1 CT Department of Health and Human Services Meeting of the NATIONAL HUMAN RESEARCH PROTECTIONS ADVISORY COMMITTEE (NHRPAC) Tuesday, April 30, 2002 VOLUME II Hilton Washington Embassy Row Ambassador Room 2015 Massachusetts Avenue, NW Washington, D.C. 20036 2 A G E N D A Tuesday, April 30, 2002 AM Session 8:30-8:45 RECAP Mary Faith Marshall, Ph.D. 8:435-10:15 UPDATE AND DISCUSSION GENETICS WORKGROUP Mary Kay Pelias, J.D., Ph.D. Chair, Working Group Professor of Genetics, Louisiana State University, HSC [10:15-10:30] Break 10:30-12:30 PRAXIS AND ACTION: CONDUCT OF RESEARCH IN THE AFTERMATH OF BIOTERRORISM Moderator: Jonathan Moreno, Ph.D. Monica Schoch-Spana, Ph.D. Senior Fellow Center for Civilian Biodefense Strategies Johns Hopkins University John Livengood, M.D. Deputy Associate Director for Science Centers for Disease Control and Prevention PM Session 12:30-1:30 LUNCH 1:30-2:30 WORKGROUP ON DECISIONAL CAPACITY Jonathan Moreno, Ph.D. Director, Center for Biomedical Ethics University of Virginia Health System 2:30-4:15 UPDATE AND DISCUSSION: SOCIAL & BEHAVIORAL SCIENCE WORKGROUP Felice Levine, Ph.D. Co-chair Working Group Executive Officer American Sociological Association Jeffrey Cohen, Ph.D. Co-chair, Working Group Director, Education OHRP/HHS PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 3 AGENDA - Continued [3:00-3:15] Break 4:15-4:30 WRAP-UP Mary Faith Marshall 4:30 Adjourn PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 4 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 PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 5 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 PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 6 1 P R O C E E D I N G S 2 [Time noted: 8:38 a.m.] 3 CHAIRPERSON MARSHALL: Good morning. 4 Well, I thought we had a superb day 5 yesterday. And I think the best thing about yesterday 6 is the fact that there is obviously very good work 7 coming out of this committee. Everybody is working so 8 hard and so well. It was really kind of delightful to 9 see how fruitful we are. So I want to thank all of you 10 again for your hard work and for having such a 11 successful day yesterday, and I think it will be just 12 as successful today. 13 I did want to make one observation and that 14 is that I think during the afternoon discussion about 15 pesticide testing in humans which itself is kind of on 16 the surface perhaps a gruesome or strange idea that 17 doing work in bioethics means that you need to let 18 emotions inform your reason, but you also have to let 19 reason inform your emotions in order to do good work 20 and critical thinking. 21 So, perhaps we could bear that in mind today 22 in terms of our civility towards one another and we 23 promise that we won't pick on Bob Levine because he's 24 devine as well as Levine -- 25 [Laughter.] PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 7 1 CHAIRPERSON MARSHALL: -- and -- 2 DR. SHAMOO: Oh, God, now we're really in 3 trouble. 4 CHAIRPERSON MARSHALL: Okay. Adil, now -- 5 [Laughter.] 6 CHAIRPERSON MARSHALL: Bob, I was just saying 7 that there are no jokes allowed that you're define as 8 well as being Levine, so I'm not letting anyone pick on 9 you today or make jokes unless they come from Susan 10 Kornetsky who is the youngest member of the committee. 11 She's allowed. 12 [Laughter.] 13 [Simultaneous conversation.] 14 DR. R. LEVINE: Is that because I've been 15 telling jokes? 16 CHAIRPERSON MARSHALL: No. I'm just making 17 sure that we don't pick on you too much. 18 So, Abbey, or not Abbey. I'm sorry. Mary 19 Kay, my brain is not in gear obviously. 20 Genetics this morning. Yes. 21 DR. PELIAS: Should I come up there? 22 CHAIRPERSON MARSHALL: Yes, please do come up 23 here. 24 [Pause.] 25 CHAIRPERSON MARSHALL: Please turn to Tab 8 PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 8 1 in your notebook. 2 DR. PELIAS: Folks, I would to start out this 3 morning with a little bit of a review of where we were 4 and where we are now. When the working group on 5 genetics decided to start putting together information 6 in anticipation of putting information into a new 7 edition of the IRB guidebook we kind of fumbled around 8 for a while until we decided that the place to start 9 would be with the chapter on human genetics research 10 that appeared in the 1993 edition of the IRB guidebook. 11 So we got this document out and gave copies of it to 12 all the members of the working group and then arranged 13 to have a conference call. 14 There in 1993 approximately 22 pages of 15 advice about how to do human genetics research with 16 respect to IRBs, and I anticipate that we'll have a 17 document when we get finished with this go round that 18 we'll have a document of approximately the same length, 19 but with considerably different content. 20 After we had a bit of a chance to study the 21 chapter on human genetics research we had a conference 22 call on April the 8th and during that conference call 23 we pretty much dissected the outline of that 1993 24 chapter. And to prove to you that we dissected, I 25 usually take pretty clear notes, but this page came out PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 9 1 of the conference call on April the 8th and then we 2 were charged with making some sense out of all of the 3 suggestions that were made to modify the outline. 4 Essentially what happened was that we distributed in 5 the outline of the 1993 chapter and asked people to 6 comment on it. 7 I have not reproduced for you today the 8 outline of the 1993 chapter. I have given you two 9 later versions of an outline that came out of our April 10 8th conference. 11 During that conference we all agreed that 12 there is a need for a shift of emphasis in what is 13 included in genetics research. The reason for this is 14 that genetics research has changed dramatically in the 15 last 10 to 15 years. 16 Before 1993 the emphasis in genetics research 17 was on family studies, on pedigrees, on locating genes, 18 linkage studies, and I would say primarily directed 19 toward identifying single genes and single gene 20 disorders. 21 And since 1993, or let's say in the last 15 22 years, we have seen a molecular revolution which has 23 brought us into an era of what I call "technical 24 wizardry" in microarrays and bioinformatics, and we are 25 now doing work that is considerably different from the PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 10 1 kind of work that we were doing 15 years ago. 2 So we are in a new technological age and we 3 are also, with regard to what we're looking at in terms 4 of hereditary problems, health problems, we are looking 5 to identifying genes that contribute to complex 6 diseases. And I think the first one that everybody 7 ever talks about, the complex diseases, cardiovascular 8 disease, sometimes diabetes and so on, generally when 9 we hear the phrase "complex disease" we are talking 10 about what we have traditionally called 11 "multifactorial" diseases which for the most part are 12 caused by contributions of alleles or genes at many 13 different loci that are acting in concert with 14 environmental factors. So we are in a much different 15 age than the kinds of problems that we were looking at. 16 We're still looking at them, but the emphasis now is 17 on considerably more convoluted or complex problems 18 with regard to genes and health problems. 19 So with acknowledging that, the shift in 20 emphasis that we've seen in genetics research, we took 21 to a practical approach of reworking the outline of the 22 chapter that appeared in 1993. 23 And for this part of our discussion, I would 24 ask you to refer to the two outlines that are in your 25 materials. The first page -- I've only given you two PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 11 1 outlines. This is not a particularly difficult 2 problem. The first page is just simply informational. 3 On the back of that page is an outline that I put 4 together after a conference call when I had this 5 completely unreadable, scribbled over outline from the 6 1993 edition. 7 And we went through this -- the old outline 8 step-by-step and wrote down these notes and then right 9 after the conference I put together a new outline which 10 is what you see here on the back of the first page of 11 the two pages that you have in your materials. 12 I generally followed the suggestions of the 13 committee and made a few changes and also included in 14 this outline the writing assignments that went out to 15 various people who were participating in our telephone 16 conference. 17 If we work our way down this a little bit we 18 would see some similarities. Of course, you want an 19 introduction, I think, with definitions. In the 20 definition sections of the introduction we have added 21 three more terms which are extremely important these 22 days in the world of genetics research and that 23 includes associations, pharmacogenetics and 24 bioinformatics. 25 And before we get finished with this and if PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 12 1 you have any ideas, I entertain all of them because we 2 want to do as complete a job as we can. If you want to 3 add more terms to this, I am completely willing to do 4 that as long as it doesn't get so convoluted that the 5 average IRB won't know what we're talking about. And 6 this is something that I have to keep in mind because 7 I'm always doing battle with my own IRB about genetics. 8 So we have added three terms to the list of 9 definitions and I don't have concise definitions for 10 these last three terms yet, but we'll get there. 11 One of the suggestions of the folks on the 12 conference call was that we should deemphasize pedigree 13 studies and we have done that. The second part of the 14 original outline was called pedigree studies. Like 15 everything we do is pedigree studies, and that's no 16 longer so. 17 There were a number of general concepts that 18 were listed under pedigree studies in the previous 19 outline and the general feeling on the conference call 20 was we should pull out a lot of the general concepts 21 and just have this as our second section. So you see 22 here under II, General Concepts, and for the most part 23 these are the same topics that were included in the 24 last one, but they would be rewritten with a bit of a 25 shift toward what we are doing these days. And what PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 13 1 I've done with regard to the materials that we're going 2 to be working with all day tomorrow is rewrite these 3 sections from the old version of the IRB guidebook into 4 something that is a little bit, perhaps more 5 contemporary. 6 After we got finished pulling out the so- 7 called general concepts, we had some things left over 8 that we needed to sort of put together. We couldn't 9 describe them entirely, but then on the other hand we 10 didn't have to have a major shift in these things. 11 So we have another section called 12 "identifying genes" and what I have here are topics 13 that represent traditional approaches to genetics which 14 are still used, in some situations they're just not the 15 focus of a great amount of attention now. These 16 include our pedigree studies and linkage studies. And 17 we have continuing issues that are waxing and waning 18 these days depending upon what the current hot issues 19 are. 20 A very important aspect of this are the 21 issues related type access to data, particularly access 22 to research data that has not been confirmed clinically 23 and is not rigorous enough to, for example, fall under 24 clear regulations, but they may well be data that 25 people might want to have access to. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 14 1 And also under this section of identifying 2 genes, we are going to deal with the question of 3 disposition and secondary use of tissue samples. This 4 is something that for me is a very, very important 5 topic because I believe that people are going to want 6 to have access in the future to information that is 7 generated in the future from samples that were stored 8 last year or whenever. So surplus samples is a very, 9 very important topic. 10 Moving on down the list to genetic testing, 11 I've put these things more or less under a rubric of 12 genetic testing, including newborn screening, carrier 13 status, pre-implantation and prenatal testing, risk 14 assessment testing, and then when we get down into 15 these last three categories here in the outline we are 16 moving into the newer areas that we're going to have to 17 expand very completely or as well as we can. 18 The first three under this heading of genetic 19 testing are generally, I would say, concern with 20 monogenetic, single gene disorders and picking up 21 things that people would want to know for their own 22 personal management and relatively -- maybe I should 23 say, relatively easy testing compared to the kinds of 24 testing that are associated with complex diseases. 25 So we have the first three related primarily PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 15 1 to monogenic problems and then the last three that are 2 related to our newer technologies and what we are doing 3 these days in the area of complex diseases. 4 I have continued to keep gene therapy 5 separated out from the rest of everything because it's 6 our anticipation that there will be a chapter in the 7 new IRB guidebook, a whole chapter dedicated to gene 8 therapy and we will acknowledge this here, but we will 9 not usurp or try to repeat what's going to appear 10 elsewhere in the new IRB guidebook on gene therapy. 11 And then the last two points down there were 12 just -- will be things that should be brought in later 13 on. But anyway, this is the outline that I put 14 together from my notes and from what I thought was our 15 mandate with the conference call of the working group. 16 And then a couple of days later, if you'll 17 look to the second page, the second page of your -- the 18 second sheet that's included in the two pages in your 19 materials, I received from two of the people who were 20 on the working group conference call another outline 21 suggested for revising this chapter on human genetics 22 research. So we have a somewhat different approach 23 which I will tell you generally contains all of the 24 information, all of the topics that are included in the 25 first outline I just somewhat rearranged and they are PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 16 1 very much expanded in the area of more complex genetic 2 considerations. 3 Now, I have a note, Jonathan -- yes, I'll 4 try. Oh, okay. 5 If you will just look over this second 6 outline, I think you will find that it's much more 7 rigorous in setting out topics for consideration with 8 complex diseases and the major difference, I think, in 9 what I had proposed and what these two members of the 10 working group proposed was that I took general 11 considerations and placed them at the beginning of my 12 outline and generally they are included toward the end 13 of this second outline. And I think our task this 14 morning and I hope we come out of this with something 15 that we can work with tomorrow, is to create an outline 16 that will be satisfactory for filling in. I believe 17 it's always rather expeditious to first write an 18 outline and then start filling in the paragraphs and 19 the topics rather than doing a haphazard thing and 20 trying to glue it all together in one way or another 21 later on. 22 So when Kate and I talked about these two 23 outlines Kate said, "let's turn this over to the 24 committee" and that's what we are going to do today. 25 And I will take your suggestions to the PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 17 1 working group tomorrow and we'll spend all day and then 2 considerably more time after that getting together a 3 draft chapter which I will -- I hope I will have to you 4 by the end of July, even actually much sooner. 5 Okay. Jonathan. 6 DR. MORENO: Just a couple of suggestions, 7 Mary Kay. Under 1(b) under your lexicon, I think you 8 should probably add pharmacogenomics, pharmacogenetics 9 and pharmacogenomics are sometimes identified, but my 10 understanding is that pharmacogenetics refers to 11 hereditary basis of disease and pharmacogenomics refers 12 to the designing drugs for particular groups or 13 individuals if I'm not mistaken. 14 DR. PELIAS: Okay. 15 DR. MORENO: I really want to focus on 3(c), 16 tissue samples and I'm sure you guys have already 17 thought about going back to NBC biomaterials report. I 18 think it's a very useful report. And they have many, I 19 think, sound things to say about this. A couple of 20 specific points, and this come out of my experience 21 with working with an NHLBI sponsored tissue registry. 22 Two things have come up that you might help think 23 about. 24 One is, when a person has decided to donate a 25 tissue sample for study purposes, if the individual PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 18 1 later on decides they don't want to be part of the 2 study anymore, does that mean that their tissue can be 3 retrieved, particularly if it's already been 4 distributed to another entity, another -- an 5 investigator or a commercial entity? 6 DR. PELIAS: Well, it's my understanding that 7 samples can be retrieved if they haven't yet had the 8 identifier stripped from them, but data cannot be 9 retrieved. 10 DR. MORENO: Right. Well, my question is, I 11 guess, how to inform people that their data -- their 12 samples may not even be retrievable if they're not 13 identified. I mean, this is kind of an interesting 14 paradox here because on the one hand you may not want 15 them to be identified for privacy reasons, but you 16 might want to get them back later so people may find 17 themselves in a bit of a crunch on that. That's just 18 something to think about how to -- 19 DR. PELIAS: This is something that I've been 20 thinking about for a while. And I don't know all the 21 nuances of all the government regulations and writings 22 that have been done on this. But I have, I think, an 23 intuitive feeling that when people are enlisted in 24 research projects and they're going to give samples, 25 they can be -- this can be discussed up front. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 19 1 DR. MORENO: Yes. 2 DR. PELIAS: And people can be told that we 3 would like to keep your samples and use them. The 4 individuals who are donating the samples can have 5 choices about whether or not they want to have their 6 identifiers retained with the sample or not, and if 7 they say no identifiers, then they give up any right to 8 further information or further disposition of what 9 comes out of those samples. 10 DR. MORENO: Interesting. Right. 11 DR. PELIAS: This is something -- I realize 12 that there is controversy about this because when I 13 first mentioned this back around 1995, we were having a 14 meeting here in Washington and I said, we could do 15 this. And the response was very loud and I was told 16 that you cannot consent to anything that you don't know 17 exactly what it is. You can't consent to future 18 research if it's not yet defined. And these ideas have 19 been percolating in genetics community since then. 20 DR. MORENO: This actually -- my last comment 21 goes to exactly that point. If consent forms for these 22 donations can be designed and in fact are designed in 23 some cases to give the donor the following three 24 options: You may agree to donate your tissue to any 25 scientific research; which is basically what you just PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 20 1 said. 2 DR. PELIAS: Yes. 3 DR. MORENO: Which you think you can't do. 4 DR. PELIAS: I think you can, but other 5 people don't. 6 DR. MORENO: Well, all right. 7 DR. PELIAS: Go ahead. 8 DR. MORENO: The second option is only for 9 the disease or diseases that are relevant to me. And 10 the third is only for a specific protocol. So you can 11 call me back later to ask me about that. And I guess 12 it would be useful for us to know what the workgroup 13 thinks about that array of options. 14 DR. MORENO: I have Bob over here. 15 DR. R. LEVINE: Thank you. That's a very 16 interesting pair of outlines. I don't know if -- you 17 seem to be concentrating your attention on the first 18 outline. But in some respects I prefer the second 19 outline partly because it mentions some topics that I'm 20 not sure would have been included in the first and 21 maybe, for example, population genetics which are very 22 important topics. It could have been included in the 23 first, but buried in another -- as a subtopic through 24 one thing that was there. I also like the general 25 structure of outline number two. It's, I think, PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 21 1 conducive to locating problems, perhaps better than the 2 first one. 3 I think the topic that Jonathan was talking 4 about, withdrawal from participation, one of the 5 complexities that's come up in that is that when you're 6 dealing with data that are either identified or linked, 7 you know, the so-called one-way link so you can find 8 it, there has been a lot of argument over the aspect of 9 the -- you and Jonathan were discussing -- can you 10 withdraw your tissue. But there's also been a lot of 11 argument about whether or not you can withdraw your 12 data, if your data are still like -- for example in 13 psychology they say in the debriefing if you don't like 14 what the investigator did deceptively you can order 15 them not to use your data. 16 But I think the controversy over genetic 17 data, particularly when geneticists can invest hundreds 18 of hours and thousands of dollars in developing a 19 dataset, it's not as easy. There's a lot more at 20 stake, and I look forward to your dealing with that. 21 The last point I would like to make is that 22 in both of your outlines you talk about the subject's 23 right not to know the results. I think an equally 24 important thing is the circumstances under which the 25 investigator should not reveal results. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 22 1 For example, early in an exercise in 2 attempting to determine a linkage between a set of 3 genetic findings and some disease or predilection to 4 some disease you really don't have enough data to know 5 what the data mean. And it would be, I think, 6 destructive in many of those cases to say, well, you, 7 you know, according to our preliminary evidence you 8 have a gene that might result in Alzheimer's, but we 9 don't really know if that's accurate. That's really 10 worse than giving no information. So I hope that can 11 be -- 12 DR. PELIAS: I appreciate that, but I would 13 like to also consider the possibility of, say, a gene 14 frequency study for breast cancer that I know about 15 that was done in this area when there is information 16 that is revealed from the gene frequency study that 17 maybe perhaps 10 or 15 of the women out of the whole 18 sample ha a suspicious allele for breast cancer, is 19 there a great burden on the investigator to inform only 20 those persons that they may wish to look into this 21 further. They may wish to have further testing done or 22 do wait until one of those women comes down with 23 metastatic cancer and goes to a lawyer? I'm worried 24 about lawyers in all of this business. 25 DR. R. LEVINE: I think that you're making an PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 23 1 important point and that point illustrates that it's 2 not a simple issue -- 3 DR. PELIAS: It's not. 4 DR. R. LEVINE: -- that I'm asking you to 5 resolve. 6 [Laughter.] 7 DR. PELIAS: Thank you very much. I 8 appreciate the assignment. 9 DR. PELIAS: Elliot, Susan and then Bob Rich, 10 and then Margaret. 11 DR. DORFF: I also like the second outline a 12 little bit better, because in particular at the very 13 beginning you spell out when genetic research is exempt 14 from review and when it's for expedited review and the 15 like. And after it's all said and done, what we are 16 charged to do is to talk about exactly those issues. 17 All right. So, I mean, it's -- the other, I 18 have several points. One is that the word or the 19 phrase "genetic engineering" doesn't appear anywhere 20 here. And I don't know if that's political reasons or 21 if that's because the research just simply doesn't deal 22 with that, or -- what I can tell you is that it 23 certainly is in the popular press. And so if you're 24 not going to talk about it, you should define it and 25 say that you're not going to talk about it, and explain PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 24 1 why. Or, if you are going to talk about it, then 2 somewhere or another the phrase has to be dealt with 3 because it certainly is in the popular mind. And along 4 with that phrase, of course, comes, you know, all kinds 5 of movies and books and things like that, and science 6 fiction. 7 So, I think it would be helpful to say, 8 what's science and what's science fiction in terms of 9 all of that. 10 The second point that I wanted to make is 11 that you talk here about identifying groups, collection 12 of data on race and ethnicity and I just want to say 13 that Ashkenazi Jews have been studied tremendously, in 14 part because it's a wonderful population for a 15 geneticist to study because there was a lot of -- in 16 marriage, and it's a relatively small population and so 17 you can trace genetic, you know, features and so on. 18 And, aside from that, Jews volunteer for all kinds of 19 studies. 20 But what that then leads to though, and 21 there's actually been a backlash in the Jewish 22 community to some extent is the worry that the Jewish 23 community would then be tainted in the minds at least 24 of some as a diseased community because you find out 25 that there are all of these various kinds of PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 25 1 dispositions for this disease and that disease and so 2 on. 3 So, when you talk about that issue, you may 4 want to talk also about what on the one hand is 5 scientifically a golden population to study, but on the 6 other hand raises some of these sociological issues in 7 terms of people's -- I don't know, understanding of 8 themselves and of others. 9 And then the last thing I wanted to mention 10 was on the right not to know. The one that I was just 11 talking about and that you were as well. The right not 12 to know, especially in the -- I mean, the case, I 13 guess, that we're all thinking about is the VRCA1 gene 14 and 2 later, the breast cancer genes, you know, I think 15 the first issue is a little bit Bob raised and I think 16 he's absolutely right about that. The part of the 17 problem at the beginning was that the initial study, 18 you know, sounded much too convinced of the connection 19 between the -- you know, between the allele and in 20 actual breast cancer, and the other real piece of it 21 was that, at least at that time, there was no research 22 as to whether a woman could do anything about it. 23 And so, I mean, I think that one of the 24 things you may want to explore is the right not to know 25 especially when there is nothing that could be done to PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 26 1 do -- you know, to change the course of the disease to 2 begin with and then does that right change when later 3 research determines that there actually are some things 4 that could be done to either avoid the disease 5 altogether or to mitigate it. 6 And in that situation, so that's one point -- 7 and the other point I wanted to make on this issue is 8 that that situation raised a very interesting question 9 about interfamilial dynamics. Let's say you have two 10 sisters, one of whom tests positive and the other one 11 tests negative. Well, the one who tests positive is, 12 you know, is not happy, obviously, because that means 13 that there's an increased chance that she's going to 14 get breast cancer. But the one who tests negative is 15 not free and clear either. 16 I mean, there's, you know, there's survivor 17 guilt very much like out of the Holocaust kinds of 18 things. Right. You know, how is it that I'm okay and 19 she's not. So, I mean, I think you may want to at 20 least -- I don't think that since our job is not to 21 talk about everything on this issue, but, you know, but 22 simply to -- these are kinds of things I think that you 23 should at least identify as concerns although because 24 the human beings that are being involved in this that 25 have a stake in knowing or not knowing, include not PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 27 1 only the subjects, but their family members. 2 DR. PELIAS: If I could comment a little bit 3 further on that, one of the really serious issues that 4 we're dealing with in the world of genetics right now 5 is whether or not there may even be an obligation on 6 the part of investigators and medical professionals 7 when they find out that other families outside of the 8 immediate physician/patient relationship might be 9 affected, whether or not there might be an obligation 10 to step outside of the immediate relationship and to 11 inform other family members, at least maybe not to 12 clobber them with specific information if we have 13 specific information, but to suggest that perhaps they 14 might want to investigate their own situation a little 15 bit further. 16 MS. KORNETSKY: I guess I'm in the minority, 17 but I like the first outline first -- best. And I 18 guess the reason that I'm reacting that way is thinking 19 about the audience of this particular document which is 20 the IRB guidebook chapter which is, in all honesty, 21 predominantly used by IRB administrators and sections 22 get pulled once in a while and go to IRB members. 23 And I guess my concern was, and maybe this is 24 not really a concern is that I looked over the second 25 part and it's very, very technical, the terminology PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 28 1 that's being used. 2 And so I guess, you know, perhaps if there's 3 a difference if an IRB has to get something and decide, 4 well, is this a predictive monogenic or is this, you 5 know, a prognostic complex, are there different issues? 6 If there aren't different issues, then I'm just 7 concerned about the complexity of it. So that's my own 8 point of view. 9 I do like the idea of the first two things, 10 the exempt and the eligible or expedited review. I 11 think that's very, very helpful to separate that out. 12 The last point that I have is -- I guess this 13 is more just about the particular group. This whole 14 CLEA business in a hospital setting really comes up. 15 And I know that we worked very carefully with our 16 director of clinical labs to try and time resolve this. 17 And there is no resolution and I know even the 18 laboratory medicine people have lots of discussions and 19 I've been given information about that. Is that 20 perspective from sort of the laboratory side brought 21 in? 22 I mean, because we've had to take a position 23 on certain things that we can't give results out 24 because it isn't replicated. And sometimes the labs 25 will replicate things and sometimes they won't. So is PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 29 1 that -- how is that being addressed within the 2 workgroup? 3 DR. PELIAS: It will be addressed in the 4 workgroup, let me put it that way. I believe we're 5 obligated to acknowledge that these issues exist and we 6 have to put something into what we write to acknowledge 7 that there are problems here. We can't solve all the 8 problems, but we will write it in. 9 One of my major concerns, and, Susan, thank 10 you very much for saying so, is that when we write this 11 up with the view to having it studied by people on 12 various IRBs, we are going to have to be very careful 13 not to be so technical with snips and ESTs and what not 14 that the people who are reading it and trying to use it 15 can't get anything out of it. 16 So I will go for simpler language rather than 17 a tremendous amount of technological language that 18 other folks aren't going to be able to understand. 19 Let's see, where are we? Susan -- Bob. 20 DR. RICH: Just to begin where we just left 21 off. I tend to agree with Susan's view that less is 22 more in the sense of trying to really write a document 23 in this case that is useful for IRBs and not a document 24 that is a primer on concepts in molecular genetics. 25 That being said, I think one of the real challenges is PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 30 1 going to be that we are trying to do this on rapidly 2 shifting ground at a time when there are other things 3 going on in the federal regulatory arena, some of which 4 are actually even in potential conflict with one 5 another. So we've had substantial discussions about 6 HIPAA, for example and HIPAA will be relevant to all of 7 the issues that we deal with in terms of databases and 8 tissues and things. 9 On the other hand, one of the discussions we 10 have not yet had are the recently raised considerations 11 at NIH on data sharing and the requirements that in 12 order to get an NIH grant you actually have to be 13 explicit or the proposal you will have to be explicit 14 with regard to your intention of how you will make your 15 data available to any qualified investigator and how 16 you will be sharing it. 17 So, there will be moves in one direction on 18 increasing privacy and reducing access to data, and 19 moves on the other hand of making data as widely 20 available as possible. But I think that because both 21 of these things are going on simultaneous with our 22 writing project, it's going to be a challenge to try to 23 come out with instructions to IRBs that will anticipate 24 in some sense where these controversies are likely to 25 come out. But in actual fact, we probably won't know PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 31 1 that for at least months and maybe longer than that. 2 One of the real challenges that I think -- 3 and it's been in a sense discussed around the table -- 4 is that the data that we'll be finding in genetics 5 either come from very large databases or very small 6 databases. And the ethical challenges are different 7 when you're dealing with very large databases and when 8 you're dealing with very small databases. 9 I would say that in the very large databases 10 one of the things that we've not talked much about yet 11 is the notion that those very large databases are going 12 to be global bases, not necessarily in the United 13 States. And, in fact, there are very good reasons for 14 that, because, as everyone knows, the defining 15 characteristic of the American populous is its 16 extraordinary heterogeneity which makes the challenge 17 of trying to identify complex diseases at the first 18 level, the genetic basis more difficult. And that's 19 why there has been a great deal of attention to going 20 into large populations which are much more genetically 21 homogeneous as the first cut of trying to understand 22 genetic basis of complex diseases. 23 That being said, I think probably everyone at 24 this table is aware of recent controversies, for 25 example, in China, where there have been considerable PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 32 1 questions raised as investigators go into these large 2 Chinese populations about just what kind of informed 3 consent processes were engaged in enrolling the data, 4 enrolling the subjects, or what kind of promises may 5 have been made with regard to medical care or other 6 kinds of things. 7 So one of the things that's going to be 8 difficult, I think, as we begin to need global data 9 will be an understanding of how those data are actually 10 obtained and validated from an ethical perspective 11 particularly when the data are based on populations 12 outside of the United States. And I think we haven't 13 resolved all of that yet. It eventually will come back 14 to American databases, I would say, because that's when 15 we'll be able to really understand is the genetic basis 16 really transcending across genetic heterogeneity of 17 population or is it defined within populations? But 18 the first cut will be in populations that are as 19 homogenous as possible. 20 And that brings me to the second point which 21 is, in a sense they're very small databases and Elliot 22 already discussed -- I mean, the very small is the 23 pedigree analysis, obviously, and that's been the 24 traditional home for monogenic disease analysis for 25 many years. But as we go beyond the individual family PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 33 1 pedigree, we then go to small, but highly, well-defined 2 genetic pedigrees such as the Ashkenazi Jews. I would 3 say even more so the one that put monogenic disease 4 analysis on the map in a sense are the old order Amish 5 where one really has a very small database of 6 extraordinary usefulness, but I think raising all of 7 the questions that Elliot has suggested with regard to 8 the Ashkenazi Jews. 9 MS. BORWHAT: I just wanted to follow-up on a 10 comment that Jonathan made about the three options, and 11 the one being that the participant could okay specific 12 protocols provided they were contacted. And I saw in 13 some of the documents that it was the obligation of the 14 participant to keep that information current so they 15 could be contacted. And I wonder that we might want to 16 look and see how practical this is, how it's worked in 17 the past, and how good an option that might be. It 18 might be very new to have much information on that, but 19 I think that's worthy of consideration. 20 I think related to that is the issue of not 21 informing participants of the results because the 22 results are preliminary and I think if we can maintain 23 the contact, I'm not sure related to what you said, 24 Elliot, that we couldn't at a time in the future 25 provide that information. I mean, the study that you PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 34 1 mentioned was treated very harshly in the press and 2 characterized as something similar to the syphilis 3 study. And I think we would want to provide some 4 guidance to, you know, prevent that type of reaction to 5 any research being currently done. 6 DR. MORENO: Can I just follow-up on 7 Margaret's good point? I am not an expert on this, but 8 my understanding is that a reason that investigators 9 often prefer not to go back to individuals even if they 10 theoretically could is the way that the information 11 has been developed for study purposes is not thought to 12 provide any sort of clinical guidance and that it's 13 simply not definitive enough to bother people with. 14 I don't know how much validity that has from 15 case to case, but it's something that warrants more 16 discussion. 17 DR. KOSKI: A quick comment on point. The 18 Secretary's Advisory Committee on Genetic Testing has 19 obviously addressed this issue and already made the 20 point about information that's going to be conveyed for 21 clinical decision-making need to reach the appropriate 22 standards as we would for all laboratory testing and so 23 on, and I think that this ties right into that so that 24 our committee's work should not obviously be done in a 25 vacuum. I know that it's not, but I just wanted to get PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 35 1 that in to the record. 2 One other quick technical comment was the 3 fact that there is genetics research that in fact may 4 not even be human subjects research, not just exempt, 5 not just expeditable, but exact research that's done 6 totally on non-identifiable issues and all that are not 7 human subjects research. It's basic research and we 8 need to make sure that that is also included in the 9 guidance. 10 DR. MORENO: And just to follow-up on that 11 prior point, Greg, I've often heard that if the lab 12 isn't CLEA approved the assumption is that the 13 information doesn't go back. Has the Secretary's group 14 commented on that? Is that a standard of practice? 15 DR. KOSKI: I think the Secretary's group has 16 commented on that. It's not in regulation or anything 17 at this moment, but I think that would be my reading of 18 the intent that information that is going to be used 19 for clinical purposes would need to meet the 20 appropriate standard for all clinical laboratory 21 testing and this is one of the challenges of 22 laboratories that are doing testing that are not -- 23 there's not a large enough body of concern for the 24 particular disease that would be developed as a huge 25 laboratory enterprise and yet there could be a need for PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 36 1 it. So finding the appropriate mechanism for those 2 laboratories that would be doing the testing in a 3 research setting, but using it for clinical purposes is 4 a challenge that needs to be addressed. 5 MS. KORNETSKY: I just want to add that the 6 definition of "using it for clinical purposes" also is 7 very murky. 8 DR. CHODOSH: I had a little bit of concern 9 about this discussion and that is that I think that we 10 are underestimating the subject's ability to be a 11 participant in this kind of research. That if they are 12 properly informed when they enter it, that this is 13 preliminary work, that it's not going to be definitive, 14 however you're in this and you should have access to 15 what comes out of it, and that you need to understand 16 in terms of what level it's at. The individual needs 17 to understand that and it needs to be transmitted to 18 them properly. And if they don't enter the study with 19 that understanding, and don't want to come out of it 20 with that understanding, they probably shouldn't be in 21 the study. 22 But I think that saying that we are going to 23 decide, you know, what a subject should know seems to 24 me a bit paternalistic, to say the least. And I think 25 that we are ignoring the possibilities that people have PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 37 1 the ability to understand preliminary results, et 2 cetera. 3 DR. PELIAS: Thank you, Sandy. Susan, are 4 you on point? 5 MS. KORNETSKY: Yes. 6 DR. PELIAS: You are and then we're going to 7 go on down the list. 8 MS. KORNETSKY: Yes, I think one of the 9 issues, at least in this are and I know that the 10 workgroup will discuss it is that if an institution has 11 a CLEA license, I mean, it may not -- I agree with what 12 Sandy is saying, you know, but there are, at least I 13 have been informed that there are possibilities of an 14 institution losing their license if information being 15 used for clinical purposes isn't done in a CLEA lab. 16 So we've -- and they've showed me, they've cited, you 17 know, the chapter and verse of the CLEA regulations, 18 so, maybe it's a little bit differently at a university 19 where you have other labs, but they have been very 20 cautious of that. And this is another area. 21 MS. MEYERS: There's a subgroup of the 22 Secretary's Committee on Genetic Testing just based on 23 rare diseases. And the problem is they call these 24 tests "home brews" because they are being done in 25 academic laboratories that are not CLEA certified. And PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 38 1 they have no way of ever becoming CLEA certified, 2 they're too small. They're just not going to be able 3 to do it. So it's not an institution that gets the 4 CLEA certification, it's the laboratory itself. 5 DR. PELIAS: Thank you, Abbey. 6 We would like to move on now. We have Adil, 7 then Alan, and then Kate. 8 DR. SHAMOO: Thank you, Mary Kay. This point 9 probably, Mary Kay, you know it better than anyone here 10 and that is, there is an emerging field of system 11 biology where the genetic components are strong or as 12 weak as any other one, and the disorders may not appear 13 at the cellular level and will appear at systems 14 levels. And that will have the same phenomena as you 15 are trying to deal with. And I was just putting that 16 for your consideration. 17 DR. PELIAS: Thank you very much. We will 18 probably get into that if we get through all the stuff 19 that we have right on the list right now. 20 Alan. 21 DR. FLEISCHMAN: Yes, I just wanted to add to 22 the mix, the National Children's Study which is being 23 proposed and developed by the National Institute of 24 Child Health in collaboration with several other 25 agencies which will be the largest longitudinal cohort PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 39 1 study ever attempted in the United States. It plans to 2 take 100,000 pregnant women and follow them and their 3 offspring for 20 or 30 years. The genetic component of 4 that study as it's being now planned will do serial 5 looks at the genome of those children to look at -- the 6 global question is, what are the effects on childhood 7 development of the environment at large. 8 So our discussions of pesticides yesterday, 9 discussions of what impacts on the genome, what social 10 and behavioral factors will impact on the development 11 of children over the long haul are all going to be 12 looked at in a comprehensive manner. But apropos to 13 the genetics committee, if we do serial looks at genome 14 in order to look at how it changes over time in the 15 same identified subjects, we have a whole host of 16 interesting questions in terms of the research ethics 17 aspects of that. 18 As children get older and then become adults, 19 as we see changes in the genome, what does that mean 20 and who are we going to tell what about what? We are 21 only studying one of a series of children within the 22 same family. One can see a tremendous amount of 23 potential good genetics research that could spin off 24 from those studies. So I just raise it because I think 25 they have an ethics committee. For my sins I'm not PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 40 1 that FACA to relate to that ethics committee. And 2 they're thinking about some of these issues, but I 3 don't think they've gotten anywhere near to the depth 4 of need, particularly in the genetic area. So as 5 you're doing this work, realize that there is a group 6 of colleagues who could dramatically benefit from the 7 wisdom of the committee. 8 DR. RICH: On point to that, I find this 9 fascinating and one of the most interesting questions 10 will be as these infants are born, their mothers having 11 consented to the entry of their genetic information 12 into this database obviously over a course of 20 to 30 13 years, these people will be assuming their own majority 14 and their own responsibility for informing. On the 15 other hand, the data by that time will have become an 16 invaluable and almost irretrievable part of a very 17 large database. And I think the complexities of that 18 are going to be a challenge, to say the least. 19 DR. PELIAS: Thank you, Bob. 20 Kate -- oh, Elliot. 21 DR. DORFF: Plato thought that you knew 22 everything before you were born. So the idea is you 23 have to get inter-utero, right -- 24 [Laughter.] 25 DR. DORFF: -- informed consent. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 41 1 [Laughter.] 2 MS. GOTTFRIED: Well, it's opportune to 3 follow-up on Alan's comment because I just want to add 4 to that that I actually sit on the ethics workgroup of 5 this longitudinal NCS study. And Alan is absolutely 6 right that there are numerous issues that have not been 7 contemplated and need to be. One thought we've had in 8 talking with Alan about this is that we would bring in 9 an individual from NICHD to talk about the NCS study to 10 the committee if that's something that might be useful. 11 And we'll consider that. 12 The other point I wanted to make just in 13 terms of the outlines in front of you, it's not sort of 14 an either/or with respect to the outlines. Certainly 15 we can meld them and this is pretty obvious, but we 16 will and we can meld the two. The point of the second 17 one, in particular, I think was just that going back to 18 the 1993 outline much of it was good, but it wasn't -- 19 it didn't take into account obviously what we now know 20 ten years later. And so we want it to be a 21 comprehensive approach. But I think we do need to bear 22 in mind what Susan said in terms of it maybe being too 23 technical. So we would want your input on that, but we 24 also want to make sure that we touch on all the issues 25 that need to be touched on. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 42 1 And, finally, just in terms of different 2 issues, the point that Elliot raised about, do you give 3 information if there's no know treatment, et cetera? 4 That's another issue that's come up in the Huntington's 5 context as well. 6 And in particular, something that Alan may 7 appreciate is also the issue of somebody who has tested 8 whether or not -- and Mary Kay and I have discussed 9 this -- about minor children and whether that 10 information ought to be conveyed. And so we need to 11 take into account the issues with respect to people of 12 majority and people of "minority" age and what the 13 implications are. And that's very controversial as I 14 understand it. And I think probably the workgroup is 15 somewhat split on how to approach these issues. So we 16 will need to look at that and also ask for your input 17 on that as well. 18 DR. FLEISCHMAN: On point, Mary Kay. My 19 understanding is that the screening issues in minors 20 has been fairly well agreed on in the genetics 21 community and in the pediatric community in terms of 22 standards. Am I not correct on that? 23 DR. PELIAS: We have worked this topic over 24 for the better part of ten years. And generally 25 speaking where we are right now is that we have a PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 43 1 consensus that you if want to test a child and you can 2 assure that the child will receive an immediate medical 3 benefit, then it's okay to investigate the genome and 4 generate genotype information on the child. 5 If on the other hand you can't guarantee an 6 immediate medical benefit, then the recommendation is 7 circumspection, step back and think about it, talk over 8 with the family the implications, the psychosocial 9 implications of generating this kind of information, 10 the possibility that if the child knows this 11 information it's going to have a negative effect on the 12 child's development and self-estimation. And do a very 13 thorough genetic counsel -- job of counseling the 14 family so that they will understand both the negatives 15 and the positives of generating the information. 16 But then I think that many of us in the field 17 now including me say that once you've done this very 18 thorough job of counseling the family about 19 implications, then you've got to step back and let the 20 parents decide whether they want to pursue this testing 21 or not. 22 And we are -- at least a lot of us are 23 pulling away from the paternalistic attitude. For 24 example, with Huntington's disease that you never test 25 a minor for that disease. There are reasons why PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 44 1 parents would want to know this information, very good 2 reasons why they would want to know the information 3 other than providing an immediate medical benefit. So 4 that's, I think, where we stand now with the issue of 5 children. 6 DR. FLEISCHMAN: And I think you would agree 7 that you need to add into that the assent of the 8 youngsters when appropriate, particularly as they get 9 older, and some of the work that's been done realizes 10 that some of our teenagers actually become mothers 11 before they have reached 18. So that it may in fact be 12 appropriate for screening with assent in some problems. 13 DR. PELIAS: That's correct. And we bring up 14 again, the problem with emancipated minors and how much 15 they have in the way of rights. Thank you. 16 CHAIRPERSON MARSHALL: Anyone of our ex- 17 officio or public members please feel free to step up 18 to the mike and we would love to hear from you. 19 And just remember to tell us who you are. 20 MR. COHEN: Jeff Cohen, Director, Education 21 Division at OHRP. A couple of things. First of all, 22 very, very practical issues. Has the working group and 23 NHRPAC interacted with the group that's preparing the 24 new guidebook? There is a committee preparing the 25 guidebook. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 45 1 MS. GOTTFRIED: Absolutely. That's how we 2 got involved in this. Because Susan Rose who is 3 overseeing that had asked us for and is inviting us to 4 give input because there -- 5 MR. COHEN: Because there is a time factor 6 involved because this is already going to an editor. 7 MS. GOTTFRIED: Absolutely. Well, from the 8 last we were told, it was not very far along. But, in 9 fact, yes, I think we're ahead of the curve in terms of 10 where the other chapters are. 11 MR. COHEN: And I would also like to 12 recommend that the other working groups also look at 13 the chapters appropriate for their working groups 14 because there will be chapters on informed consent and 15 chapters on social and behavioral sciences and so 16 forth. And I think it's a very important way of 17 getting the guidebook to be a more effective tool. 18 MS. GOTTFRIED: Yes, although I'm sure the 19 working groups are going to be delighted to accept more 20 work. 21 MR. COHEN: Well, I think this -- 22 MS. GOTTFRIED: No, I'm joking. Obviously 23 absolutely -- 24 [Simultaneous conversation.] 25 MR. COHEN: In terms of helping IRBS be the PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 46 1 most effective use of -- 2 MS. GOTTFRIED: Yes. 3 MR. COHEN: A couple points just in -- and 4 also, I do want to mention, because Bob Rich made a 5 point about this is evolving or a shifting field or 6 shifting playing field. The guidebook is designed to 7 be a living document, unlike the last one that which 8 was done in '93 and done, this is designed to be a 9 living document and to be continually updated in both 10 the mechanics of it and the media that are going to be 11 used and so forth or hopefully will allow for that to 12 be a living document. 13 Two points. One, I would suggest that a very 14 important point be included in the section and that has 15 to do with the expertise of the IRB. This is one of 16 the major areas where many IRBs are limited in their 17 expertise and an important statement that the IRB must 18 either have that expertise on its membership or get 19 consultation before it makes reviews and approves 20 protocols involving genetics, and that's a very 21 important point that has to be made up front and very 22 strongly and I think to the benefit of both the IRBs 23 and the researchers. 24 Secondly, I want to reiterate Elliot's point 25 about communities. Having just come from two weeks ago PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 47 1 a workshop that we did for tribal colleges and 2 universities, the indian groups are very concerned 3 about genetics research. This is a high priority 4 concern for them. I think there definitely has to be a 5 section in there on communities and the impact of 6 genetics research on communities. In fact, we heard an 7 excellent presentation on genetics research in Indian 8 communities from an American Indian genetics researcher 9 who I could put you in touch with if that would help. 10 DR. PELIAS: By way of adding to that, both 11 the American Society of Human Genetics and the American 12 College of Medical Genetics are presently investigating 13 this question of communities and will probably have 14 papers out within a year on the issues that we're 15 considering with communities and genetics. Thank you. 16 DR. SHAMOO: Can I have a comment on that? 17 Just on that? 18 Five, six years ago there was a meeting of a 19 group of 20 to 25 people, ethicists, Indian 20 communities, other ethnic group sponsored by Center for 21 Mental Health Services, SAMSA. And there is an 22 internal document that was supposed to be published 23 that's never been published, but internally is 24 available from SAMSA where they discussed all these 25 issues in a three-day conference and Paula Applebaum PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 48 1 from Boston was a member of that group as well as, like 2 I said, there was two or three Indian Chiefs other 3 ethnic groups, even they had to my shocking, somebody 4 new with the Keldian in Detroit are. That's a small 5 community of a quarter of a million population. So I 6 just thought if you get it -- 7 DR. PELIAS: Adil, do you have more specific 8 information so that if we attempt to track that down we 9 can be specific that you could then send us? 10 DR. SHAMOO: Yes, I could trace my own folder 11 on it because I'm a member of that group. 12 DR. PELIAS: That would be great. 13 DR. SHAMOO: And Paul Applebaum is another 14 source. 15 DR. PELIAS: Okay. Great. 16 DR. SHAMOO: Sure. 17 MR. SCHATZ: Good morning. My name is Gerald 18 Schatz. I'm a former member of the NICHD IRB. I'm a 19 lawyer and an ethicist. Yes, the two do go together 20 sometimes. 21 It is very helpful in doing the guide to 22 remember as the first set of authors did, that there's 23 lot of law out there, not just our own regulation. In 24 this respect the NIH addressed the problem of CLEA in 25 disclosure with an advisory letter not too long ago PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 49 1 that said, "where a Privacy Act issue arises, the 2 subjects or the patient's right to obtain a record or a 3 report under the Privacy Act trumps the CLEA 4 regulation." That is their interpretation. 5 Additionally we must be mindful, especially 6 in the cross-linkage studies, that there is a great 7 deal of state tort law about invasion of privacy. 8 DR. PELIAS: Thank you very much. 9 MS. GOTTFRIED: Mary Kay, just one thing to 10 add to that on point with respect to the state laws is 11 obviously, and this is something we'll have to address 12 in the chapter, I think, as well. But there is 13 tremendous variability from state-to-state, both with 14 respect to minors and other aspects of, you know, 15 various laws, privacy included. So we do need to be 16 mindful of that and address that. 17 DR. PELIAS: I have a note here that we might 18 want to enter some information about the composition of 19 the working group in the record. We have sort of 20 revised the composition of the working group in the 21 last couple of months and I've been very fortunate to 22 enlist the help of three colleagues who are in the 23 world of medical genetics and genetics research. The 24 first I will mention is Dr. Rodney Howell who is at the 25 University of Miami as Chairman of Pediatrics there and PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 50 1 has tremendous experience in the world of genetic 2 testing, particularly related to newborn screening also 3 with regard with related to cystic fibrosis and a 4 number of single gene disorders. 5 We have also enlisted the assistance of Dr. 6 Grody, Wayne Grody who is at UCLA who has been very 7 active in the world of CLEA testing and keeping us in 8 order with regard to what we're supposed to do in that 9 area. Wayne will be working with us and also Dr. Steve 10 Warren who is at Emory and is going to be assisting us 11 in the information that we have to assemble on the 12 world of bioinformatics. So we have some new blood in 13 the working group and we will be very grateful for 14 their input. 15 MS. KORNETSKY: Mary Kay -- 16 DR. PELIAS: Yes. 17 MS. KORNETSKY: -- a question on point and 18 forgive me, I don't remember the other working group. 19 Is there a member of the working group from industry or 20 a biotech company? 21 DR. PELIAS: Yes, we do have at least two 22 folks on the working group. Thank you. 23 DR. SHAMOO: Is there a member of the group 24 in behavioral disorders, genetics of behavioral 25 disorders, mental illnesses? PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 51 1 DR. PELIAS: At this time, I don't think so. 2 I hear what you're saying. 3 DR. SHAMOO: And there is quite a number -- 4 yeah, quite a number of those and -- 5 DR. RICH: I would say that Dr. Warren's 6 expertise, in particular, is in mental retardation, at 7 least. So the genetic basis of mental retardation. 8 It's a little bit different, but it raises many of the 9 same issues. 10 DR. SHAMOO: But behavioral issues are 11 broader, much, much broader issues. 12 DR. PELIAS: We did have the assistance of a 13 colleague in psychiatric genetics, but he had rotated 14 office at work, so I assume you urge us to get another 15 person of that -- 16 DR. SHAMOO: Yeah, I would think so. And 17 there is one at University of Virginia. One of the 18 good people. 19 DR. PELIAS: All right. 20 CHAIRPERSON MARSHALL: Anything else in the 21 genetics arena that anyone would like to bring up, 22 committee members, ex-officios, folks who are our 23 public members? 24 MS. KORNETSKY: I just want to say, Mary Kay, 25 that you've hit so many of the issues and I think it's PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 52 1 going to be very welcome for the community and thank 2 you for thinking it all through so clearly. 3 DR. PELIAS: I don't know that I've thought 4 it all through so clearly yet, but I know the pile of 5 things that I have to organize and come out from 6 underneath. So thank you, Susan. 7 MS. GOTTFRIED: We also owe some gratitude to 8 Dr. Collins who really encouraged us to take up the 9 handbook chapter as one of our priorities and so we are 10 glad that we can be of use in that respect. 11 CHAIRPERSON MARSHALL: Well, we find 12 ourselves a little bit ahead of schedule which is a 13 good thing. But I'm a little worried about moving 14 forward too quickly because we may have folks who are 15 coming for, you know, the part of the discussion that 16 begins in theory at 10:30, I believe. So what we might 17 want to do, we have some extra time, obviously, is 18 break and then begin the discussion on bioterrorism and 19 research in the aftermath of bioterrorism a few minutes 20 early. 21 What do you think, Jonathan? Does that sound 22 -- yeah, one of our speakers is not here yet. 23 So why don't we do that? Why don't we take 24 until let's say five after ten and then we'll begin 25 just a few minutes early. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 53 1 Thank you. And Mary Kay, thank you so much 2 for your leadership and great work. 3 [Applause.] 4 [Brief recess taken at 9:50 a.m.] 5 CHAIRPERSON MARSHALL: Let's resume. 6 We are going to begin with Jonathan Moreno 7 who has kindly consented on the spot to give us an 8 overview of bioterrorism and research opportunities, I 9 suppose, that had been occasioned or that we have 10 become more thoughtful of after the events of September 11 11th. So, Jonathan, thank you very much, and we're 12 just sort of turning the rest of the morning over to 13 you. 14 DR. MORENO: Thank you, Mary Faith. 15 Apologies in advance to those of you who have 16 heard one or more portions of this talk before. A pun 17 that I like to make in getting ready for this talk and 18 preparing people for it is that in my view the history 19 of human research ethics is not at all tangential to 20 this morning's topic. 21 That, in fact, in order to understand the 22 history of human research ethics, we really need to 23 understand what has not been, for the most part, an 24 element of the literature in bioethics which is the 25 military medical interest historically and the national PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 54 1 security interest historically in experiments having to 2 do with preparation for nuclear, biological and 3 chemical attacks. And so my -- there are long, medium, 4 and short versions of this talk, and this, you'll be 5 happy to know, is the short version. 6 I would like to start by noting that our 7 moral intuitions about these matters perhaps 8 unbeknownst to us probably have changed a bit since 9 September 11. For example, exactly one week before 10 September 11, the New York Times had this story in 11 which a couple of investigative reporters got the 12 Defense Intelligence Agency and the CIA independently 13 to accede to the fact that the DIA was engaged in 14 attempts to reproduce an anthrax strain that has been 15 thought to be in Russian refrigerators since the 1980s, 16 but to which we have never been given access. 17 And the CIA indicated that it was going to 18 develop a replica of a bomblet that it is believed the 19 Soviet Union developed in the 1980s contrary to the 20 biological and toxin weapons convention of 1972 for the 21 dissemination of biological and chemical agents. 22 I, as somebody who is interested in this 23 stuff, was waiting for the human rights activists and 24 the lawyers to protest that this was a violation of the 25 biologic and toxin weapons convention and that I PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 55 1 thought there would be quite interesting public debate 2 about that. But, of course, that debate never 3 materialized because of the events of September 11th, 4 and my guess is, that some of us in this room, at 5 least, who might otherwise have been poorly disposed 6 toward these projects might not feel the same way now. 7 That all goes by way of the advertisement of 8 my book which -- what the hell, that's the only payment 9 I get is the ability to advertise my book. Maybe I'll 10 show it to you again -- 11 [Laughter.] 12 DR. MORENO: -- just in case you missed it 13 the first time. The story begins -- the book is called 14 "Undue Risk" which is -- and it was published by 15 Rutledge last year and it's a history of the use of 16 human subjects in atomic, biological and chemical 17 weapons experiments. This is the most important person 18 that I'll be talking about today because he's the most 19 famous graduate of the University of Virginia Medical 20 School, this is Walter Reed. 21 Walter Reed actually plays a very important 22 role in the history of what we're talking about this 23 morning. Not only because when he was called to Havana 24 in 1900 to deal with the yellow fever epidemic, as the 25 country's most eminent virologist and immunologist at PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 56 1 the time, as an Army doctor, but also because as part 2 of his work in Havana, by order of the Surgeon General, 3 his job was to figure out the vector of the epidemic 4 which turned out to be a silver-backed female mosquito. 5 In the course of identifying the vector of yellow 6 fever, he, as well-known, engaged in a number of human 7 experiments. 8 Some of the experiments involved his own 9 commissioners, doctors, in his group, one of who, Jesse 10 Lazier [ph] in his early 30s, was a civilian doctor. 11 Another was a nurse named Clara Moss. 12 Clara Moss parenthetically is the only person 13 who has a stamp in her honor from both Cuba and the 14 United States. 15 I used to say that the next person will 16 surely be Illian Gonzalez, but everybody has forgotten 17 about him. 18 Not only did the commissioners themselves 19 self-experiment, a tradition, by the way, that is 20 virtually unheard of today. And we can have another 21 conversation, perhaps, at a future meeting of NHRPAC 22 about why that is. But also a number of Spanish 23 workers and soldiers, the American soldiers stationed 24 in Cuba, agreed to be subjects of the experiment 25 probably because of concerns about later Sir William, PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 57 1 then Dr. Oceler's denunciation of another set of yellow 2 fever experiments being done by an Italian named 3 Sanarelli [ph] in Brazil. 4 The Surgeon General and Walter Reed developed 5 a consent form as we would today call it, in those days 6 they would have called it a contract or a release and 7 this is the Spanish version of the form that the 8 workers signed. By the way, the American soldiers, 9 apparently, did not accept the money that the Spanish 10 workers were offered. This is actually -- this is the 11 English translation of the form. It's actually a 12 pretty good consent form, given what was known at the 13 time. 14 It says basically that you're in Cuba and so 15 you could get yellow fever and die whether in this 16 experiment or not. But if you take the bite, we'll 17 give you $100 in American gold. If you get sick we'll 18 give you $100 in American gold, and if you die, we'll 19 give it to your family. Not a bad deal. 20 And it specified that they were volunteering 21 and so forth. So not too bad as consent forms go and 22 certainly in plain English and plain Spanish, I'm told, 23 by people who can read Spanish. And so it probably 24 would have passed muster. 25 None of the soldiers who were in the -- or PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 58 1 the workers who were in the experiment died, by the 2 way. For the next 40 years, I'd like to say, military 3 medicine and the whole area of human experimentation, 4 although occasionally controversial, was largely 5 inoculated, pun intended, by the both moral and medical 6 public health success of Walter Reed's experiments. 7 Walter Reed, himself, of course, became a 8 hero. He died a few years later because of a doctor's 9 -- a fellow colleague's ill treatment. But nonetheless 10 he became a hero, a kind of culture hero. There was a 11 play about him called "Yellow Jack" which is the sort 12 of popular term, jargon term for yellow fever. Also 13 became a movie. He became a culture hero. I'm sure 14 that the misconception that he actually took the bite 15 himself -- he didn't because he decided after Jesse 16 Lazier died that he was a little too old for that. 17 Probably have as something to do with the fact that 18 they're building his -- the Army hospital is named 19 after him. It probably should be called the Jesse 20 Lazier Army Hospital. 21 In any case, of course, during and after the 22 second world war when it was learned that both the 23 Nazis and later on -- much later on that there had been 24 Japanese experiments involving human testing of 25 biological and chemical agents and delivery and PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 59 1 disbursal methods of those agents, particularly by the 2 Japanese in Manchuria, guards really came to the public 3 consciousness less confidence in the self-direction of 4 military medicine, but not enough to be a fundamental 5 challenge. 6 The Nuremberg Code and the AMA policy that 7 was part of the Nuremberg Code developed actually 8 during the trial, but that's another story, resulted 9 from the trial of the Nazi doctors. There was no 10 similar trial of the Nazi researchers even though -- 11 excuse me, of the Japanese researchers even though 12 their contributions to what is known about the methods 13 of disseminating biological and chemical weapons was 14 far greater than what the Germans did. Hitler seems to 15 have not been a big fan of chemical and biological 16 agents. He was gassed during World War I and so he 17 apparently didn't like the idea, but some of them were 18 done anyway in the camps. But not nearly as much in 19 that area as did the Japanese for whom there was no 20 trial. 21 This is a disturbing familiar image to many 22 people of one of the experiments in the Dachau 23 Concentration Camp, a freezing or hypothermia 24 experiment. This is the dock of the doctors' trial. 25 There were 23 defendants. Only 19 of the defendants PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 60 1 were medical doctors. The other four were bureaucrats. 2 Interestingly of the seven who were hanged for war 3 crimes, four -- all four were the non-doctors and only 4 there were doctors. So I'd like to say, if you're 5 going to commit crimes against humanity, it's probably 6 better to have an M.D. 7 [Laughter.] 8 DR. MORENO: And there were various sorts of 9 experiments including experiments on battle field 10 injuries, experiments with early sulfa drugs to treat 11 those injuries. They would create injuries and try to 12 treat them in various ways. There were also, of 13 course, biological and chemical experiments. 14 The trial that was thought by the Army 15 lawyers to be an open and shut case took eight months 16 instead of a couple of months as they thought because 17 defense lawyers for the Nazi doctors had some very 18 interesting evidence to put on. For example, they were 19 able to note that on June 3rd, 1945, "Life Magazine" 20 published this story called "Prison Malaria" in which 21 800 federal prisoners at penitentiaries in Georgia, 22 Illinois, and New Jersey were deliberately exposed to 23 malaria laden mosquitos. You can see it in the young 24 man's stomach. 25 In cross-examination the defense lawyers PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 61 1 said, "How come they were the only prisoners?" If you 2 guys are so holy, how come you only used prisoners? 3 Well, the prosecution expert, Andrew Ivy, Dr. Ivy, the 4 AMA representative said, well, I guess because they're 5 more easily available than teachers and businessmen. 6 This is the rest of the article. Obviously 7 this was not a secretive experiment in any sense. This 8 is something that the prison officials are very proud 9 of and as you can see some of these guys got very sick. 10 They were treated with quinine, what was then being 11 developed for the treatment of malaria, atabrine, none 12 of them died. And in at least one memoir of this 13 experience years later, the individual writing the 14 memoir said that this was the greatest thing he did in 15 his life, being part of this experiment because he was 16 part of a patriotic endeavor. 17 Well, the Nuremberg Code, if it applied to 18 anybody applied to prisoners, but prison experiments, 19 of course, did not stop, another story in the United 20 States, at least, until later in the 1970s and having 21 nothing to do with Nuremberg, but having more to do 22 with Tuskeegee and the Attica Prison riot and Mitford's 23 article comparing the prison experiments to the Nazi 24 experiments. 25 During the war there were also radiation PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 62 1 experiments that were secret. Perhaps the most famous 2 of them is that of the 17 plutonium injections of 3 hospitalized patients by the Manhattan Project trying 4 to figure out excretion rates for plutonium for the 5 sake of protecting the young lab workers. They were 6 worried about plutonium as an internal emitter about 7 which they knew nothing. There was also a kind of a 8 theory that maybe since plutonium is a bone seeker, it 9 could turn out to be a magic bullet for bone cancer in 10 which case they would both have gotten some important 11 national security information and maybe found a magic 12 bullet for cancer. 13 Unfortunately, about a third of the 17 people 14 who were given the plutonium without their information 15 or consent were misdiagnosed. 16 This is an example of some of the 17 communication that took place. This is a letter or 18 rather a telegram to Wright Langham and Lou Hempelman 19 who were two of the people who were involved in 20 analyzing the data from the plutonium injections from 21 Dr. Fink at Rochester, University of Rochester was one 22 of the places where they were doing this. And you can 23 see HP3 and HP4 referred to and then HP5, that's Human 24 Product 3, Human Product 4, and Human Product 5. That 25 three Rochester subjects in the plutonium injections. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 63 1 Surely had this been known by the defense lawyers at 2 Nuremberg for the Nazi doctors, they would have had an 3 even more powerful case to make. 4 When the Atomic Energy Commission discovered 5 this, they were obviously rather concerned about it. 6 They decided to keep the plutonium injections secret. 7 They wrote two letters to professors who had been part 8 of the plutonium injection experiments during the war 9 who, of course, after the war wanted to do what all 10 professors want to do, which is publish their data. 11 And they said, okay, you can publish your data from 12 these injections. By the way, nobody died from the 13 plutonium injections, I should add. 14 You can publish your data from the plutonium 15 injections, but these are the rules that you have had 16 to have followed in order to publish your data, did you 17 follow these rules? And this is one letter that was 18 written by the general manager of the AEC, and this is 19 the second, and to my mind even more interesting 20 letter, same spirit but it includes the term informed 21 consent for the first time in English, that I know of. 22 Bob mentined the Amicus brief from the surgeons in 23 '57, the legal case, this I think actually had -- there 24 was no more thought given to the term informed consent 25 in '47 in this case than there was in '57 in that PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 64 1 instance. But this came from whom? From MIT 2 engineers, administrators and lawyers. And if you look 3 at it carefully you can see that the ethics 4 requirements are even greater than ours today and 5 probably unethical because the next of kin would also 6 have to give informed consent for somebody to be in an 7 experiment. I don't think we even accept that today. 8 But the term "informed consent" comes up in 9 what context? In a national security context. 10 This is the only document that shows that a 11 federal agency ever actually adopted the Nuremberg 12 Code. And if I were to ask the people in the room, 13 what federal agency was this that actually adopted the 14 Nuremberg Code verbatim, most of you would probably be 15 surprise to know, unless you've heard me talk about 16 this before, that it's the Pentagon. 17 In 1953 the Pentagon adopted in top secret 18 the Nuremberg Code verbatim, word-for-word. In fact, 19 if they had been in my class I would have to flunk them 20 because they plagiarized, they didn't cite it as the 21 Nuremberg Code. And I can't go through the whole -- 22 the preface to it is very important for the purposes of 23 this session because it was developed in a vacuum -- in 24 a policy vacuum. The DOD wanted to do a nuclear or 25 they called at the time "atomic biological and chemical PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 65 1 weapons experiments" and it very carefully says, "for 2 defensive purposes." They wanted to do these 3 experiments, they wanted to use human subjects, 4 soldiers, or perhaps people who were in Army or Navy 5 hospitals, but they didn't have any policy to cover 6 this, so the needed a policy. 7 They looked around, it's an interesting 8 story, fascinating story how they came up with this 9 policy. The Army, the generals, the admirals and the 10 doctors were very opposed to this policy. The lawyers 11 and the administrators and the political people in the 12 Pentagon said you had to have it. Why? Because we 13 just finished hanging seven Germans based on the 14 Nuremberg Code. Actually, they were wrong about that. 15 They weren't hanged based on the Nuremberg Code. The 16 Nuremberg Code came after the trial. 17 So this is the voluntary consent of the human 18 subjects is absolutely essential if the famous first 19 line of the Nuremberg Code, there it is along with all 20 the rest of it. You can see this was a top secret 21 document. Don't worry, you're not going to go to 22 Guantanamo because you saw this. It was unclassified 23 in 1975. 24 You can ask yourself the question, how did 25 this get disseminated? The answer is, not well. And, PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 66 1 in fact, here is for example a memorandum -- a cover 2 your butt memorandum from the Air Force Officer who was 3 in charge of the flash blindness studies that I briefly 4 mentioned yesterday. 5 He's told there's a policy, is what he is 6 saying here. But he doesn't know what the hell it is. 7 And so he's like any good responsible bureaucrat he's 8 saying, I am not going to be responsible for going by a 9 policy that nobody has bothered to show me. And I've 10 just written a letter to the higher ups to tell them 11 that I expect to see this policy because I don't know 12 what the hell I'm doing. Meanwhile, he has had at 13 least two pilots become temporarily blinded by his 14 study. So he's concerned. 15 Another problem is the fact that I mentioned 16 yesterday that I want to emphasize again today. 17 Everything turns into what you consider to be research. 18 The 200-plus-thousand men who were deployed at Desert 19 Rock, Nevada from '53 to '62 for the test shots, the 20 atomic test shots were not considered to be research 21 subjects for the most part. And yet information was 22 gained about exposure to radiation from them in various 23 ways. And this is just something -- I'm also on a 24 National Academy of Sciences panel on the dose 25 reconstruction of the atomic veterans exposures. And PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 67 1 this gives you a sense of where they were when at one 2 of the test shots, Shot Hood, 4:40 a.m., they were in 3 the trenches. The bomb goes off at 4:55. They do 4 double time, 2,000 marines in this case, to ground 5 zero. They run around in ground zero for a couple of 6 minutes and then they go back to their landing zone 7 where they arrive by 7 a.m. 8 What were they doing there? Well, they were 9 being trained. They weren't human subjects. And yet 10 the term "experiment" often appears in documents that 11 have been declassified, but not in medical experiment. 12 Ultimately the Nuremberg Code policy fails. 13 In many ways, and I'll simply summarize it by pointing 14 out, the Army Inspector General, himself determined in 15 1975 that there was a startling lack of consistency in 16 the interpretation of those regulations. 17 I'm not going to talk very much about Sidney 18 Gottlieb and the CIA except to say he also has a UVA 19 connection. He died in the hospital about -- well, 20 when I was finishing my book, unbeknownst to me. This 21 is one of the early MKULTRA documents that authorizes 22 the beginning of the LSD and other hallucinogenic 23 experiments. You can see it's pretty heavily redacted, 24 still. But it says enough to give us an idea what was 25 going on. Gottlieb was in charge of the LSD PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 68 1 experiments and also was the guy who developed the 2 botulin laced cigars that we tried to get in Fidel 3 Castro's mouth unsuccessfully. 4 This is Frank Olsen, the CIA Anthrax expert, 5 by the way. He was an Anthrax expert during the second 6 World War. Interestingly, he was assigned to Fort 7 Detrick, he was said to have been dosed with LSD and 8 the committed suicide -- because he was psychotic -- by 9 jumping out the 13th story of a hotel across from what 10 is now Penn Station. This is his obituary. I happen 11 to believe that he was -- in fact, that that was a 12 cover story, but we'll never entirely know the truth. 13 So the revelations of MKULTRA, the LSD 14 experiments influenced public support for new federal 15 requirements concerning human subjects research. We 16 often forget that it wasn't only Tuskeegee and the 17 other -- we'll call civilian scandals -- it was also 18 the revelations of MKULTRA and the Army's LSD 19 experiments that led to these regulations. 20 And, incidentally, the relationship between 21 the -- what seemed to be the civilian experiments and 22 the military experiments turns out to be rather 23 complicated. Can anybody tell me, for example, who 24 first provided the funding for the Hepatitis 25 experiments at Willow Brook? PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 69 1 [No response.] 2 DR. MORENO: 1957, it was the Armed Forces 3 Epidemiologic Board. So, although we think of sort of 4 the non -- the civilian pocket and the military pocket 5 to be distinct, in fact, there's a close and very 6 interesting relationship. 7 I'm not going to go through the rest of this. 8 There are a couple of nice images of one of my 9 favorite buildings, other than Mr. Jefferson's Rotunda, 10 also on the list of historic structures there is the 11 famous Eight Ball at Fort Detrick which you can still 12 go see. It can't be torn down by law because it is on 13 the list of historic structures. It's a million liter 14 cloud chamber that was used in the '50s and '60s to 15 conduct biological weapons experiments. This is a 16 lovely plexiglass model of the Eight Ball that's on the 17 cover of my book. You can see the portholes up there. 18 These are the dosimeters at the base of the eight 19 ball, checking the size and the nature and quantity of 20 the molecules. What were they doing? They were 21 inhaling Rick Valley Fever, Q Fever, Tularemia, 22 Venezuelan [inaudible] encephalitis, whatever happened 23 to be the agent of interest at the time. Here are a 24 couple of the volunteers. This is not a secret 25 experiment. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 70 1 These were Seventh Day Adventists, about 2 2,400 of them were used and volunteered between 1953 3 and 1972 with the enthusiastic cooperation of the SDA 4 church. This is a copy of one of the pages of the 5 brochure that they disseminated -- the church 6 disseminated showing the -- they were called the "White 7 Coats." This was part of a group called "Project White 8 Coat." 9 And I like the -- watching I Love Lucy in the 10 bottom picture on the old black and white TV, probably 11 the same one I watched. 12 There are reunions of the White Coats, like 13 the prisoners in the malaria experiment they are still 14 very proud of their participation. Detrick will follow 15 -- Usamarit, I should say, will follow and monitor 16 their medical condition. There is no validated 17 complaints relating to their exposures during the '50s 18 or '60s. 19 I am not going to run through all of the 20 Radiation Advisory Committee Findings, I've done that 21 before. These are the recommendations. I can show you 22 again later, if you like. Essentially the conclusion 23 is that we are still waiting for the full 24 implementation of the recommendations for classified 25 research that were offered by -- in fact, accepted by PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 71 1 the Clinton Administration which leads us to our 2 conversation today. And so now I think we can move to 3 our guests. 4 CHAIRPERSON MARSHALL: If Monica and John 5 could just come on up, we'd love to invite you both to 6 the table. 7 DR. MORENO: So our first guest is Monica 8 Shoch-Spana. Dr. Shoch-Spana is a senior fellow at the 9 Center for Civilian Biodefense Strategies at Johns 10 Hopkins University and we also welcome Dr. John 11 Livengood, Deputy Associate Director of Science or the 12 Centers for Disease Control and Prevention. 13 Dr. Shoch-Spana. 14 DR. SHOCH-SPANA: Good morning. I much 15 appreciate the invitation to present to the advisory 16 committee this morning and other individuals in the 17 audience. 18 I had a sneak peak at Dr. Livengood's 19 presentation, so I've tried to construct mine in such a 20 way so that it complements the information. And I am 21 taking more the perspective of the needs of the 22 researcher in the aftermath of a bioterrorist incident. 23 And while that's being fired up, let me give 24 you an overview of the ideas I wanted to cover today. 25 First is just to review the urgency with which we PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 72 1 should go about conducting research in the aftermath of 2 a bioterrorist incident. The urgency is both of a 3 short-term and a long-term duration. That does not 4 mean we put protections on the shelf. What it means is 5 we need to look very carefully at our review mechanisms 6 such that we can provide full review of research so 7 that it can transpire in that particular context. 8 We also need to come back to issues of how to 9 define research in practice. 10 I want to talk about the timing of the impact 11 of research into the aftermath of a bioterrorist 12 incident and the different realms in which knowledge 13 can be put. But there are certain imperatives in these 14 very different realms and I will go into that. 15 I want to talk very generally about whether 16 the current IRB universe in terms of it being a 17 practical regulatory structure, does it fit the needs 18 of biodefense in its current state? 19 I would like to illustrate some of those 20 generic observations with some concrete examples of our 21 experience at the Johns Hopkins Center for Civilian 22 Biodefense Studies. They are very impressionistic, 23 anecdotal. It's just us, but we think that they might 24 be reflective of some trends within the current IRB 25 structure. And then a list of very, very preliminary PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 73 1 recommendations or some thoughts on how the committee 2 should proceed. 3 [Simultaneous conversation.] 4 DR. SHOCH-SPANA: This little machine, though 5 it is light, is very slow to wake up. So let me just 6 jump in to talk about the exigency of research in the 7 aftermath of bioterrorism. 8 There were three compelling real reasons or 9 three compelling dimensions that speak to the urgency 10 of this type of generalizable knowledge. The first is 11 the demonstrated vulnerability of U.S. civilians and 12 the global population to bioterrorism and other forms 13 of attack; and this was demonstrated last fall. 14 The second is that we have lived through a 15 bioterrorist incident that was incredibly disruptive, 16 even though there were few cases and few deaths. But 17 in order to be proactive, we need to think about the 18 serious and growing dangers that bioweapons pose in 19 general. That is, we can consider the fall of 2001 and 20 the problem with Anthrax dissemination as a prologue to 21 the problem. That's why we need to think and act 22 proactively now. 23 And just very quickly the reasons why 24 bioweapons are a serious and growing danger, just to 25 recall things that have been covered and discussed very PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 74 1 much in recent time is what they call the four Ds and 2 the V. There is of course the destructive and 3 disruptive capacity of these weapons. There's a whole 4 range of bioterrorist scenarios that cover hoaxes, what 5 we saw last fall which was a limited number of cases 6 and death, but incredible social disruption, and then 7 at the far end we have the potential for a catastrophic 8 outbreak of infectious disease and potentially a global 9 pandemic. 10 There's the dual use nature of these weapons. 11 The problem with bioweapons is that they have the 12 technology and the knowledge relevant to this type of 13 weapon has varied in legitimate uses such as beneficent 14 vaccine production. It's very hard to control. 15 There's the issue of the desirability of 16 these weapons, the proven and growing demand for this 17 type of weapons capacity both among state actors and 18 non-state actors. 19 There's the fact that we're in the dawn of a 20 more potential bioweapons arsenal. You have to 21 understand that we are now in the age of big biology. 22 And every leap in scientific knowledge of life 23 processes can be subverted. We are looking at genomic 24 advances, enhanced computation power, and let us not 25 forget the entrepreneurial spirit of people in PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 75 1 biotechnology. So we are going to see incredible leaps 2 and bounds in our knowledge of biology which could 3 potentially be subverted to destructive ends. And then 4 there's the issue of a global vulnerability to 5 infectious diseases should something be unleashed in 6 the population. 7 So we've got demonstrated vulnerability, a 8 growing problem with biological weapons at the third -- 9 and then thirdly we have an absence of relevant 10 knowledge to dealing with the aftermath of this type of 11 weapon. 12 And this is like something out of Star Trek. 13 Forgive me. 14 So that's so I can speak to the urgency of 15 this type of knowledge. 16 I did want to also just very simplistically 17 perhaps talk about the different realms in which 18 generalizable knowledge, just taking out the definition 19 of research, systematic investigation that contributes 20 to generalizable knowledge, there are three realms in 21 which knowledge of the aftermath of a bioterrorist 22 incident can have an effect. Each of these realms has 23 different imperatives and also a different time cycle 24 embedded within it. 25 We have individuals such as political PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 76 1 leaders, leaders in medicine and public health, public 2 health and safety institutions and the general public. 3 We have their interest in data, information, 4 knowledge, that can hance the immediate response to a 5 biological attack. It's the type of feedback one would 6 need in trying to contain the medical and public health 7 effects of this type of weapon. It's an immediate 8 need, for knowledge. 9 There is the realm of policy development 10 which can be -- can exist in a crisis context, in a 11 non-crisis context, but the temporal dimension of this 12 is tied to the policy decision-making cycles. Okay. 13 Issues of budgets, issues of legislative sessions, and 14 more -- and different levels of government taking a 15 look at policy in terms of biodefense. But it's a 16 different temporal dimension compared to emergency 17 response. 18 And then, thirdly, there's the realm of the 19 advancement of scientific knowledge which we could 20 think of as being the open-ended, iterative, 21 accumulation and advancement of scientific knowledge. 22 Now, these are not -- these realms are 23 connected to one another. So it's a bit -- it's a 24 simplistic schematic, but I want you to think in terms 25 of the decision-making cycles that are inherent in PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 77 1 these three different realms. 2 I think that it's probably easiest to imagine 3 the systematic investigation of the effects of medical 4 interventions as the type of research that we're 5 talking about. But there's a wide range of potential 6 research scenarios in the aftermath of a bioterrorist 7 attack. And these research emphases could incorporate 8 varying degrees of clinical, behavioral, social, and 9 political phenomena. And the research subjects 10 themselves could range broadly and manifest different 11 thresholds and needs for protection. 12 I just wanted to throw up some concrete 13 examples of topics that have been discussed within the 14 biodefense community as research priorities so you get 15 a feel for the type of research ventures that have been 16 under way or are considered to be priorities. 17 We've talked about the efficacy of untested 18 medical regimens, I think Dr. Livengood can speak in 19 greater detail about that. The mental health impacts 20 of bioterrorism, both of short- and long-term 21 durations. Issues of effective strategies for leaders 22 and health officials in communicating with the public. 23 Let us recall that bioterrorism is an 24 instance in which we have the vagaries of infectious 25 disease mixed with a thinking enemy. So we don't have PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 78 1 baseline knowledge in which a great deal of it in which 2 to deal with this type of new phenomenon. New -- 3 there's old and new aspects of this phenomenon, but in 4 terms of the higher-end effects of bioweapons we need 5 to think about this very seriously. 6 There's the issue of successful 7 organizational strategies in managing a biological 8 disaster. Elements of community resiliency, this is a 9 priority for mental health professionals. They want to 10 understand how it is that communities survive this 11 particular type of disaster. And then also the social 12 and economic aftereffects of bioterrorism. So that's a 13 range of potential topics that we're talking about. 14 Just some generic issues about the fit 15 between the current institutional review board process 16 and the priorities within biodefense. I'm going to 17 illustrate these with some concrete examples of the 18 Johns Hopkins Center for Civilian Biodefense Studies 19 and our interaction with our local IRB, our 20 institutional review board. 21 Is the committee familiar with us? Should I 22 give a few minutes -- 23 DR. MORENO: Give a little -- 24 DR. SHOCH-SPANA: Okay. The Center was 25 founded in -- well, formally in September of 1998, PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 79 1 although there were some meetings convened prior to 2 that time. The founding director was D. A. Henderson 3 who is the current director of the Office of Public 4 Health Preparedness in Health and Human Services. 5 It was an enterprise or it is a joint 6 enterprise of the Schools of Medicine and Public 7 Health. The mission of the Center is to prevent the 8 development and use of biological weapons, but should 9 prevention fail, we also want to arrest the human 10 suffering that is attendant with the effects of a 11 bioweapons, i.e., an epidemic. 12 Our objectives in carrying out that mission 13 are to raise awareness about the medical and public 14 health aspects of bioterrorism. We needed to bring 15 medical and public health professionals to the table 16 because when the center was founded, that type of 17 expert knowledge was not adequately considered within 18 government programs to deal with the problem of 19 bioterrorism. 20 There was in the mid- to late-90s an 21 overemphasis on traditional first responders like fire 22 departments, search and rescue and police. And there 23 wasn't enough of an effort to involve clinicians, 24 nurse, epidemiologists, infection control professionals 25 in this particular problem although their knowledge was PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 80 1 most relevant to the health effects of an epidemic. 2 So we were attempting and continue to attempt 3 to raise awareness around bioweapons as a medical and 4 public health problem. We also are interested in 5 building up the knowledge base related to biological 6 weapons response and prevention. And we see ourselves 7 as trying to catalyze effective response systems to 8 deal with the after effects of a biological attack. 9 We are sort of -- I love this phrase -- "the 10 redheaded step child of the university" because we see 11 our constituents to include not only our peers in 12 medicine and public health, but policy makers. We want 13 our knowledge to be relevant to the development of 14 national policy around prevention and response of -- 15 response to biological weapons. So we may write for an 16 academic audience, or we may write to and speak to a 17 policy-driven audience as well. 18 So our academic peers have some difficulty 19 with us because we have this recognition of these 20 different cycles or these different realms with 21 different temporal dimensions and what effect our 22 knowledge production activities can have. 23 The IRB also looks at us as not your 24 traditional academic enterprise. And we can come back 25 to that. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 81 1 Some of the generic issues that have been 2 raised about sort of the fit of the current IRB 3 structure is -- the problem of defining research versus 4 practice. And we can discuss this. I would rather -- 5 we can handle that in a question and answer session, 6 but the question of who and what activity gets 7 regulated, and the need to revisit -- need to revisit 8 definitions of research and practice. Distinguishing 9 these does not mean removing protections for human 10 subjects, but we do need to go back to how it is we 11 have structured our review processes about protecting 12 human subjects. 13 The issue of benefits and risks. There's the 14 preeminent moral status of the individual, of the 15 protections that have been put into place often times 16 in a reaction to biomedical, the reactions to problems 17 in the biomedical realm, certainly not exclusively, but 18 others have commented on the hegemony of the biomedical 19 model of IRB review. And we can come back to that. 20 But there's also a larger trend. So the 21 biomedical emphasis on the individual and then through 22 the IRB emphasis on protecting the individual. That's 23 a more complicated issue but we can come back to that. 24 But I guess there's more -- that issue is 25 also tied up within, I guess, a larger cultural process PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 82 1 in the United States of possibly a move toward zero 2 tolerance of individual risk in our highly litigious 3 society at the expense of any value placed on societal 4 benefits. With regard to biological weapons, we are 5 looking at a population-wide impact. We need to 6 revisit the question, what is at stake in the knowledge 7 that is produced and used regarding bioweapons 8 prevention and response. 9 In terms of the IRB review process, the 10 aspect that we've run into is the potentially 11 inflexibility of this review process in time-sensitive 12 contexts. And some examples of that are, or issues 13 related to that is, the ephemeral nature of phenomena 14 being studied in the crisis context. So there's a 15 need for -- felt among some researchers -- to get to 16 the field -- the research field as soon as possible 17 because of the transient nature of what is being 18 studied. 19 All we have to do is to think back to our own 20 personal states of mind and behaviors immediately post- 21 911 and October 4th when we heard about the first 22 inhalational Anthrax death to recall that it is a 23 different social, political, economic, and 24 psychological environment. So there's an ephemeral 25 nature to that crisis context. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 83 1 There's the issue of the research cycle as 2 it's currently constructed and there's an emphasis on 3 that third realm, the open-ended, iterative production 4 of scientific knowledge that perhaps IRB and -- I'm 5 just going to speak in gross, broad generalization, so 6 please forgive me -- but that our notion of research, 7 research protections is tied to that more lengthier 8 decision-making cycle and the sense of our knowledge 9 base in general, not as it's used in policy development 10 or in emergency response. But we have to realize that 11 with this particular topic there are critical windows 12 of opportunity for change in the world that will be of 13 benefit to society, both in terms of emergency response 14 and in terms of policy development. 15 So we need to go back and think, is there 16 anything within the current structure of the IRB review 17 process that might impede the benefit of the knowledge 18 produced in the aftermath of a bioterrorist incident. 19 And then lastly there's these two -- and, 20 again, very impressionistic. It's been our very 21 limited experience that at least our IRB is very -- 22 gets a little jittery when issues of bioweapons and 23 national security come before them. So you can call it 24 sort of the -- in bioweapons you have to understand, 25 they are -- it is a taboo and has been a taboo subject PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 84 1 in the academic setting. So when we submit things to 2 the IRB, we have little red flags going up because we 3 are now moving into controversial waters. We talk 4 about national security and we sit in a school of 5 public health and it really makes the institution as a 6 whole uncomfortable, but also the IRB. 7 But it makes all of us here today 8 uncomfortable. We're in a new world. There are risks 9 in our world related to bioweapons. 10 These generic issues come out of our 11 experiences -- and I'll just go through this quickly 12 because I would love to hear from Dr. Livengood myself. 13 But I wanted to bring examples of three -- oh, I have 14 plenty of time. Okay. There are three projects that 15 have been conducted or are currently being conducted 16 that sort of speak to these generic issues. We have a 17 project we call the "Anthrax Chronicles." And this is 18 an attempt to talk to public health, medical and 19 administrative experts who had direct involvement in 20 response to the anthrax dissemination crisis last fall. 21 In order to derive lessons learned that impinge on the 22 interactions between the realm of public health and 23 medicine. We want to understand what went well. What 24 didn't go so well in terms of the exchanges of 25 information across these two realms during that PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 85 1 critical moment in responding to this bioterrorist 2 emergency. 3 And I've mentioned who the research subjects 4 are. It is -- these are open-ended semistructured 5 interviews. Most of them over the telephone, some in 6 person. 7 Some of the issues that came to the fore with 8 this particular project. The Biodefense Center 9 originally approached this project as a form of 10 practice. That is, we were speaking to peers in 11 medicine and public health about their experiences 12 during this crisis. 13 Again, just to speak to the unusual quality 14 of the biodefense center. We're in an academic 15 institution, we try and effect national policy, and 16 during this crisis we went operational. Okay. People 17 were desperate for information about how you could -- 18 how you responded to this type of medical and public 19 health emergency. They were calling us for basic 20 information, clinical management of inhalational 21 Anthrax, how you run a hospital in this type of 22 setting. Calls from the general public about, do I go 23 buy a gas mask, or do I need to stockpile cipro. 24 So you have to understand, we were 25 transformed in this moment and became operational. So PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 86 1 I just want you to understand the blurring of the 2 boundaries that occurs. During this type of -- in this 3 crisis context because it happened to us. 4 So when we originally approached this 5 project, we considered it practice. That is, 6 practitioners talking to practitioners trying to 7 understand wht happened so that we could then help 8 precipitate guidance to our peers our peers in medicine 9 and public health and to also inform policy. But then 10 we sort of stepped back and said, well, you know, this 11 reeks of research. And we are systematically 12 collecting information. Perhaps we need to go to the 13 IRB. So we did. And wht did we find when we went 14 there? Well, people -- well, at Hopkins I think we all 15 realized -- 16 [Laughter.] 17 DR. SHOCH-SPANA: -- the pressures that have 18 been placed on the Hopkins institution as a whole and 19 in particular its IRB and its principal investigators 20 and so on. Anyway so everyone is on high alert. High 21 alert about IRB-related matters. 22 But what we encountered when we went through 23 the review process these are two things that came up, 24 sort of the issue of the balance between individual 25 protections and the societal benefits of this type of PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 87 1 inquiry. And the IRB, to its credit, gave due 2 diligence to the protection of research subjects. You 3 will recall that the research subjects are medical, 4 public health, and administrative experts. Okay. 5 People who held positions of authority and who were 6 responsible for protecting public health and safety. 7 The IRB was very concerned though about the 8 potential. This is one risk. Our priority risk was 9 the potential for some research subjects -- the 10 potential for the job loss due to sort of the 11 whistleblower effect. Should someone, even though 12 holding a position of authority, say something that 13 indicated that there was an egregious error 14 particularly of the preventable kind that might have 15 had some impact. Not just on the credibility of the 16 institution, but down the road someone could see it as 17 somehow affecting the morbidity and mortality rates 18 that transpired during this period. So the IRB did 19 practice due diligence about making sure that we 20 thought through the potential risks to this highly 21 placed research subject population. 22 That emphasis though on protecting these very 23 well placed individuals in addition to recommendation 24 that we get a certificate of confidentiality so that we 25 wouldn't be compelled to turn over our raw data, PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 88 1 perhaps indicates a tendency -- this is not passing 2 judgment. I'm just trying to find some transfer 3 discussion that the tendency to elevate individual 4 protections above the population's benefit of public 5 health advances and improved public policy. 6 We must return to questions of relative risks 7 and benefit. And so that's the Anthrax chronicles. 8 It took seven weeks, maybe this is speedy in 9 the world of the IRB. But it took about seven weeks 10 with multiple phone calls and e-mail exchanges, a 11 little nudge here and there to get this expedited 12 review of the project. 13 So there was the delay in beginning research 14 into this timely topic. Again, just to reference back 15 to the ephemeral nature of responses in the crisis 16 context and a delay in beginning research into a topic 17 with immediate relevance, immediate relevance to 18 national policy development. We've just allocated $1.1 19 billion to state and local health departments in order 20 to improve response to bioterrorism incidents. 21 That's a lot of money with good directions 22 coming out of HHS. But that's just so you understand 23 the context, the policy context for this type of 24 information. 25 One has to just sort of compare the PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 89 1 constraints upon researchers of the academic kind to 2 researchers of the journalist kind and the incredible 3 impact that their generalizable knowledge has upon 4 policy development in the United States. Again, we're 5 not advocating for reduced protections for human 6 subjects. But we need to understand the -- again, 7 these different time cycles for impact of bioterrorism- 8 related knowledge. 9 How are we doing on time? Fine? Okay. 10 Another project, this one is still going 11 through review. It was first submitted in January, the 12 beginning of January. We call it the "persephone 13 effect," but let me give you the more boring title. 14 Arresting biological weapons development self 15 governance for the bioscience community. The purpose 16 of this project is to try and analyze and posit 17 possible new governance models for biological science 18 that would diminish the risk of beneficent science 19 being misused by others in order to further bioweapons 20 research or development. 21 Now, this is not per se research in to the 22 immediate aftermath of the bioterrorist incident. I 23 bring this case study to you today because it speaks to 24 sort of the IRB discomfort with potentially 25 controversial issues in those that overlap with PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 90 1 national security. Basically we want to talk to 2 biological researchers about their own concerns about 3 the subversion of beneficent biological research to 4 destructive purposes. There is black -- so-called 5 black science out there, that is, scientific knowledge 6 that is deliberately produced for the purpose of 7 improving bioweapons, okay. So that's just -- the 8 commitment is to using technical expertise to build a 9 better bioweapons. 10 The persephone effect is about this gray area 11 that speaks to the dual-use nature of biotechnology and 12 the potential now applications of scientific knowledge 13 and biotechnology that has been produced for beneficent 14 purposes. 15 So we wanted to talk with scientists about 16 their own concerns about that, the persephone effect, 17 if you remember your Greek mythology, persephone was 18 picking flowers one day and stolen away and taken to 19 Haites and was allowed to return to earth on for part 20 of the year. So we're talking about the capture of 21 good science for bad purposes. So we're talking to 22 scientists about that and their own ideas about models 23 of governance for the scientific community. 24 Superficially, it looked like a pretty simple 25 project. We're talking about the conversations with PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 91 1 very highly placed individuals about their publicly 2 available research which we found by using just 3 google.com and the regular internet search engines, 4 tenured professors, heads of academies of thus and so. 5 So those are our research subjects. 6 The IRB, again, was exercising due diligence 7 about protecting research subjects. Concerns over, for 8 instance, if we sort of fingered someone whose research 9 could potentially be misused, that perhaps the FBI 10 would be interested in scrutinizing their potentially 11 criminal acts related to controls over special agents 12 and such. But there was concern over potential 13 scrutiny of this research subject population by figures 14 in law enforcement. 15 The potential loss of respect, credibility 16 and reputation in the field. If someone was seen as an 17 unintentional perpetrator of bioterrorism, perhaps. 18 These are very high stakes inquiries and we, 19 again, wanted as much attention paid to the societal 20 benefits of this type of research as was given to 21 individual protections for the research subjects. 22 Again, a very highly placed population, again, 23 vulnerable to certain things. And I've spoken to the 24 bioweapons taboo. The title made a lot of people, we 25 heard, indirectly that the title seemed to be PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 92 1 unsettling for members of the IRB, arresting bioweapons 2 development. They thought we were actually going out 3 to investigate biological researchers about their own 4 perpetration of this type of bad or black science. 5 Interestingly, there was another -- there is 6 another research team out there in the world who is 7 doing the very same type of inquiry. They, however, 8 don't come from a medical and public health 9 perspective. They come from a political science 10 perspective. It never crossed their minds. In fact, 11 they were floored that we had gone through IRB. It 12 never crossed their minds that their parallel inquiry 13 might need to be subjected to review by their local 14 IRB. And this speaks to, again, just the generic 15 issues within the overall universe of IRB-related 16 matters, is the different approaches within various 17 professions about human subjects protection. 18 Now, I come from cultural anthropology and we 19 have our own ethical legacy about how it is one goes 20 about protecting our research subjects. It does not 21 always overlap. It does not overlap 100 percent with 22 what I see within my medical and public health 23 colleagues. And I know that there are some -- there 24 are issues of whether social and -- you guys deal with 25 this more than I do, but I just want to point out that, PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 93 1 again, we have that generic issue coming up in this 2 particular realm. 3 And then just lastly, one last case study 4 which is the people's role. The people's role refers 5 to our interest of the biodefense center in helping 6 inform policy about the need to create a positive and 7 constructive role for the public in responding to 8 bioterrorism. There is a tendency to sort of think of 9 the public as either a passive population who is just 10 going to do what it's told by authorities or a rock- 11 throwing mob who is not going to do anything it's told 12 and it's going to use violence to acquire scarce 13 medical resources like antibiotics and vaccines. So 14 these very simplistic stereotypical notions of what the 15 public is capable of doing in the aftermath of a 16 bioterrorist incident. So we are interested in 17 speaking to the capacity for constructive reactions and 18 the need to take them in consideration in our response 19 systems not just to worry exclusively about negative 20 psychological and social impacts. This is about 21 empowering the public, empowering the people to help 22 stop the effects of a bioweapons attack. 23 So to that end we led a rapid response 24 research team up to New York to study the local 25 humanitarian response to the World Trade Center tower PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 94 1 attack. We were interested in the way in which from a 2 manager's perspective volunteers were being organized 3 or were not being organized in such a way to enhance 4 the emergency response to this problem. 5 The subjects in that case were more 6 individuals at the managerial level. Because we were 7 allowed to do observation, there were indirect -- sort 8 of the volunteers who were being organized by these 9 managers, but that was strictly in an observational 10 mode. We had an emergency expedited review. And I use 11 the word "emergency," but it was given an expedited as 12 in timely review. And that was a successful 13 interaction with the IRB. 14 In subsequent interactions with the IRB, 15 we've talked about the generic need. No one expected 16 911 and the need for us to go so quickly to the field 17 to study a phenomenon. We just didn't anticipate that. 18 But now that we know that that's altogether 19 possible, that we could face another attack, that we 20 wanted to take proactive steps with the IRB so that 21 they understood that we wanted that capacity to respond 22 rapidly from a research perspective. So we've had 23 conversations with them and we've talked about several 24 solutions, one of which is if it is more in the realm 25 of practice, not systematic, but more practitioner-to- PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 95 1 practitioner gathering of information. And, again, 2 this is sort of vague. 3 There's been no actions on this, it's just 4 sort of preliminary conversations. There's that, 5 talked about that, what constitutes research and what 6 needs to be regulated. The issue of potentially having 7 the IRB review a generic proposal where we talk about 8 the types of bioterrorist incidents we would like to 9 respond to rapidly, the types of research subjects we 10 anticipate encountering, the types of research 11 methodologies and so on. 12 I'm very sort of everything in the kitchen 13 sink, everything that we could anticipate. There's 14 that possibility and then also they're agreeing to 15 allow for an emergency -- again, an emergency expedited 16 review of a project. 17 Now, these are the options that we've talked 18 about. But interestingly we find that -- and, again, 19 we typically go through the school of public health 20 IRB. There is not a whole lot of familiarity with 21 rapid response teams. And I draw a comparison to the 22 University of Delaware which has the Delaware Disaster 23 Research Center where their IRB works with the DRC in 24 both emergency reviews and then these more sort of 25 generic, on-the-shelf approvals that can get activated PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 96 1 when a disaster goes down. 2 Our IRB is not familiar with that type of 3 concept. We've had to engage in a lot of education 4 about that. I don't know about other IRBs, but that's 5 something that's come up with ours. So just to 6 conclude and thank you for your time today. 7 We need to clarify realms of research and 8 practice and applicable protections. 9 The need to recognize the qualitatively 10 different realms in which bioterrorism-related research 11 can have an impact. 12 Okay. Emergency response policy development 13 and the advancement of scientific knowledge. 14 We need to readdress our social approaches 15 and our institutional approaches to balancing 16 individual protections and societal gains. Okay. 17 And, again, that's in the context of this 18 increasing tendency towards zero tolerance of risks. 19 And it's just not in the IRB realm. Okay. It's out in 20 our culture. And the need to articulate, it's 21 incumbent upon researchers in biodefense to articulate 22 very well the societal benefits of their ventures. 23 We need our review institutions to think 24 about the balance of these two things and the way in 25 which we allow for a good balance. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 97 1 And lastly, to consider guidance to local 2 IRBs on the time sensitive nature of research in the 3 aftermath of a bioterrorist incident. Speaking to 4 things such as rapid response, the needs of rapid 5 response research and how to facilitate that. And 6 that's just one concrete example. 7 Thank you very much. 8 [Applause.] 9 DR. MORENO: Thank you very much. 10 Dr. Livengood. 11 DR. LIVENGOOD: Thank you. I'm glad to be 12 here this morning. 13 My presentation is going to be somewhat of a 14 different focus, because, after all, I work for the 15 Centers for Disease Control and Prevention, the 16 nation's public health agency. I am very happy and 17 proud to be a public health practitioner where I've 18 spent basically my entire career since I finished my 19 pediatrics training. And where I also supervise, as 20 part of my functions, the Human Research Protection 21 Program at CDC. 22 So very much the types of things that I'm 23 going to talk about I think meld very well with what 24 was covered previously, but try to illustrate it in 25 terms of the practical examples that we have recently PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 98 1 or are currently facing in trying to address dealing 2 with some of these issues in the potential context of 3 bioterrorism. 4 As soon as they get the things up we'll 5 start. 6 What I'm going to talk a little bit, just a 7 little bit of context because, after all, I think 8 everyone here realizes what the context is, these 9 things changed recently and things are different and 10 probably will never go back to the way they were 11 previously. 12 I'm going to provide you a little bit of 13 background on some of the agents, just for familiarity. 14 I'm not an expert on Anthrax. I am somewhat more of 15 an expert on vaccines, that being my particular 16 background. But I'm not from the part of the Agency 17 that has the technical knowledge about these. I'm 18 going to try to be talking about the human subjects 19 issues as they presented themselves to us at CDC. 20 And I think the issues that I'm most going to 21 spend my time on are two. One of which was already 22 quite some covered, so I'll try to be a little briefer 23 on that part, and that has to do about whether what 24 you're doing is research or it is not research, it is 25 practice. It is something you are doing. And that's a PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 99 1 very hard concept in many ways in some of the 2 permutations such as we faced recently. 3 The second one I'd like to talk about a 4 little bit as well is the process by which you can 5 obtain voluntary informed consent in the middle of an 6 emergency. It's almost a contradiction in terms to be 7 in that type of sitting to have subjects who you know 8 are participants who are being torn by a lot of 9 different conflicts and, you know, to be in a position 10 of showing them an eight-page consent form written at 11 the 12-plus-grade reading level because lots of people 12 have been involved in drafting it and to think that 13 that is, in fact, obtaining informed consent from 14 people because you may be complying with the legalistic 15 regulations on these. 16 I'm going to talk a little bit about the 17 implications of some of these things, in particular 18 with the several examples. The two main examples, 19 although I do have a third one I'll talk a little bit 20 about if we don't run on too much are anthrax and small 21 pox. I think those are the two things most in the 22 news, most current in terms of people's thinking on 23 this issue and we'll be glad to deal with that as well. 24 I'm going to try to spend a brief period of 25 time talking about some of the lessons I think we've PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 100 1 learned. And if some of you read Monica's paper in 2 advance, let me tell you, the lessons learned are out 3 there. They're pretty broad, but they're important 4 because you run up against them all the time. And then 5 I'm going to end up a little bit with just a summary at 6 the end where hopefully can lead into some discussions 7 and answer questions from the group here. And that 8 might build on some of the examples as well. 9 Okay. Going on with the context. I mean, 10 after September 11th lots of things changed. I mean, 11 the world was different for us. Preparedness which had 12 been something CDC had been funded somewhat to do, but 13 it became reinvigorated. Suddenly it was much more 14 important to be prepared, to know what the responses 15 would be. A lot more detail took what had been an 16 activity, but activity more at the planning level of 17 how do we ship emergency supplies here or there, very 18 much at the logistical level and not so much at the 19 scientific or human subjects level. 20 And then once the anthrax activities happened 21 shortly thereafter, bioterrorism became a real world 22 event again. Because, after all, this was the second 23 bioterrorism event in the United States which I mention 24 for both personal reasons and for background reasons as 25 well. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 101 1 And I think it was quite clear you said 2 earlier, the impact went way beyond the unfortunate 3 people who became sick or died due to anthrax or even 4 the thousands of people who took antimicrobial 5 prophylaxes during that time. The effect was 6 incredibly widespread. I mean, many more people, many 7 more children died during this time interval from not 8 wearing their bicycle helmets. I mean, there's just -- 9 but that's not the story, anthrax is the story. So to 10 some extent I think we need to deal with that. 11 Okay. The previous bioterror attack, since I 12 mentioned that. Many of you may remember that 13 followers of the Bagwan Sri Rajniche [ph] intentionally 14 poisoned salad bars in Dows, Oregon in 1984. They were 15 doing this to try to create terror in the community but 16 also if they could incapacitate a large enough 17 proportion of the county voters, most of whom resided 18 in the Dows, they could vote and take over the county 19 government. This was a dry-run, if you will, during 20 September for what was anticipated to be an attempt to 21 take over the county government because the county 22 government had been very hostile to them. 23 I know because I was the epidemic 24 intelligence surface officer assigned to Oregon in 25 1983-85, and although I was out of the country when PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 102 1 this happened, it's somewhat of a thing, and it has 2 been published in JAMA and some of the other places. 3 Because until recently it was the only documented 4 attempt ever to have a bioterrorist. 5 Some of the lessons learned from the talks I 6 gave after that are the same lessons we are now 7 relearning again, by the way. And you've already heard 8 some of them referred to. 9 Let me go back one, I'm sorry. Can you go 10 back two, please? 11 Some of the funding for -- back one more, 12 please. Thanks. 13 The funding for -- that come in primarily 14 went towards building a national pharmaceutical 15 stockpile. There's a lot of different antibiotics and 16 things that -- it was already stressed, even during 17 this interval, but has been subsequently greatly 18 expanded. A laboratory response network was 19 established whereby many state labs had added reagents 20 and added a detection capacity for bioterrorist agents, 21 and they played a role in this detection of this 22 outbreak. State and local bioterrorism plans were 23 developed, but funds were not made available to 24 actually implement any of those until the cooperative 25 agreement funds that are now in the process of being PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 103 1 reviewed at CDC. 2 And they developed a series, I believe, of 3 eight, what they called, "push packs" which were huge 4 collections of supplies and materials that might be 5 needed in a bioterrorist thing and they were 6 distributed -- "predeployed," I think, is the word 7 around the country. 8 But there was relatively limited staffing 9 provided for people so things that are in fact very 10 resource intensive in terms of human resources such as 11 writing draft consent forms, getting IRB approval for 12 things, talking with the FDA about what would need to 13 be done for various investigational new drug or new 14 device exemptions were not actually being done in 15 advance. Though were being done, but not in a complete 16 way. 17 I've got to learn to pause each time after 18 it. 19 I want to talk briefly, and very briefly just 20 about the agents and the interventions because as some 21 of these things come up, it might be helpful to have -- 22 back one, please. 23 First anthrax. Anthrax is a bacteria. That 24 means certain things about it in terms of its 25 prevention and control. The disease takes several PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 104 1 forms from relatively benign forms such as cutaneous 2 anthrax to relatively more severe or deadly forms such 3 as inhalational anthrax. The anthrax bacterium itself 4 naturally occurs in environment, although certainly one 5 wouldn't expect a background detection of anthrax in a 6 Florida office or a Senate thing, there are places in 7 the United States where you do find it in the soil and 8 there are naturally occurring anthrax cases in the 9 United States. 10 And it's not transmissible from person to 11 person. It is more similar in some ways to a chemical 12 agent than an actual infectious agent that transmits 13 from person to person. You're either exposed or you're 14 not exposed generally at that time. 15 Small pox is very much different in that it's 16 a virus. There is no natural small pox anywhere in the 17 world. Small pox is the only disease humans have ever 18 intentionally eradicated from the face of the earth and 19 it remains a great public health irony that we spend so 20 much time preparing about and talking about new vaccine 21 development, talking about a lot of expense put into 22 the only thing that in fact we supposedly have already 23 eliminated from the face of the earth. It is 24 transmissible from person to person. That's how it's 25 transmitted. That's the very nature of the thing. So PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 105 1 it has a lot of attributes that would make it very 2 different from what we actually observed in terms of 3 the anthrax. 4 In terms of treatment and prevention you've 5 got various modes you could use. Antibiotics are quite 6 good for both the treatment and the prevention, a 7 preventive prophylaxis to anthrax. You have antiviral 8 agents which are probably not as well documented at 9 this point, but certainly are under investigation for 10 potential treatment of small pox or for use, perhaps, 11 as opposed to exposure prophylaxis. 12 You have vaccines for both of these diseases, 13 both of which have certain considerations about them. 14 Vaccines for pre-exposure, that is something you would 15 give to somebody before they were exposed to prevent 16 them from contracting disease should they come down 17 with it, as well as vaccines you can give after 18 exposure to moderate or reduce the risk of disease. 19 There's issues around the detection and 20 diagnosis of these things. These reagents are not in 21 common use. CDC frequently in this situation produces 22 reagents which they ship around the United States. But 23 clearly until recently it was thought that there would 24 never be any market for an actual test kit that could 25 detect anthrax in the regular hospital laboratory, or PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 106 1 could detect anthrax spores in the environment. 2 Both of these have different issues around 3 isolation, doing things with buildings to prevent 4 subsequent exposure or even moving on to maybe the old 5 line public health intervention of considering 6 quarantine of people who were exposed or have these 7 diseases that play a role as well. 8 A point that was made previously and I would 9 like to reiterate here is the information on the 10 natural disease was actually of limited applicability 11 in this setting. One of the things that came up in 12 writing the anthrax consent form, as we had to explain 13 so many things that we did not know, we don't know 14 this, we don't know that, and, you know, we got 15 questions saying, well, why don't you know that. It's 16 because this had never happened before. This is not 17 how natural anthrax was transmitted in the United 18 States. This was not the natural form of the bacteria. 19 So this was very much a different route of 20 exposure in doses that frankly were not even 21 anticipated in the military in terms of protection. 22 The staff members in Senator Daschle's office were 23 exposed to huge numbers of spores, beyond that which we 24 had ever even seen modeled in military battlefield 25 exposures. This was a completely different situation PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 107 1 in many cases than what we anticipated. And, for many 2 of these things, you know -- 3 DR. R. LEVINE: You're talking about 4 developing a consent form. What are you having -- what 5 aspect of your studies is this? Is this a vaccine 6 trial or what? 7 DR. LIVENGOOD: Where we'll end up with this 8 is the consent form that was actually used in making 9 the vaccine available to people who had been exposed 10 and the late period post-exposure. That's where we'll 11 end up. Although there is a little bit, as you know, 12 about research that's ongoing in this area as well. 13 For small pox and to some extent for anthrax, 14 the information that's available is dated, it's not 15 current. I mean, we talk about what the death rate 16 from small pox would be, but do we really know what it 17 would be in a modern hospital setting with different 18 things and other impacts. 19 And the prevention or the treatments in this 20 case were limited. Some cases, actual physical 21 availability. Anthrax vaccine had had regulatory 22 problems, was not actually available outside of the 23 military sector at the time that this procedure began. 24 And they all had regulatory limitations, and by that I 25 mean, limitations, unlicensed uses, use of coverage PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 108 1 under FDA regulations that also is a source of a 2 challenge that we go over. 3 Human protection issues. Again, we've talked 4 whether it's research or not research. In some 5 settings, clearly we want to do research and some 6 settings we are clearly not interested in doing 7 research at all. Some settings we actually have two 8 desires we might want to do. And I'll try to give a 9 brief illustration of that. But generalizable 10 knowledge is what we're talking about here when we're 11 using the term "research" because we're trying to deal 12 with the context of being a federal agency and subject 13 to 45 C.F.R. 46 and the subparts. 14 But how does that differ from when you're in 15 an emergency response situation where you're trying to 16 crisis -- respond to a crisis, per se, right there but 17 the desire is not in any way, perhaps to develop 18 generalizable knowledge? It is possible that 19 subsequently generalizable knowledge might be derived 20 from the information that happened during this time 21 interval, but that's not the focus of actual thing. 22 The second issue I mentioned before in the 23 informed consent process how do you inform people and 24 obtain consent in this type of setting? And how can 25 you deal with the issue of trying to obtain voluntary PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 109 1 informed consent when in fact somebody's choice to or 2 not take a vaccine such as in the case of small pox 3 might also impact on the decision of whether or not 4 they're going to be allowed to go home, or whether 5 they're going to get an all-expense-paid holiday 6 courtesy of the federal government in some beautiful 7 location yet to be specified on the outskirts of town? 8 I mean, I think that those types of concerns 9 have to be brought to people's attention, but it is 10 very different from the way -- and particularly most 11 IRBs -- would look at a consent form. And, you know, 12 you're not -- you don't suffer any loss of rights or 13 benefits to which you might otherwise be entitled, but 14 you may not go home if you say no. Actually, you may 15 not go home if you say yes too in some settings with 16 small pox. So it is fairly complicated. 17 What do we do in this setting for treatment 18 of adverse events? I mean, no vaccine, as I used to 19 say, in many a talk is perfectly safe or perfectly 20 effective. No antibiotic is perfectly safe. Moreover, 21 what do you do in terms of treating people for 22 potential adverse events that they might have because 23 of this or compensation should they have lingering 24 events or be unable to work or some of those issues? 25 That was quite a big concern as we went forward in PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 110 1 this. 2 And then a whole series of regulatory 3 concerns which I think we will cover as well. 4 With the implications for research, by 5 "research" here I really mean the research definition 6 which means that this will be subject to 45 C.F.R. 46 7 and the provisions of that. Why would that be an issue 8 for us? Well, when you're looking at something like an 9 emergency response where I do not know today where the 10 vaccine program will be established, will it be in a 11 school, will it be in a hospital, will it be in a local 12 health department, you have a lot of issues around 13 performance sites. We don't know where those sites 14 are. We don't know where they'll be. 15 How will we get local IRB review in all these 16 sites overnight before we do things? 17 And then there's the issue of assurances and 18 compliance which since most of the settings in the 19 public health do not have pre-existing assurances at 20 this time, at the local level. That we would have to 21 also get assurances of compliance. And, also, too, in 22 many of these things there are required elements of 23 consent, one of which would be to tell people it's 24 research. But if it's your supposition that what 25 you're doing is emergency response and it is not PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 111 1 research, then you get a consent form where you have to 2 include the words "you are free to participate or not 3 in this research." You must use the word there. 4 There were a lot of implications separate 5 from the research, non-research determination here 6 because these products were subject to FDA regulation. 7 And as I believe most of you know, clearly it makes no 8 difference whether it's research or not if you're using 9 an FDA-regulated article in a way subject to regulation 10 you are subject to the regulations and it doesn't make 11 any difference what your intent or your purpose is. 12 So we attempted to conduct this emergency 13 response and be responsive to the FDA regulatory 14 requirements. 15 One of the questions here would be how to 16 make a determination that is appropriate to the 17 situation when the goal of this emergency response is 18 to make available a treatment or a prevention to people 19 that for whatever reason is not otherwise available or 20 licensed for that in the United States. 21 Some of the implications for the consent 22 process. I have already talked a bit about the 23 voluntary nature of this. And it's very difficult 24 because in public health a lot of what we deal with is 25 a balance between both the individual rights and the PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 112 1 rights of the community and the population as a whole. 2 We very much see ourselves as caring for the 3 population as if the entire population were our 4 patient. Singular, not plural, not our "patients" our 5 patient. So we want to do things which sometimes are 6 intrusive to individuals, but it's for the benefit of 7 the population as a whole. You can see this, for 8 example, in issues around treatment of tuberculosis. 9 Somebody might be quarantined for a couple weeks until 10 they get their tuberculosis treatment. I've often told 11 people, I believe it's probably intrinsically intrusive 12 for you to be in the STD clinic and somebody asks you 13 who all you've had sex with while you're there getting 14 treatment. 15 There are thing public health routinely does 16 that are intrusive to the individual, but are designed 17 to protect the community. 18 Information. How do you present information 19 to people when you're in the context of trying to make 20 a recommendation or trying to give them the information 21 for a choice when there's an absence of definitive 22 data. I cannot tell you, and we condemned this very 23 much with this anthrax availability consent form, I 24 can't tell you whether you're truly at risk, I can't 25 tell you whether this is going to be in benefit, all I PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 113 1 can tell you is I'm making it available to you and if 2 you want to take it, you can. 3 That didn't go over very will with the 4 participants. Why you, you're the government, you're 5 the experts in this, you should tell me what I need to 6 do. And to not be able to make a recommendation 7 because there weren't clear data underlying what we 8 would hope would be a recommendation based on evidence 9 was very difficult. 10 And then trying to convey the information in 11 the context of an emergency setting or a brouhaha, it 12 was just -- it was very, very difficult. 13 Then issues around documentation of consent. 14 We still face those to this day in trying to decide is 15 a signature anywhere? Could you waive documentation? 16 After all, the person did listen to the information and 17 is still standing there in the line and gives you their 18 shoulder to give the shot. What are some of the issues 19 around documentation? 20 And I'm willing and continue to think about 21 this in great detail, what options or alternative 22 methods could we use? And we're trying to explore some 23 of those as well. 24 Implications of the adverse events, I mean, 25 costs of treatment of adverse events. If we were a PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 114 1 sponsor trying to do this study to get this vaccine 2 licensed for this indication in the United States, your 3 IRB probably would require us to pay for any medical 4 treatment that would occur for these adverse events. I 5 believe that's pretty close to being standard practice. 6 However, we're the federal government; and, two, we're 7 not trying to do this to produce a profit; and, three, 8 we apparently have very limited legal options available 9 to us to do this. So, I me, when we're giving an 10 intervention that has a known risk, I think that's one 11 option. That's one situation. 12 When we're dealing with events that may occur 13 to people because they're exposed or because it's an 14 emergency setting and they may have no or an uncertain 15 relationship to the intervention we're giving, or when 16 we're giving intervention with unknown risks. And you 17 may say, well, that would never happen, but consider 18 the small pox vaccine from adventist Pasteur recently 19 discovered, last licensed 50 years ago, not in the 20 United States, and the discussion is underway at high 21 levels in the department that we might need to use that 22 or we might need to use the new vaccine that's just 23 about to be produced which has not yet gone into the 24 first person anywhere in the world. I mean, there are 25 going to be concerns as to how we should deal with PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 115 1 this. 2 Connecticut, one of the sites of the anthrax 3 availability program, the Attorney General of 4 Connecticut called me and said, "The United States 5 Government should waive sovereign immunity." Since 6 we're the U.S. Government we can't be sued unless we 7 can say you can sue us. 8 And that certainly was acceptable to me, but 9 that takes an act of the United States Congress. I 10 can't sign. That's not one of my duties at CVC to -- 11 [Laughter.] 12 DR. LIVENGOOD: -- authorize waiver of 13 sovereign immunity. 14 And then also related to that is 15 compensation. Because I think we are dealing with 16 things that might potentially have issues around 17 compensation, but we don't have an approach in the U.S. 18 Government that's standard for this. And the standard 19 approach is just saying, you know, you or your 20 insurance company will be responsible for this probably 21 is not adequate in this setting. Because, again, we 22 are using these in situations where they're truly isn't 23 voluntary informed consent in some of the usual 24 standards. 25 Some of the regulatory issues, use of PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 116 1 unlicensed products. Some of the products potentially 2 that could be used here are not licensed for use in the 3 United States. Some of them are not licensed for use 4 anywhere when we are into off-label use of licensed 5 products. And here where it's you as a physician could 6 see somebody in your practice and as part of the 7 practice of medicine use a licensed medication for 8 whatever indication you wanted, we are not permitted as 9 public health agency to ship products across state 10 lines to be given for an off-label use. Just to point 11 out, ciprofloxacin, doxycycline are licensed -- are 12 labeled for use for anthrax. Cipro has never been 13 tested in children. Doxycycline is contraindicated in 14 children. We shipped ampicillin to give to the 15 children based on the reasoning that penicillin will 16 kill anthrax, but that was an off-label use of a 17 medication shipped across state lines and represents a 18 technical violation in what needs to be done. 19 Use of unlicensed laboratory tests. The 20 detection of the Florida case was made based on use of 21 one of these lab reagent tests that we had shipped to 22 Florida to be conducted for surveillance. Normally we 23 say that's okay, because we're not diagnosing patients. 24 But it isn't really a stretch to see that detecting 25 anthrax in various settings doesn't have implications PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 117 1 for whether the people who worked in that setting say 2 it's an environmental thing. We're exposed so they get 3 the ciprofloxacin so there are potential treatment 4 outcomes that are related to use of these tests even in 5 unusual ways. The tests -- I mean, were completely 6 unevaluated prior to this time for the detection of 7 environmental samples. We had always thought they 8 would be used on samples from humans, and then suddenly 9 we began doing environmental samples. 10 And I guess the question here, I'd say, is 11 the IND and the ID mechanism optimal in this situation? 12 I mean, we're taking an available mechanism and we're 13 making ourselves try to fit into it, but to me it feels 14 very much that we're trying to round off a little bit 15 the edges of this square peg and fit it right into the 16 round hole. And it leaves both the federal government 17 and the participants, I think, in an unsatisfactory 18 situation. 19 A little bit anthrax, briefly. The initial 20 case was detected through the surveillance system at 21 the Florida State lab which was using reagents we had 22 supplied to them as part of the laboratory response 23 network. And it was confirmed at CDC in our labs. 24 When we run our own tests in our own labs, we're not 25 covered by FDA regulations. So frequently we do try to PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 118 1 gear up and run confirmatory tests personally at CDC. 2 With the contaminated letters in the Senate 3 we got into prophylaxis of exposed persons and we 4 started dealing with issues that there were children 5 there in the Senate office at the time and we didn't 6 really have correct things present for that. We began 7 detecting of exposure by screening persons and 8 discovered in fact that there was a very high exposure 9 level among persons. We began detecting exposure among 10 the environment and when we moved on to the post office 11 we used the screening method not so much to try to 12 detect whether an individual person had been exposed, 13 but was there any exposure in that area so a larger 14 group of people who had been exposed at that area could 15 be given prophylaxis. 16 We ended up very much later, as I was 17 alluding to, to the use of the vaccine or prolonged 18 antibiotics based on very limited information. 19 In a research study previously involving 20 monkeys not given such finely milled doses of these, 21 but one of the monkeys had viable anthrax spore 22 detected in the lungs at 97 days post-exposure. That 23 turned out to be very discomforting to us. One because 24 they were wet mound preps and not as easily inhaled as 25 what the people had seen. We were giving 60 days of PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 119 1 antibiotics based on somewhat limited information. 2 So we decided very late in the process we 3 would offer people the opportunity to continue on 4 antibiotics for another 40 days for which there is no 5 licensed indication in any antibiotic for 100 days post 6 exposure to treatment and the anthrax vaccine to 7 potentially build immunity. 8 There's fair evidence that three doses of 9 vaccine will produce an antibody response in you. Will 10 that protect you? That's not really known because 11 anthrax vaccine is not really licensed for post- 12 exposure use at all. And at the time we were doing 13 this the licensed product was unavailable and in fact 14 all licensed product -- all license had been suspended 15 by the Food and Drug Administration for production of 16 this pending regulatory compliance by the manufacturer. 17 This was a very regulatory, complicated 18 environment to try to get information to people. 19 What were some of the uncertainties? We 20 didn't know exactly how much anthrax everybody had been 21 exposed to. I mean, we had a perception that the 22 people standing next to the clerk in the Senate office 23 who opened the envelope were exposed to a large amount. 24 But how much was the postal worker who walked past 25 that machine sometime after lunch on the day that that PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 120 1 letter went through, how many, how much, so we didn't 2 know what degree of exposure was or what the potential 3 impact would be. 4 Therefore it was nearly impossible for us to 5 tell any individual whether they would have any 6 potential benefit from taking the vaccine. And we 7 debated this back and forth, because as you can imagine 8 writing a form that somebody signs that says we don't 9 know if this will give you any benefit or not, and by 10 the way, here are the known risks of anthrax vaccine. 11 It's very hard to do that. 12 What should be the choice or duration of 13 treatment? We talked a little bit about 60 days, we're 14 now up to 100 days. Antibodies are not benign to take. 15 A great number of the people had gastrointestinal side 16 effects from this. The availability of the vaccine was 17 complicated. As we said, it wasn't really available. 18 When, if you were going to give it post exposure, you 19 should do it early on. It became available, so we 20 offered it 60 days after that. Certainly not a 21 strategy anyone would picked a priori. 22 And how to best inform or guide exposed 23 persons. And that was a conundrum -- I think you can 24 tell by the reaction in the press -- we freely 25 acknowledge we had to make success in this. We seemed PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 121 1 to do fairly well and make some people satisfied who 2 tended to be highly educated workers at the Senate who 3 the Senate physician told them it was his opinion they 4 should take it. And we seemed to do very poor with the 5 postal workers who felt that we should tell them one 6 way or the other. And when it came right down to it, 7 they didn't really believe us anyhow. But the 8 situation was very complicated and the reactions were 9 totally different across these two populations. 10 Briefly on small pox, you know, as we said, 11 it's gone. But apparently not forgotten. We spend a 12 lot of time talking about it. How can you talk about 13 the risks and benefits of vaccination when the benefit 14 can only possibly come if there is still small pox and 15 if it's used in an event where you become exposed. 16 Would you even consider, as some people have suggested, 17 a universal vaccination program where we have no 18 documented evidence there is even this agent in the 19 world that would be used in this. 20 How do you balance risks and benefits to the 21 population? Vaccine formulation issues. We have a 22 vaccine that was licensed previously, but it's past its 23 expiration date. The diluent has gone bad and we're 24 having unlicensed diluent that we're using in it. We 25 have conducted research that has said we can dilute it PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 122 1 one to five with additional diluent and make more 2 doses. But we're in this thing. 3 The vaccine here we do know a bit more about 4 because we know it is effective in preventing small pox 5 when you give it post -- pre-exposure and early post- 6 exposure. So we have some more information here than 7 we do in others, but then what should the strategy be 8 if we were going to do that. 9 Next. 10 What are some of the uncertainties? You 11 know, the government has let a contract to produce 12 millions of doses of new vaccine through a new method 13 that has never been licensed or tested, or right now 14 for the most part evaluated in persons. What's the 15 risk of exposure to the agents as I've talked about? 16 What should be our optimal strategy post-event? 17 I mean, public health people we would like to 18 go find the people directly surrounding the person and 19 vaccinate them. But it's not a realistic strategy in 20 the middle of what may be a panic situation. And it's 21 not immediate panic, one that would gradually build in 22 demand for the vaccine, over that time. So we may need 23 to have simultaneous types of measures. 24 If we went with universal pre-event 25 vaccination, what would the tolerance for adverse PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 123 1 events be? Small pox vaccine is not benign. The 2 literature describes the death rate of about one in a 3 million doses, one in 100,000 for encephalitis. I 4 mean, you're talking about people who would die during 5 the vaccination effort because of vaccine when we don't 6 know that there's a risk. So how would that be 7 tolerated in the United States? 8 People say, well, just go ahead and do 9 voluntary. But I don't think just making it 10 voluntarily available to people covers all the 11 contingencies and all the considerations you would need 12 there. 13 And what impact is an old immunization 14 program person -- what impact would trying to do 15 something like this, and the resultant brouhaha have on 16 our other essential vaccination programs that we have 17 right now? That's one that bothers me. 18 And at some point, I mean, if we do get into 19 a small pox thing, we will have some sort of consent 20 form, but we have some untried adjunct therapies, 21 vaccinia, immune globulin that we might be trying to 22 use, there's going to be other investigational products 23 used in combination with the vaccine should we ever 24 need to do that. 25 What are some of the lessons learned? I PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 124 1 think the first is the obvious, it's very difficult to 2 work in this environment. Communication is vital at 3 all stages. You need two levels of communication. You 4 need to be as cognizant of the general public as you do 5 the exposed persons. Because there's just tremendous 6 interest in this. And the second one, I guess is also, 7 long, complex consent forms are not ideal in this 8 setting. We need to find other ways. We don't really 9 have terminology to say it's not research, but it's 10 investigational. We lost the average person a long -- 11 right at the beginning of those forms and that process 12 there. 13 And we need to have some clarity of 14 recommendations when we offer things to people. We 15 need to tell them why we think they should do it or 16 not. It just seems to me it's impossible to truly 17 leave it completely open to a person, particularly when 18 there might be other impacts on them. 19 So what has happened here, you know, the 20 world has changed. The bioterrorist threat is now 21 officially here to stay. Most of our colleagues who 22 went around saying, it's not a matter of if, it's just 23 a matter of when, now will have to find something else 24 to say, you know, because it's already happened. 25 I think we have really worked enhanced PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 125 1 preparedness and response efforts. And we clearly need 2 more research. Whereas, I don't think the emergency 3 response things are research. I think there is a need 4 for research in this area. And some of it that's gone 5 on has been very good so far, the small pox dilution 6 study clearly research, has a lot of implications, but 7 it's research, its desire is generalizable knowledge. 8 We're conducting a clinical trial of anthrax to change 9 doses and routes of administration. These are research 10 things. 11 We'll be conducting new vaccine development. 12 Clearly that is a research effort to develop new 13 vaccines and to develop the safety and efficacy profile 14 that you would need, preferably to get licensure. And 15 lots of applied research around how you deliver these 16 things, what are people's perceptions, what's the best 17 way to communicate with people that will be needed? 18 Emergency response or this type of 19 availability program doesn't fit well in the research 20 mode. It was confusing to people to get a consent 21 form. It had too many research trappings to then tell 22 them it's not research, but it sort of looked like it. 23 People were very confused. 24 And I think there is room here for some 25 harmonization and some better working interplay between PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 126 1 the 45 C.F.R. 46 and the FDA regulations. 2 I mean, how do you adequately protect 3 subjects in this setting? I mean, simply saying that 4 this set of rules or this set of regulations applies 5 probably is not adequate here to really assure, because 6 you need to still protect people, you need to still 7 provide them the information, but the framework maybe 8 needs some adjusting. 9 How to best give them the information to make 10 this choice and how to pay for the injuries or 11 compensation that may come from these. Because right 12 now that's an issue of a lot of difficulty for this. 13 And I'm going to stop there, but I certainly 14 would appreciate any comments for NHRPAC or anything 15 about the role NHRPAC may play in this. 16 [Applause.] 17 DR. MORENO: Thank you. Those were two 18 thorough, excellent and very complimentary 19 presentations. 20 I have Alan, Adil, Bob, Felice, Susan, Sandy, 21 Margaret. 22 DR. LIVENGOOD: Just start at the one end and 23 go around. 24 DR. MORENO: Bob. Who doesn't want to talk, 25 maybe that's the way to do. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 127 1 DR. SHAMOO: Take my name off. 2 DR. MORENO: Oh, good. Fine. Thank you very 3 much. That makes things easier. Okay. And I saw 4 another hand. Okay. We'll get there. I'm sure 5 everybody will get a chance. Alan. 6 DR. FLEISCHMAN: Let me start because John 7 had the second comment with John. First of all, thank 8 you. Thank you for sharing the information, but more 9 importantly thank you for those months in which you had 10 to worry about these issues. You're final comment 11 about informing and playing more of a clinician's role 12 than a researcher's role, I think is critical one. And 13 many of us who observed the lack of having a nation's 14 doctor in the informing were concerned when Dr. 15 Copeland and Dr. Satcher and others were not doing what 16 clinicians do every day at the bedside. And that is 17 take uncertainty and make recommendations to patients. 18 And I think we saw that response. 19 And I think your conclusion that this may 20 have some trappings of research because you want to 21 learn from what you're doing doesn't mean that it ought 22 to have all of the regulatory structures of research in 23 some of our dealings. So, you know, I think we need to 24 learn from that going forward and do what we can 25 prospectively to assure that you have the flexibility PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 128 1 that you need within a complex governmental structure. 2 That business of moving drugs across state 3 lines without a -- that really was -- that one was 4 truly amazing to me. I would never had dreamt that 5 that would preclude your activities. 6 But, to Monica, I had a few responses. One, 7 all of us around this table are sympathetic to the 8 unique circumstances of the Johns Hopkins University in 9 the fall of 2001. 10 [Laughter.] 11 DR. FLEISCHMAN: And I think you know that 12 Dr. Miller started our two days with a presentation and 13 he's going to solve all of your problems by the end of 14 2002. 15 We also appreciate the distinction you've 16 made between the academic medical center, the school of 17 public health and investigative journalism and even 18 political science investigation and we're interested in 19 that in looking at some of those distinctions. But in 20 my opinion there's nothing inherent in the common rule 21 or an IRB process that mandates inefficiency and 22 insensitivity to the science or the investigator. And 23 I think that's an important thing that at least some of 24 us are aware of. You know, most of us think that most 25 research subjects are educable, rapidly. And almost PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 129 1 all of us think that most IRB members are educable, 2 rapidly. 3 At the New York Academy of Medicine, by the 4 afternoon of September 11th, we understood that there 5 was a research urgency. And the IRB, as well as the 6 administration of the institution convened with its 7 investigators to answer the question, how could we 8 facilitate good research which would be ethically done? 9 And we did. And I think we are very proud of our 10 contributions in that regard. So if you would like to 11 move the Center to New York, we would be happy to talk. 12 [Laughter.] 13 DR. FLEISCHMAN: Since one of our major 14 researchers we did extract from your School of Public 15 Health as you well know. 16 But I think that is an important issue that 17 the academic community has to demand of the deans and 18 the leaders within academe to understand the importance 19 of what you're doing. And the other thought that we've 20 had, and we've already begun to work on, we have two 21 approved protocols with a great deal of specificity 22 with approved informed consent processes for the next 23 event. We've gone down that route knowing that we want 24 to do some intervention work within the first hours of 25 an event. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 130 1 So we've actually already talked about those 2 protocols and we are in the process of getting, you 3 know, all the "t"s cross and "i"s dotted. And I think 4 other IRBs can do that kind of work, prospectively, not 5 just putting on the shelf kind of, you know, anything 6 you might ever think of. But actually specific 7 protocols which you have thought about. So I think 8 there's a lot that can be done in that regard and 9 should be done, but it isn't inherent in the process to 10 do bad work. 11 DR. R. LEVINE: Thank you. I have three 12 comments, two of which are related to what Alan just 13 said. 14 My first comment would be to second the 15 thanks to both of you. In response to Dr. Schoch- 16 Spana's presentation, the idea of the IRB finding a way 17 to accommodate a rapid response can be found in the 18 reports of the National Commission for the Protection 19 of Human Research Subjects. 20 The National Commission recommended that 21 expedited review be made available by the IRB or to the 22 IRB based upon the particular experience of a 23 particular IRB. The National Commission in retrospect 24 very foolishly added a set of procedures to its 25 recommendation, the set of procedures that were being PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 131 1 considered for expedited review by the clinical center 2 at NIH, and then they were kind of frozen chiseling the 3 stone of the Federal Register and that became 4 everything that was eligible for expedited review for 5 many years thereafter. It had nothing whatever to do 6 with the expertise of a particular IRB. And then 7 recently there was some loosening up of the expedited 8 review procedures, but it's still a uniform, nationwide 9 policy. 10 And from what I hear from you it would have 11 been well within the intent of the National Commission 12 to say that places like Delaware and Johns Hopkins with 13 their experience could be able to give an expedited 14 review in response to your need to engineer a rapid 15 response. In saying that, I would say that as of this 16 month, this would not at all be appropriate at Yale 17 University because we have never reviewed such a thing. 18 But after we reviewed one or two, perhaps we 19 would be able to consider expedited review appropriate 20 there. Another point I want to make elaborates on 21 John's observations of the anthrax and cipro study. 22 A little bit of the history that you may have 23 left out in the interest of time was that an initial 24 response in the Senate was by the White House 25 physicians. And they moved right in thinking they were PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 132 1 doing something good for people and used the general 2 license -- you know, unwritten license to use 3 investigational products under sort of a compassionate 4 use concept. What happened then is that postal workers 5 said, "What about us?" And the motivation was 6 precisely the same. CDC, well, let's do the same good 7 thing for the postal workers and then somebody said, 8 "Whoa, this is an off-label use" and all of a sudden 9 the consent form and procedures became enormously more 10 complicated. 11 And what happened as an effort to do good for 12 postal workers in response to the postal workers' 13 wishes ended up having only 2 percent of the postal 14 workers were willing to accept this thing after it had 15 the consent form buffed up to meet regulatory 16 expectations. I'm part of the committee that 17 recommended that you pull back on some of these 18 warnings and anxious statements of uncertainty. 19 The final comment. I think, though, that 20 what we're hearing about has a lot in common with what 21 we talked about yesterday, and that is how using a 22 uniform algorithm for consent discussion or consent 23 form actually accomplishes the opposite of what we all 24 together want to accomplish. Although yesterday we 25 were talking in the context of social and behavioral PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 133 1 sciences. 2 My last comment has to do with what appears 3 to be an unwillingness of some agencies to get 4 prepared; for example, the Department of Defense. 5 During the early days of the -- and I'm not saying it's 6 the whole agency, but the particular individuals who 7 seem to be given responsibility from time-to-time. 8 During the early days of the Persian Gulf 9 experience, I was called by DOD and asked if I would be 10 their consultant on whether or not the drugs being used 11 in the Persian Gulf were investigational, and to 12 respond to the allegations that had been made, 13 actually, in a law suit that DOD plus FDA were using 14 troops in the Persian Gulf as guinea pigs. I said, 15 "All right, I'll do that. What's the name of the 16 drugs?" They said, "Oh, we can't tell you, they're 17 secret." 18 I said, "Well, is it fair to assume that 19 they're the same ones that were mentioned in the New 20 York Times this morning?" 21 [Laughter.] 22 DR. R. LEVINE: And they said, "Yes, that's a 23 fair assumption." I said, "All right." But I said, 24 "First, this experience is going to end, you know. And 25 what you have to do immediately is get ready for the PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 134 1 next Persian Gulf." There is going to be another 2 crisis somewhere down the line. "Oh, absolutely" they 3 say. 4 Well, as soon as the judge kicked that case 5 out of court on grounds that it wasn't research, which 6 was remarkably perceptive of the court, my contacts in 7 DOD vanished. And I called once or twice and said, 8 "Well, what about getting ready for the next one?" 9 They said, "Well, you know, don't call me, we'll call 10 you." And they haven't. 11 I think we have to also motivate the people 12 in the agencies that are called upon to respond to 13 these crises and emergencies to develop what you call 14 some long-range planning attitudes. Thank you. 15 DR. MORENO: For the second time, I would 16 like to collect comments and ask Monica and John to 17 respond collectively, if they would, at the end. 18 Because we've got, all of a sudden, a lot of people. 19 Is your response right on point? Then why 20 don't you go ahead. Because I do want to let our ex- 21 officio members be part of this. 22 MS. BOLL: Hi, I'm Patty Boll with the 23 Department of Defense. And real short, we finally are. 24 [Laughter.] 25 DR. MORENO: That was wonderful comment from PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 135 1 you, Patty. From the point of view of the moderator. 2 Let's try to follow the DOD's example. 3 Felice. 4 DR. F. LEVINE: I guess my comment is as much 5 to all of us. I thought both presentations were 6 extraordinarily important. Actually all three, 7 Jonathan. I think I've heard your short version 8 before. But each time I do I -- 9 DR. MORENO: I make up something new every 10 time. 11 DR. F. LEVINE: Ah-ha. Well, I find it very 12 riveting. 13 I think that both of you emphasized that the 14 world has changed. You know, sometimes when those of 15 us who are involved in global change research and 16 transnational studies in the last decade and a half 17 wondered whether we're just reinventing the wheel. And 18 500 years ago, of course, others were saying the world 19 is rapidly changing, so is it or isn't it? But clearly 20 something quite different has occurred. It has created 21 not only the kinds of challenges the two of you 22 discuss, but actually challenges for human research 23 protection around the world with many other forms of 24 research that are not going on both in the health area, 25 in the biomedical arena, in the emergency relief area, PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 136 1 and of course in both the social and political, and 2 economic dimensions of those studies. 3 And I made mention in October that I had been 4 invited last June -- and I only say this again because 5 it was all before 911 -- to participate in a conference 6 that the committee on populations for the National 7 Research Council was holding on humanitarian 8 emergencies. And I was invited to speak on human 9 subjects issues and I thought at that moment that I was 10 going to go and that I was going to address disaster 11 research and how disaster researchers have addressed 12 that issue in the context of human subjects protection 13 as this committee was turning to that. 14 Of course, then about six weeks before which 15 was still before 911 I looked through the papers to 16 think about what in the heck I was going to start 17 preparing about only to learn that the focus of this 18 work was on refugee status in forced migration. And it 19 seems to me in this arena where we do have some models, 20 you made mention of the Delaware Center of Disaster 21 Research of the kinds of considerations that you made 22 -- each of you -- I thought very important and 23 compelling ones between the difference actually between 24 practice and research. You knew that you needed to 25 step back at a very important point of time and say PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 137 1 that there was some difference between just answering 2 those inquiries, talking to those medical doctors to 3 build information. And there was a point at which you 4 really made a transition to really developing research 5 at a research protocol. 6 And it seems to me it's really a very 7 important challenge in this mix of areas, these: 8 bioterrorism, disaster research, humanitarian 9 emergencies -- I think there's no other committee 10 better situated than ours to offer some to the IRB 11 process. There's no committee that really has engaged 12 with us. 13 So I hope that what we've -- you know, I 14 know, Alan, you've been working on this and developing 15 some working papers and that we can figure out a way of 16 engaging and giving some input to an area where I think 17 we've got many lessons learned and something that we 18 could say that would really inform the process and 19 contribute to national awareness and anticipation on 20 these issues. I hope we do. 21 Thank you. 22 DR. MORENO: Susan. 23 MS. KORNETSKY: My question is really for 24 John, but I'll just start by saying that Monica spoke 25 about the trials and tribulations of working with an PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 138 1 IRB in this type of situation. And her IRB was very 2 unfamiliar with the type of issue and I think most are. 3 Certainly the CDC has not had to work with 4 anything with bioterrorism but has had more experience 5 thinking about disease outbreaks, requiring fast 6 turnaround time, research versus investigation, public 7 health surveillance, and the idea of sort of risk 8 analysis for the public health versus, you know, the 9 benefit. 10 I guess my question is, in taking aside sort 11 of the regulatory issues that you had to deal with, how 12 did the CDC IRB sort of react to the things that you 13 were doing? And is there anything that we can learn 14 from that because I can't think of another IRB who 15 would have thought about some of these issues more than 16 that. 17 DR. MORENO: Why don't you make note of that 18 and hold it until the end. 19 Sandy. 20 DR. CHODOSH: John, you mentioned that 21 there's no way that the government can compensate for 22 adverse events. However, the VA does that. The VA 23 takes care of all subjects whether they're veterans or 24 not, if they're in a VA-approved study. So there is a 25 mechanism there somewhere in the government to PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 139 1 accomplish that. 2 And I may be wrong about this, but it seems 3 to me that vaccine producers, and you should know this, 4 some of the drug companies will not develop a vaccine 5 unless there is some protection against liability by 6 the government. Am I wrong about that? I think that's 7 correct. So there are some mechanisms that can be used 8 and perhaps should be looked into ahead of time. 9 My other concern is -- and I'm sure that 10 neither one of you really meant it to come across that 11 way, but it just hit me that way, and that is the talk 12 about we have to sometimes put aside individual rights 13 and benefits for the public good. 14 I immediately said, we're back to Nazi 15 Germany. We have to be very careful when we tread down 16 that road. And it all makes good scientific sense, but 17 I'm not sure that it makes good moral sense or good 18 ethical sense. And I'm sure that you didn't mean that. 19 But it sounds like that. And if that becomes in the 20 hands of a political group that decides that, yes, we 21 must do this for our good, for the public good, then 22 indeed individual rights go down the tube again. 23 So I just make a plea for that. 24 DR. MORENO: Bob, did you -- 25 DR. R. LEVINE: Just a very quick PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 140 1 clarification. In the regulations there are separate 2 statements about provision of medical therapy for 3 research induced injury which the VA does offer and 4 compensation for disability which is like the workers' 5 compensation which no U.S. agency provides. And it's 6 been recommended by every prestigious national 7 deliberative body since the mid-1970s. 8 DR. MORENO: Abbey's turn. 9 MS. MEYERS: Thank you. I really appreciated 10 the presentations very much, especially the work that 11 CDC is doing because it's always had this leadership in 12 this whole field of public health emergencies. But I'm 13 really worried about the amount of attention and 14 funding that's going to be diverted for the 15 bioterrorism diseases. You know, the rest of the 16 field, for example, there are some very good scientists 17 who have very good diseases and they have a very hard 18 time getting funded for diseases that are not reserved, 19 you know, money isn't reserved; some Congressman has 20 put it aside and earmarked it or whatever. And so 21 after years of a huge chunk going off to AIDs and then 22 a huge chunk going to the genome project, we are now 23 going to have a huge chunk for the bioterrorism 24 diseases. 25 And the bioterrorism diseases are basically PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 141 1 third-world diseases that we should have been studying 2 all along. You know, it's not just the two that you 3 mentioned. We know that there are a lot of -- there's 4 a lot of talk about the bleeding disorders like lasa 5 [ph] fever and all of them that are potential. But we 6 should have been doing it all along. 7 The reality is that if these things are 8 really studied and you come up with vaccines, you're 9 not going to get them manufactured because the industry 10 is not even manufacturing the mumps vaccine at this 11 point. You know that we have these shortages of 12 childhood vaccines where the liability has been taken 13 care of. There's a Child Vaccine Compensation Act 14 which puts a little tax on each vaccine and so anybody 15 who is harmed by the vaccines could collect for their 16 lifetime from that federal pool of money. And, yet, we 17 don't have companies making enough of the vaccines. 18 They've had manufacturing problems and there's a 19 terrible shortage and CDC is rationing the vaccines to 20 pediatricians. 21 So we have a very big problem aside from 22 that. But, again, I feel that it is not right to put 23 aside a large chunk of money to study these diseases 24 and to take away from the rest of the field by doing 25 that. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 142 1 DR. MORENO: Greg. 2 DR. KOSKI: Just a couple of points. Bob 3 talked about the -- using the opportunities for 4 expedited review in order to facilitate some of these 5 processes in certain situations. It's obviously a 6 great suggestion, the trouble is, it presumes a certain 7 robustness to the process that in fact, if you read 8 "Time Magazine" last week and all, it's not clear to 9 the vast majority of the public that in fact the 10 current process for protection of human subjects is at 11 the point that, you know, they can have confidence that 12 it in fact is going to be done and indeed when we have 13 instances where the expedited review process is not 14 used in an appropriate way, but in fact to circumvent a 15 process that's intended for -- that undermines 16 confidence. 17 Part of the problem with the postal workers, 18 of course, is that when we find ourselves in that 19 situation where the postal workers adamantly see 20 research as using them as guinea pigs, then in fact, 21 you know, we're at a situation where again we have sort 22 of shot ourselves in the foot by allowing a situation 23 to develop whereby they see the research participation 24 not as something that would be an opportunity, but in 25 fact would be something that's undesirable. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 143 1 And while you stated, Bob, that, you know, 2 the process that they went through resulted in postal 3 workers only 2 percent of them who were eligible to 4 take the vaccine to actually take it. While that 5 presumes that there would have been some advantage to 6 them in taking the vaccine, but in reality the analyses 7 that have been done suggests that it made no difference 8 whether or not anybody took the vaccine, or for that 9 matter, whether or not anybody even took an additional 10 course of antibiotics that the frequency of actual 11 occurrence was so small that we don't know. 12 I guess my biggest concern in this is that 13 the situation that existed, you know, back when people 14 were about to come off the course of recommending 15 antibiotics was one that was ideally suited to 16 conducting a well-designed, meaningful research study 17 to find out whether or not there would be efficacy in 18 giving additional vaccine, or additional antibiotics 19 with or without the additional vaccine. And, indeed, 20 we in a sense squandered the opportunity to get 21 meaningful data that would guide us in the future where 22 we could actually make recommendations as to whether or 23 not something was going to be safe and effective 24 because of, in a sense, a fear that conducting research 25 would be something that would be unacceptable to the PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 144 1 American people. And that is, I think, a very damning 2 situation to be in and one that I hope, you know, as we 3 look at these processes we can begin to move toward a 4 more functional environment. 5 I don't want to see us get constrained also 6 in these discussions into using, trying to force these 7 activities into existing models. I think we need to 8 really think beyond that and recognize that in a 9 situation such as a large scale release of small pox or 10 something that's a situation that we haven't seen 11 before and there may need to be, in the sense of 12 preparedness, much greater thought given to an 13 appropriate, say, declaration by the president of a 14 national public health emergency under which specific 15 new procedures that could be developed in advance of 16 the crisis could be actually set up. So that people 17 know and it can be discussed with the American people 18 and they'll be prepared. 19 So that let's not shoehorn everything into 20 this model and say, how do we get our base to move 21 faster. Let's think about how the process really ought 22 to work in a prospective way. 23 DR. MORENO: Elliot, I'm knocking you off the 24 list because we're a little late here. But I want to 25 give Monica and John a chance to respond and then open PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 145 1 it up to the floor. 2 DR. LIVENGOOD: Yes, I'll try to be fairly 3 brief. I think you're quite right in how you pointed 4 out that the CBC IRB had some unique experiences in a 5 wide range of even members who have unique experiences 6 that wouldn't necessarily be share with others. 7 We had previously also looked at anthrax 8 protocols for emergency use under INDs under various 9 scenarios. This particular one as sort of Greg 10 implied, the decision made so late, the availability of 11 the vaccine and no prior conception that we would ever 12 use that really did strain both, I think it's fair to 13 say, Greg and my time as well as others in the 14 department as this was debated at very high levels. 15 And the IRB met in emergency session starting about 16 7:30 on the Wednesday night before the program started 17 on Thursday. 18 So, really, I think the process can work. We 19 had to convene emergencies, we had tremendous number of 20 people working on this, both at CDC and elsewhere. It 21 was very difficult though when you go to local cites 22 and you're saying, please don't send this to your IBR. 23 Or even one of the states that did do it, then working 24 with that IRB for all night the next night as you try 25 to explain why it's not research and what the FDA PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 146 1 regulations say and why you chose this particular 2 wording which was developed by a committee to try to 3 adequately represent the murky science around there. 4 Even in the setting where I agree we're 5 somewhat specially constituted and experienced in this 6 type of thing, it was very difficult. 7 One of the things we have done is make a 8 uniform application to FDA to not to waive local IRB 9 review if we ever get into any of these emergency 10 responses again for that issue. 11 I wanted to mention just briefly the 12 Department of Defense also compensates for its 13 participants in research in terms of treatment for 14 adverse events. We very much would like to do that. 15 We do not have a clinical facility at CDC. So that's 16 one major impediment to us. When we try to tell our 17 grantees that we would like them to treat medical 18 injuries we can't blanket authorize that in advance 19 because that's an illegal procurement in the federal 20 grant system. We could authorize them to buy 21 insurance, but in the middle of the anthrax clinical 22 trial we've been unable to find anybody who would 23 provide insurance -- 24 [Laughter.] 25 DR. LIVENGOOD: Yeah, we're asking an PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 147 1 insurance company to insure against anthrax vaccine 2 after all that's happened. I mean, that's not the most 3 surprising result. 4 It is a little difficult, for example, in our 5 anthrax clinical trial where Walter Reed is one of the 6 sites that will provide medical care for the 7 participants at that site should they be. And with 8 anthrax vaccine, although I believe it is a safe and 9 effective vaccine, there are people who will get a big 10 swollen arm and have to go back to the emergency room 11 and might need a course of antibiotics, may need to be 12 off from work for several days. 13 I mean, those are known things. Those are 14 not saying that there's anything particularly wrong 15 with that. That will happen to people. And I think I 16 agree with your point that it's really unfortunate that 17 we tell that person, well, you know, if your insurance 18 won't pay, which most of them wouldn't for that, you'll 19 have to pay. There needs to be some way around that. 20 DR. MORENO: Monica. 21 DR. SHOCH-SPANA: Thanks to Dr. Fleischman 22 and Robert Levine for helping dealing with our Hopkins' 23 specific woes. 24 [Laughter.] 25 DR. SHOCH-SPANA: And then to Ms. Levine's PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 148 1 remarks that it would -- guidance on dealing with 2 disaster and crisis context related research would be 3 heartily welcomed as a practitioner -- I mean, as a 4 researcher in the field. Thank you very much. 5 On the issue of -- and going over my remarks 6 and listening to myself, even before I come here and 7 present them, I did, and I continue to worry about this 8 juxtaposition between, you know, individual sacrifices 9 and the public good. I mean, once you get into that 10 dichotomy, you lose sleep and rightly so. And so thank 11 you very much for bringing that to my attention. It 12 does bother me when I use that type of language. We do 13 need better language to discuss those tensions. And we 14 can't juxtapose a theoretical individual subject with a 15 theoretical public good. Because we do then get into 16 the political situation that you mentioned. We need to 17 be very specific about what the particular tradeoffs 18 are and be attentive to those. 19 I think we're at a moment where we as a 20 nation do need to foster open conversation at local and 21 national levels about our strategies for dealing with 22 the effects of a bioterrorist attack. That we need to 23 improve our research review process, but as a nation we 24 need to talk about those interventions that governments 25 -- our government and other institutions will take in PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 149 1 order to stop the effects of a biological attack. 2 For instance, we need an open publicly 3 informed debate about national vaccination -- small pox 4 vaccination strategy. We need to have that to be an 5 open process. And the decision-making around the 6 policy options needs to be participatory. And so there 7 needs to be right now those ongoing debates about 8 specific medical and public health management of this 9 problem. And I know members of this committee are 10 doing that as well. 11 We do have a moment also to act to be 12 proactive about what type of research review processes 13 we really want. Now is the time to envision those 14 ideal review processes and then build them as opposed 15 to acting in a reactive fashion. Thanks. 16 DR. MORENO: A very short sentence. 17 DR. DORFF: Just a reminder of Alan's point 18 in October. Part of those processes have to be how do 19 you guarantee that research properly approved by 50 20 IRBs from all over the country don't end up sending 50 21 teams of researchers to the World Trade Center to 22 interview the exact same people. 23 DR. MORENO: Okay. I'm going to give John 24 Mather a chance to tell us if the VA will cover 25 everybody or not. Yes or no? PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 150 1 [Laughter.] 2 DR. MATHER: Maybe. There is a statutory 3 requirement for us to take care of any individual that 4 has been enrolled in a research protocol that's been 5 conducted in the VA. There's one caveat though and 6 that is that participant must be shown and has shown 7 that they are compliant with the protocol. More 8 especially we are not talking about a long-term 9 disability benefit. We are talking about perpetual 10 medical care. If you're a veteran you may get 11 disability, but if you're a non-veteran, you will not 12 necessarily get anything other than cash payment. 13 Jon, could I just go on a little different 14 tag -- 15 DR. MORENO: No. 16 DR. MATHER: -- very briefly? 17 DR. MORENO: No. No. 18 DR. MATHER: Because I think it's -- 19 [Laughter.] 20 DR. MATHER: -- preparedness. 21 DR. MORENO: Go ahead, John. Go ahead. 22 DR. MATHER: Well, the VA has a great concern 23 about it being a health care system with 170 VA medical 24 centers and 600 community outpatient clinics. And here 25 is a system of health care that classically is a PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 151 1 national resource that could be used in this particular 2 arena. And I'm aware of an Office of Security and 3 Preparedness being prepared to come into existence. It 4 will be working closely with DOD. So, I just want to 5 give you a sense that there's another agency in this 6 that has a very significant health care system can 7 apply itself and indeed has an office, the Public 8 Health Environmental Medicine that works closely with 9 CDC as John well knows. So there's another side to 10 this that I think is important to just put on the 11 table. 12 DR. MORENO: That was a worthwhile extra 13 sentence. 14 Thanks again to our guests. Mary Faith. 15 [Applause.] 16 CHAIRPERSON MARSHALL: Thank you very much. 17 Those were just superb presentations beginning with 18 Jonathan and Monica and John as well. 19 I think we need to, you know, consider, to 20 answer your last question, where NHRPAC goes and what 21 NHRPAC does with this and sort of look to the agencies 22 that are involved in terms of their needs and 23 perceptions as to the most appropriate questions and so 24 forth. So I imagine we will be going down that road in 25 the interim, perhaps between now and the next meeting. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 152 1 We need to go to lunch so that we can come 2 back and work on time and expeditiously because people 3 need to catch planes and so forth this afternoon. 4 Kate has asked me to ask whether anyone has 5 seen or accidentally picked up a motorola phone 6 recharger? Hers has taken a walk. We will see you 7 back here at 1:30. 8 And, thank you, again, a great panel. 9 [Applause.] 10 [Whereupon at 12:39 p.m., the meeting was 11 recessed to be reconvened this same day at 1:30 p.m.] 12 PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 153 1 A F T E R N O O N S E S S I O N 2 [Time noted: 1:36 p.m.] 3 CHAIRPERSON MARSHALL: We are going to go 4 ahead and begin so that we can try and end on time so 5 that people can make their planes, et cetera. 6 We are putting Jonathan to work today. That 7 is your day, Jonathan. 8 DR. MORENO: And I love it. 9 CHAIRPERSON MARSHALL: He's going to segue 10 into the workgroup on decisional incapacity or decision 11 capacity, actually, not "incapacity." Sorry about 12 that. 13 DR. MORENO: Incapacity, you're incapable. 14 CHAIRPERSON MARSHALL: I'm incapable we knew 15 that was a because -- 16 DR. MORENO: I'm going to begin by saying 17 again several things that I said before about this 18 effort. First, there's a long complex history to this 19 problem. I hope we -- I think the workgroup certainly 20 has appreciated it, I hope that the rest of us 21 appreciate that we can deal a priori with all the 22 issues and cases that are going to come up in the 23 coming years. We're going to have to continually 24 revisit this. This is an iterative process. 25 Secondly, this unlike the NBC report is PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 154 1 dealing with -- we are dealing with all those who are 2 lacking decisional capacity regardless of the reason or 3 the source or etiology of their lack of capacity. But 4 not including emergency research which is covered by a 5 waiver and not including kids. 6 Thirdly, as you all note, from the document, 7 unlike the NBC report, we have incorporated a 8 tripartite risk scheme which is perhaps the single most 9 innovative part of this report at the federal level, 10 although as Alan Fleischman who I am sure will remind 11 me, our group in New York some years ago did the same 12 thing. I also want to point out by way of introducing 13 the report that -- and remind people that the 14 providence of this report or the impetus of this 15 report, I should say is the fact that DHHS responded to 16 the NBC report and asked OHRP to come to grips with 17 several issues with which they were not on all fours 18 with the NBC report. 19 But at the same time, there were seven or 20 eight recommendations from NBC that the DHHS group 21 found unobjectionable, found acceptable, and there were 22 a number of others that weren't relevant to them 23 because they had to do with admonitions that the NBC 24 gave to state law, for example, around who counts as a 25 legally authorized representative for research PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 155 1 purposes. And then there are one or two 2 recommendations to the NIH for further research on some 3 of these topics. That also did not require further 4 comment with respect to DHHS perhaps implement 5 guidelines or regulations. 6 So we are specifically focusing on one, 10, 7 11, and 12, for those of you who are keeping score, of 8 the NBC recommendations. Excuse me, two, 10, 11 and 9 12. Somebody is keeping score, fortunately for me. 10 And in the introduction we specify, and I 11 don't know how to be more emphatic about this, that 12 none of the rest of this is acceptable to the workgroup 13 unless the NBC recommendations, one, three, four, five, 14 seven, eight, nine, and 17 are taken as part of the 15 package. And I have not committed to memory, even 16 though I helped to write them, each of these 17 recommendations. But anybody is free to go on the web 18 and see what they are. We can talk about them -- 19 necessary, but those did not seem to be objectionable 20 to the DHHS group that received them. 21 So let me move to the recommendations. And I 22 suppose that what we are going to be looking for today 23 is a motion to accept these recommendations but with 24 the proviso that there are a number of issues, as 25 you'll see at the end of this document, and probably PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 156 1 others as well, to which the workgroup appreciates it 2 will need to return in order to flesh out these 3 recommendations. 4 So let me simply start with recommendation 5 one. This starts -- the language here is very 6 familiar. It actually rides the language of the 7 pediatric regulations to a very great extent. And I'll 8 not rehearse the intimate relationship that Bob Levine 9 could do better than I of the way the National 10 Commission thought through the Pediatric regs and the 11 so-called -- or their pediatric proposals and the so- 12 called Institutionalized as Mentally Infirmed Report 13 which did not ever become regulation. 14 So in a certain sense we are -- we are 15 bringing forward the work that was done 23 years ago by 16 the National Commission. 17 We believe that research may be conducted or 18 funded that does not involve greater or minimal risk if 19 the subject -- and you notice that there is a footnote 20 here about the disagreement about what term should be 21 used to describe people who are in research as subjects 22 or participants or volunteers. We use the language of 23 "subject" in this document because it's still the 24 language that's in the regulations. We can debate 25 about that, but it didn't seem to us to be critical to PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 157 1 the spirit of the report. 2 If the subject has given informed consent or 3 if a legally authorized representative has given 4 permission for a subject who lacks decision-making 5 capacity. Now, I'm going to open this up for 6 discussion in a moment. But let me just point out that 7 what we've tried to do here is preserve what many 8 critics of the NBC report felt was a problem, namely 9 that the -- what seemed to them, although I don't 10 agree, what seemed to them was a presumption that 11 people who have mental disorders lack decision-making 12 capacity sort of a priori. 13 Here you see this is written in such a way 14 that that presumption is not made. And so that the 15 capacity of the individual has to be presumably 16 assessed. So, I'm going to leave this up now for 17 discussion. Adil. 18 DR. SHAMOO: For information, I think the NBC 19 report with all due fairness to them, they mention that 20 not in the same recommendation, but prior to that in 21 the introduction there is no assumption that mentally 22 ill means incapable, decisionally impaired, in terms of 23 informed consent. They make that very clear. So those 24 who misunderstood it, either did not read the whole 25 report or I don't know what else they did. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 158 1 DR. MORENO: You say that because among some 2 people particularly in the psychiatric community there 3 was a concern that there is a stigmatization of people 4 who have mental disorders. But, again, we're moving 5 beyond the scope of people with mental disorders to the 6 -- capacity in general. Alan. 7 DR. FLEISCHMAN: I'm not going to debate 8 that. I have one question about what would the product 9 of this workgroup look like if we were to approve it 10 today? Is what we're looking at the product? 11 DR. MORENO: Yes. This would be this 12 document unless people want to table it or work on it 13 electronically with various emendations. This would be 14 the product of the workgroup. 15 DR. FLEISCHMAN: I guess -- and we can talk 16 about this later, but I think it will be more helpful 17 to people reading it if those NBC recommendations were, 18 you know, attached somehow or somewhere nearby. 19 DR. MORENO: They will be appendized. 20 DR. FLEISCHMAN: Do you know what I mean? 21 Because I like this a lot and I don't have much problem 22 with any of it. But, I think, you know, it needs a 23 little context. 24 DR. MORENO: No problem. 25 DR. FLEISCHMAN: Now, I do have a question. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 159 1 And that is, the clarification of the "legally 2 authorized representative," and how does the workgroup 3 perceive that playing out in the provinces? 4 DR. MORENO: Right. This, Alan, is, of 5 course, one of the matters that at the end of the 6 document we indicate is probably going to be a topic 7 for further discussion. Number five, and one of the 8 difficulties here as you well know is that that is a 9 state matter. And so, like NBC, the best any group can 10 do is offer advice to state legislatures on this 11 question. And I don't really know how else to handle 12 it. But I'll be open to suggestions. 13 DR. FLEISCHMAN: Well, my hope would be that 14 the workgroup would think about what would constitute a 15 reasonable surrogate. And whether we could try to move 16 the discussion in the direction of recommending, if 17 there are natural surrogates who would have the 18 capacity to consent to clinical judgments. 19 My problem here really just is this business 20 of lawyers interpreting this very narrowly as someone 21 appointed as a legal guardian. Even though most of 22 know there are others who are legally authorized to 23 make choices, it just seems to me that we would be 24 better off saying, what do we mean by that? How do we 25 think we would be most helpful to the community? PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 160 1 DR. MORENO: That's fine, thank you. 2 I have Greg and Bob and Felice and Elliot. 3 DR. KOSKI: A quick technical point, Alan -- 4 Jonathan. 5 I would ask that you consider framing this 6 particular working group not specifically in the 7 context of the NBC recommendations, but rather the HHS 8 working group -- interagency working group response to 9 that. We don't want to loop back to the original 10 thing. There's already 18 months of work that's gone 11 into the process at this point. So if you could do 12 that since there is in that working group report 13 discussion of each of the issues and so on. 14 The other quick technical point is that I 15 don't see Glen Dew out there, but I believe in fact our 16 office has already sent as recommended by the HHS 17 working group a letter to the State Attorneys General 18 to sensitize them to the issues so they can at least 19 start thinking about it. And if this committee were to 20 offer further advice on who should be a legally 21 authorized representative they may be receptive to 22 that. 23 DR. SHAMOO: And just on that point. I think 24 we need to look at the Maryland Attorney General's 25 Office, they have a Maryland Health Care Act. They PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 161 1 have what constitutes legally authorized and surrogate 2 and the have a tree. And as a matter of fact, the 3 group that was one of the diverse group of research, 4 there was one thing they agreed on, that tree was good. 5 There was no discussion sort of disagreement on that 6 one when we were discussing decisionally impaired. So 7 I would recommend that we see that as a good tree. 8 DR. MORENO: Bob. 9 DR. R. LEVINE: Thank you. I have four 10 comments. The first is that you departed greatly from 11 the NBC report by reinstating the minor increase above 12 minimal risk category. I want to applaud that with 13 great enthusiasm. 14 Secondly, in that same recommendation, number 15 three, (b) -- 16 DR. MORENO: We're just on one right now. 17 DR. R. LEVINE: I beg your pardon. Then I've 18 only got -- 19 DR. MORENO: But I'll take your applause for 20 the time being. 21 [Laughter.] 22 DR. R. LEVINE: Right. 23 DR. MORENO: We'll come back to you for the 24 rest. 25 DR. R. LEVINE: Well, then I'll come -- PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 162 1 before recommendation number one, I'm concerned about 2 the definition of the category of people to which this 3 applies. All persons involved in research who have a 4 condition or a disorder that disposes them to impaired 5 decision-making that includes a very much larger set of 6 people than I think we should be interested with here. 7 That would, for example, include people high fevers. 8 I don't think I need to -- I think you really want to 9 narrow this down to the people you are really 10 interested in. And I'll reserve my most serious 11 criticism to when we get to number two. 12 DR. MORENO: I think I can speak for the 13 workgroup when I say that we precisely did not want to 14 narrow it down to another group. But you can make a 15 judgment about that as you will. 16 DR. R. LEVINE: So you want all people with 17 high fevers to go through all these four 18 recommendations? 19 DR. MORENO: Well, it will very much depend 20 on what the risk level is and what kind of study is 21 being proposed. 22 DR. R. LEVINE: Well, I will resist then. I 23 think it's an overly broad application. 24 DR. MORENO: Understood. 25 DR. RICH: To that point. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 163 1 DR. MORENO: Yes. 2 DR. RICH: The difficulty it seem to me is 3 the word "disposes them toward." I mean, because being 4 disposed toward impaired decision-making is an 5 exceedingly broad motion. I mean, there are many, many 6 things that may dispose you toward that that cannot be 7 demonstrably associated with impaired decision-making. 8 And to associate myself with Bob's point of view, I 9 think that that would be the word that would trouble me 10 a great deal because I think one here wants to be 11 concerned with people who have demonstrably impaired 12 decision-making and not a disposition toward that. 13 DR. MORENO: Greg, did you want to -- 14 DR. R. LEVINE: I mean, this could be anybody 15 with a history of depression. 16 DR. RICH: Or alcoholism or lots of things. 17 DR. R. LEVINE: Or social drinking. 18 DR. RICH: Yes. 19 [Laughter.] 20 DR. MORENO: All right. Let's try not talk 21 about ourselves. 22 [Laughter.] 23 DR. MORENO: I respect your confidentiality, 24 even if you don't. 25 Let's go back in order, Felice and then PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 164 1 Elliot and them Mary Faith and then Adil. 2 DR. F. LEVINE: I only had a modest point 3 until Bob just made his point which I'm hoping maybe we 4 can go back and bracket and discuss that because it 5 slipped by me until you made the point. And I think 6 it's an important one for us to reflect on. But, I 7 think it's a friendly amendment and that is that I feel 8 that in general in our report we might not want to 9 address the issue of funding just because of the 10 practice of the human subjects protection system isn't 11 making the allocated funding decisions, so it's 12 conducted or funded where it's as if in this working 13 paper for the first time NHRPAC would be speaking to 14 funding decisions. So I just would sort of edit out 15 the "or funded" part of this throughout. That's in 16 number one, so I raise it. 17 DR. MORENO: It just tracks the 45 C.F.R. 46. 18 DR. RICH: Okay. Well, I don't know why -- 19 DR. KOSKI: 45 C.F.R. 46 speaks to supported, 20 not funded. 21 DR. F. LEVINE: It made it sound as if it was 22 advice on external funding and, you know, sort of 23 federal funding. I just think we should sort of avoid 24 that role. 25 DR. MORENO: Thank you. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 165 1 DR. R. LEVINE: A point on that point. Do I 2 infer then that you don't means this to apply to FDA- 3 regulated research? 4 DR. MORENO: Due to the extent that the FDA 5 requires that the investigators have complied with 45 6 C.F.R. 46, that's out of our hands. 7 DR. R. LEVINE: But they don't do that. They 8 have their very similar-looking regulations which are 9 not concerned with funding at all. 10 DR. KOSKI: Let me just sort of cut that one 11 off because I think clearly the department's intent 12 here would be to move toward a uniform standard for 13 dealing with this. 14 DR. R. LEVINE: Whatever the department's 15 intent, I would rather this commission -- this 16 committee said what it intended -- what we intend. We, 17 I trust, don't intend to limit these recommendations to 18 federally regulated research that's connected with 19 funding the research. 20 [Simultaneous conversation.] 21 DR. F. LEVINE: That's why I made my point. 22 DR. R. LEVINE: Yes, I'm agreeing with you. 23 DR. F. LEVINE: I knew you were. 24 DR. MORENO: We'll do a universal 25 substitution of "funded" with "supported", Bob. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 166 1 DR. F. LEVINE: We don't want it -- 2 DR. R. LEVINE: It's not supported either. 3 In the FDA's case it's required. 4 DR. F. LEVINE: Yes, it's federally 5 regulated. 6 DR. SHAMOO: I don't think there is a 7 difference between -- I mean, it's just a matter of 8 choosing the right words to mean the same thing. All 9 of you have the same goal. That is, regardless of what 10 research is, whether it's FDA or NIH-funded, the one 11 which Abbey is saying the word "regulated" that's the 12 intent, and I don't see the argument back and forth 13 continuous. 14 DR. MORENO: Then write what you intend to 15 say. 16 DR. KOSKI: I think the department would 17 welcome the committee's recommendation on the scope of 18 the applicability of this set of recommendations. 19 DR. MORENO: We'll just say "conducted"; 20 how's that? 21 All right. Elliot. 22 DR. DORFF: Just a very simple question. The 23 role of children in this, in particular teenagers. 24 DR. MORENO: Irrelevant. 25 DR. DORFF: Well, it's not defined anywhere PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 167 1 here. Right? In other words -- 2 DR. MORENO: We're not talking about -- 3 right, we're not talking about children. We're not 4 talking about legal minors. 5 [Simultaneous conversation.] 6 DR. DORFF: Well, I think you need to say 7 that. 8 MS. GOTTFRIED: We should just state that it 9 only applies to adults. 10 DR. MORENO: Thank you. 11 Mary Faith. 12 CHAIRPERSON MARSHALL: I guess this is more 13 general, Jonathan, but I would think that at some point 14 perhaps we could outline a couple of caveats, and those 15 would be that these were recommendations obtained in 16 the context of all efforts having been made to optimize 17 or enhance decisional capacity and that regardless of 18 the level of capacity that the individual, the research 19 subject participates in decision-making to the -- you 20 know, highest degree possible and that those are 21 understood background conditions that obtain 22 throughout. 23 DR. MORENO: I think that once we have the 24 recommended appendix of the NBC recommendations that 25 we're also presuming will cover that, but if they're PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 168 1 not we'll -- 2 CHAIRPERSON MARSHALL: Yes, I would think if 3 we could specifically articulate those background 4 conditions. 5 DR. MORENO: Right. Thank you. 6 PARTICIPANT: [Off mic.] 7 CHAIRPERSON MARSHALL: I'm just trying to get 8 the sentiment across that we need to -- you know, that 9 -- 10 [Simultaneous conversation.] 11 CHAIRPERSON MARSHALL: -- level of their 12 capacity they're involved in decision-making and that 13 we do all we can to enhance that. 14 DR. MORENO: All right. Adil, you want to -- 15 you're on the list. Are you off the list? 16 DR. SHAMOO: Mary Faith just made that 17 comment. 18 DR. MORENO: All right. Mary Kay. 19 DR. PELIAS: In line one I don't think you 20 need to say "conducted" either. You can just say, we 21 believe that research that does not involve greater 22 than minimal risk. You don't need either "conducted" 23 or "funded". 24 And one question, are we going to entertain 25 any discussion about subjects and participants, or is PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 169 1 that done with for now? 2 DR. MORENO: It's your ball. You can do 3 that. 4 PARTICIPANT: [Off mic.] 5 DR. PELIAS: Or an adverb. 6 [Simultaneous conversation.] 7 DR. SHAMOO: I'm glad I didn't write this 8 one. 9 DR. PELIAS: My concern with the question of 10 "subject" and "participant" is that I find in research 11 with human subjects what I call a fiduciary imbalance. 12 The subject is not on an equal level with the 13 researcher most of the time. And the researcher does 14 have a heightened obligation to make sure that 15 something doesn't happen to the subject or participant. 16 And I like bringing in the idea of something of a 17 fiduciary imbalance, but it would have to be done with 18 rewriting this footnote. 19 That's all. 20 DR. MORENO: I hear you. 21 Sandy. Then we'll come back to this 22 disposition issue. 23 DR. CHODOSH: Actually, I'm going back to 24 Bob's statement about acute and chronic impairment. 25 And I think that probably the working group should PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 170 1 address those two separate categories as two different 2 things. But nevertheless, they both have impaired 3 ability and it may well be that we need to deal with 4 them differently. But I think that they need to be 5 addressed because it's something that comes up very 6 frequently in our IRB discussions. 7 It has to do with whether we're discussing 8 whether someone with a high fever and there are many 9 other situations like that where the person is 10 temporarily impaired, nevertheless important to obtain 11 consent if possible or need to have a mechanism of 12 knowing how to proceed with that situation. We 13 certainly would not want to impede research in that 14 area, but I think that we shouldn't just say, you know, 15 that doesn't -- we're not talking about them. I think 16 we have to talk about them, but talk about them 17 separately. 18 DR. MORENO: Bob and then Adil. 19 DR. R. LEVINE: Let me clarify that point. 20 What I object to is not having special procedural 21 protections. And even substantive protections for 22 people who actually have or look like they might have 23 impaired decision-making capacity. I'm concerned with 24 the language that says, "conditions or disorders that 25 dispose them." And I would not want to see this whole PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 171 1 apparatus trotted out for every patient that has a high 2 fever or for every patient that has a stroke. I want 3 there to be a different threshold where you define a 4 population of people who it's a serious concern. 5 Well, no, you've got to -- in order to invoke 6 the procedural protections you have to be able to 7 locate a population who might have it, but might not 8 have it. And then the first thing you do is to 9 determine whether or not they do have it, and then all 10 the rest gets triggered. But you don't want to be 11 looking at everybody with a stroke. 12 DR. MORENO: Can I just observe, this has 13 been one of the traditional problems with getting off 14 center with this topic. Kids or kids or not, pregnant 15 women, and fetuses, or pregnant women and fetuses are 16 not, prisoners or prisoners are not. But this 17 population is -- the problem of definition has been the 18 traditional stumbling block. 19 Adil. 20 DR. SHAMOO: However, I think there is a 21 consensus the word "disposes" is too general. I agree 22 with Bob and that was not the intent, I think, of the 23 workgroup discussion. However, intermittent decisional 24 capacity or incapacity is the same whether you have 25 high fever and you are impaired, or you are depressed PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 172 1 and in a psychotic episode. During that period when 2 you are decisionally incapable you don't give them an 3 informed consent to sign. 4 However, when they have a clear, three, four, 5 five, six days or a week or a month and you give them 6 the informed consent that that will be okay. This is 7 what this means, whether we have written it to mean 8 that or not, that was the discussion. And even with 9 schizophrenia probably a third of them are capable of 10 signing informed consent and we have agreed to that for 11 the past five, six, seven, eight years. I think it's a 12 red herring raising it all over again. No one should 13 tell mentally ill patients that they are all the time 14 decisionally impaired. That is inhumane and unethical 15 and we are not doing that. 16 DR. MORENO: I'm tempted to jump into the 17 foray here and suggest another word which will, of 18 course, shift away from the concern about capacity 19 assessment. And the word that I have in mind is 20 something like, "that renders them incapable." 21 PARTICIPANT: [Off mic.] That predisposes 22 them -- 23 DR. MORENO: It does. 24 PARTICIPANT: -- they have been so rendered. 25 DR. MORENO: Yes. And we are in between PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 173 1 [indiscernible] and should this here. Either we have a 2 framework that requires this assessment and therefore 3 of whom and under what circumstances and by whom. Or 4 we presume that there has been an adequate assessment 5 and then develop the framework for those who haven't 6 gotten over the threshold capacity. 7 DR. SHAMOO: Jonathan, again, NBC dealt with 8 that. That is, if you are dealing with a group of high 9 fevers, you don't worry about it. Most likelihood they 10 are not continuously and decisionally impaired. If you 11 deal with schizophrenia patient, most likelihood you 12 will have a certain percentage with decisional 13 incapacity and therefore for that group you have 14 greater built-in safeguards than those who are on high 15 fever. 16 DR. MORENO: Renders them chronically -- 17 DR. SHAMOO: Exactly. 18 DR. MORENO: -- incapable. 19 [Chorus of no.] 20 DR. MORENO: Gone too far. See. 21 DR. F. LEVINE: Jonathan, I don't know if 22 this will help, but -- 23 DR. MORENO: Go ahead. 24 DR. F. LEVINE: -- "should apply to all 25 persons involved in research when they have a condition PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 174 1 or disorder that impairs decision-making capacity." 2 DR. R. LEVINE: It allows more wiggle room. 3 DR. RICH: Well, does one even need 4 "condition" or "disorder"? Can you simply -- 5 DR. F. LEVINE: Well, at least it is not 6 disposing and it is when, it's only under those 7 circumstances when. 8 DR. RICH: Can one simply say, "to all 9 persons involved in research who have impaired 10 decision-making capacity"? 11 DR. MORENO: That is not exactly what Felice 12 -- 13 DR. RICH: No, I'm asking whether that 14 alternative which is simplifying language -- 15 DR. MORENO: Does this avoid the high fever 16 problem? 17 DR. RICH: Well, I think it -- I mean, the 18 onus then is that what you're looking at is the 19 capacity and not the condition or the disorder or the 20 predisposition to it. You're really focused on the 21 impaired decision-making capacity. 22 DR. MORENO: Right. Okay. We like that. I 23 like that. 24 DR. CHODOSH: Perhaps what needs to be done 25 is some guidance about the fact of determining that and PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 175 1 then proceeding. In other words, it should be a 2 determination of the capacity. And I'm not thinking 3 about testing necessarily, but, you know that there are 4 certain circumstances where one can expect there might 5 be impaired capacity. And in those situations it 6 should be assessed before obtaining -- 7 DR. MORENO: Well, I want to hear some 8 comments about this. Susan. 9 MS. KORNETSKY: Yes, I think that if you took 10 those few statements that Robert just said and put that 11 in the introduction in saying that this is what it is 12 supposed to be, that that will help clarify how the 13 words are. That this is what the concentration is on 14 when they have the incapacity. And I think it just 15 needs to be stated here. 16 DR. MORENO: And this is -- how does this 17 interpolate with the process of assessing capacities? 18 DR. SHAMOO: Jonathan, this is a whole 19 different issue. And, again, NBC dealt with it and we 20 have dealt with it by deferring it because it's a 21 sticky point. 22 DR. MORENO: Exactly. 23 DR. SHAMOO: He said "independent capacity 24 assessment" that's one of the outstanding major issues. 25 I don't think you could insert it in every single PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 176 1 paragraph we are writing. You have to assume in this 2 first part -- I'm defending Jonathan's writing -- in 3 this first part that they have decisional incapacity 4 and during that what will happen in terms of these 5 categories of research and informed consent. That's 6 really what this is. 7 DR. MORENO: This is a chicken and egg 8 problem, in effect. Elliot. 9 DR. DORFF: I just wanted to recapture 10 Sandy's point though which is that -- and I think Bob 11 Rich's revising of this is right. All persons involved 12 in research who have impaired decision-making capacity. 13 But then maybe a sentence after that, something like 14 this impairment may be temporary or permanent. And 15 then talk about what happens if it's temporary and what 16 happens if it's permanent. 17 DR. SHAMOO: That's difficult, how long and 18 how -- 19 DR. CHODOSH: You're really talking about 20 when you obtain consent. You know, someone can give 21 you consent for an Alzheimer study, apparently a couple 22 years before they have Alzheimer's with the idea that 23 there's a point at which they will become impaired. 24 And so it's at the time that consent is obtained. And 25 once you obtain the consent unless a legal PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 177 1 representative pulls you out of it, you know, you 2 essentially have done it. 3 DR. MORENO: Greg and then Mary Faith. 4 DR. KOSKI: I find the language that Bob 5 recommended to be attractive because having an impaired 6 ability to do something doesn't mean that you have no 7 capability of doing something. I may have, you know, 8 an impaired ability to walk, but it doesn't mean I 9 can't walk at all. And so I think the goal here is to 10 try and determine when it is possible for someone to 11 make a legitimate decision for one's self and when it's 12 not and afford special protections in those instances 13 where it's deemed that that's not possible. So I'd 14 find some attractiveness of the language of impairment 15 as opposed to incapability. 16 DR. MORENO: Right. Mary Faith. 17 CHAIRPERSON MARSHALL: I think we should be 18 mindful that what we say here reflects sort of the 19 paradigm shift, if you will, in how we can see about 20 informed consent. And what I'm hearing sort of 21 reflected in the discussion, it may not be intended, is 22 the event model rather than the process mode, decision- 23 making, ongoing conversation. And we are really 24 talking about functional criteria for decision-making 25 and they may wax and wane or they may stay the same. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 178 1 And I think that's why the language is that, you know, 2 the requirement for continuing to enhance or optimize 3 decisional capacity involving the individual to the 4 degree possible in decision-making is important as 5 well, in an ongoing way. 6 DR. R. LEVINE: I think Mary Faith has just 7 made a very important point. But I think to assume 8 that the consent process is, you know, that the horizon 9 for being able to say something final is way out there. 10 We have to also acknowledge that there's a goodly 11 number of people who are crafting the so-called 12 research living wills. And the -- I think the most 13 thoughtful among these people are those who designate 14 somebody holding a durable power of attorney to speak 15 for them. And when specific contingencies come up that 16 couldn't be specified in the original document. 17 But still, I also sympathize with Sandy that 18 at the time you do something of that sort, you need an 19 individual who has the capacity to make that decision. 20 And it probably is a good idea to be dealing with 21 somebody who looks likely to retain that capacity at 22 least for a reasonable amount of time. 23 One thing that's missing from the NBC report 24 and or may not be in what we haven't seen here is the 25 idea that is developed so well in the report of the PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 179 1 president's commission. There's one we haven't heard 2 mentioned this time yet. Where they talk about 3 capacity being evaluated along a sliding scale 4 depending upon just what's at stake. So you would be 5 less rigorous about imposing a high standard of 6 capacity if all you're doing is asking somebody to 7 respond to an interview than you would be if you were 8 asking somebody to decide to participate in a 9 randomized clinical trial. Where is it? 10 I haven't noticed it in here -- 11 [Simultaneous conversation.] 12 DR. SHAMOO: That kind of discussion we said 13 commensurate with risk. We said that in the working 14 group. I don't know if it's reflected by words here, 15 but by deed that was the intent of the working group. 16 DR. R. LEVINE: I meant to accommodate that 17 possibility when I limited my remarks only to what's on 18 these three pages. It might be in one of these other 19 recommendations. 20 DR. MORENO: All right. Well, let's see if 21 we have any more discussion about either the first 22 paragraph after "recommendation" or the first 23 recommendation? I've taken careful notes, I want you 24 to know, which I can't read, but they're very careful. 25 DR. R. LEVINE: Could I say something about PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 180 1 number two? 2 DR. MORENO: Number two is now on the floor. 3 I haven't read it. Do you want to have a silent 4 meditation on two? I'll read it for you since that's 5 the ritual. 6 "The workgroup also concludes that 7 research may be conducted that 8 involves greater than minimal risk 9 but presents the prospect of direct 10 benefit to subjects if: (a) the 11 risk is justified by the intended 12 benefit to the subjects; (b) the 13 relation of the anticipated benefit 14 to the risk is at least as 15 favorable to the subjects as that 16 presented by available alternative 17 approaches; and (c) adequate 18 provisions are made for obtaining 19 the informed consent of the 20 subject, or a legally authorized 21 representative gives permission for 22 a subject who lacks decision-making 23 capacity." 24 Bob. 25 DR. R. LEVINE: This is what I found to be PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 181 1 the most unacceptable component of the NBC report. 2 What it succeeds in doing is recreates the foolishness 3 of therapeutic research. 4 When I confronted NBC with this I asked them, 5 would you say that a placebo controlled trial is 6 therapeutic or beneficial or non-beneficial? And I got 7 an even split in the responses. What all the rest of 8 the regulations have to do with and what Alan's group 9 so clearly presented yesterday is that what we are 10 evaluating is each component of the research. If one 11 procedure or intervention holds out the prospect of 12 direct benefit, then we justify it in these terms. If 13 another component does not hold out such a prospect 14 then we evaluate it in terms of whether it meets the 15 minimal risk threshold. 16 But to put it all together about risk -- 17 research maybe conducted that involves greater than 18 minimal risk but the prospect of direct benefit 19 recreates what I call the fallacy of the package deal. 20 Jonathan has heard that so often he recites it before 21 I do. 22 You don't want to do this. If anybody here 23 needs convincing of this, I will give you examples of 24 package deals that have been approved by IRBs and 25 funded by the federal government. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 182 1 For example, putting catheters in coronary 2 arteries in order to administer placebos. I'm not 3 saying that can't be justified ethically, but it should 4 not be justified in terms of the prospect of direct 5 benefit, if you were evaluating the whole protocol as a 6 package. 7 DR. RICH: I think the last phrase, though, 8 buys out of that problem, Bob, and that is to the 9 subjects. And the point that I'm making is that the 10 word is plural. So if one says, "to the subjects" 11 plural, then one says, is the intent of the study as 12 opposed to the -- in other words, is there intended 13 benefit in the study as opposed to is there intended 14 benefit to the individual? 15 DR. R. LEVINE: Let me finish then. In the 16 protocol I'm talking about, there was an evaluation of 17 thrombolytic treatments of myocardial infarction. It 18 was classified as therapeutic research because the 19 thrombolytic therapy itself held out the prospect of 20 direct benefit. But that meant you accepted the whole 21 package. And the coronary artery catheterization in 22 order to give a placebo was swept up into the -- under 23 the rubric of therapeutic research and justified 24 accordingly. 25 So what I'm saying is that you do not PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 183 1 evaluate the entire protocol. You evaluate each 2 component. And you might say, yes, we really like the 3 idea of evaluating thrombolytic therapy and we think 4 that the prospect of direct benefit justifies the risks 5 involved. On the other hand, we don't like the idea of 6 sticking a catheter in the coronary artery for no 7 purpose other than to give a placebo. 8 If you look at the component analysis it 9 gives you the possibility of making more nuanced 10 approvals or disapprovals of particular protocols. 11 Another example was the National Gallstone 12 Project where they approved doing liver biopsies on the 13 placebo controlled group for no purpose other than 14 maintaining the double blind. I can go on and on with 15 these things. 16 You need to have some vocabulary that allows 17 you to evaluate specific components of research 18 protocols. 19 The other thing is that everybody else seems 20 to have recognized this, after 25 years we finally got 21 therapeutic research out of the so-called subpart B. 22 Even the World Medical Association has tried to get rid 23 of it. Let's not lead a regressive move in this 24 regard. 25 DR. MORENO: Anyone else? PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 184 1 DR. SHAMOO: Yeah, I didn't hear them, but I 2 want to make my comment anyway. And that is -- 3 DR. R. LEVINE: [Off mic.] 4 DR. SHAMOO: -- I won't quote you, Bob, 5 anymore. 6 Someone who is a few years older than me said 7 -- no -- this is borrowed from the regs for pediatrics 8 and that's why we try to maintain that language. 9 That's one thing. 10 Second, there are linguistic use, it doesn't 11 mean what a language expert will tell us to mean. It's 12 an accepted after using it for, what, 20, 30 years now 13 and therapeutic versus nontherapeutic even though I 14 agree with Bob in his absolute interpretation of those 15 two words. However, now it's accepted what they mean 16 by "therapeutic" it means there is some benefit to the 17 group at large and maybe direct medical benefit not 18 every single piece of the protocol is direct medical 19 benefit. The compilation of those procedures they may 20 be benefit to the individual. It's an accepted now and 21 that's the way we go. We are not going to change the 22 language every few years just because Bob keeps 23 insisting on it. 24 DR. R. LEVINE: Let me repeat what you 25 missed. The regulations on research involving children PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 185 1 were the first regulations in the United States to 2 explicitly repudiate the distinction between 3 therapeutic and non-therapeutic research. It uses the 4 language that Alan Fleischman and his group faithfully 5 copied and presented to us yesterday. It says, 6 "interventions or procedures that hold out the prospect 7 of direct benefit." 8 It does not say "research that holds out the 9 prospect of the direct benefit." 10 Now, people who only read the pediatric 11 regulations superficially read the subtitles that were 12 written after the national commission signed off on it. 13 The subtitles have it all wrong. But the actual text 14 of the regulations calls for a component analysis. 15 Thank you. 16 CHAIRPERSON MARSHALL: I just want to caution 17 us not to have ad hominem in our remarks and to stick 18 to the content of the recommendations. 19 DR. R. LEVINE: [Off mic.] 20 CHAIRPERSON MARSHALL: No. 21 DR. MORENO: Just in case. If we -- the 22 language interventions of procedures, Bob, will that 23 care of this concern here? 24 DR. R. LEVINE: If you just copied what Alan 25 gave us yesterday. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 186 1 DR. MORENO: Done. 2 DR. R. LEVINE: Thank you. 3 DR. MORENO: Alan, would you rewrite this, 4 please? Another job for you. 5 All right. Any other comments on number two? 6 DR. SHAMOO: Is the assumption all these, 7 (a), (b), and (c) has to be satisfied? 8 DR. MORENO: Yes. 9 DR. SHAMOO: I think somewhere should be the 10 word "and" at the very -- after (b) then. 11 DR. MORENO: Well, the colon is supposed to 12 function that way, but we'll do that. 13 DR. MORENO: Anything else? 14 [No response.] 15 DR. MORENO: Okay. We're going to move to 16 number three and things get even more fun. 17 "We also conclude that research 18 involving a minor increase over 19 minimum risk that does not" 20 and then we will substitute the preferred language to 21 the whoever we're talking about -- 22 "but is likely to yield a 23 generalizable knowledge about these 24 individuals" 25 and now we have another caution here about the use of PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 187 1 the word "condition" which is footnoted -- 2 "or disorder may be conducted if: 3 (a) the" -- 4 ah, I knew we did something right -- 5 "the intervention or procedure 6 presents experiences to subjects 7 that are reasonably commensurate 8 with those inherent in their actual 9 or expected medical, dental, 10 psychological, social, or 11 educational situations." 12 Now, we went around the block a few times in 13 the workgroup to try to figure out if there were more 14 dimensions of human experience that need to be added to 15 this list and we decided that ultimately this list is 16 about as good as we can get without being even more 17 redundant than this list. 18 And then we just have this historical note 19 about the use of the word "inherent" which some people 20 thought we ought to have in there. And with help from 21 Al Johnson in helping us understand the role of the 22 word "inherent" in the National Commission statement. 23 "(b) the intervention or procedure 24 is likely to yield generalizable 25 knowledge about the subject's PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 188 1 disorder or condition which is of" 2 -- uh-oh -- 3 "vital importance" -- 4 We'll come back to that, I'm sure -- 5 "for the understanding or 6 amelioration of the subject's 7 disorder or condition." 8 "(c) adequate provisions are made" 9 and these are all with an "and" between them 10 -- 11 "adequate provisions are made to 12 solicit the informed consent of the 13 subject or for a subject who lacks 14 decision-making capacity, a legally 15 authorized representative is given 16 permission." 17 Comments? Bob. 18 DR. R. LEVINE: Let me just repeat what I 19 said out of place before and that is, I'm really happy 20 to see that you've linked the analysis to the 21 intervention or procedure at least in number -- in the 22 (a) and (b). 23 The other thing I wanted to flag is something 24 I think you've already flagged by saying, "uh-oh." I 25 want to recall the discussion we had yesterday about PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 189 1 vital importance. Everything that was said yesterday 2 against vital importance is -- ought to be -- we ought 3 to think about this, it was vitally important as Felice 4 puts it, yes. Thank you. 5 DR. MORENO: Thank you. Adil. 6 DR. SHAMOO: I have a couple comments on 7 this. The footnotes could be construed to be 8 disingenuous because it says the term "condition" may 9 be too broad or too narrow. I can understand too 10 broad, but trying to put those out equivalent or too 11 narrow, condition how could it be too narrow? One is 12 talking about cosmos and one is talking about the 13 earth. And you're saying, "condition" be anything, 14 literally. Like I said, the dictionary definition of 15 "condition" is state of being and it could be height, 16 weight, race, gender, anything. So that's only to make 17 the two are equivalent and therefore the workgroup took 18 a happy medium between the two positions for the 19 definition of "condition." And I think that footnote 20 should be corrected. That's one. 21 Second, everything we discuss and everything 22 I said, when we were discussing the pediatrics, about 23 the condition and how the pediatric regs and the 24 National Commission's comment that there was 25 specificity to those research related to the condition PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 190 1 should be copied verbatim into this paragraph because 2 that is supposed to be there as equivalency. 3 DR. MORENO: Which paragraph, Adil, just so I 4 make sure? 5 DR. SHAMOO: Wherever we mention the word 6 "condition" we should reinsert the narrowness. 7 Remember the National Commission required this is a 8 specific ethical consideration that this is not meant 9 to be so broad to include anything, et cetera. 10 DR. MORENO: All right. 11 DR. R. LEVINE: Adil, if I recall correctly 12 what you read in order to help us understand what the 13 Commission intended was the quotation of its chairman 14 that was written by a journalist. And I don't see 15 that. I happened to be there when the Commission 16 expressed its intent and it was very clear that they 17 did intend to include condition because they wanted to 18 relativeize this to something more than simply 19 disorders. 20 DR. MORENO: Felice. 21 DR. F. LEVINE: Well, I'm -- 22 DR. SHAMOO: Can I ask for a moment? What 23 the chairman said was part of the National Commission's 24 report. I mean, transcript, not the journalist. What 25 I read about Ken Ryan. Okay. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 191 1 DR. R. LEVINE: There were some remarkable 2 things in that transcript. For example, it quoted 3 Donald Sullivan as illustrating autonomy by saying, "I 4 move your arm." There are typos in transcripts. I am 5 telling you what the content was of the discussion that 6 led into the crafting of that passage. 7 DR. SHAMOO: Well, all I could go is by the 8 -- 9 DR. MORENO: Felice. 10 CHAIRPERSON MARSHALL: You don't want me to 11 come out there and referee gentlemen, it will be 12 painful. 13 DR. MORENO: Felice. 14 DR. F. LEVINE: I'm hoping that when this 15 migrates from what was perhaps difference in view 16 within the working group that maybe we could reach a 17 meeting of the minds in NHRPAC so that it is -- that we 18 don't have to have an either/or. And I'd like it to 19 have the same fit as we have in the children's working 20 group and that is that we did -- we were able to see 21 condition as broader so that if it's of benefit in 22 advancing knowledge about that condition, the 23 generalizable knowledge about the condition that it 24 might be conducted. So I would like us, ultimately as 25 NHRPAC to resolve the footnote and also have a fit PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 192 1 between our other uses of condition, most in particular 2 with the children's working group where we did not have 3 that internal ambiguity in that working group. 4 DR. MORENO: Elliot. 5 DR. DORFF: I just have two editorial things. 6 Of vital importance, I think just as significant for 7 the understanding of amelioration of the subject's 8 disorder or condition, or just "important" if you want 9 that. But I think "significant" is a little bit nicer. 10 And (c) is not -- this is my mother the 11 English teacher speaking -- (c) is not a sentence. You 12 need -- these are -- you have, "adequate positions are 13 made to solicit the informed consent of the subject or, 14 for a subject who lacks decision-making capacity a 15 legally authorized representative." 16 DR. MORENO: I'm not sure we need the comma 17 there, but I'll check with the grammarians. 18 DR. DORFF: All right. 19 DR. MORENO: I appreciate it. 20 Other comments? 21 [No response.] 22 DR. MORENO: All right. So what I take from 23 this is that we need to rethink vital importance along 24 the lines of our discussion yesterday. I am going to 25 make an effort to revisit the problem of condition or PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 193 1 disorder. But I'm not entirely sure exactly how that 2 is going to work out. So I'm still interested in 3 recommendations on that. 4 Susan. 5 MS. KORNETSKY: Jon, I think yesterday -- I 6 mean, my own view on this is that we somehow came to 7 some agreement on some language that Alan was going to 8 try for vital importance and condition and if it means 9 the same thing for children as we're trying to get 10 across for this, then I would say I'm not -- you know, 11 maybe we should talk -- 12 DR. MORENO: Alan and I will talk. 13 MS. KORNETSKY: -- Alan and talk and use the 14 same stuff. 15 DR. MORENO: We'll work on it. 16 DR. DORFF: Can I just mention that basically 17 the idea was that research -- research is not always of 18 vital importance. I think I said 2 percent of research 19 is probably of vital importance. But nevertheless, 20 that doesn't mean it shouldn't happen. Because the 21 vitally important research will not happen unless 22 somewhat less vitally important research happens along 23 the way. And that's just the way that human knowledge 24 gets expanded. 25 And so consequently what you need is PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 194 1 significant. Right. In other words, this is not a 2 fishing trip. Right. 3 DR. RICH: You don't need an adjective there 4 at all. 5 DR. DORFF: All right. So just as important. 6 DR. RICH: It's either important or it's not. 7 DR. DORFF: Or significant. 8 DR. RICH: Significant importance to me is -- 9 DR. DORFF: No, no, no. No, what I was 10 saying is -- I wasn't saying that. What I was saying, 11 which is of significance for the understanding or 12 amelioration of the subject's disorder or condition. 13 That's what I was arguing for. 14 DR. MORENO: I think we're going for 15 important here, but Alan and I will talk more about 16 this. 17 PARTICIPANT: [Off mic.] You could also use 18 the word "meaningful." 19 DR. DORFF: Yes, that's another possibility. 20 DR. MORENO: That's a very sensitive word. 21 DR. FLEISCHMAN: In the children's 22 regulations we are, quote, "stuck with" a certain 23 language that we need to interpret. Here we are not 24 "stuck with" that language, so we can then -- 25 DR. MORENO: Be a little more creative. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 195 1 DR. FLEISCHMAN: -- use language with more 2 creativity. However, I would like to point out that in 3 our conversations yesterday Adil and I made quite clear 4 that we were disagreeing about the definition of 5 "condition." And I would lay on the table that I 6 continue to disagree with Adil's definition of 7 "condition," and I think we reached consensus, although 8 not unanimity yesterday, that "condition" would be 9 fairly broadly viewed. 10 DR. MORENO: And, again, in this case it may 11 not be possible to reach unanimity, but at least we can 12 harmonize our use of the language within the NHRPAC. 13 Abbey, Felice. 14 MS. MEYERS: I think I said yesterday that 15 the reasoning that was used when those words were put 16 into the Orphan Drug Act was that a disorder is a 17 syndrome or a disease, but a condition could be from a 18 trauma. It doesn't necessarily mean that it's a 19 diagnosable disease. It could be a broken leg. And so 20 I would feel that the word "condition" should be there. 21 I think the wording is right on this. 22 DR. MORENO: Thank you. Felice. 23 DR. F. LEVINE: I think I was making the 24 point that as we rewrite, as I've done with other of 25 the social behavioral science working group documents PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 196 1 from it being a working group document to a NHRPAC 2 document that the difference in view in the working 3 group becomes, in a way, moot, because if NHRPAC 4 reaches a consensus which we think we did, then we can 5 just say, NHRPAC conceives of condition as, and 6 whatever language -- 7 DR. MORENO: Well taken. Right. 8 Anyone else on anything in 3(a), (b) and (c)? 9 [No response.] 10 DR. MORENO: All right. I'm going to read 11 four then. 12 "The workgroup recommends that 13 research not otherwise approvable, 14 which presents an opportunity to 15 understand, prevent, or alleviate a 16 serious problem affecting the 17 health or welfare of persons with a 18 condition or disorder that may 19 affect decision" -- 20 excuse me -- 21 "affect the capacity -- 22 "affect capacity -- 23 I'm worried about Elliot here. 24 "to give informed consent may be 25 conducted if the Secretary" -- PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 197 1 and the rest of this will certainly be as 2 familiar as the previous portion to those of you who 3 have been reading the regs. 4 "-- after consultation with a panel 5 that includes both experts in 6 pertinent disciplines" -- 7 and I have added a few here -- 8 "e. g., medicine, psychiatry, 9 neurology, ethics law, and persons 10 knowledge about the experience of 11 the population with the disorder or 12 condition" -- 13 and here I've written, "e.g., or the 14 workgroup that wrote -- 15 "e.g. groups that represent the 16 problems and interests of the 17 population, and following 18 opportunity for public review and 19 comment has determined that: 20 (a) The research presents an 21 opportunity to understand, prevent 22 or alleviate a serious problem 23 affecting the health or welfare of 24 persons with a condition or 25 disorder that may affect capacity PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 198 1 to give informed consent; 2 (b) The research will be conducted 3 in accordance with sound ethical 4 principles;" 5 I don't think anybody is going to object to 6 that. 7 (c) Adequate provisions are made 8 to solicit the informed consent of 9 the subject or for a subject who 10 lacks decision-making capacity, a 11 legally authorized representative 12 has given permission." 13 DR. DORFF: Period. 14 DR. MORENO: All right. No, LARs, give 15 permission, not consent. 16 DR. DORFF: [Off mic.] -- you solicit the 17 informed consent of the subject or a legally authorized 18 representative -- 19 DR. MORENO: Representatives give permission 20 not consent. Only the individual can give consent. 21 DR. DORFF: I see. Okay. 22 DR. MORENO: All right. Bob and then Alan. 23 DR. R. LEVINE: I think that our discussion 24 of "condition" -- which is repeated here -- a few 25 minutes ago was too abrupt. I want to make it clear PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 199 1 that the Commission's choice of the term "condition" 2 was not capricious or meant to be overly broad. In 3 particular, in studying in the recommendations on 4 research involving children, some research is justified 5 in relation to a condition that is not a disorder. 6 For example, there are separate passages on 7 those who are wards. These is separate -- there was 8 commentary on children who were orphans. Being an 9 orphan is a condition which is not a disorder. 10 With regard to what the Commission called 11 "mentally infirm" it made a difference to the 12 Commission whether they were institutionalized or not. 13 It would be legitimate to select people with mental 14 impairment or incapacity -- decisional incapacity, for 15 participation in the study on the effects of 16 institutionalization on these people and to establish 17 it as your eligibility criteria that you had to be in 18 an institution. 19 So the term "condition" is there for a 20 meaningful purpose. 21 Thank you. 22 DR. MORENO: Thank you. Alan and then 23 Elliot. 24 DR. FLEISCHMAN: Harking back to some of the 25 problems we've had with the 407 in the children's PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 200 1 regulations, perhaps we ought to include in number four 2 that the local IRB would wish to approve the protocol, 3 but it is not permissible under the prior three 4 statements and that they in a sense are advocating -- 5 DR. MORENO: That's interesting. 6 DR. FLEISCHMAN: -- approval. I think that 7 in the 407 committee report that has circulated 8 previously there is some conversation about that and it 9 seems to me to be a very reasonable approach to that -- 10 you know, to that -- excuse me, elevation to the 11 Secretary level. 12 DR. MORENO: That's interesting. Anybody 13 want to speak to that? 14 DR. SHAMOO: Would you please repeat it 15 because I didn't -- I did not get it. 16 DR. MORENO: Before it gets kicked up to the 17 Secretary local IRB should express its wish to approve, 18 but can't -- but can't approve. 19 DR. FLEISCHMAN: The children's regulations 20 has this an approach for very important work that 21 cannot otherwise be permitted by an IRB. What I think 22 has been observed in some of the 407 committee work is 23 that the IRBS have not voiced their idea about this. 24 So the local IRB says, we can't approve it, and we 25 punt. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 201 1 I think it would be -- 2 CHAIRPERSON MARSHALL: Wait -- 3 DR. FLEISCHMAN: No? 4 CHAIRPERSON MARSHALL: Just to clarify. It 5 doesn't say we can't -- well, it says, we're sending 6 this to the OHRP because we have made the determination 7 that it could be approved under 407. And that here is 8 why it can't be approved on all the other things, so we 9 are asking you. 10 DR. FLEISCHMAN: No, but my argument is that 11 there should be a "should" -- not "could." 12 CHAIRPERSON MARSHALL: Yes. I'm not taking 13 issue with that. 14 DR. FLEISCHMAN: Okay. 15 CHAIRPERSON MARSHALL: I just wanted to 16 clarify the process that exists. Sorry. 17 DR. FLEISCHMAN: Okay. I'm just suggesting 18 that it seems to me that if there's an investigator in 19 a local institution and the local IRB has reviewed it 20 and says that this could be approved, I think it would 21 be helpful and maybe even decrease the numbers of 22 protocols that move in this direction that the IRB 23 would have to say, it should be approved. We believe 24 it's a good thing. It just cannot be approved except 25 through this mechanism. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 202 1 DR. MORENO: Alan, is there a danger that 2 that could short circuit the review process in the 3 sense that it should be approved if this "UBER" [ph] 4 IRB that the Secretary is going to appoint approves it? 5 There seems to be some lack of fit there. It 6 should be reviewed, not that it should be approved; 7 right? 8 DR. FLEISCHMAN: Yes. It's a recommendation 9 that the UBER IRB take seriously this proposal because 10 the local IRB would have wished to have approved it if 11 it could have. 12 DR. MORENO: Right. 13 DR. FLEISCHMAN: The reason why I'm 14 suggesting is because my anecdotal or perhaps 15 idiosyncratic belief is that there are an increasing 16 number of proposals being sent for 407 review based in 17 kind of a conservative interpretation of what's 18 permitted among IRB reviews. So at least the IRB would 19 have had to do the hard work of thinking through these 20 standards and saying, yes, I think it reaches this 21 level of importance, but we do believe we do not have 22 the authority locally to approve it. 23 So I'm just throwing it on the table as 24 something I think would be helpful on the children's 25 side, and I think would be helpful here. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 203 1 DR. MORENO: Okay. Other comments? Did you 2 want to -- okay been said. 3 Okay. Elliot and then -- 4 DR. DORFF: I don't want to endorse that. 5 And in particular I think what that would do is that it 6 would prevent the possibility of, you know, researchers 7 trying to trump the local IRB. In other words, the IRB 8 said, no, but I'm going to try to appeal it to a higher 9 court, as it were. 10 DR. MORENO: Well taken. 11 DR. SHAMOO: That's not usually what will 12 happen. The local investigator cannot trump 407. What 13 they will do, they will push it to 406 and that's why 14 you told us yesterday there's only two cases that has 15 ever gone to this Secretary that is prior to recent 16 times. And so I have trouble with your argument. From 17 one side you want to give the IRB all the leeways, at 18 the same time what you are doing now, you want to take 19 them a step further and you want them to overstep their 20 mandate, their federal regs mandate. There is no 21 mandate in the regs to say they should or should not 22 recommend. 23 And why should they recommend? Either way, 24 that is outside their purview basically. 25 DR. MORENO: Greg. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 204 1 DR. KOSKI: I think it's essentially implicit 2 in the regulations as written that the IRB will go 3 through the process and -- I mean, it would be, in my 4 mind, somewhat foolish to take research that would be 5 disapproved by the IRB and send it for 407 approval. 6 So that in the process -- I think there's an implicit 7 assumption that they've reviewed this and they do not 8 believe that it can be approved under the others, but 9 if they didn't think that it should be approved, then 10 in fact it would never go. All Alan is doing is 11 saying, rather than having that be an implicit 12 assumption making it an explicit designation in the 13 exercise of the covalent of a 407 protection may not be 14 a bad idea business it lays out there for everyone to 15 see exactly what the thinking of the local IRB might 16 be. 17 DR. MORENO: Greg, who actually has the 18 authority -- doesn't the investigator on his or her own 19 have the authority to take it up? No? 20 DR. KOSKI: It has to go through the IRB. 21 CHAIRPERSON MARSHALL: Can I say something to 22 this point? 23 DR. MORENO: Sure. 24 CHAIRPERSON MARSHALL: I just send -- Greg 25 and I have been sending notes back and forth like we PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 205 1 were in school, we are in a sense, but I just wanted to 2 say that we will put on the agenda for the next meeting 3 an update from the OHRP on the current 407 process 4 which does live again. And I think that would be 5 helpful for all of us and the research community to 6 understand how that's working these days. 7 Jeff, do you want to add something? Just 8 step up to the microphone and just identify yourself 9 for the transcript. 10 MR. COHEN: My name is Jeff Cohen from OHRP. 11 407 does state -- 407(a) does specifically states that 12 the IRB finds that research presents a reasonable 13 opportunity to further the understanding, et cetera, et 14 cetera. So it does require that the IRB thinks this is 15 good stuff. 16 DR. MORENO: Does it? 17 MR. COHEN: That's what it explicitly says in 18 407. 19 DR. MORENO: Okay. We're cooking. 20 MR. COHEN: Okay. 407(a) it says: 21 "The IRB finds that the research 22 presents a reasonable opportunity 23 to further the understanding, 24 prevention or alleviation of a 25 serious problem affecting the PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 206 1 health or welfare of children." 2 DR. MORENO: Hm -- I must have redacted my 3 Bible somehow. Thank you. 4 Abbey. 5 MS. MEYERS: Yesterday I had mentioned that a 6 lot of what's written in the regs are for people who 7 aren't sick or are minimally sick. And what it looks 8 like to me is that any kind of drug research, clinical 9 research on a new drug would have to go through this 10 number four because it might -- it represents more than 11 minimal risk. And something like Clozaril would have 12 never been approved for schizophrenia, you know, for a 13 clinical trial. I don't understand this because it 14 really doesn't address -- number four, does not address 15 the question of people who are very sick and are 16 willing to take more of a risk and it also puts all of 17 the work into Greg's office and he doesn't have the 18 manpower to look at several hundred protocols. 19 DR. MORENO: I think number two is intended 20 to do what you suggest. Bob. 21 DR. R. LEVINE: Yes, this is what I was 22 talking about a few minutes ago. The procedures or 23 interventions that hold out the prospect of direct 24 benefit are not to be evaluated according to the 25 standards of minimal risk or minor increase. Clozaril PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 207 1 would be one such intervention. They're to be 2 evaluated much more like procedures are evaluated for 3 prescription in the practice of medicine in terms of 4 the risk benefit balance for the individuals involved. 5 So this is one of the reasons that I insist 6 that we get rid of this business of beneficial 7 therapeutic or non-therapeutic research, it's the 8 specific intervention that has to be evaluated. And if 9 it holds out the prospect of benefit, then we don't 10 think minimal or anything like that. 11 DR. MORENO: Well taken. 12 Elliot had his hand up a long time ago. 13 DR. DORFF: Yes, my question is just it's a 14 number four and it's on a different issue. Alleving 15 the serious problem affecting the health or welfare of 16 persons with a condition or disorder that may affect 17 capacity -- may be conducted and so on. Is this only 18 going to be for the condition that leads to the 19 incapacity to give informed consent? Or do you want it 20 to be broader than that? 21 So like, for example, if you had a 22 schizophrenic person who also had kidney disease, could 23 that person be part of a study of some kind of kidney 24 drug? 25 DR. MORENO: One of the NBC recommendations PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 208 1 that we want to accept is that if there's an 2 opportunity to do this with a population that has 3 decision-making capacity, you should do it with them 4 and not with others. 5 Thank you for putting that -- 6 DR. SHAMOO: Yes, as a matter of fact, in 7 answer to Abbey, remember, these are for global people 8 who we have decided that they are decisionally 9 impaired. And, therefore, even according to the common 10 rule or any other code of ethics, we have a greater 11 responsibility of raising the ethical bar for their 12 protection. The rule gives us that right to have 13 greater protection because they are vulnerable. They 14 could be exploited, and that is why we are dealing with 15 this. 16 If somebody has a serious disease and he's 17 competent, this doesn't -- it doesn't have to follow 18 that and they could volunteer and sign informed 19 consent. There is no problem. So your examples are 20 fine. But these are for a group of people who are 21 decisionally impaired in the society basically or the 22 surrogate, or whoever it is, is making those decisions 23 for them. And we have a greater responsibility. 24 MS. MEYERS: Where is the clinical trial on a 25 risky drug fall under this draft? PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 209 1 DR. R. LEVINE: It doesn't. 2 [Simultaneous conversation.] [Off mic.] 3 DR. R. LEVINE: [Off mic.] No, it's number 4 two, it's not any of these numbers. You don't apply 5 minimal, minor increase or anything like that if the 6 intervention or procedure holds out a prospect. 7 DR. MORENO: Bob. Microphone. 8 MS. MEYERS: What does number four cover? 9 Give me an example of what Number four would cover? 10 DR. R. LEVINE: Let me finish what I was 11 saying. 12 DR. MORENO: Go ahead. 13 DR. R. LEVINE: The prospect -- I was not 14 referring to number two as it is written here, but 15 number two as it will be rewritten after they sort out 16 the -- 17 DR. MORENO: Right. 18 DR. R. LEVINE: -- intervention or procedural 19 language. And then this 2(a) will no longer be located 20 there. 21 DR. MORENO: Right. In answer, Abbey, to 22 your question, you know, I learned a long time ago in 23 graduate school that we're prisoners of our examples. 24 But I think what we're thinking about here is some 25 potential great breakthrough. You know, Interleukin PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 210 1 for schizophrenia, I mean, pull something totally out 2 of the air -- that has, for various reasons, given 3 people some hope, but doesn't -- requires a national 4 conversation and very public and transparent discussion 5 before you put people in that position. 6 MS. MEYERS: [Off mic.] If it's a drug study 7 -- drug company -- discretion of their -- 8 DR. MORENO: That's not our problem. And, by 9 the way, they might. I mean, if they're going to make 10 a billion dollars a year. Bob. 11 DR. R. LEVINE: Interleukin two for 12 schizophrenia probably would not be in this category. 13 Because, by the time you were ready to start the trials 14 of interleukin you should have already developed some 15 information that would support a statement that it held 16 out the prospect of direct benefit. What they were 17 talking about in the what we're now calling 407 18 category was a breakthrough in the basic understanding 19 of a disorder. So, for example, to follow your 20 analogy, a promising lead that says you might find 21 interleukin two receptors in patients with Alzheimer's 22 disease that would be a 407 thing. And once you found 23 them, then you do a little preliminary work and you're 24 moving back into hold out the prospect of direct 25 benefit research. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 211 1 DR. MORENO: Thank you. 2 Sandy, you wanted to say something a long 3 time ago. 4 DR. CHODOSH: [Off mic.] Yes, very brief. I 5 just want to be really sure that the -- thank you, that 6 in four you put the "and"s in. 7 DR. MORENO: The "and"s are going in. 8 DR. CHODOSH: Because if one were to stop at 9 (a), one could have Tuskeegee. 10 DR. MORENO: No Tuskeegees allowed. 11 DR. SHAMOO: You said that before. 12 DR. CHODOSH: But we did it for the others, 13 but it's more important here. 14 DR. MORENO: Thank you. 15 DR. SHAMOO: Yeah, I agree. 16 DR. MORENO: Mary Faith. 17 CHAIRPERSON MARSHALL: No. 18 DR. MORENO: All right. Any other comments 19 on any of this from the members of the committee? If 20 not -- yes, Alan. 21 DR. FLEISCHMAN: Are we going to talk about 22 the future work list? 23 DR. MORENO: Well, I would like to do that. 24 I'm getting -- yes, all right. Let's talk about the 25 future work list. Anybody want to add some work to PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 212 1 this, obviously we're going to go back and revise this 2 document in light of this very helpful discussion. But 3 we're also talking about work that is implicated by 4 this topic on this list. And there may be other topics 5 as well. Keep in mind that we want to finish this in 6 the 21st Century if we can. And I'm not going to be 7 around that much longer. 8 DR. SHAMOO: Can I? 9 DR. MORENO: Yes. 10 DR. SHAMOO: In the future list, I think we 11 need to elevate to number one the independent capacity 12 assessment. Because it is so intertwined with the rest 13 of the document. So we need to deal with that first 14 before we go on advance directives or placebo. Because 15 those almost stand on their own. 16 DR. MORENO: I would have thought in the 17 capacity assessment and the legally authorized 18 representative problem. 19 DR. SHAMOO: Yeah, I agree. I agree. 20 DR. MORENO: Okay. Anybody else? Alan and 21 then -- well, go ahead, Sandy. 22 DR. CHODOSH: Just logical, however, and Greg 23 can speak to this, knowing what's number and that 24 current number one will take in order to enact. We 25 don't have a mechanism for this, I don't think. This PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 213 1 is establishing a new special standing panel. How long 2 does that take? And if so, that should be started 3 while we're doing the other things. 4 DR. MORENO: Well -- 5 DR. CHODOSH: Because there's no sense in 6 getting this whole process in place and not having 7 that. 8 DR. MORENO: Well, the panel in part four 9 shouldn't be construed as the special, standing panel 10 that NBC was talking about. That was a standing panel, 11 not an ad hoc panel. And it's not -- if this document 12 is roughly acceptable as we go on, then we may not even 13 -- there may not even be a roll for that panel. 14 DR. CHODOSH: 407(a) won't cover this now. 15 DR. MORENO: Well, I'm not sure. It might. 16 It would be protocol by protocol, that's all. 17 I think we do need to open it up and so we'll 18 hear from our ex-officio members, first, anybody who 19 would like to take the microphone, and please identify 20 yourself. 21 David. 22 MR. TRAU: I'm David Trau with the National 23 Institute of Health. I'm very pleased that you decided 24 to change the wording from this order that this poses 25 to since the various problems that would come up in PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 214 1 that at regard were certainly aired during the NBC 2 discussion. 3 In terms of Dr. Levine's point regarding the 4 range of impairment that may occur, certainly now we're 5 seeing much more use of consent monitors, IRB 6 representatives, third party clinicians or advocates to 7 assess whether people who might have an impairment 8 really do have an impairment or not. But my concern is 9 that while these additional safeguards are already 10 called for in the regs and can be required by the local 11 IRB, it seems unclear whether a person who is evaluated 12 for capacity based on these provisions and found able 13 to consent, it's not clear to me whether that person 14 would then fall into this just because they had a 15 questionable impairment, and if the person is found not 16 to be significantly impaired, would they in fact go 17 back to the adult regulations rather than be treated 18 like a child which is what these do. 19 My more specific comments or questions have 20 to do with number one. It doesn't mention consent 21 waivers which, of course, are currently part of the 22 adult regulations. Is it your intention to outlaw 23 consent waivers for individuals who have some 24 impairment of capacity? 25 And the final question that I'll ask, because PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 215 1 I know time is of the essence at this point, concerns 2 number four, and the question of how long you expect 3 this process to take? People have told me that going 4 to a Secretary's panel is in effect a death sentence 5 because it will take a matter of years before they get 6 an answer. I told people that was not the case, but, 7 unfortunately I was wrong. Is there some way to 8 indicate in this language that this is to be done in a 9 reasonably timely fashion so that the research is not 10 impossible to do by the time a decision is made? 11 DR. MORENO: You could say "all deliberate 12 speed." 13 Greg, did you want to comment on either of 14 those? 15 DR. KOSKI: Yeah, on a couple of things. I 16 think we want to be careful, David, in using terms 17 like, you know, treating people with impaired decision- 18 making ability like children. While there are 19 analogies, certainly between the constructs here there 20 are also special provisions for protection of prisoners 21 that are similar as well now as in protection of 22 pregnant women and fetuses and so on. So I understand 23 the sensitivity. There is an analogy there and I think 24 we would want to be careful in the way we use the words 25 there. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 216 1 With respect to the process and I can tell 2 you no one is -- or no group is more concerned about 3 the slowness of the process that's been, you know, 4 there for dealing with some of the special panel 5 requests that have come up within the past year, as has 6 been stated previously, although this stuff was in 7 regulations for 20 years, in fact, there had only been 8 two situations where in fact those had been invoked 9 over those two decades. And, indeed, a lot had changed 10 over two decades. When the regulations were written, 11 those people who had -- you know, the majority of 12 things weren't done in multi-center trials and so on. 13 They're still not the majority, but I think the only 14 point is there are a number of difficult issues around 15 privacy, intellectual property, as well as multi-center 16 trials, a whole host of things for which there was no 17 process. And as you all know, developing and 18 implementing processes within the federal bureaucracy 19 is not always a minor undertaking. 20 So I want to credit the crew in our office 21 who have had to take this bull by the horns, and 22 particularly Annette Baden and Cliff Sharkey as well as 23 Irene Stith-Coleman who have really been dealing with a 24 number of compensated issues here and people, some of 25 whom are on this panel, who have contributed their time PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 217 1 to those reviews. We will get a full -- I think Mary 2 Faith mentioned it, we would like to give a full report 3 and updating on that process, how it works, will work. 4 I think though that we share your sense that this has 5 to occur in much less than a year in order to be 6 effective. It has to be something that helps to 7 support research that in fact has already been 8 determined that it holds out a prospective -- we have 9 to look at it that way while we move forward with 10 making sure that there are adequate protections there. 11 And, again, you know, we're making a commitment to you 12 to ensure that the process moves forward in a timely 13 manner, and I don't think that needs to be specifically 14 written into the regulations. Thank you very much. 15 DR. SHAMOO: I think Dr. Shore made the other 16 comment that if you -- if the person -- decision 17 suspect of decisional impairment was tested and found 18 not decisionally impaired of course he goes back to the 19 regular adult regulations, the normal, that's the whole 20 purpose. That's all in here and in all the NBC 21 recommendation and in all working group. So I think it 22 doesn't even need an argument, at least in my mind. 23 DR. MORENO: Jeff. 24 MR. COHEN: I'm Jeff Cohen again from OHRP. 25 I want to go way back to Mary Faith's comment early on PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 218 1 in the discussion about the fact that we need to focus 2 on the consent process. And particularly we need to 3 get the individual subject involved in the process as 4 much as is possible depending on their individual 5 circumstances. I think that should be very explicit in 6 this section. Because we have to take every 7 opportunity to make that case as strongly as possible 8 and to make it clear that if you get away from this 9 event, considering consent is an event concept, and in 10 light of that, I would also like to ask if the working 11 group considered asset issues involved in this that the 12 individual, even if they have decisional impairment 13 still should be involved in the process and the concept 14 of assent as it's applied in the children's regulations 15 may be appropriate. 16 DR. MORENO: It's also included in the 17 invisible NBC recommendations that are presupposed. 18 Thank you, Jeff. 19 Bob. 20 DR. R. LEVINE: I think Dr. Shore -- his 21 concern about whether this might be ambiguous is very 22 well founded. Because each of the recommendations say 23 that adequate provisions are made to solicit informed 24 consent which implies that the thing he's concerned 25 about may actually be true, that anyone who is PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 219 1 considered would have to be tracked in this system 2 rather than going to what we are now horrified to say 3 -- 4 DR. MORENO: Standard system. 5 DR. R. LEVINE: -- what we are now calling 6 the adult regulations. 7 DR. MORENO: Standard system. 8 DR. R. LEVINE: I think though that if we 9 mean this to apply only to those who are found to be 10 decisionally incapacitated that we've got to take 11 informed consent out of each of the recommendations and 12 replace it with assent. If they can give consent, 13 they're not incapacitated. 14 David, am I hitting on what you were 15 concerned about? 16 MR. SHORE: I think that's a large part of it 17 point that it's unclear whether people who may be -- 18 DR. MORENO: Step to the microphone, please, 19 David. 20 MR. SHORE: I think that's exactly right, 21 Bob, that the issue is whether people who might be 22 impaired or might be considered as was originally in 23 the language to have a condition that might impair 24 their capacity whether the current means to evaluate 25 that, the additional safeguards would be sufficient to PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 220 1 not require a person to be in this particular scenario. 2 And I think if you mean what Adil suggested 3 that it would be useful to say that here because 4 certainly that wasn't the impression that I took from 5 reading this in the same way that I had a problem with 6 the language about disorder that it disposes them to or 7 as Jonathan said in his introductory remarks, people 8 who are actually lacking capacity. Because that's a 9 very, very different distinction. 10 I would also like to remind you about my 11 question about consent waivers and whether you would 12 eliminate them from this group. 13 DR. MORENO: I feel awkward talking about 14 this because the workgroup did not discuss the consent 15 waiver question. So I think we're going to have to 16 take that on advisement and I really don't feel I can 17 say anything about that right now for the workgroup. 18 Is there anybody else who wants to say 19 anything about this document at all? 20 DR. FLEISCHMAN: Do we want a Mark Barnes 21 motion? 22 DR. MORENO: No, no, let's not Mark Barnes it 23 yet. I think in fact what we've learned is there is 24 more work to be done. And this discussion has been 25 extremely helpful, I think. We have advanced the ball PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 221 1 down the field as it were, at least five yards or so, 2 which is a lot for this topic, if I do say so myself. 3 Greg, did you want to say anything at all, 4 before I -- 5 DR. KOSKI: I think in fact you've gone a lot 6 further than five yards. And I want to congratulate 7 you. And this is really tough work, but I think you're 8 making very significant progress on that. 9 I just wanted to -- I think we're either 10 going to break or move on to something else. I'll talk 11 just very quickly about process. As you know the 12 department has remanded its working group report to us 13 to move forward. We need the advice from NHRPAC on 14 these four specific points and it sounds like we're 15 close to getting that. There will be additional work 16 to be done. 17 Once we do have that advice our intent is to 18 work with the other federal agencies, our policy group 19 will look at this and the department has essentially 20 two courses of action that it can take here. One is to 21 offer, you know, further guidance on these issues or if 22 the Secretary were to choose to do so, then the 23 Department could move forward with specific 24 regulations, perhaps the subpart to the existing 25 regulation to afford special protections. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 222 1 Again, the decision is to how the department 2 will be moving forward is one that will be determined, 3 you know, by the Secretary's Office, basically. And, 4 as I said, in concert with the other agencies within 5 HHS. And I do think that we would like to see this as 6 Jonathan said, move forward in this century. 7 So I'm happy to see it moving forward and 8 thank you all very much. 9 DR. SHAMOO: I want to thank Jonathan for his 10 leadership. It's really hard work. This has been an 11 intractable seven-year-old problem and we have made 12 progress, and I think this panel should appreciate that 13 despite there are some differences here, here and 14 there, and remaining. So we are grateful to Jonathan. 15 DR. MORENO: Thank you. Elliot did you want 16 to -- 17 DR. DORFF: Here, here. 18 [Applause.] 19 DR. DORFF: This is just a light sort of 20 comment on the issue of vitally important research. 21 There was David Dalvi a professor of law at UC-Berkeley 22 was giving several lectures at the University of 23 Judaism and I was driving him from one place to another 24 and he said that there are two problems that academia 25 has always had and he has the solution to both of them. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 223 1 One of them is that freshmen never get full 2 professors and the other one is that professors need to 3 publish this inane research simply to be able to get 4 promoted. So the solution is very simple. When you 5 get your Ph.D. you are appointed a full professor, that 6 way freshmen get a lot of full professors. And then 7 every time you publish a book you're demoted. 8 [Laughter.] 9 DR. DORFF: Now that would be vitally 10 important research. 11 [Laughter.] 12 [Applause.] 13 CHAIRPERSON MARSHALL: We will break for 15 14 minutes. I guess that brings us back at 20 after three. 15 But before we -- folks, don't leave. 16 Before we break for our -- stand up for our 17 break I want to acknowledge because I know that 18 Jonathan has to leave a little early, I want to 19 acknowledge the fact that Elliot's term is nearing to a 20 close. Our desire is that he be reappointed to the 21 committee. We are sort of in the process of moving 22 along with those things and I'm not sure what the 23 outcome of that might be. But, Elliot, I want to thank 24 you and we would like to thank you for all of your hard 25 work and for being here and for your charm and good PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 224 1 humor and your most wonderful scholarship. And I also 2 want to say that he's not going necessarily that far, 3 because he does co-chair this very important workgroup 4 and I think that detail might be for life. 5 [Laughter.] 6 CHAIRPERSON MARSHALL: And I'll say goodbye 7 later too, but I wanted, because some folks may have to 8 wander out early or leave early, to thank you, 9 especially. 10 [Applause.] 11 CHAIRPERSON MARSHALL: And now we can break. 12 We'll be back at 20 after. 13 [Brief recess taken at 3:05 p.m.] 14 CHAIRPERSON MARSHALL: Thanks to everyone who 15 is still here. We have had such a productive and 16 fruitful two days. We are really doing good work, I 17 think. Just super work. 18 I want to make just a couple of housekeeping 19 announcements before we move on just because I know 20 some of you may not be able to be here until the bitter 21 end. One is that Kate and I have been talking about 22 this for a while, but what we are going to do at our 23 next meeting and all of our future meetings is to have 24 two sets of tables, actually, sort of up here in the 25 front of room, one for the committee and one for the PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 225 1 committee ex-officio members. We'll be sending out 2 sort of an announcement or an invitation so all of the 3 ex-officios know that they will have a seat and a 4 microphone and name plaque and that we will invite 5 their even more active participation than we have had 6 in the past. 7 [Paragraph deleted.] 8 CHAIRPERSON MARSHALL: So let's move on to 9 Felice and Jeff and they are going to update us on the 10 very hard work that the social and behavioral sciences 11 workgroup has been doing at the wee hours of the 12 morning, I do believe. Felice, truly does not sleep. 13 DR. F. LEVINE: It's amazing how many coasts 14 you can hit. At two in the morning you get the five 15 o'clock people getting up. 16 Thank you. 17 We actually have one item that was, I guess I 18 would say, mentored and developed under the aegis of 19 the social and behavioral science working group, but 20 was accepted actually with a tremendous amount of 21 enthusiasm by NHRPAC in January and that was the 22 confidentiality statement. And then two of us were 23 designated with the task of making some revisions to 24 that and I passed it out yesterday, and that is Susan 25 Kornetsky and I as with our NHRPAC hats on were PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 226 1 designated with what I call a process of migrating this 2 to being a NHRPAC document, but actually there were 3 only two elements of recommended change for those of 4 you in the audience who didn't -- we had a stack of 5 copies, but who might not have picked one up. And that 6 was that in the embracing of the document to make it 7 clear that this was generic and that recommendations 8 with respect to confidentiality were not in any respect 9 sui generous to the social and behavioral sciences 10 although that may be a particular issue with respect to 11 risks that we were conscious of safeguarding. 12 And the other which was a little bit more 13 modest statement was to ensure that in our saying that 14 as risk goes up confidentiality protections also need 15 to handshake and be as secure and as firm as possible 16 that the antithesis of that is not the case, that as 17 risk goes down that one's clear visions of 18 confidentiality are agreed on that that doesn't mean 19 that that is any less resolute. But obviously the 20 numbers of firewalls, I guess you would say, needed to 21 be more secure. 22 So what we want to do really on behalf of 23 both the working group, and in a way NHRPAC, is to 24 review these and hopefully NHRPAC will be in a position 25 to take action on that. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 227 1 Then move to just a brief overview of what 2 the social and behavioral science working group is 3 working on now which will be very brief so that one of 4 the key issues that we discussed at our meeting on the 5 22nd of April, and that is the discussion of course 6 research and student training in courses. We can have 7 an initial discussion and report on because then we 8 want to work on that more and bring a more final report 9 and recommendations to the group in July. And Jeff 10 will sort of take the lead in presenting that. So 11 those are really, from our point of view the sort of 12 two key issues that are on our agenda today. 13 There was a subgroup and I can't remember all 14 of my colleagues, I know it included Elliot and I think 15 it included -- I think it actually included Abbey, but 16 several of us do need to do the same thing that we did 17 with confidentiality for risk and harm which was also 18 supported in January. And, indeed despite my staying 19 up all night, that was one that slipped from the menu. 20 So we'll bring that back in July. 21 With that, let's -- Susan do you want to say 22 maybe a few introductory words about the 23 confidentiality? 24 MS. KORNETSKY: The only thing that I think 25 we had brought up last time was it was written so well PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 228 1 and so beautifully and I just kept thinking about it 2 from a biomedical perspective and there was nothing 3 there that didn't apply. And I thought it was all 4 important. So Felice went through and we have just 5 made changes and maybe inserted a couple of examples of 6 areas that may apply in the biomedical. There was no 7 enormous number of changes. I don't think the content, 8 the context changed just to really expand it to make it 9 applicable. 10 DR. F. LEVINE: You can see that from the 11 opening line and then in a lot of the "e.g." whereas in 12 the third paragraph we had previously drug abuse, high 13 risk sexual behavior and violence as areas where 14 confidentiality protections really need to be secure. 15 We added the spread of HIV and genetic 16 predispositions as to other similarly situated arenas 17 of work. So that was well within the spirit of being 18 more inclusive. Similarly on page 2, third paragraph 19 from the bottom, where we're trying to explain that 20 when confidentiality is provided, it must be secure, 21 and that indeed there needs to be a higher level of 22 scrutiny in more vulnerable kinds of circumstances. 23 And we had one example from the social and behavioral 24 sciences. 25 We juxtaposed laboratory studies on the level PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 229 1 of boredom which if confidentiality is provided it 2 certainly needs to be protected and secure and then we 3 said, "associated with repetitive tasks does not 4 involve the same risk of data disclosure as surveys of 5 personal sexual orientation and experience." 6 And then Susan added a very nice one, 7 "clinical laboratory data does not involve the same 8 risk of disclosure as genetic testing." So that we 9 tried to kind of achieve that inclusive balance. I 10 wanted to cite that one in particular because that was 11 also an area where we wanted to make very clear that -- 12 and we say, "explicitly in all cases where 13 confidentiality is included in the consent agreement it 14 must be granted and secured regardless of the level of 15 risk." 16 So that's an absolute, you know, that's 17 floor. 18 So I open it up to my colleagues. 19 DR. SHAMOO: I would presume your 20 recommendation number you is the same for biomedical. 21 Because if it is, it's a good recommendation. The 22 report looks really very reasonable. However, if I was 23 the other investigator and all I have to do is sign up 24 a sheet of paper that I'm going to abide by everything, 25 it doesn't have the impact. There has to be some kind PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 230 1 of a process. So the new investigator who has not been 2 involved in IRB or I think the protocol et cetera, to 3 impact on him, this is an important issue and you've 4 got to really conform to all the needs of 5 confidentiality, et cetera. 6 So I would sort of have that paragraph either 7 have a process sort of defined a little bit or 8 emphasized just for your thoughts. 9 DR. F. LEVINE: I think that point is well 10 taken. In a way it grafted on to the public use 11 recommendations on the one hand and also with data that 12 are not accessible but somehow analyzed by other 13 investigators that ORP should develop guidance to make 14 it clear to those investigators that they must abide by 15 all original agreements if there's any sharing with 16 other investigators of that data. 17 We could add a few words beneath that to -- 18 although I think it's actually above it and hopefully 19 it made it clear, but we'll take another look, I guess. 20 Susan, did you -- 21 DR. CHODOSH: Doesn't that bring up this same 22 issue of how does that get transferred, that 23 information from the IRB that originally approved it to 24 an investigator in another -- in the jurisdiction of 25 another IRB that these are the conditions? That part PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 231 1 isn't clear. And it seems to me that there are some 2 logistical problems and perhaps legal problems that 3 happen when you're going from institution to 4 institution. You know, we're saying that other 5 investigators using the data must abide by the 6 confidentiality that was originally granted, but it may 7 not have been granted by the same IRB. Is that a 8 problem? 9 MS. KORNETSKY: I think what this is saying 10 -- what this is saying here is that acknowledging that 11 this is an issue when investigators share data, whether 12 it's even within the institution or with outside, and 13 we can either -- this not solving that problem, but 14 it's basically saying is OHRP should develop guidance. 15 Now, I guess this group feels that we're the ones to 16 develop the guidance, then we can take that forward. 17 But this is acknowledging that it is an issue and there 18 needs to be guidance. 19 DR. CHODOSH: Except what we're talking about 20 is the investigator's responsibility, but, yes, each 21 one has a responsibility to their IRB. And maybe 22 something about the IRB's responsible must insure. I'm 23 not sure about that, but it seems to me that like all 24 it says is that the investigator is now under the 25 control of another IRB because he has to follow the PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 232 1 rules of that IRB in terms of the confidentiality that 2 they imposed. 3 DR. F. LEVINE: Let me just say, I think in 4 this case we were not suggesting that -- we were really 5 trying to underscore that the confidentiality must be 6 maintained under any circumstance both by the 7 investigator in bringing a protocol forward and the IRB 8 in reviewing it. And this was not making a statement 9 about one IRB deferring to another because it was also 10 dealing with restricted datasets, not just public use 11 datasets. So it was only trying to address the limited 12 notion, that confidentiality cannot be -- I guess it 13 was saying, could not be waived by a -- in any way 14 could not be relaxed by an IRB or an investigator under 15 a second set of circumstances. 16 Alan. 17 DR. FLEISCHMAN: I think we're all agreeing, 18 but one process approach which our IRB has used is to 19 obligate the investigator who is giving the dataset to 20 assure that before the dataset is given there are 21 adequate confidentiality protections created. Since, 22 you know, our IRB can only obligate our investigators. 23 I think that's Sandy's point. I think that's a way of 24 doing it that just makes it clearer. 25 DR. F. LEVINE: Why don't we add that, that PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 233 1 we do it both ways. And this was addressing the 2 sharing of nonpublic use data. So there is a 3 subsequent IRB in this case. So let's add a sentence 4 that reaffirms the binding nature of the primary 5 investigator as well as any secondary end user. That 6 would meet it? Okay. 7 DR. CHODOSH: The identified data is then not 8 really a great problem. It just then becomes a problem 9 when it's still identified. 10 DR. MORENO: Move approval? 11 CHAIRPERSON MARSHALL: We'll take a verbal 12 vote. All of those in favor? 13 [Chorus of ayes.] 14 CHAIRPERSON MARSHALL: Those opposed? 15 [No response.] 16 CHAIRPERSON MARSHALL: Any abstentions? 17 [No response.] 18 CHAIRPERSON MARSHALL: Vote carries. 19 I left out the discussion part, didn't I? 20 [Laughter.] 21 MS. DeWOLF: I'm Jenny DeWolf and I work at 22 the Committee on National Statistics at the National 23 Academy. I know a little bit about confidentiality 24 protection and de-identification is necessary, but not 25 a sufficient step. I don't have the document, by the PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 234 1 way. 2 Felice, in this document did you deal with 3 the record linkage, the linkage issue, of the potential 4 of someone taking a de-identified dataset and merging 5 it with another dataset on certain variables and 6 inferring the identity of the anonymous participants. 7 Am I being clear? 8 DR. F. LEVINE: Yeah, Janet. This document 9 is really focusing on the confidentiality provisions 10 and the firewall at the front end. I think in the 11 public use dataset, I think, recommendations, we were 12 explicit that the linking of two otherwise anonymized 13 datasets does require rereview because you might create 14 a new linkage. 15 MS. DeWOLF: What happens if -- 16 DR. F. LEVINE: And that was in the other set 17 of recommendations. 18 MS. DeWOLF: I'm listening as closely as I 19 can, and let's say the New York Academy of Medicine's 20 IRB where Alan is, allows a PI to release a dataset. 21 Right? To share a dataset. What prevents the 22 recipient from trying to re-identify those individuals? 23 DR. MORENO: A de-identified dataset? It 24 should not be possible for that to happen if it's 25 appropriately de-identified. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 235 1 MS. DeWOLF: It depends on -- there's a 2 researcher at Pittsburgh, LaTonya Sweeney who has re- 3 identified the medical records of the former governor 4 of Massachusetts by matching -- it's been de- 5 identified, no names, but it had zip code and age, and 6 she bought the voting records from Cambridge and was 7 able to match on three variables finding out Governor 8 Weld, I guess is his name, information. Now, as a 9 statistician you don't release universe data. Maybe as 10 a medical person you do. But there is so much stuff ou 11 there, how do you know that it's not going to happen? 12 DR. F. LEVINE: I think we covered that 13 adequately or sought to in the public use data files 14 recommendation. This, to the extent that this has one 15 section on confidentiality -- on data sharing it is in 16 the limited situation where non-public data are shared 17 in accordance with the protocol. So this isn't -- the 18 confidentiality statement doesn't deal with public use 19 data files at all. 20 DR. MORENO: Can I suggest that when we 21 create these kinds of recommendations, we're taking 22 about people whose intentions are honorable. And, you 23 know, that we're trying to make a system so that 24 confidentiality is maintained with people who not 25 intending to do bad things. PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 236 1 So the only way to get around, I would think, 2 people with evil intentions is to punish them. 3 MS. DeWOLF: I'm sort of playing a devil's 4 advocate role because faculty members have students -- 5 I'm sorry, students think this is a great thing. I'm 6 just going through hypothetical inadvertent disclosure, 7 okay. Somebody says, I want to add this other dataset 8 to this file, and I want to do my own research. It's 9 going to be groundbreaking. And all of a sudden they 10 figure out that it's, you know, Greg Koski. I don't 11 know, I'm making this up. 12 [Laughter.] 13 MS. DeWOLF: But they -- 14 DR. KOSKI: I have no secrets. 15 MS. DeWOLF: I know, I figured you don't. 16 But I'm not trying to say that anyone is evil or 17 malevolent, I'm just trying to say that even with 18 nonpublic microdata there is a risk. And, again, I 19 have read that document, because I didn't pick up a 20 copy yesterday and there's no more out there, there are 21 no more out there. But the federal statistical system 22 deal an awful lot with the reidentification risk even 23 in non-public data. And I just raise it as an issue. 24 DR. F. LEVINE: The public use data file 25 recommendation explicitly says, "Users seeking to merge PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 237 1 public use data files or enhance a public use data file 2 with identifiable or potentially identifiable data, 3 need to obtain IRB review and approval." So that -- 4 MS. DeWOLF: [Off mic.] -- the same thing 5 occur if Alan gave me a data file? 6 DR. F. LEVINE: Correct. 7 MS. DeWOLF: [Off mic.] So I would have to 8 get -- okay as long as it's covered. I just wanted to 9 raise it -- 10 DR. F. LEVINE: Yes. We -- 11 CHAIRPERSON MARSHALL: Just remember, use the 12 microphone because we do publish our transcripts on the 13 web site and we would like to have everything there for 14 those who want to read it. 15 DR. F. LEVINE: I'm just curious that from 16 what you're saying, for example, drug companies in 17 order to tell how well their salesmen are doing 18 purchase information from your local drug store about 19 how many prescriptions were written for which medicine 20 so that they can say, okay, the salesman did well in 21 this district, but not in the next district. And so, 22 you know, what are the laws for violation of 23 confidentiality for somebody purposely going and 24 looking up to see what medicine you take from your 25 local drug store, or student? As you said is there a PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 238 1 punishment? Federal punishment? 2 DR. FLEISCHMAN: Actually, John Fanning may 3 want to address that, but for information that is 4 available in the public domain, in fact, I'm not aware 5 that there is any penalty for putting it together and 6 identifying someone apart from, you know, if someone 7 did something to harm someone as a result of that, then 8 there would be legal recourse under the legal system. 9 But just because there's information that one group 10 has, another group has, you know, if it's all publicly 11 available and the people who have made it available 12 more or less know it's available one way or another, if 13 they signed the acceptance agreements when they sign up 14 for their new software that they're going to download 15 and all that. They may not be paying close attention, 16 but there, in a sense a buyer-be-ware caveat emptor 17 mentality to all of that. 18 That's not what I got up to say though. I 19 was going to simply comment that a properly -- one of 20 the lessons that we've learned from LaTonya's work, or 21 she was only capable of doing that because she was at 22 MIT at the time, but I think one of the lessons that we 23 learned from her work was that we have to be careful 24 about what we call "non-identifiable" because in fact 25 we can string together birth dates, which it's PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 239 1 interesting, but, you know, birth dates tend to 2 identify to a certain extent a group of people born on 3 that day and it narrows it down somewhat. 4 So I think we've learned from those lessons 5 and properly constructed and de-identified a database 6 for public use, it really should not be "practicable" 7 -- is the word -- in order to do that. But, again, I 8 think that this is part of the construct that came 9 forward from the working group of defining a 10 essentially a standard whereby these datasets could in 11 a sense be certified as to meeting a standard for de- 12 identification that would prevent that from happening. 13 DR. FLEISCHMAN: And that's essentially the 14 recommendations that were approved and sent forward on 15 public use data files, though to, let's say, dot the 16 "I"s between the confidentiality, we actually make 17 textual reference to this so that, well, why don't we 18 put a footnote that actually sites that recommendation 19 to make it very clear to someone looking at this that 20 this links to a broader discussion of public data, but 21 that this is addressing non-public data. 22 Jenny, am I seeing a head shake? 23 MS. DeWOLF: I just think it should be 24 acknowledged just because somebody honorable says 25 something, you know, and somebody honorable receives PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 240 1 it. You just don't know what happens and so it should 2 be -- you know, caution should be taken. So that would 3 be a good approach, I think. 4 DR. F. LEVINE: Okay. Did we call the 5 question? 6 DR. MORENO: We called the before the 7 discussion. 8 CHAIRPERSON MARSHALL: We still have a 9 quorum, I'm assuming. So shall we have vote then? 10 Those in favor? 11 [Chorus of ayes.] 12 CHAIRPERSON MARSHALL: Those opposed? 13 [No response.] 14 CHAIRPERSON MARSHALL: Any abstentions? 15 [No response.] 16 CHAIRPERSON MARSHALL: Motion carries. 17 [Pause.] 18 CHAIRPERSON MARSHALL: Yes, conflict of 19 interest and risk and harm, yes. Third parties. 20 We repressed that, Abbey, but -- 21 DR. F. LEVINE: All right. I think that 22 given the time we would like to turn to courses in 23 student research. 24 DR. COHEN: This topic of student research is 25 one, if you remember we began our efforts as a working PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 241 1 group by reaching out to professional organizations and 2 trying to get input from the research community, the 3 social and behavioral science research community about 4 problems that they perceive with IRBs and so forth. 5 And one of the most prevalent problems and one of the 6 most irritating and troublesome problems that the 7 research community was having had to do with student 8 research and with IRB review of student research and 9 the issues regarding IRB review of student research. 10 And so that prompted us to turn our attention to that. 11 And what we have done is come up with some 12 questions. We really haven't -- we're just at the 13 beginning part of our discussion about this and we've 14 posed some questions so what we are looking for is 15 input and feedback to these questions as the working 16 group proceeds with some recommendations with regard to 17 student research. 18 The first point on the handout you're getting 19 is probably the most important one to keep in mind and 20 that is most student research is not covered by 45 21 C.F.R. 46, because it doesn't generally constitute 22 generalizable knowledge as much as we would like it to, 23 perhaps. It rarely does. 24 DR. RICH: [Off mic.] I think if you're 25 going to say that you need to say undergraduate student PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 242 1 research. Because graduate student research is -- 2 DR. COHEN: Well, some graduate student 3 research does. Certain thesis and dissertations 4 certainly do. 5 DR. RICH: I would not make an assertion that 6 student research is not intended to lead the 7 generalizable knowledge. I mean, I think that's a very 8 dangerous assertion and I would, at the very least say 9 a sense, you know, in the event that it's not intended 10 to lead to generalizable knowledge then it may not be 11 covered. But I certainly would not assert that as a 12 generalization. Because I think that many professors 13 hope that their student research -- and, in fact, even 14 undergraduate student research, if it's done well, I 15 suspect sometimes is used by a professor in the course 16 of some scholarly work. So I think this is an 17 important issue. 18 DR. COHEN: Okay. That's a very good point. 19 I think we are focusing at our questions here and our 20 discussion does primarily focus on that research it is 21 not intended to. Although it also addresses some of 22 the types of student research that is intended for the 23 general knowledge. 24 The point the working group wanted to make 25 was that even if it did not -- it was not covered by 45 PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 243 1 C.F.R. 46, that did not mean that it did not need 2 oversight. And that there needed to be some guidance 3 on what appropriate oversight over student research it 4 consists of. 5 And the main issue that has come up 6 repeatedly is that some institutions require all 7 student research to go an IRB, in which case on 8 occasion maybe even often, that it is extremely 9 burdensome and perhaps on occasion overly burdensome 10 and in some cases prevents the research from being done 11 in a semester's time when it needs to be done. And so 12 that's some of the questions that we were addressing. 13 Should all class projects that involve data 14 collection go through a formal IRB process? 15 What conflicts might arise between 16 pedagogical and IRB issues? 17 To what degree can submitting a brief 18 proposal to an IRB fulfill an educational role? I 19 mean, to say it shouldn't go -- that no student 20 research should go to an IRB because it's not covered 21 under 45 C.F.R. 46, are we doing the students a 22 disservice because they're not getting the full 23 research experience? 24 Should undergraduate students be required to 25 submit the same type of proposal as faculty and PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 244 1 graduate students? 2 Should the process be streamlined? 3 Should undergraduate students who conduct 4 original research projects for course credit be 5 required to go to an IRB? 6 Should faculty who give a class assignment be 7 allowed to submit a blanket proposal? 8 Should IRBs set a broad exemption criteria 9 for student research? 10 And when IRBs do review student research, how 11 might they expedite the process? 12 I think the main points that the working 13 group was focused on in this discussion in its last 14 meeting is that there should be oversight, but the 15 oversight should be appropriate to the student 16 research. And going through a full IRB review may not 17 necessarily be the appropriate procedure, but some 18 procedures might be appropriate. 19 DR. F. LEVINE: Let me just add before we 20 open it up that these were intentionally framed as 21 questions because these are the kind of questions we 22 are grappling with. So in a way we are in our early 23 phases of deliberation having had this issue come to us 24 from the field fairly repeatedly. And this is a very 25 important issue across all field, but why it's coming PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 245 1 up, we think, in the social and behavioral sciences is 2 because these are fields where training and education 3 in the doing if those sciences begins very early on in 4 the career line, indeed sometimes in high school. And 5 in a way that it does in physics and chemistry, et 6 cetera, but where probably the first set of human 7 sciences where it happens so expansively even including 8 on issues of health and well-being at an undergraduate 9 level. So while it has broader implications, of 10 course, for all human subjects research, it's probably 11 not surprising that it percolated first within the 12 contours of our field as opposed to other kinds of 13 feedback we've gotten. 14 Why don't you go first. 15 DR. RICH: I think for exactly that reason 16 that's why it's particularly important that students 17 learn the processes and procedures early on as part of 18 what they do. Whether or not it is explicitly required 19 by 45 C.F.R. 46. I mean, I think there are some 20 pedagogical opportunities to teach about how one does 21 human subjects research. 22 That being said, I think the other thing that 23 I would suggest somehow get into this is that there at 24 the very least should be formal mechanisms in the 25 classroom setting for determining exemption in a formal PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 246 1 kind of way and that that exemption ought not to be 2 made -- the decision on exemption obviously ought not 3 to be made by the professor. It ought to be made by 4 the IRB. So that there should be a mechanism where the 5 IRB declares that this proposal is exempt as opposed to 6 simply somebody deciding without any review whatsoever 7 that it's exempt. And I think -- because much of this 8 research would be exempt. I don't think there is 9 probably too much question about that. But I am always 10 concerned about people deciding for themselves that 11 their research is exempt as opposed to having some sort 12 of process in place that the decision on exemption is 13 at arm's length from the research. 14 DR. F. LEVINE: Alan and then Sandy. 15 DR. FLEISCHMAN: Well, I guess, Bob, I was 16 just thinking about this research a little differently. 17 I mean, I don't know whether it's exempt or it isn't. 18 And I would have been really more comfortable if the 19 working group started out by making an assessment as to 20 what harms or risks do human subjects have from human 21 research. I don't think student research is inherently 22 benign. In fact, it might be very risky to human 23 subjects in terms of confidentiality breeches and 24 various things. I mean, I can think of students who 25 might want to do some really very creative PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 247 1 anthropologic or sociologic research that would be 2 incredibly risk to the subjects of the research. So, 3 one thing I think we have to say is that there could be 4 harms. And therefore, there is some need for some 5 supervision. 6 And then the second issue is, what is the 7 responsibility of the professor or teacher? And if the 8 students are required to do research within a 9 professor's course, and ought not the professor be 10 responsible for the student's ethical conduct? 11 So that as part of the course not only do you 12 get a pedagogical benefit, you actually, you know, 13 obligate the teacher to be responsible. 14 I'd feel much more comfortable if I knew that 15 the professors were taking the responsibility to assure 16 the ethicality of the work. 17 DR. F. LEVINE: Sandy. 18 DR. CHODOSH: Well, I guess just reading this 19 as it just came to us that I'm a little bit concerned 20 that the approach wasn't from a point of view of the 21 protection of the human subject which really speaks to 22 some of the things we're talking about and that that 23 shouldn't be the primary concern for then how we build 24 a system that's going to work for students. 25 Having had experience with a nursing school PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 248 1 that required a research project by a nurse before they 2 could graduate with a masters, we used to get an 3 amazing number, you know, of protocols which were very 4 bad. And some of them were rather sensitive, talking 5 to pregnant teenagers for content, et cetera, et 6 cetera. And when I called the mentor the professor, 7 she said, "Well, I don't really know much about 8 research." 9 Now, how can a -- you know, I'm sure this 10 goes on in many places. It's a requirement set down by 11 that school, but without putting in requirements for 12 those who are monitoring the students at least be 13 knowledge and be the teacher. So that I think, you 14 know, we really need to have protection in this area. 15 I agree that we probably had to think out of the box in 16 order to know how to do this. And it may be that 17 people have to develop their projects before they even 18 start the course, you know, which is a tough thing to 19 do, but that might be one of the possibilities. 20 DR. COHEN: One of the particular 21 complexities of that is issue that we've wrestled with, 22 and I'll tell you how we've dealt with it is the issue 23 of certification of investigators. Because that adds 24 another complexity to all of this, is who has to be 25 certified if they're going to be doing this kind of PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 249 1 research. We have a special pathway for certification 2 of social and behavioral scientists so that it's a 3 different exam, it's a different curriculum than the 4 biomedical scientists. But we require the professors, 5 at least, to go through the certification process. 6 And I agree completely with Alan that this is 7 a place where you put the onus on the professor and 8 then the -- I mean, the professor basically passes that 9 burden, in a sense, onto the student, but it's not 10 practicable to certify every student in the conduct of 11 social and behavioral research just because they're 12 going to be in a course doing a particular project. 13 But it is practicable to require the professor go 14 through that process. 15 DR. F. LEVINE: It's hard to really know when 16 you're getting such a range of feedback from a range of 17 persons at a variety of institutions. I think the 18 faculty do in general own -- take responsibility. The 19 question is how to align that with what goes on the 20 classroom and how that grafts into the human research 21 protection system. So I think this conversation has 22 been really very helpful in conceptualizing and then 23 coming up with some models that could work and offer 24 the human subjects protections system in colleges and 25 universities some options to consider in a way that it PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 250 1 achieves both goals. 2 Greg. 3 DR. COHEN: One of the things that the 4 working group in its discussion focused on, one of the 5 reasons we have IRBs and don't leave it up to well- 6 trained investigators to make these determinations -- 7 there needs to be some independent, objective review. 8 And so that concept of independent, objective review 9 also applies in the classroom research. 10 The instructors who often are teaching 11 assistants in large institutions are too close, just as 12 the principal investigator is too close to the 13 research. They have a pedagogical motive to doing this 14 and they are very close. So the question is, what kind 15 of outside -- or what kind of independent review is 16 appropriate? And I think that was, a lot of the time 17 at the working group was spent discussing that. 18 DR. KOSKI: I would just comment that the 19 notion of allowing investigators be they students or 20 others to engage in human subjects research without 21 participating in the appropriate process for protection 22 of human subjects just reinforces what is a perception 23 among too many investigators still that either this 24 process is somehow a pain in the butt that's to be 25 avoided at all costs or that in fact they don't need PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 251 1 to. 2 So I think there really is value. I would 3 agree strongly with Bob and others who said there is 4 true value in incorporating at the earliest possible 5 opportunity the education as to what responsible and 6 ethical conduct of research and protection of human 7 subjects is all about as part of are research training. 8 So I would strongly endorse that and I think it should 9 be inherent in the way whatever recommendations might 10 come out. 11 But two approaches that have actually been 12 used in many instances and I don't -- I haven't heard 13 them mentioned, so obviously I'm not there. One is to 14 accept this notion that the faculty member is indeed 15 responsible as the investigator. The investigator, 16 that faculty member submits an overall protocol for the 17 research that would be done in the student environment 18 and says, these are the types of studies that we are 19 going to do. It establishes a framework for the kinds 20 of projects that are done by the students in that 21 particular educational setting where it does involve 22 real human research and then the faculty member as the 23 investigator is charged with making sure that the 24 research that's done is in fact within that framework. 25 And that's been one mechanism to have an IRB oversee PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 252 1 the protocol, if you will, but allow for this 2 flexibility and implementation in the actual 3 educational setting. That's worked well in many 4 places. 5 Another approach is to take advantage of 6 what's there under the regulations for using a 7 designated member of the IRB for expedited review and 8 basically assign some willing volunteer to serve in 9 that function on behalf of the IRB so that the 10 protocols that are developed by the students under the 11 supervision of a faculty member can go to this 12 individual who can then make the determination on 13 behalf of the IRB whether it's exempted, whether it's 14 human subjects research, or whether it's something that 15 would be either approvable by expedited review in which 16 case they can do that and can do it on the spot or for 17 those instances where it involves significant risk 18 that's not expeditable. It can be then sent to the 19 full IRB. Those are two very functional models we 20 already have wide experience with. They both work, 21 they're both consistent with the regulation. 22 DR. COHEN: A third model which I've been 23 sort of promoting and haven't been adopted yet, and 24 that's the idea of a student IRB. And you have to take 25 advanced students and train them and set them up and PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 253 1 really do peer review. I think one of the main points. 2 DR. FLEISCHMAN: You could combine that with 3 Greg's suggestion and have the expedited reviewer -- 4 DR. COHEN: Sit on the -- 5 DR. FLEISCHMAN: -- sit on it or chair it 6 with the students as members. 7 DR. COHEN: One of the main points that the 8 working group discussed was the idea that because much 9 of this research does not fall under 45 C.F.R. 46 gives 10 more flexibility to the institutions to be creative in 11 how they adopt the appropriate oversight. So I think 12 there are institutions that I've heard of and others 13 that have taken the position, well, it's not covered 14 under 45 C.F.R. 46, so we don't have to do anything. 15 And one of the points we want to make and we feel 16 NHRPAC should make is that is probably not the 17 appropriate response, nor is having it go through 18 thorough, equivalent, full IRB review necessarily the 19 appropriate response. But -- 20 DR. F. LEVINE: Sandy. 21 DR. CHODOSH: I'm sorry, but if an 22 institution has an assurance which covers, quotes, "all 23 research" not just funded research, and most assurances 24 now read that way, doesn't that mean that it is 25 covered? PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 254 1 DR. COHEN: No, it covers all research that 2 meets the definition of research under 45 C.F.R. 46. 3 This research -- 4 DR. CHODOSH: We're not allowing students to 5 do non-research -- non-scientific work as research? 6 DR. COHEN: This goes back to the point of 7 not for -- in order to meet the definition under 45 8 C.F.R. 46, it has to further generalizable knowledge. 9 DR. CHODOSH: Yes. 10 DR. COHEN: And most student research -- some 11 student research does not meet that definition. 12 DR. RICH: It's like when you go into the 13 organic chemistry lab, are you really doing research or 14 are you doing an exercise? And I mean, I think that's 15 an analogy from somebody with a scientific background 16 understands. You go into the lab -- 17 [Simultaneous conversation.] 18 DR. RICH: -- you go through an exercise. In 19 this case it happened to involve human subjects. So, I 20 mean, I happen to think that part of the learning about 21 how you do human -- part of the exercise ought to be 22 learning something about human subjects protections 23 too. 24 DR. SHAMOO: Two questions. One, do we know 25 what percent of magnitude of research now is done with PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 255 1 human subjects? Which they don't go through an IRB in 2 universities? 3 DR. COHEN: You mean student research? 4 DR. SHAMOO: Yes, student research, of 5 course. 6 DR. COHEN: It's a lot. 7 DR. SHAMOO: Okay. So there is a lot. 8 DR. COHEN: That's a highly sophisticated 9 qualitative analysis. 10 DR. SHAMOO: Okay. 11 DR. F. LEVINE: But -- I'm going to also say, 12 but a lot doesn't increasingly so just as a lot of non- 13 funded research now does as well. 14 DR. SHAMOO: The second question is, students 15 have only 15 weeks in a course. Are we now going to 16 expand it such that we're going to interfere so much 17 with the educational process that they are going to be 18 inhibited from doing those exercises because there are 19 so much limitations of time and money and resources, 20 especially in undergraduate colleges, those are not 21 medical schools. So I in one way promote greater human 22 research protection, at the same time I want to stop 23 the educational process of the students and training 24 them. So I am really concerned about that. 25 DR. COHEN: I think that's the point of the PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 256 1 his discussion is to provide assistance to institutions 2 to come up with creative ways, efficient ways to do 3 that -- to provide the oversight without unduly 4 interfering with the educational process. 5 DR. F. LEVINE: Well, indeed integrating the 6 two. Phil. 7 PARTICIPANT: And that's already happening, 8 that inhibitory effect. The extremist -- or the most 9 extreme example being the case raised by a linguist, 10 Gregory Ward in a case where IRB potentially being 11 brought in with a student at a blackboard and the 12 student is asked by the instructor to go -- well, to 13 say -- you write a word on the board and say, please 14 pronounce that word. And someone said, well, this 15 needed to be subjected to a potential IRB review 16 because of potential embarrassment to the participant 17 in the classroom. So we don't want a chilling effect 18 on stuff. At the same time I totally agree with Greg. 19 My suggestion on the way to do this is we 20 should instill an ethical culture throughout the 21 research enterprise and promote that. That's that 22 message that I would like to hear and let the 23 universities -- a message that we think they should 24 promote it, we shouldn't see a chilling effect and 25 either handle it at the departmental level, but that PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 257 1 should be part of the educational system. 2 And Jeff's idea was very innovative of how 3 the student IRBs -- whatever it is to instill an 4 ethical culture is the goal we should have. But we 5 should be very careful that we don't get the IRBS 6 involved in this except where they need to be or the 7 chilling effect will get worse. At the same time 8 protection of the participants is the primary goal. So 9 a bit of common sense should be also instilled. If 10 somebody sees anybody in the process, any potential for 11 harm coming in, they should immediately step in. 12 DR. F. LEVINE: Karen. 13 MS. : I'm Carolyn [indiscernible] 14 from the Bureau of Prisons. I'm also on the working 15 group. I would just like to see if there would be some 16 way to add into the recommendations something that says 17 along the lines of, if the student research isn't 18 contributing to generalizable knowledge that we should 19 encourage them not to try to use vulnerable 20 populations. I think that would be a nice addition. 21 DR. COHEN: Just speaking from my experience 22 at the university before I came to OHRP where we did 23 actually have a very broad requirement that all student 24 research went to the IRB. And our incentive to get 25 students who were inexperienced not to work with PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 258 1 vulnerable populations or do very risky research was to 2 say that that research had to go to the full IRB. We 3 didn't say you couldn't do it, but the odds of your 4 completing your study within this semester were 5 minimal. 6 [Laughter.] 7 DR. COHEN: But if you wanted to do research 8 that was exempt or eligible, for expedited review, here 9 was a nice easy way to do it and that was an incentive 10 without being authoritarian about it. So there are 11 ways to do that. 12 DR. F. LEVINE: Well, I think from our 13 advantage we got the quality of feedback that we both 14 wanted and needed to help give this the kind of form 15 that will let us continue this conversation and indeed 16 from posting on web sites and web pages as well as in 17 our next rounds of meetings with the research 18 community. We are also getting very fine examples of 19 how it's done well. And I think therefore it can be a 20 full report that we'll bring to you in July. 21 Thank you. 22 CHAIRPERSON MARSHALL: Thank both of you. 23 Thank you very much, and to the members of your group. 24 Super work. 25 [Applause.] PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 259 1 CHAIRPERSON MARSHALL: I just want to observe 2 that as soon as those couple of changes are made in the 3 confidentiality draft document, we will be putting that 4 on the web. So that should be happening very soon. 5 We may actually adjourn a little bit early 6 today. I think that we've really had a productive 7 meeting both days. We've got lots of good products 8 coming, lots of hard work being done. 9 Greg and I and Alan were talking a little bit 10 during the break and one thing that I think we need to 11 be mindful of is that although there are lots of 12 wonderful opportunities waiting for us in terms of 13 things that we have been asked to put on our agenda and 14 would like to put on our agenda for the future is that 15 we focus our energy on the tasks that we have at hand 16 as well and not become too diversified and so bring 17 some of things, you know, our front-burner projects to 18 fruition and then once those are done we will replace 19 them with the other things that we would like to do and 20 that others have very much asked us to do. 21 So, I would like to thank all of you, 22 committee members, and ex-officios, and public members 23 for the very hard work that you've been doing, not just 24 here over the last couple of days but I think primarily 25 in the interim between the meetings. I also want to PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 260 1 say or just observe that Kate is, you know, sort of 2 single-handedly running this committee and she works 3 tremendously, tremendously hard and is passionate and 4 dedicated to the work that we do. And Greg and I are 5 going to be meeting and talking about how we can beef 6 up the resources that are available to her and to the 7 committee. But I do want to acknowledge Kate's 8 invaluable assistance to all of us. 9 [Applause.] 10 CHAIRPERSON MARSHALL: Yes, Mary Kay. 11 DR. PELIAS: A few of us are going to be here 12 tomorrow for a meeting. The genetics workgroup is 13 going to be meeting and there was a question about 14 whether or not we're going to get started at 8:30 or at 15 9:00. Whether or not we're going to 5:30 or whether we 16 intend to quit at 4:00. The official e-mails that have 17 come out of this group said 8:30 to 5:30, but Kate, I 18 distinctly remember that you and I talked about 9 to 19 4:00. So -- 20 MS. GOTTFRIED: I think you're right. And I 21 think though, I don't know if the official message 22 about 9:00 -- particularly the starting time of 9:00 23 got transmitted, so let's assume that we'll start at 24 8:30. I will be at the front of the HHS building at 25 8:30. I think, Bob, Mary Kay, Sandy, and Margaret are PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 261 1 the members of this workgroup -- committee who will be 2 on that workgroup and should be there then by say 8:25 3 and we'll -- and you're going to call in. Right. 4 Because my concern is that those people calling in may 5 be calling in at 8:30. So we want to make sure we're 6 there. 7 And certainly if we end by 4:00 or whatever, 8 that's fine. 9 DR. PELIAS: Okay. So we'll all be there at 10 8:25. We'll be there at 8:25 and we'll get started 11 about 8:30. 12 CHAIRPERSON MARSHALL: All right. And thank 13 all of you and ex-officios you'll have a seat at the 14 table the next time. So forewarned and so forth. 15 [Whereupon, at 4:25 p.m., the proceedings 16 were adjourned.] 17 - - - PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443 CERTIFICATE OF OFFICIAL REPORTER This is to certify that the foregoing proceedings before the National Human Research Protections Advisory Committee held Tuesday, April 30, 2002, was held as herein appears, and that this is the original verbatim transcript thereof, and is a full correct transcription of the proceedings. Cynthia D. Thomas Official Reporter PAGES INK 752 West Kingsway Road Middle River, MD 21220 Ph: 410 576-6420; Fax: 410-574-6443