm injured and I have to come back into the hospital? 

             15      Who is going to pay the bill?  They're very much 

             16     interested in that. 

             17               DR. DORFF:  You probably have more than you 

             18     need on your plate, frankly, but one of the things I 

             19     would be interested in knowing is the degree to which 

             20     those kinds of documents actually do protect 

             21     institutions from legal suit.  Given the fact that 

             22     everybody knows that they're signed without ever being 

             23     read, let alone understood.  The real question is, what 

             24     have the courts done with these documents when push 

             25     comes to shove? 
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              1               MS. MEYERS:  We only know about Jesse 

              2     Gelsinger and Ellen Roche, the two deaths that we've 

              3     heard about.  So we don't really -- never went to 

              4     court, so --  

              5               DR. DORFF:  Okay.  I have Susan, Bob, Alan, 

              6     anybody else?  Oh, Mary Kay again, and Margaret.  Okay. 

              7               MS. KORNETSKY:  I have a couple different 

              8     comments and I don't know if they're specifically for 

              9     Abbey or for Judy or whatever because it sounds like a 

             10     lot of these things are sort of flowing from one group 

             11     to another.  But whatever the workgroups do and I 

             12     understand -- I'm now being put on this group as well. 

             13      I think it's important to think, Abbey, about a 

             14     variety of methods and we talked a little bit about 

             15     this at lunch, that I'm very against sort of 

             16     proscribing one particular thing for assessing the 

             17     informed consent process. 

             18               There have been discussions about 

             19     ombudspersons in the informed consent process.  We 

             20     actually had a situation where we tried that.  We 

             21     wanted to try it.  It was an AIDS trial and we ran into 

             22     all kinds of issues with confidentiality and having a 

             23     third party there.  There are also limitations in 

             24     certain types of studies with testing.  Afterwards, if 

             25     someone understands immediately after, do they remember 
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              1     in a week, do they remember in two months?  Does that 

              2     mean they weren't informed, does that mean informed, so 

              3     there are also limitations that are there.  None of 

              4     these I'm saying that shouldn't be done, but I think 

              5     there's no one solution. 

              6               I think the other thing is, even looking at 

              7     ways of presenting information and helping people 

              8     understand.  There have been some studies that use 

              9     videos to help provide information that people can take 

             10     home.  There's also the format of the form.  Things 

             11     like that are important to avoid over legalese type 

             12     things.  There are flow charts, there's different types 

             13     of things within the process. 

             14               And I also really also speak to the fact of 

             15     what Mary Faith mentioned about it being an ongoing 

             16     process.  I recently spoke with some nurses who get 

             17     consent in oncology trials and said to them, you know, 

             18     can you really truly get informed consent at that first 

             19     time and they said, there's no way that you can do 

             20     that.  However, what their commitment was, every time 

             21     when the individual comes in to go over what's being 

             22     done, to remind them that it's voluntary and to have it 

             23     as part of the process continue as part of the trial. 

             24               And, lastly, there are other types of things 

             25     that can be done.  If there are ways to have 
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              1     individuals talk with other participants in research, 

              2     also educational types of efforts, helping individuals 

              3     understand the types of questions they should be asking 

              4     during an informed consent process throughout the 

              5     trial.  So I'm not sure where these comments that may 

              6     go into many of the different groups, but I don't think 

              7     there's a one-size-fits-all and just the groups have to 

              8     be flexible.  And I think what IRBs can use most are 

              9     some creative ideas and ways of thinking about it. 

             10               DR. DORFF:  Bob's next.  

             11               DR. R. LEVINE:  Thank you.  The issue of 

             12     videotaping, that's been tried.  There's one famous 

             13     study where people went through a very meticulous 

             14     informed consent process to open heart surgery and two 

             15     weeks later were questioned about the experience.  Two-

             16     third of them said there had never been any informed 

             17     consent, much less what the details were.  

             18               I don't think this is at all surprising.  I 

             19     think that whenever we're called upon to make a big 

             20     decision, we take all of the information, we process it 

             21     one way or another, if you follow the advice that Abbey 

             22     just gave and which we at Yale also do, ask people to 

             23     take the consent document and the protocol to talk it 

             24     over with their doctor, their family, whoever they 

             25     consider a good consultant, at one point you have it 
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              1     all together and you make your decision and then you 

              2     clear the circuits for the next decision.  

              3               I think earlier today somebody invoked the 

              4     memory of Ted Woodward.  I want to invoke the memory of 

              5     Ted's son Bill who did a study at the Maryland State 

              6     Prison System where he found a way to get people to 

              7     remember the details of informed consent.  He assembled 

              8     the prisoners, and he said, we're going to do some 

              9     research on an anti-cholera drug.  And I'm going to 

             10     give this group a lecture and I'm going to come back 

             11     tomorrow and give you a test.  And if you don't get a 

             12     passing grade on this test, you're not allowed to be a 

             13     research subject. 

             14               Not only did they all get a passing grade, 

             15     but they did better than the second-year medical 

             16     students in the pharmacology course --  

             17               [Laughter.]  

             18               DR. R. LEVINE:  -- I'm not finished.  They 

             19     did better than his colleagues in the tropical medicine 

             20     department.  Because they had a motivation, they wanted 

             21     to be research subjects.  So we know a little bit about 

             22     what can motivate people to remember.  What we don't 

             23     know is whether or not that's the most important aspect 

             24     of informed consent. 

             25               I think the most important aspect is 
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              1     comprehension.  And there are devices to measure 

              2     comprehension during the process.  I'm not going to 

              3     bore you with the details now. 

              4               Finally, I want to say, there can be no doubt 

              5     about it that the purpose of the written document is to 

              6     protect the institution and the investigators against 

              7     the subject.  The process is to give the subject or 

              8     prospective subject the wherewithal to protect her or 

              9     his own interest.  But the document turns it around.  

             10     We do our best to create documents that also serve some 

             11     of the interests of the subjects.  

             12               Elliot asked, is there any evidence that 

             13     these things are good at protecting the interests of 

             14     the institution?  To that I would respond that we've 

             15     been at it now since, let's say the late 1960s.  So far 

             16     there has been no successful litigation at a reported 

             17     case level that people have failed to get informed 

             18     consent to research when the research has been reviewed 

             19     and approved by an IRB.  And that can be contrasted 

             20     with, I would roughly estimate that there are 20 or 30 

             21     successful cases a week in the context of medical 

             22     practice. 

             23               One of the big differences is the meticulous 

             24     detail of the consent form and the presumption the 

             25     court usually makes is that if you looked at this piece 
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              1     of paper, you should have understood all this stuff 

              2     before you agreed to go along with it. 

              3               I'm not saying that's evidence that we've 

              4     accomplished something that I think is wonderful, but 

              5     it is evidence that responds to your question, Elliot, 

              6     they are effective defenses if that's what we want to 

              7     create. 

              8               I've said enough.  Thank you.  

              9               DR. DORFF:  Alan. 

             10               DR. FLEISCHMAN:  Elliot, the report that 

             11     Abbey gave us was from which of the workgroups? 

             12               DR. DORFF:  This is on the informed part.  In 

             13     other words, how do we make sure that information has 

             14     been transmitted?   

             15               DR. MORENO:  Which means assessing.  

             16               DR. DORFF:  That's right.  Which has amounted 

             17     to -- which means assessing understanding. 

             18               DR. FLEISCHMAN:  Okay.  

             19               DR. DORFF:  In other words, that we 

             20     understand that it doesn't -- that it no longer means 

             21     just simply cognitive information, but that it means 

             22     comprehension or understanding. 

             23               DR. FLEISCHMAN:  May I suggest that perhaps 

             24     you may need another mini-workgroup.  And that is --  

             25               [Laughter.]  
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              1               DR. FLEISCHMAN:  Hey, I didn't say you should 

              2     do it all at the same time, but on the content.  

              3     Because I don't see it here.  Everything that you're 

              4     focusing on is process and assessing whether people 

              5     have heard something.  But most IRBs are faced with 

              6     documents that are five, eight, 12 pages long. 

              7               Now some people talking about executive 

              8     summaries of documents which, you know, kind of sounds 

              9     a little strange.  But, I think we need to come to 

             10     grips with that in this whole question of informed 

             11     consent as to how much is too much, and, you know, what 

             12     is the appropriate reasonable amount that would be both 

             13     reasonable and ethical and legal. 

             14               Second comment, I want to add to Mary Faith's 

             15     comment.  I think we have in the information explosion 

             16     a great opportunity to do what I think a lot of people 

             17     have begun to call it continuous informing, or 

             18     continuous information delivery.  By that I mean the 

             19     process of informed consent can continue throughout the 

             20     entire study.  I think that's really what Mary Faith is 

             21     talking about and that we ought to be developing new 

             22     and innovative methods of informing subjects and 

             23     continually informing subjects.  And even subjects who 

             24     don't have computers at home will be back to the 

             25     clinic, will be back to the academic center and will be 
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              1     able to use those materials.  And I really think we 

              2     could do a service by thinking about how to study the 

              3     effectiveness of these things. 

              4               I'm very nervous about prescription, like 

              5     Susan.  These are all questions that can be empirically 

              6     studied as to whether at the end of the day or at the 

              7     end of the week or the end of the six weeks we will 

              8     have done any good before we prescribe.  So one of the 

              9     things the informed consent workgroup may come out with 

             10     is a challenge to NIH or others to come up with 

             11     research RFPs to look at some of these questions that 

             12     we might help them lay out as we, you know, begin to 

             13     think about some of these alternative methods to do 

             14     this work. 

             15               DR. DORFF:  I have Margaret and then Mary 

             16     Kay, and then I wanted to say something, and the 

             17     Felice.  Okay. 

             18               Oh, I'm sorry, Kate, go ahead.  

             19               MS. GOTTFRIED:  Just two points.  One in 

             20     relation to what Alan just said.  Are you talking then 

             21     again, not being too prescriptive but sort of coming up 

             22     with a guideline for a generalized inclusion criteria 

             23     of what ought to be in the informed consent. 

             24               DR. FLEISCHMAN:  You know, I guess I was 

             25     talking about two different things at the same time so 
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              1     I wasn't clear.  One is I think yes, we need to talk 

              2     about the content and the inclusion criteria.  And 

              3     second, apropos to the process and ascertainment of 

              4     whether people are understanding what's going on.  I 

              5     think we need to think about that in a non-prescriptive 

              6     way that can be studied. 

              7               MS. GOTTFRIED:  Right.  Okay.  And the other 

              8     point, just so when you talked about sort of an ongoing 

              9     iterative process, that is something that came up in 

             10     another mini-workgroup that Judy will report on.  

             11     Because that is something -- that group is focusing on 

             12     who ought to be engaged in the process of obtaining 

             13     informed consent and one of the issues raised was in 

             14     fact how ought the process ought to be conducted and 

             15     should it be in an ongoing basis intermittently 

             16     throughout the life of the protocol.  

             17               DR. DORFF:  Okay.  Margaret. 

             18               MS. BORWHAT:  A lot of the comments have 

             19     already been said, but briefly, I would like to 

             20     reinforce Abbey's position that the documents be able 

             21     to go home.  I know a lot of people make their decision 

             22     based on the influences of their family member and in 

             23     fact are inclined to perhaps change their decision.  I 

             24     think they should have access to the full protocol.  

             25     And I would suggest that perhaps audiotaping might be 
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              1     easier especially for those with limited funding, they 

              2     would be able to bring that home and use that at home. 

              3      And if they didn't have a particular device, that's at 

              4     a cost point where it's cheap enough for people to be 

              5     able to provide that, lend that to them for them to 

              6     bring it home and use it at home. 

              7               DR. DORFF:  Mary Kay. 

              8               DR. PELIAS:  Thank you.  I'd like to throw 

              9     another wrinkle into this which is going to create 

             10     another series of headaches and that is how state 

             11     legislatures have dealt with this problem of consent 

             12     and the question of protecting the interests of the 

             13     institution as opposed to the subjects or the patients. 

             14      Some state statutes, for example, create a presumption 

             15     in their dealing with informed consent.  They create a 

             16     presumption that in individual subject's or patient's 

             17     signature on a document is -- that the individual's 

             18     signature implies an understanding of everything in the 

             19     document.  So if it goes into court, the presumption 

             20     is, with the signature that the individual subject or 

             21     patient understands everything.  And then if it goes a 

             22     step further, and the patient or the subject decides to 

             23     take an issue to court, feels that he or she has been 

             24     wronged, the burden of the proof then shifts from -- it 

             25     shifts to the plaintiff or the subject who may have 
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              1     very little understanding of what is going on, but is 

              2     then saddled with the burden of the proof.  

              3               And this is not the only state statutory 

              4     approach to it, but I think it's something that needs 

              5     to be at least acknowledged and that not only 

              6     acknowledged but that there are different state 

              7     approaches to this problem as well.  Thank you.  

              8               MS. MEYERS:  Yes, I think that that's a 

              9     question that we have to look at in a lot of issues 

             10     that we're dealing with whether the state law should 

             11     take precedence over the federal law.  And since a lot 

             12     of the informed consent process is put back into local 

             13     control, I would assume that some state laws would 

             14     override it.  But we would need our lawyer to figure 

             15     that one out and what should be recommended. 

             16               DR. DORFF:  Okay.  I have Felice and then 

             17     it's my turn and then Jonathan. 

             18               DR. F. LEVINE:  I sort of had a responses at 

             19     a variety of levels.  And I think, Abbey, that you're 

             20     kind of cutting into this in useful ways.  I think that 

             21     we -- it seems a threshold question is what do people 

             22     need to know to make an informed decision and then how 

             23     to engage in that process in a way that indeed permits 

             24     an informed decision, reduces social desirability 

             25     responses, and other kinds of noise that affect and 
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              1     provides information in a concise and accessible way 

              2     and tells them indeed what they need to know and not a 

              3     lot of things that perhaps they don't need to know. 

              4               I the emphasis on it being a continuous 

              5     process is an important one.  It also is a developing 

              6     process.  At different stages you may need to know 

              7     certain things that you don't need to know at earlier 

              8     stages depending upon where you are at. 

              9               I think for me the biggest challenge for the 

             10     working group, and I want to say this as a colleague 

             11     scientist and researcher and citizen, not as a social 

             12     scientist at this table, and that is, how do we have -- 

             13     it's a challenge with all of our groups, but I think 

             14     this -- there's no issue that's more important than the 

             15     consent. 

             16               I mean, I know we've got two working groups 

             17     and this one is a big and important one and yet both 

             18     the expertise of the working group and our expertise is 

             19     largely both health of which actually a lot of my own 

             20     is largely both health and clinical.  And so the 

             21     conversation unfolds with just a very narrow piece of 

             22     the pie Susan started mentioning.  We need to look at 

             23     different methods of inquiry, different topics.  We're 

             24     talking about how, of course, the regulations reaches 

             25     all forms of research.  Research in educational 
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              1     settings, work settings, in different countries and 

              2     cultures, in families at home, on the street, and yet 

              3     not -- the direction in which we're thinking about 

              4     perfecting and enhancing is really a very critical but 

              5     small piece of that pie.  So I'm very interested in how 

              6     we elaborate the consideration of this issue to embrace 

              7     the various topics and nature of inquiry.  I'm going to 

              8     stick away from fields of science; methods, topics of 

              9     inquiry. 

             10               Also we're talking about intervention.  

             11     Remember, it's also interaction.  And so that we need 

             12     to be thinking about work where there isn't an 

             13     intervention, but where there's an interaction.  We use 

             14     the language every time the subject comes in, well, a 

             15     vast amount of research the subject isn't coming in at 

             16     all.  The researcher is going out.  Or the research is 

             17     going out. 

             18               Just this past week I received two surveys in 

             19     the mail.  It must be national survey week. 

             20               [Laughter.]  

             21               DR. F. LEVINE:  One approaching me on -- 

             22     luckily I could say I wasn't a forensic psychologist.  

             23     I guess I was one once in may last life.  So I was able 

             24     to check that off.  But, indeed, a lot of work 

             25     approaches and reaches people in a variety of 
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              1     distributional mechanisms. 

              2               And so I think the biggest challenge, or one 

              3     of the biggest challenges for the informed consent 

              4     working group and the three areas is how to address the 

              5     range of context of research and the range of modes of 

              6     inquiry.  And I'm very interested in us getting a jump 

              7     on this because I think it could be a terrific paradigm 

              8     for what we want to do more generally in the code and 

              9     that we have to get that jump early on in any way that 

             10     we can help do that.  

             11               DR. DORFF:  I have myself down next on the 

             12     list.  I have two things.  One is that it occurred to 

             13     me that there are people whose professional expertise 

             14     is how you educate.  And we probably ought to be 

             15     contacting some professional educators as to how you go 

             16     about gaining understanding.  Because, you know, 

             17     because they might have some very good ideas as to how 

             18     to go about doing this. 

             19               The second thing that I wrote down, I 

             20     remember when I was on the way here, when I was reading 

             21     Cathy's point, is that we have to be careful -- we have 

             22     to be clear about the goals of getting this information 

             23     in the first place.  One is to -- I'll tell you three 

             24     that came to my mind.  And I don't know that all these 

             25     three goals are valid, but I think that if -- and I 
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              1     think that the goal should determine the way that we 

              2     get the information. 

              3               One is to provide autonomy.  Right.  In other 

              4     words that we value the individual making decisions for 

              5     herself or himself and that therefore we have to give 

              6     the person enough information to be able to make a 

              7     decision. 

              8               Second, is to -- a second goal would be to 

              9     avoid assumed risks.  In other words, the reason why we 

             10     are imparting information is because there are some 

             11     dangers involved in what we're about to do and we have 

             12     a duty to try, first do no harm.  We have a duty to try 

             13     to protect people from harms and so if they are going 

             14     to be assuming certain risks, then we have to at least 

             15     warn them.  And third, a third goal behind providing 

             16     information is to produce participation.  And so -- I 

             17     mean, after it's all said and done, what we're 

             18     interested in is having research on human subjects so 

             19     that all of us can ultimately gain from that research. 

             20               Now, to that extent, the question then 

             21     becomes, well, don't we have -- I mean, we have 

             22     conflicting interests and on the one hand doing this 

             23     kind of human research and on the other hand, you know, 

             24     in which case we would not want to scare people too 

             25     much.  And on the other hand, we want to make sure that 
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              1     they have enough information so that they can protect 

              2     themselves. 

              3               So, I mean, I think that in terms of the 

              4     information that's provided, it's the kind of thing 

              5     that you have in the clinical setting also where you 

              6     want to provide enough information so that people know 

              7     what are reasonable risks without telling them every 

              8     possible thing that might go wrong, which is, of 

              9     course, everything.  

             10               So, I mean, there's got to be some standard 

             11     by which we measure the information that is conveyed to 

             12     make it reasonable for these goals, but not overly 

             13     burdensome. 

             14               MS. MEYERS:  One thing we did discuss, we did 

             15     discuss this whole thing about there is a presumption 

             16     that if the subject signs the informed consent that's 

             17     what's expected of them and it's like you win.  And if 

             18     they walk out without signing it, it's like a failure 

             19     and that presumption has to be taken care of because it 

             20     -- the subject has not only every right to decline, but 

             21     you have to expect that many of them will and you don't 

             22     want to be biased against them because they did.  

             23               DR. DORFF:  Okay.  I have Jonathan, Adil, 

             24     Greg, Sandy. 

             25               DR. MORENO:  I have a miscellaneous set of 
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              1     comments, but that seems to be the spirit of the 

              2     conversation.  I don't think we should be too jaundiced 

              3     about how far we've come in the last 30 years.  I mean, 

              4     there is one accomplishment in the several decades in 

              5     which people have been talking about this that I think 

              6     we ought to recognize namely that for the most part 

              7     people know they are in research when they are in 

              8     research.  That was not the case so far as we can tell, 

              9     30 or 40 years ago, and that is really an 

             10     accomplishment.  That's the first threshold you have to 

             11     get over.  

             12               The subject interview study that Jeremy 

             13     Sugarman ran for the Radiation Advisory Committee which 

             14     interviewed or surveys 1900 subjects in radiation 

             15     oncology, medical oncology and cardiology studies that 

             16     concluded that 92 percent -- 92 percent said that they 

             17     were in research and they were.  Conversely, over 30 

             18     percent said they were in research and they weren't.  

             19     Which raises other interesting questions about people's 

             20     level of paranoia about these things.  It's probably 

             21     healthier than we think, or at least higher than we 

             22     think. 

             23               An exception, of course, is procedures, 

             24     particularly surgical procedures which may well be 

             25     research and which are not called research in all 
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              1     cases, but I'll leave that to another occasion.  

              2               Secondly, they are contracts, these forms, 

              3     they've always been contracts.  In fact, it's only 

              4     since the pointy-headed ethicists and research 

              5     advocates, the human research subject advocates in the 

              6     last 30 years or less started worry about the 

              7     interpersonal relationship between the investigator and 

              8     the subject that there has been any concern about that. 

              9      And then there had been lots of ambitious statements 

             10     made by theologians and philosophers about how they 

             11     areal estate really co-adventurers in the process and 

             12     so forth.  So in fact, in that respect also the 

             13     conversation has gotten richer than it was 30 or 40 

             14     years ago.  So we've gotten a little further and we 

             15     shouldn't be too hard on ourselves.  But it is -- 

             16     certainly there are lots of things we can do to move 

             17     things along, I agree.  

             18               I was surprised when Susan said that the 

             19     research ombudsman or advocate concept didn't fly in 

             20     Boston because -- well, the general clinical research 

             21     centers, as a number of people here know, have been 

             22     funded by NIH and there are about 75 GCRCs or CRCs, 

             23     each of them to have their own research subject 

             24     advocate and I think those people have just had their 

             25     first meeting.  I know Greg was there, spoke to them. 
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              1               There is probably some information that we 

              2     should have as this work goes forward from that group, 

              3     perhaps two or three of them or some representative 

              4     person from that group of -- that's a group that's 

              5     actually going to be learning how to do this and 

              6     sharing information and so forth.  And presumably they 

              7     didn't have a confidentiality problem.  I don't know 

              8     why and I presume they're all medical staff and so 

              9     forth.  So perhaps that's the reason it's not an issue. 

             10               The term, Elliot, that's often used to 

             11     distinguish between what is perhaps minimally accepted 

             12     cognitively and what we really would like, which I 

             13     think what you were talking about is from understanding 

             14     to appreciation.  Appreciation being the level at which 

             15     we get to apply, we're able to apply our own values and 

             16     goals and quality of life, life plans, life objectives 

             17     to this decision. 

             18               I think we are in a funny position when we 

             19     talk about autonomy and then talk about making sure 

             20     that people can take it home to talk to everybody that 

             21     they know about this decision.  And maybe somebody like 

             22     Felice can help us with this because really what we're 

             23     talking about is not autonomy or self determination in 

             24     some socially atomic way, but the reality that people 

             25     operate in families and communities and maybe your 
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              1     group can advance the conversation by making it less 

              2     artificial with respect to how these decisions actually 

              3     get made.  And maybe they're going to have to recruit 

              4     Felice or another social scientist to talk about that. 

              5               Finally, there's one, not only is it true as 

              6     Mary Kay mentioned that people are illiterate in their 

              7     problems with language, people are also enumerate.  And 

              8     so how risks get communicated needs to be a topic, it 

              9     seems to me, not just what this is about, but how do I 

             10     -- how competently can people assess their chances?  

             11     One out of 100, well, that's me.  So, should those 

             12     kinds of numbers be in forms?  Lawyers do like to have 

             13     all the numbers that the investigators have in the 

             14     form, but those numbers need to be interpreted.  And 

             15     there are a few people, not many, who are working on 

             16     how you communicate risk to people who -- to ordinary 

             17     folks and to people who even have less than the 

             18     standard capacity to understand what numbers mean. 

             19               DR. DORFF:  Adil is next. 

             20               DR. SHAMOO:  Thank you, Elliot.  

             21               When we talk about state/federal relationship 

             22     laws, I think I would recommend Jack Schwartz who is in 

             23     the Maryland Attorney General's Office and he was the 

             24     consultant for NBAC that we consult with him.  He is 

             25     really an expert between state and federal relationship 
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              1     when it comes to human research protection issues.  He 

              2     has been involved in this issue for about six, seven 

              3     years.  

              4               Having said that, my understanding is that 

              5     state laws do not preempt federal laws unless the 

              6     federal law is embedded in it, a section saying that 

              7     they are allowed to do so.  And that's rarely the 

              8     federal government gives that right to the states.  And 

              9     furthermore, Mary Kay talked about that the states, 

             10     they may have a law, et cetera.  However, going to 

             11     federal courts preempts that as it becomes the state 

             12     law, whatever they have said about informed consent is 

             13     irrelevant and some of these lawsuits have gone to the 

             14     federal court and some of them at least have been one, 

             15     at least one I know of has been one. 

             16               Furthermore, Bob Levine said about there 

             17     hasn't been that many cases in court about research 

             18     subject issues.  

             19               DR. R. LEVINE:  [Off mic.]  Bob Levine said 

             20     no such thing. 

             21               DR. SHAMOO:  That's correct.  Okay. 

             22               DR. R. LEVINE:  [Off mic.]  

             23               DR. SHAMOO:  Okay.  You said what you said.  

             24     Exactly since I can't verbatim say -- none of here can 

             25     say verbatim exactly what you said. 
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              1               DR. R. LEVINE:  [Off mic.]  What you quoted 

              2     me as saying conveys different meaning.  I don't mind 

              3     if you change the words, but not the meaning. 

              4               DR. SHAMOO:  What is your meaning?  Let's 

              5     make sure what is your meaning?  You --  

              6               DR. R. LEVINE:  Almost no cases --  

              7               DR. SHAMOO:  Yes. 

              8               DR. R. LEVINE:  -- when research has been 

              9     conducted according to a protocol reviewed and approved 

             10     by an IRB have been found against the investigators on 

             11     grounds of failure to get informed consent consent.  

             12               DR. SHAMOO:  Okay.  That was my correct 

             13     understanding despite what you said.  Despite what you 

             14     said, there has been a case on dignitary harm in 

             15     Florida have been one in federal court. 

             16               DR. R. LEVINE:  That did not get tried in 

             17     federal court.  That was an out-of-court settlement, 

             18     $3.8 million. 

             19               DR. SHAMOO:  Okay.  I stand corrected.  

             20     Anything else? 

             21               DR. R. LEVINE:  No.  

             22               DR. SHAMOO:  Wait a minute.  And having said 

             23     that, that the informed consent has been used as a 

             24     contract and I'll give you an example of that, the lead 

             25     case in Maryland has been sued based on negligence.  
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              1     And what I'm trying to say, the message is that there 

              2     may have been a lot of cases where it is research 

              3     except lawsuits have been on negligence, medical 

              4     negligence because there is a huge amount of court 

              5     cases and it's easier for them.  And the case in 

              6     Maryland that is the basis of it is negligence, medical 

              7     negligence, not research subject issue. 

              8               DR. R. LEVINE:  What you say is correct, but 

              9     utterly unrelated to anything I said.  I'm talking 

             10     about informed consent. 

             11               DR. DORFF:  Okay.  We need to go to Greg and 

             12     Sandy and then I want to ask Judy to talk about 

             13     subgroup two.  

             14               DR. KOSKI:  Elliot, I want to just take issue 

             15     with one of the things that I thought I heard you say 

             16     and that is that one of the goals of the process of 

             17     informed consent was to gain participation.  Now, that 

             18     may, in fact, be the case in the way that it has been 

             19     conducted, but I would argue that conceptually, and 

             20     perhaps attitudinally that's flawed because in fact, I 

             21     think I mentioned this in the last meeting when we were 

             22     talking about this, the very use of the term, informed 

             23     consent, implies an outcome of the process that in fact 

             24     leads us down a road that is not really where we want 

             25     to go.  
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              1               The goal here is to help the individual that 

              2     we're asking to participate to make an informed 

              3     decision.  And, indeed, if you put this process into 

              4     the context of a continuing process, informed 

              5     participation would be something that we would want to 

              6     achieve.  So I'm just cautioning the use of the words 

              7     and the -- again, the approach that is taken is one 

              8     that we need to be careful about.  Because the notion 

              9     of trying to use the process to gain participation, in 

             10     fact, may be contrary to the desired outcome. 

             11               DR. R. LEVINE:  Let me make a comment on that 

             12     point.  That the original term was voluntary consent in 

             13     the Nuremberg Code.  The reason that it was replaced in 

             14     1957 by the word "informed consent" was curiously as a 

             15     result of an amicus brief filed by the American College 

             16     of Surgeons who on this occasion were opposing the 

             17     whole idea.  But they persuaded the judge that 

             18     "informed" was the same as "voluntary" and here we are. 

             19               DR. KOSKI:  Well, I guess my point, Bob, is 

             20     that I would hate to see the group get somehow trapped 

             21     by it's own words in terms of where that leads you with 

             22     respect to process so that again, moving away, even as 

             23     we said, to the notion of informed decision-making, 

             24     informed participation or voluntary, whatever, is 

             25     something that, again, helps us get beyond the box that 
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              1     we're currently in.  

              2               DR. DORFF:  Greg, I agree with you, that's 

              3     the reason why I said of the goals.  I'm not completely 

              4     sure that all of them are good goals, but these are the 

              5     kinds of things that people might have in mind when 

              6     they think about this.  And what you're saying is 

              7     right, I think, that the last of those goals that I 

              8     mentioned is problematic.  I think you're right about 

              9     that. 

             10               Sandy. 

             11               DR. CHODOSH:  I just want to come back to 

             12     something that Felice mentioned and it's something that 

             13     apparently has not been considered.  And that is, I 

             14     guess I've obtained or been involved in obtaining 

             15     consent from several thousand subjects over my career. 

             16      In most of those they were in studies studying acute 

             17     pulmonary infection.  You can't send someone home for a 

             18     day to think about are you going to -- you know, do you 

             19     really want to do this because that's unethical.  So 

             20     that there are some special concerns that have to be 

             21     taken into consideration in all kinds of emerging 

             22     situations where you must start something right away.  

             23     So, therefore, special care needs to be taken in how 

             24     you obtain consent in those situations.  

             25               Now, fortunately, most of these situations 
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              1     are those in which, quotes, the subject is going to get 

              2     some kind of treatment.  It may not be considered to be 

              3     -- I know some people are purists and say, that's not 

              4     treatment, but indeed it is treatment and they know 

              5     that and it does sway them.  So you have to be careful 

              6     that that is not the predominant feature of why they 

              7     say yes.  But that has to be in there.  And there are a 

              8     lot of emergency situations where you can't get 

              9     conformed consent. 

             10               DR. DORFF:  Okay.  We move now to subgroup 

             11     two.  Judy, if you would.  This is about the process. 

             12               DR. SIEGEL:  A lot of what I'm going to say 

             13     has actually been said.  I'm going to say it anyway, 

             14     again, but with a different twist, hopefully.  

             15               [Laughter.]  

             16               DR. SIEGEL:  I just want to read what I think 

             17     is how we understand what the question is to our group 

             18     which is in the larger context of issues around gaining 

             19     informed consent.  There is a question of who should be 

             20     involved in the informed consent process and help bring 

             21     the research subject to the point of initial consent 

             22     and continuing consent thereafter. 

             23               So that's the sort of general -- again, 

             24     continuing on the question, it is assumed that the 

             25     informed consent process is in place to educate the 
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              1     subject about the research study for which they are 

              2     volunteering to insure that they have been given all 

              3     the information about the study, what's generally 

              4     included in the informed consent form, but we would 

              5     also go on to say, and also outcomes during the 

              6     research process so that they're getting all of the 

              7     information and that they understand the possible risks 

              8     to themselves engendered by participating in the 

              9     research, et cetera, et cetera.  

             10               The process of informed consent does not end 

             11     with the signing of the informed consent form and it is 

             12     the responsibility of the investigator or whoever to 

             13     ensure that the subject continues to remember and 

             14     understand the elements of the research and continues 

             15     to agree to participate.  So I think that's sort of the 

             16     context in which we're talking about who should be 

             17     giving informed consent. 

             18               What we've done is we've listed sort of an 

             19     overview of varying points that discussions with 

             20     potential participants and participants occur from 

             21     initial screening that may be phoned into a phone-in 

             22     number all the way through the treatment phase of the 

             23     study and to the end of the study.  And we've asked 

             24     some questions about who is, should be, or could be 

             25     involved in each one of those -- at each one of those 
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              1     points.  And some of the general questions are, what 

              2     issues about obtaining informed consent accrue back to 

              3     the person who is responsible for the discussion?  

              4     Examples are, is the person impartial and how impartial 

              5     does a person have to be who is having these 

              6     discussions with potential subjects or actually 

              7     subjects who have already consented to participate? 

              8               Does the person who is actually having these 

              9     discussions adequately understand the study and the 

             10     issues that the person who is actually being asked to 

             11     participate have in participating in the study.  Does 

             12     this person, whoever they are who is engaging in this 

             13     discussion with the subject have the skills to 

             14     facilitate a good informed consent discussion?  And I 

             15     don't think we've actually talked about what those 

             16     skills actually might be. 

             17               And then, in general, does the IRB or the 

             18     investigational site or whoever is involved really 

             19     understand what is involved in a good informed consent 

             20     discussion and how to maintain it throughout? 

             21               We also then sort of talked about, well, what 

             22     are the potential problems for a subject if the wrong 

             23     person is giving informed consent and what are some of 

             24     the risks?  And then who should be involved and why? 

             25               So, again, we have this whole laundry list 
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              1     that we can apply to various points during the consent 

              2     process.  To someone's point before I actually had a 

              3     very nice back and forth of e-mails with Jeremy 

              4     Sugarman saying, well, we've laid out the questions, 

              5     can you help point me -- sort of chairing this about 

              6     the literature I should go to.  And his comment back to 

              7     me, Mary Faith, was, "this was huge" big letters.  

              8               [Laughter.]  

              9               DR. SIEGEL:  You know and so one of the 

             10     questions that I would like to ask as we sort of start 

             11     to put this together is, this could be a huge document. 

             12      This is at least a framework for maybe asking some of 

             13     the questions and how far into the literature or to 

             14     Alan's point do we actually need to get some more 

             15     research on this, do we actually want to go to put this 

             16     together? 

             17               DR. DORFF:  Okay.  

             18               MS. GOTTFRIED:  Well, in partial response, I 

             19     had thought about that some and I did have occasion to 

             20     touch base with Jeremy as well recently about this 

             21     particular issue and how extensive it is.  And one of 

             22     the thoughts that I had in talking with him was in fact 

             23     commissioning a paper by somebody with particular 

             24     expertise in this area.  And he was going to think of 

             25     some names and get back to me shortly. 
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              1               The other thing is, I think, Susan, it might 

              2     be useful for you to mention what you said about your 

              3     attempt to get some access to the NIH monies and what 

              4     your institution is endeavoring to do. 

              5               DR. SIEGEL:  Well, we don't have the funding 

              6     yet.  But we are -- our institution is applying for 

              7     funding as many institutions are for money from NIH 

              8     that's available.  And what we have thought about doing 

              9     is to hire someone for a year's period of time at our 

             10     institution to really, number one, go through the 

             11     literature about the informed consent process, what is 

             12     known and to do something like that.  But then to 

             13     really spend time within the institution speaking with 

             14     lots of investigators, lots of research nurses, lots of 

             15     subjects who could be in focus groups, interviews, or 

             16     whatever, really to come up for our institution.  The 

             17     purpose is for our institution within pediatrics about 

             18     some guidelines about ways that we can improve the 

             19     process and in how we can evaluate whether that 

             20     improvement is taking place. 

             21               So that was, you know, some of our ideas.  It 

             22     may or may not be funded, and if it is, we'll be doing 

             23     something during the next year, hopefully. 

             24               DR. DORFF:  Okay.  Let me just take Alan and 

             25     then -- okay, go ahead.  
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              1               DR. FLEISCHMAN:  Judy, could you unpack this 

              2     concept of impartiality a little bit?  I had never 

              3     heard that suggested and I've certainly never seen it. 

              4      So where are you going with that? 

              5               DR. SIEGEL:  Well, I think the whole 

              6     discussion of is the investigator the appropriate 

              7     person to actually have the discussion?  And there's, I 

              8     guess, a certain group that says, well, maybe in fact 

              9     the investigator is the only one who can adequately 

             10     explain what is about to happen and then there is 

             11     another group that says, and, in fact, they may really 

             12     believe in this and be sort of overly.  So that's what 

             13     I meant by impartiality. 

             14               Us there a way to get the appropriate 

             15     information, which may be very detailed and complicated 

             16     to someone one without sort of pushing in the direction 

             17     that says, I really believe in this and so I want you 

             18     to -- you know, to Elliot's point, you know, are we 

             19     pushing people to participate in some way? 

             20               DR. DORFF:  Okay.  Kate and then I'm just 

             21     going to describe to you very quickly what the third 

             22     group has done and then Bob is on for 15 minutes, I 

             23     understand and then we're going to break.  Is that 

             24     right?  

             25               MS. GOTTFRIED:  Right.  Alan, also it sort of 
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              1     follows up on the issue that I think also came up in 

              2     the children's workgroup to some extent, the notion 

              3     that sort of an ombudsperson who would be sort of 

              4     divorced from the process, per se, the protocol, and 

              5     could ensure that there is a more objective, unbiased 

              6     process that unfolds so that we're obtaining, 

              7     quote/unquote, "informed objective consent."  And this 

              8     came up, I believe, at the hearing, also where -- was 

              9     it Shirley McThias, I think brought this issue up at 

             10     the hearing as well, and I heard this at a meeting I 

             11     was at recently too where thee's a request that there 

             12     be some sort of process built in for some sense of 

             13     impartiality, whether that would be in tandem with 

             14     someone from the protocol team who might be required 

             15     because of their expertise, et cetera.  

             16               DR. FLEISCHMAN:  I just think it would be 

             17     important to separate out the concept of consent 

             18     monitoring which has been talked about and written 

             19     aboiut, and creating a kind of new standard of 

             20     impartiality of informing.  That's a -- I mean, I'm not 

             21     opposing it.  I'd be interested in hearing more about 

             22     it.  But I think it's a very radical -- radical meaning 

             23     different, not radical meaning bad -- but very 

             24     different approach.  And I think, you know, it remains 

             25     to be seen how that gets sorted out. 
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              1               MS. GOTTFRIED:  Right.  

              2               DR. SHAMOO:  Elliot, just on that point.  We 

              3     have proposed probably, Alan, you know, for about six, 

              4     seven eight years that there be an independent 

              5     physician or independent professional who is 

              6     responsible for advising the subject whether it should 

              7     --  

              8               PARTICIPANT:   [Off mic.]  

              9               DR. SHAMOO:  No, should subject -- this came 

             10     up when we were talking about psychiatric research 

             11     because the psychiatrist have such a relationship with 

             12     their patients that it could be coercive when that 

             13     psychiatrist says, here is the type of research I want 

             14     you to enroll and you, blah-blah, you could benefit 

             15     from it.  And that's the context it was put into.  And 

             16     the 1998 NIH points to consider proposed that was one 

             17     of the points for consideration for the research 

             18     community in the mental health field. 

             19               And I'm sure Bob is going to find something 

             20     wrong in what I said.  

             21               DR. CHODOSH:  Oh, just along those lines.  

             22     Are we talking about a professional witness?  I mean, 

             23     you know, we talked about using witness signatures.  

             24     Are we really talking about a professional witness, or 

             25     whatever you want to call it? 
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              1               DR. DORFF:  It's something for you to think 

              2     about, Judy. 

              3               DR. SIEGEL:  Right.  

              4               DR. DORFF:  Okay.  Let me just tell you about 

              5     the third one, just very briefly.  The third group had 

              6     its first conference call last Thursday based upon a 

              7     paper that Skip Nelson had prepared for the VA 

              8     conference on informed consent in March of 2001.  And 

              9     based upon that we raised two primary questions.  The 

             10     first question is the one thing that we want to get to 

             11     is some kind of conceptual clarity as to what we mean 

             12     by "voluntary."  And here all of the literature in the 

             13     philosophic world about free will and all of that will 

             14     come to the fore. 

             15               Skip, himself, in the paper uses the 

             16     definition of a voluntary choice in Black's Law 

             17     Dictionary which is, "unrestrained by interference, 

             18     unimpeded by another's influence, spontaneous acting of 

             19     ones self, done by design or intention, preceding from 

             20     the free and unrestrained will of a person."  As usual, 

             21     when you have that many clauses you're in trouble. 

             22               One of those clauses is "unimpeded by 

             23     another's influence."  Well, of course, every single 

             24     one of our choices is impeded by other people's 

             25     influences.  I mean, maybe even vanilla, chocolate or 
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              1     strawberry.  So the thing is that it's a -- and it 

              2     should be mint chocolate chip anyway.  So anyway what 

              3     we are after is -- if not cherry garcia.  Anyway, what 

              4     we are after is conceptual clarity.  Okay.  As to 

              5     exactly what we're talking about when we're talking 

              6     about voluntary.  To what extent -- when do the various 

              7     influences that lead a person to decide X as opposed to 

              8     Y become undue influences?  That's really what we're 

              9     after. 

             10               And then the second question is, how do we 

             11     measure voluntariness?  It's hard enough to measure 

             12     information.  That's the kind of thing that Abbey was 

             13     talking about and conveying of understanding and 

             14     appreciation.  But how do you measure voluntariness? 

             15               Now, obviously there are some populations 

             16     where that's especially an acute concern like 

             17     prisoners, or people, or the decisionally impaired, 

             18     that's another group though.  But even if you're 

             19     talking about people who are mentally competent and who 

             20     are not under any particular restraints that we can 

             21     tell, that we can identify, how do you know when, you 

             22     know, the person is actually choosing this of his or 

             23     her own volition and when not?  And how do you measure 

             24     that.  So those are the two primary things that we 

             25     wanted to talk about. 
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              1               Okay.  We are already over because I guess 

              2     Bob has been promised 15 minutes and so if you would. 

              3               DR. R. LEVINE:  Do you want me to speak from 

              4     here? 

              5               CHAIRPERSON MARSHALL:  Why don't you come up 

              6     here, Bob.  

              7               DR. R. LEVINE:  I'm hoping I won't need the 

              8     entire 15 minutes.  I'm not as well prepared as I wish 

              9     I was and that's because all of the contents of the 

             10     hard drive of my computer vanished recently.  

             11               CHAIRPERSON MARSHALL:  His dog ate the 

             12     computer, I think is the story.  

             13               DR. R. LEVINE:  I beg your pardon? 

             14               CHAIRPERSON MARSHALL:  The dog ate your 

             15     computer. 

             16               DR. R. LEVINE:  The dog ate my computer.  I 

             17     don't know, I think it was a dragon, actually, the 

             18     Dragon Naturally Speaking program.  But I don't know 

             19     about that. 

             20               What I'm going to do is give a report of one 

             21     of the subcommittees of the subcommittee that's headed 

             22     up by Felice Levine and Jeff Cohen on the 

             23     interrelatedness of social behavioral research to the 

             24     -- or special problems in social and behavioral 

             25     research as regards protection of human subjects.  And 
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              1     more particularly I'm going to talk about the problems 

              2     with informed consent and consent forms in the 

              3     mainstream of social and behavioral research.  And this 

              4     is based upon a report that was draft by Joan Sieber 

              5     and me.  Joan couldn't be with us today, so I will 

              6     present it.  

              7               It's a long report.  It would take me much 

              8     more than 15 minutes to read it, so I'm just going to 

              9     pick out a couple of the highlights of the report. 

             10               For those of you who don't know, I'm not a 

             11     social scientist and I'm not a behavioral scientist.  I 

             12     am by training and inclination a natural scientist, a 

             13     clinical pharmacologist.  

             14               The biomedical focus has always posed 

             15     problems for social and behavioral research since it 

             16     set a default condition that was generally 

             17     inappropriate to social and behavioral research.  These 

             18     problems existed even in the 1970s through 1990s when 

             19     most IRBs more loosely interpreted the regulations in 

             20     ways that were generally not unduly restrictive of 

             21     social and behavioral research. 

             22               More recently things have taken a drastic 

             23     turn.  There has been a great concern around the 

             24     country amongst IRBs that they be very, very careful to 

             25     require anything that it might seem anyone else might 
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              1     consider would be required.  In large part this has to 

              2     do with the reports of various university research 

              3     centers being closed.  And when the reasons or what 

              4     people read as the reasons for these closures appear in 

              5     the newspapers, there's been a great concern about 

              6     making sure that these errors were apparent errors were 

              7     not repeated. 

              8               An important example of the nature of the 

              9     problem is the very surprising interpretation of the 

             10     definition of "human research subject" that gave us 

             11     what we have been calling the "third-party issue." 

             12               Now, for this reason, many IRBs in their 

             13     effort to go by the book require a signed consent form 

             14     even when this would be highly disrespectful of the 

             15     subjects.  For example, in cultures in which persons 

             16     are illiterate or do not believe in signing documents, 

             17     more generally within the mainstream western culture 

             18     Singer and Trice have found that a significant number 

             19     of subjects will refuse to participate even in surveys 

             20     or in studies and experiments if required to sign a 

             21     consent form, but would otherwise very gladly 

             22     participate.  The studies that I'm most familiar with 

             23     are those of Eleanor Singer who shows a very 

             24     substantial reduction in people willing to participate 

             25     even if after they finish their participation if 
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              1     they're asked to sign a document authorizing it. 

              2               No kidding.  They say, you're not allowed to 

              3     use my data. 

              4               Most social and behavioral research presents 

              5     no more than minimal risk.  The statement, quote, "no 

              6     procedures for which written consent is normally 

              7     required outside of the research context" is stated 

              8     with reference to medical procedures.  

              9               Consent forms are not used to document the 

             10     patient's willingness to be interviewed or to complete 

             11     questionnaires.  To cut to the bottom line here, our 

             12     group would like to present the argument that if we 

             13     apply the same standards to social research as are 

             14     applied to biomedical research, that it's rare that 

             15     social research gets much more invasive or threatening 

             16     than what's asked in a routine family history during a 

             17     routine medical examination.  And this then is one of 

             18     the criteria for waiving the requirement for 

             19     documentation of consent.  

             20               In the current regulatory climate many IRBs 

             21     treat social and behavior research as if it were very 

             22     risky.  The focus on very minor or unlikely risks has 

             23     resulted in lengthy negotiations between IRBs and 

             24     investigators and overly detailed, insultingly 

             25     paternalistic, informed consent procedures.  
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              1               That's our preamble.  I want to go and read 

              2     excerpts from the specific recommendations.  

              3               Recommendation one.  Informed consent should 

              4     take the form of an open, easily understood 

              5     communication process.  Typically this means a friendly 

              6     verbal exchange between researcher and subject. 

              7               Instead of having a consent document for most 

              8     encounters where the subject and the researcher 

              9     actually meet, there should be an information sheet.  

             10     This would be designed to uphold the interests of the 

             11     subject and the only person to sign it would be the 

             12     researcher and the subject would be given the copy. 

             13               Another point against using written documents 

             14     in lieu of consent discussions is there's been an 

             15     extreme focus in recent years on the readability level 

             16     of consent forms.  Those IRBs who do this usually are 

             17     striving to accomplish a sixth grade reading level.  

             18     What they seem not to pay attention to is that in our 

             19     cities as many as 25 or 30 percent of the subject 

             20     population can't read at any level.  When you rely on 

             21     the document then you are completely leaving out those 

             22     people who are less literate than a sixth grade reading 

             23     level. 

             24               The second recommendation, if there may be 

             25     risk of harm or inconvenience to certain subjects, it 
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              1     is important that subjects receive enough easily 

              2     understood information to judge whether the risk is at 

              3     a level they can accept.  I trust that that's non-

              4     controversial.  

              5               The third one is that the subject should be 

              6     informed very clearly that they're free to ask 

              7     questions at any time.  But they should always take 

              8     into account the context of the research. 

              9               As Felice pointed out earlier, sometimes the 

             10     investigator and the subject never meet.  But even in 

             11     these conditions, the subject can be provided with a 

             12     telephone number to call in case they want to ask some 

             13     questions. 

             14               Number four, when the subject can readily 

             15     refuse to participate by hanging up the telephone or 

             16     tossing out a mailed survey, the informed consent can 

             17     be extremely brief, often stated in one or two 

             18     sentences. 

             19               Number five, verbal informed consent need not 

             20     be detailed and written consent is not appropriate when 

             21     the research is not concerned with sensitive personal 

             22     information and when the subjects are peers or 

             23     superiors of the researcher.  This is what the social 

             24     scientist will refer to as studying up rather than 

             25     studying down.  And this is one of two recommendations 
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              1     on that point. 

              2               Number six, the cultural norms and lifestyles 

              3     of the subjects should be considered in deciding how to 

              4     approach informed consent.  This is something that's 

              5     been incorporated in the CIOMS international ethical 

              6     guidelines since 1993 where it's conceded that the 

              7     typical American IRB can't possibly understand what 

              8     counts as private information, what counts as informed 

              9     consent, what counts as undue inducement in the many, 

             10     many cultures that have elaborate gift exchange 

             11     traditions and so on.  So what we are hoping is that 

             12     somehow the system can be set up so that people who are 

             13     in a decision-making position can make their decisions 

             14     based upon a true knowledge of the cultural norms and 

             15     lifestyles of the actual subject population. 

             16               Number seven, IRBs should be flexible in 

             17     considering a wide range of media for administering 

             18     information.  This could include video tapes, 

             19     brochures, group discussions, web sites, community 

             20     newsletters, and Joan would also rely on the grapevine 

             21     in a way that I must learn how to understand a bit 

             22     better.  That's the only difference that Joan and I 

             23     have in this document at this point. 

             24               Number eight, when written or signed consent 

             25     to place the subjects at risk a waiver of the 
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              1     requirement for written documentation should be 

              2     considered.  That's very close to what the current 

              3     regulations say except that we would take on step 

              4     beyond.  The current regulations say, when the document 

              5     is the only thing that links the subject to the 

              6     research and confidentiality is the -- breech of 

              7     confidentiality is the only threat, we would go beyond 

              8     that and say, just because there's one link doesn't 

              9     justify creating yet another link to the private 

             10     information. 

             11               Number nine, to the extent that it may 

             12     enhance respect for and well-being of research 

             13     subjects, it may be desirable for the researcher to 

             14     consult with community representatives or leaders.  And 

             15     in certain types of projects it might be of value to 

             16     engage in a full fledged community consultation.  We 

             17     want to make it clear though that this recommendation 

             18     is not ever meant to provide a substitute for 

             19     individual and informed consent.  It's just designed to 

             20     create a setting in which it's more clear that the 

             21     research has the understanding support of the community 

             22     and also to begin to educate the members of the 

             23     community about the research program before anyone's 

             24     approach for individual informed consent. 

             25               Here is another one that was controversial 
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              1     within our group, but I hope we got it so that it's 

              2     less controversial now.  In organizational research 

              3     conducted by an outside investigator not commissioned 

              4     by the heads of the organization it is essential to 

              5     obtain the superior's permission to study subordinance. 

              6               The clarification that we achieved during our 

              7     group discussion is, we're not getting permission to -- 

              8     the permission that we get from the so-called superior 

              9     is the permission to enter the institution.  This does 

             10     not take the place of informed consent or the freedom 

             11     of particular individuals within the institution to say 

             12     yes or no.  

             13               I'm getting near the end. 

             14               Recommendation number 11, there are various 

             15     kinds of research that cannot be validly carried out if 

             16     all details are disclosed at the outset.  The 

             17     alternatives to outright deception of subjects are:  

             18     one, to obtain permission to provide only a description 

             19     of what the subject will experience with an agreement 

             20     that the full details of the study will be disclosed 

             21     afterward. 

             22               Two, to obtain permission to engage in 

             23     concealment or deception with the understanding that 

             24     pilot research has shown that peers of the subject do 

             25     not find such concealment or deception objectionable 
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              1     and that a full explanation will follow their 

              2     participation. 

              3               And third, and last, to explain that the 

              4     subject might be enrolled in one of several possible 

              5     conditions and to engage permission -- to gain 

              6     permission to enroll the subject in an undisclosed one 

              7     of these conditions to be disclosed in the general case 

              8     at the end of the research. 

              9               Number 12, in certain circumstances persons 

             10     are not in a position to decide whether to consent 

             11     until after their participation.  This includes brief 

             12     sidewalk interviews which persons are likely to 

             13     welcome.  Deferred consent is an option.  

             14               Thirteen, and I feel it necessary to say, 

             15     there will be a total of 14.  

             16               [Laughter.]  

             17               DR. R. LEVINE:  Reminded of Tom Leher saying, 

             18     "you have yourselves to blame if I'm too long you 

             19     should never have let me begin." 

             20               Debriefing is an important and complex 

             21     understanding that is not always appropriate.  I'm not 

             22     going to go into detail about that now.  But I would be 

             23     willing to discuss some circumstances in which 

             24     debriefing would not be appropriate. 

             25               And then finally, another one that's somewhat 
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              1     controversial within our group.  Elite interviews.  And 

              2     by that we refer to interviews with important persons 

              3     or experts or what the regulations refer to public 

              4     persons.  Typically these are open-ended and defer to 

              5     the expertise of the respondent to direct parts of the 

              6     dialogue.  Such respondents are rarely low powered 

              7     persons and some of the usual trappings of informed 

              8     consent may be seen by these respondents as too 

              9     paternalistic to be appropriate.  

             10               In the remaining 30 seconds, I'll be glad to 

             11     respond to your questions.  

             12               CHAIRPERSON MARSHALL:  Felice, and brief.  

             13     Yes, we really need to stop. 

             14               DR. F. LEVINE:  Less of a comment, just a 

             15     little overview of the process of where we are.  Our 

             16     group -- in part, these were two working papers that we 

             17     started on as early as last July that then were knitted 

             18     into one well before an informed consent group was 

             19     established.  And our group has continued that 

             20     deliberation. 

             21               We met either virtually or face-to-face 

             22     depending upon who was there on the 22nd and now we've 

             23     discussed the full report and the recommendations and 

             24     what our anticipation is, is to rework them and advance 

             25     them as soon as we can to the informed consent group 
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              1     which we think will be sooner than later, meaning 

              2     probably within the next several weeks.  But we really 

              3     didn't have a chance.  You could tell the tentativeness 

              4     is we didn't have a chance to rework each in light of 

              5     the conversation and that's sort of the process that 

              6     it's in now.  

              7               DR. R. LEVINE:  Thank you, Felice.  I was 

              8     willing to take the whole blame for that. 

              9               Susan. 

             10               MS. KORNETSKY:  Yes, I guess I just had one 

             11     question.  There wasn't, I don't think, any one of 

             12     those issues that I couldn't have agreed with in 

             13     certain types of research.  This is for what?  For 

             14     behavioral and social research in general, in certain 

             15     types? 

             16               I mean, how is this -- like I said, there's 

             17     nothing in there that I disagreed with in specific 

             18     circumstances, but how is that going to be communicated 

             19     with it?  Because I can think of certain types of 

             20     behavior or social research where certain things would 

             21     certainly not be appropriate. 

             22               DR. R. LEVINE:  I agree wholeheartedly.  And 

             23     the purpose of this is to try to paint an 

             24     impressionistic picture of the whole field.  And an 

             25     awful lot of what I said would tip over into some 
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              1     research that is typically considered biomedical, but 

              2     uses similar devices, particularly such things as 

              3     epidemiology -- much epidemiology, not all 

              4     epidemiology. 

              5               Nothing I said applies to all social or all 

              6     behavior research.  But everything that I said applies 

              7     to some more or less well-defined areas within those 

              8     two fields and some areas of biomedical research. 

              9               I think our job then will be to take a next 

             10     step and try to flesh out perhaps by giving examples 

             11     what we mean by all of this. 

             12               MS. KORNETSKY:  I would definitely agree 

             13     because I think the harm is, you know, sending mixed 

             14     messages to the research community on when some of 

             15     these things are appropriate or not.  So, I think you 

             16     need to somehow define when these types of things are 

             17     appropriate. 

             18               DR. R. LEVINE:  I want to respond that -- oh, 

             19     I'm sorry. 

             20               CHAIRPERSON MARSHALL:  Well, I just want to 

             21     say, I feel as though we're imposing on the good will 

             22     of the folks who are sitting in the room.  So we really 

             23     need to sort of wrap up.  If we need to revisit some 

             24     things tomorrow, then I think that we can.  So brief 

             25     comments at the podium and then --  
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              1               PARTICIPANT:  My question was whether we 

              2     could revisit this tomorrow because it was an enormous 

              3     amount of information that was imparted very quickly at 

              4     the end here.  To go over 14 points at breakneck speed 

              5     and I'm a fast note taker, it just -- you know, was 

              6     just too much too late in the day. 

              7               And I guess I should just start with number 

              8     one which was simply that I cannot conceive that you're 

              9     saying that there should be no need for patient 

             10     consent, just give the signatures which was your very 

             11     first point, of the person who gives the patient the 

             12     sheet itself.  There should be a friendly, open 

             13     exchange, but to remove the patient consent form and 

             14     just have the person that gives the information sign-in 

             15     sheet doesn't make sense to me. 

             16               CHAIRPERSON MARSHALL:  Let me just explain 

             17     where we are in terms of process.  

             18               PARTICIPANT:   Sure. 

             19               CHAIRPERSON MARSHALL:  This is very 

             20     preliminary.  This is for information only.  So we -- 

             21     it hasn't even been fleshed out by the informed consent 

             22     workgroup yet.  So we are not at the point where we're 

             23     bringing it to the committee for debate or discussion. 

             24      This is just FYI. 

             25               So just to reassure you that there will be, 
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              1     you know, ample opportunity, not only in -- you know, 

              2     within the setting of our meeting, but also in terms of 

              3     public comment because these things will be posted on 

              4     the web.  So this is just -- it's been put on our 

              5     horizon and that is it.  

              6               PARTICIPANT:  Okay.  Thank you.  

              7               MS. BLEVINS:  Brief comment.  You wanted 

              8     facts, I just wanted to share a few quick facts.  I 

              9     can't get into detail. 

             10               I'm going to share this with Abbey, the 

             11     consumer voice, and hopefully she can share this with 

             12     you.  It's a gallup survey on how patients feel about 

             13     consent and involving research.  And I would highly 

             14     recommend -- I know sometimes you think, well, we're 

             15     just hearing from those privacy advocates over there, 

             16     but we wanted to go out and find out how ordinary 

             17     citizens feel across the country and they really do 

             18     want consent before any further research is obtained. 

             19               And we're talking here about going through 

             20     medical records, doing the sociological research, not 

             21     just biomedical research.  So I would highly urge you 

             22     to look at the will of the public in making these 

             23     decisions. 

             24               CHAIRPERSON MARSHALL:  I can assure you, we 

             25     certainly will.  And thank you very much.  And, you 
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              1     know, anything that you feel in the future needs to be 

              2     brought to our attention, don't wait for the meeting, 

              3     send it on. 

              4               Thank you. 

              5               Bob, do you need a last word? 

              6               DR. R. LEVINE:  No. 

              7               CHAIRPERSON MARSHALL:  Elliot, would you like 

              8     a last word?  

              9               DR. DORFF:  Not if you put it that way.  

             10               CHAIRPERSON MARSHALL:  Thank all of you.  

             11     That was some very interesting out-of-the-box ideas 

             12     here.  I commend you on your work and thank all of you 

             13     all for staying overtime.  We will see you tomorrow, I 

             14     hope. 

             15               [Whereupon, at 5:45 p.m., the proceedings 

             16     were adjourned, to be resumed at 8:30 a.m., on Tuesday, 

             17     April 30, 2002.] 

             18                              - - - 

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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 Monday, April 29, 

                    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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